IgM > IgG / complement / ADCC / organ-specific (Goodpasture’s, pemphigus) / receptor-specific (Grave’s, Myasthenia gravis) / hemolytic anemia / Derm: pemphigus, bullous pemphigus, herpes gestationis, epidermolysis bullosa

Treatment: immunosuppression, plasmapheresis

Type III immune-complex (derm)

leukoclastic vasculitis (PAN) / fibrinoid necrosis / polyarthritis, skin, serum sickness, arthus reaction

Treatment: anti-inflammatory agents, immunosuppression

Type IV delayed-type hypersensitivity

Th-1 - contact dermatitis, Tb, sarcoidosis, Wegener’s, IBD

Treatment: corticosteroids, cytotoxic agents, antimicrobials

GVHD

Affects: skin, liver, GI tract, eye, kidney (reports)

Occurs following transplantation (e.g. BMT) / patients at high-risk for fungal infections for several weeks/months after engraftment (current debate over when and what to use for prophylaxis 1/07) / immunosuppressive agents used to prevent GVHD can look like EM [pic] [dermis]

Immunodeficiencies

Systemic Diseases Causing Defects of:

T-cells: HIV, sarcoidosis, steroids

B-cells: asplenia, SLE, CLL, steroids

Some genetic Immunodeficiencies may present in adulthood: CVID, CMC, more.

Defects of mainly T Cells

DiGeorge

no thymus (no T-cells), no parathyroids / failure of 3rd (upper parathyroids), 4th pharyngeal (lower parathyroids) pouches / presents with tetany owing to hypocalcemia

Chronic Mucocutaneous Candidiasis (CMC)

T-cells do not respond to Candida albicans

Defects of mainly B Cells

IgA deficiency

1 in 500 (most common immunodeficiency) / B-cells have it, but can’t secrete it / risk factor for celiac sprue

Presentation: recurrent sinusitis, GI infection (giardia), otitis media

Note: do NOT give IVIG due to presence of anti-IgA antibodies (44%)

Common variable immunodeficiency (CVID)

Most common primary immune deficiency requiring medical attention / 1 in 50,000

sporadic / 10% familial / 15-35 yrs

Mechanism: hypo-IgG from various defects (CD27+ memory B-cells cannot differentiate into plasma cells) / suspected genes involved (BAFF, APRIL, TACI, ICOS)

Presentation: pyogenic infections (e.g. respiratory), chronic diarrhea (e.g. giardia), and increased incidence of autoimmune diseases (sprue-like syndrome, gastric atrophy, bronchiectasis, pernicious anemia) / associated T-cell abnormalities (10%)

Diagnosis: can test for response to Ag (e.g. tetanus, pneumovax)

Related syndromes: hyper IgM type 3 (CD40), autoimmune lymphoproliferative disorder (ALPS), TNF-receptor associated periodic fever syndrome (TRAPS)

Treatment: IVIG q 2-3 wks / do NOT give live vaccines

Bruton’s X-linked agammaglobulinemia

XLR / no functional B-cells (cannot get EBV infection) / low Ig / recurrent bacterial infections beginning at age 6 months / low IG predisposes to chronic aseptic meningitis (with secondary dermatomyositis)

Duncan’s Syndrome (X-linked Lymphoproliferative Disease)

XLR / impaired response to EBV nuclear antigen (2/3 mortality ) / survivors develop hypogammaglobulinemia and/or B-cell lymphomas / decreased NK function and ADCC against EBV-infected cells

Defects of B and T Cells

Wiskott-Aldrich

XLR / mutation of WASP gene / B and T-cells regress / cannot mount IgM response to capsular polysaccharides

elevated IgA, normal IgE, low IgM / recurrent pyogenic infections, eczema, thrombocytopenia / increased incidence of lymphoreticular neoplasm

Ataxia-Telangiectasia

B and T-cell deficiency, with associated IgA deficiency / presents with ataxia, spider angiomas / recurrent infections / can get lymphomas / secondary diabetes mellitus?

Severe Combined Immunodeficiency Syndrome (SCIDS)

no functional B and T cells / defective IL-2 receptors, MHC II, or ADA (½ of autosomal

forms)

Adenosine deaminase deficiency (ADA)

excess ATP and dATP provides negative feedback on ribonucleotide reductase, prevents DNA synthesis, lowers lymphocyte count / can produce SCID

Defects of Phagocytes [NEJM]

Guideline: these are rare but important diseases, and can be diagnosed by examination of peripheral phagocytes and a few special stains / must catch these early and consider IFN-gamma, g-CSF, broad antibiotics

Cyclic Neutropenia

Autosomal dominant / ?mutation in neutrophil elastase (ELA2)

recurrent neutropenia ( < 200 cells/mL) lasts 3-6 days / cycle usually ~21 days, but in 30% of patients, ranges from 14-42 in 30%

During neutropenia: fever, apthous stomatitis, gingivitis, stomatitis, cellulitis, cervical LAD

Severe congenital neutropenia

Autosomal recessive in 90% (unknown mutation) / heterozygous in 10% /

Presents during first year of life / cellulitis, perirectal abscess, peritonitis, stomatitis, meningitis (Staph, Burkholderia) / increased risk for myelodysplasia, AML

Labs: < 500 neutrophils, but increased circulating monocytes, eosinophils

Treatments: nearly all improve with exogenous g-CSF

Schwachman-Diamond Syndrome

Autosomal recessive (rare) / Presents within first yr of life / average life expectancy 35 yrs

Exocrine pancreatic insufficiency, skeletal abnormalities, bone marrow dysfunction, recurrent infection / all have neutropenia (cyclic or intermittent), and 10-25% also have pancytopenia / increased risk of marrow aplasia, myelodysplasia, AML

Treatments: exogenous g-CSF (not considered a risk factor for malignant transformation)

CD18 (leukocyte adhesion deficiency type 1)

Autosomal recessive loss of B2 integrin adhesion molecules (from lack of CD18 or B-chain) / neutrophils cannot aggregate or bind endothelial cells / life expectancy is < 10 up to 40 yrs (depends on amount of CD18)

Delayed separation of umbilical cord, severe periodontitis (early tooth decay), recurrent infections of all mucosal surfaces, AND delayed wound healing (enlarging borders, dysplastic scars)

Leukocyte adhesion deficiency type 2

Growth retardation, dysmorphic features, neurological deficits / lack of sialyl-Lewis^x (ligand for selectins) / Treatment with oral fructose has proven helpful

Job’s syndrome

neutrophils fail to respond to chemotactic stimuli (C3a, 5a, LT-B4) / recurrent cold staph abscesses / dental problems / elevated IgE levels / ?Rac2 (predominant GTPase in neutrophils)

Defective INF-gamma/IL-12 Axis

Autosomal recessive and autosomal dominant forms / complete loss of ligand-binding chain causes disseminated NTM in infancy or fatal BCG vaccination / partial loss is less severe (NTM develops in early childhood) / defect of IFN-gamma receptor signaling chain resembles complete loss of ligand-binding chain / defect in IL-12 receptor (B1 chain) and IL-12 increases susceptibility to NTM and Salmonella infections

Treatment: all respond to exogenous INF-gamma except (complete loss of ligand and receptor signaling)

Chronic Granulomatous Disease

XLR (gp91^phox) make up 70% / presents within first 2 yrs / neutrophils lack hydrogen peroxide burst (myeloperoxidase system) /

Autosomal recessive (P47^phox) make up 30% / onset may be later

Organisms: S. aureus, Burkholderia cepacia, aspergillus, nocardia, serratia, proteus, E. coli

Obstructive granulomas of GI/GU tracts, pneumonia, skin infections, osteomyelitis, liver abscesses, draining adenopathy (at BCG injection site, but mycobacterial disease still rare)

Diagnosis: can be delayed by blunted fever, inflammatory symptoms / severe resistant facial acne and painful inflammation of nares, gingivitis, apthous ulcers, NOT periodontal disease

Nitroblue tetrazolium test or flow cytometry with dihydrorhodamine dye

Treatment: bactrim (one/day) may reduce serious infections from 1/yr to 1 every 4 yrs / IFN gamma reduces bacterial and fungal infections by 70% / stem-cell transplantation and gene therapy protocols under investigation

Myeloperoxidase deficiency

50% have complete loss / no chlorine formation in azurophilic (primary) granules / usually asymptomatic except in diabetics who have increased risk of disseminated candidiasis

Chediak-Higashi

Autosomal recessive mutation in LYST (microtubule and lysosomal defects)

Recurrent staph and strep, partial albinism, mental retardation, platelet dysfunction, severe periodontal disease, and in those patients surviving into 20s, striking peripheral nerve defects (nystagmus, neuropathy)

Labs: mild neutropenia and normal IG levels

Course: 85% have fatal infiltration of CD8+ and macrophages with eventual pancytopenia

Neutrophil-Specific Granule Deficiency

S. aureus, S. epidermidis, enteric bacteria (skin/lungs) / abnormal migration and atypical nuclear morphology / lack of primary granule defensins, lack of eosinophil-specific granules

Felty’s Syndrome (see rheumatology)

neutropenia, splenomegaly, from long standing RA

Complement deficiencies [labs]

most are recessive, all occur at similar rates (except C2 may be more common, 1% prevalence) / C3 (severe disease) / C5-8 à GC meningitis, arthritis

Biology of Complement [activation cascade]

Functions: lysis, opsonization, anaphylatoxins (degranulation), chemotaxis

Classical: Ag:Ab complex, C1, C4, C2

attachment, activation, amplification, attack

Alternative: microbe + P, D, B, C3b

Lectin (new): MBP opsonizes foreign carbohydrates

C3a, C5a also anaphylatoxins

C5a is also a chemotactic factor

Deficiency syndromes

Clq, C1r, C1s, C4, C2	SLE, some get infections
C3	Repeated infections, partial lipodystrophy, SLE / C3 or C4 nephritic factor stabilizes convertase of alternate or classical pathway
C5-C8	Neisseria infections, arthritis
D and properdin (XLR)	Recurrent meningococcal meningitis
C1 inhibitor (AD)	Hereditary angioedema / may occur in SLE, lymphoproliferative disorders, paraproteinemias
MBP (3^rd pathway)	Infections in SLE
DAF and CD59	Paroxysmal nocturnal hemoglobinuria
Factors H and I	Pyogenic infections, urticaria, glomerulonephritis, secondary C3 deficiency

Complement Studies

Normal C3 / Normal C4

Normal C3 / Decreased ↓C4

Alterations in vitro (improper specimen handling)

Coagulation-associated complement consumption

Inborn errors (other than C4 or C3)

Immune complex disease

Hypergammaglobulinemic states

Cryoglobulinemia

Hereditary angioedema

Inborn C4 deficiency

Decreased ↓C3 / Normal C4

Decreased ↓C3 / Decreased ↓C4

Acute glomerulonephritis

MPGN

Immune complex disease

Active SLE

Inborn C3 deficiency

Active SLE

Serum sickness

Chronic active hepatitis

Subacute bacterial endocarditis

Immune complex disease

C1 inhibitor (acquired or AD)

hereditary angioedema / may occur in SLE, lymphoproliferative disorders, paraproteinemias

recurrent GI attacks of colic are common / no pruritis or urticarial lesions

Allergy

Anaphylaxis

Most common à B-lactams / ⅓ of cases are idiopathic

5-60 minutes following exposure, but delayed reaction is possible

Angioedema with or without urticaria (not true anaphylaxis without life threatening hypotension or laryngeal edema)

Presentation: pruritis, flushing, urticaria, angioedema, diaphoresis, sneezing, rhinorrhea, congestion, hoarseness, stridor, laryngeal edema, dyspnea, tachypnea, wheezing, bronchorrhea, cyanosis, tachycardia, bradycardia, hypotension, cardiac arrest, arrhythmias, nausea, vomiting, diarrhea, abdominal cramping, dizziness, weakness, syncope, sense of impending doom, seizures

Treatment:

· Epinephrine, IM (anterolateral thigh is fastest absorbed)

· Recumbent position, elevate legs, oxygen

· Volume replacement, pressors as needed

· Benadryl 50 mg PO or IV every 4 hrs

Ddx: EM minor (urticarial or bullous lesions), SJS, TEN [these syndromes cause fever, headache, malaise, arthralgia, corneal ulcerations, arrhythmia, pericarditis, electrolyte abnormalities, seizures, coma, sepsis]

Dilantin hypersensitivity: very common, ranges from minor to life-threatening, mechanism unclear

Iodine allergy: not true allergic reaction; hyperosmolar dye causes degranulation of mast cells/basophils

Pretreatment protocol: 40 mg prednisone 24 hrs before then 12 hrs, etc… / H2 blockers (ranitidine), benadryl / avoid contrast dye with renal insufficiency and sickle cell disease / normal maximum dye load would be 2 CT scans within a 24 hour period (assuming normal renal function)

Drug Fever or Drug Rash

maculopapular rash, resolve after removal of agent

Timecourse: most occur several days after starting treatment, but can happen weeks after initiation of offending agent

Labs: elevated eosinophils, CRP, LFT’s (e.g. one study found increased LFT’s in 20% of cases of maculopapular rash)

Note: if you see it on the outside, the same thing can be happening on the inside (such as the liver, etc)

Serum Sickness

7-10 days after primary exposure, 2-4 days after secondary exposure

Findings: fever, polyarthralgia, urticaria, lymphadenopathy, glomerulonephritis

Treatment: removal of agent, antihistamines, NSAIDs

Atopy

asthma, eczema, and seasonal rhinitis and conjunctivitis

allergic rhinitis: varies with season, treated with antihistamines/topical nasal steroids, itchy

vasomotor rhinitis: perennial (no seasonal variation), not itchy

Food allergies

Most common à peanuts (soy beans, shellfish, eggs, milk, nuts) / incidence believe about 1 % / breastfeeding may reduce chance of developing in those predisposed / skin testing (radioallergosorbent tests or RAST ) not as good as a simple food diary / reactions usu. in GI and skin but can cause anaphylaxis/respiratory / best treatment is avoidance

Dust mite

common allergen / grow better in warm, humid environment (so humidifier actually makes worse) / can do skin testing for diagnosis of allergy

Insect allergies (e.g. hymenoptera)

range from local reactions to anaphylaxis / honeybee (Apis family) is not cross-reactive with Vespid family (e.g. wasps, hornets, yellow jackets) / venom immunotherapy is indicated with history and/or positive skin testing

Latex allergy

ranges from mild to anaphylaxis / can do scratch test

Rheumatology

Bone Malformations Bone Fractures Bone Cancer Osteomyelitis

Joint Rheumatoid arthritis, SLE , Scleroderma, Sjögren’s, MCTD, JRA, Sarcoidosis

Osteoarthritis (OA), gout, pseudogout

Infectious arthritis

Spondylarthropathies: AS, psoriatic, Reiter’s and Reactive, IBD

Fibromyalgia

Muscle Polymyositis/Dermatomyositis, PMR, RS3PE, eosinophilic fasciitis, eosinophilic myositis, other myopathy

Vascultides GCA, Takayasu’s, Kawasaki’s, PAN, Wegener’s, Churg-Strauss, Buerger’s

Ortho Low Back Pain, Knee Pain, carpal tunnel

[Rheum H&P] [HLA associations]

Rheum History and Physical Exam

History

General: CC/Chronology/demographics/functional impact/FH/ROS

Pain

Distal (RA), proximal (PMR, fibromyalgia)

Gentle activity often improves inflammatory but not pain of OA or fibromyalgia

Pain worse as day goes on (OA), wakens from sleep (severe OA, cancer)

Stiffness

Morning stiffness > 1 hr (RA, PMR)

gel phenomenon (worse on initiation/resumption of activity)

Swelling

Articular (arthritis), periarticular (tenosynovitis, ganglion cyst), entire limb (lymphedema), other (lipoma, tumor)

Dependent à worse as day goes on

Weakness

muscle vs. neurological

Constitutional

Fever, inflammation (weight loss) vs. chronic pain (weight gain)

Sleep

Fibromyalgia and inflammatory disease often poor sleepers (may also have sleep apnea, nocturia, narcolepsy)

Raynaud’s

Three Stages

Ischemic pallor - vasospasm (arteries/arterioles) [pic]

Cyanosis – dilation / deoxygenated blood pooling

Rubor – reactive hyperemia

Primary

Secondary

Collagen vascular disease (SLE, SSc, others)

Arterial occlusive disease

Pulmonary HTN

Neurologic disorders

Blood dyscrasias (e.g. Waldenstrom’s)

Trauma

Other: thoracic outlet syndrome (decreased blood flow, short rib)

Arthritis Ddx by category

Acute polyarthritis

Infectious: bacterial sepsis, Neisseria, HIV, other virus, Lyme, rheumatic fever

Non-infectious: sarcoid, many CTD’s, Spondylarthropathies, juvenile chronic arthritis, gout/CPPD, HSP, HOA, sickle cell, leukemia

Intermittent Arthritis

Mechanical: loose bodies, partial tears, ligament laxities

Crystals: gout, pseudogout, hydroxyapatite

Infectious: Lyme, whipple’s

Other: palindromic RA, episodic RA, intermittent hydrarthrosis, FMF, Sarcoid

Chronic Arthritis

RA, JRA, other CTD, crystals, spondylarthropathies, HOA, hypothyroid, metabolic/infiltrative bone/joint disease

Acute Monoarthritis

Note: these can present with only one joint first, of course

Trauma, sickle cell, osteonecrosis

Crystals, bacteria, spondylarthropathies, RA, palindromic RA, JRA

Chronic Monoarthritis

Non-inflammatory

OA, mechanical, osteonecrosis, neuropathic, reflex sympathetic dystrophy, adjacent bone lesion (tumor/infection)

Inflammatory

Tb, fungal, lyme, crystals, RA, JRA, spondylarthropathies, hemophilia, synovial neoplasm, pigmented villonodular synovitis

Low Back Pain

Etiologies:

Inflammatory: AS, Reiter’s, Psoriatic, enteropathic (reactive)

Infectious: infectious sacroiliitis, osteomyelitis

Musculoskeletal: vertebral compression, degenerative facet joint disease, herniated disc, muscular ligamentous injury

Neurologic

Psychogenic, worker’s comp

Visceral/vascular, referred pain

Primary or metastatic malignancy

Congenital

Conditions:

· musculoskeletal

o lumbar sprain or strain (70%): acute or chronic / young adults

o degenerative disk disease (10%)

o spinal stenosis (3%): pain often bilateral lower legs / usu. > 60 yrs / worse w/ extension, relieved by flexion, worse with walking (uphill)

o intervertebral (herniated disc) disease (4%): worse with sitting (lying may help)

o spondylosis: defect in pars interarticularis, either congenital or secondary to stress fracture

o spondylolisthesis: anterior displacement of upper vertebral body on the lower body (can mimic symptoms of spinal stenosis) / condition results from spondylosis or degenerative disk disease in elderly

o cauda equina syndrome: difficulty in micturation, loss of anal tone, saddle anesthesia, progressive motor weakness, sensory level

o facet joint syndrome: back pain referred to buttock, worse with extension, relieved by flexion / gradual, chronic / more in older patients / may have paravertebral muscle spasm at level

· inflammatory: onset < 40, morning stiffness, peripheral joints, iritis, rash, urethral discharge

· non-mechanical low back pain (1%)

· referred or visceral pain (2%)

Diagnosis: history and physical usually enough / don’t get XR unless suspecting tumor, infection because 60% of asymptomatic patients will have positive findings on XR (which will be useless information) / MRI reserved for severe cases and/or when considering surgery

o Straight-leg raising (not very sensitive or specific)

o Patrick maneuver distinguishes pain from sacral-iliac joint (patient externally rotates hip, flexes knee, crosses knee of other leg like a number four while examiner presses down on flexed knee and opposite pelvis)

Duration: acute: < 3 months / early: 3 to 6 months / intermediate: 6 to 24 months / late: > 2 yrs

Red flags: young or old presentation, previous CA, steroids, drugs, HIV, constant (non-mechanical), thoracic, wt loss, ESR > 25, vertebral collapse on XR

Treatment: most cases of acute low back pain resolve in 1-6 weeks w/ analgesics (NSAIDs, other), bed rest NOT recommended, physical therapy NOT necessary (3-5% remain disabled for > 3 months)

	Pain distribution	weakness	Reflex affected	Screening test
L3-4	anterolateral thigh, anteromedial calf to ankle	Quadriceps	knee	Squat and rise (L4)
L4-5	lateral thigh, anteromedial calf, medial dorsum of foot between 1^st and 2^nd toes	Dorsiflexion of foot	none	Heel walking (L5)
L5-S1	gluteal region, posterior thigh, posterolateral calf, lateral dorsum of sole and foot between 4^th and 5^th toes	Plantar flexion of foot	ankle	Walk on toes (S1)

Referred pain

facet joints, intervertebral discs

Lumbar à hip pain localizing to buttock, lateral thigh

Cervical à axilla, shoulder

hips à groin, anterior thigh

knee à

heart à shoulder, jaw, arm (pericarditis à trapezius ridge)

pancreas à back

liver à shoulder

renal (stones, etc) à flank/groin/testicle

uterine à lower back

PUD/spleen/pneumonia à right shoulder

throat à ear (via recurrent laryngeal nerve)

Joint Diseases [Synovial Fluid Table] [Polyarticular Ddx]

Inflammatory Joint Disease

Infectious arthritis

Crystal-induced: Gout, pseudogout, hydroxyapatite, calcium oxalate, LLM

Trauma: fracture, internal derangement, hemarthrosis

Osteoarthritis, RA and JRA

Spondylarthropathies: psoriatic arthritis, ankylosing spondylitis, Reiter’s, reactive arthritis

Ischemic (avascular) necrosis: Kasan’s, alcoholics, Gaucher’s

Foreign-body synovitis

Tumor: mets, osteoid osteoma, pigmented villonodular synovitis (benign, brown-yellow on MRI)

GI disease: intestinal bypass, Whipple’s, reactive arthritis (Shigella, Salmonella, Yersinia, Chlamydia, Campylobacter), IBD (Crohn’s and ulcerative colitis)

Viral infections: Parvovirus B19, rubella, HBV, HCV

Uncommon: mumps, coxsackie, echovirus, adenovirus, VZV, HSV, CMV

Other causes of arthropathy:

Relapsing polychondritis

Neuropathic joint disease

Hypertrophic osteoarthropathy and clubbing

Fibromyalgia

Psychogenic rheumatism

Reflex sympathetic dystrophy syndrome

Costochondritis or Tietze’s syndrome (with swelling)

Musculoskeletal disorders associated with hyperlipidemia

Arthropathy of acromegaly, hemochromatosis, hemophilia, hemoglobinopathies,

Polyarticular

Rheum: RA, OA, gout, CPPD, SLE, vasculitis, scleroderma, PM/DM,

Still’s, Behçet’s, relapsing polychondritis, sarcoidosis, palindromic rheumatism,

FMF, malignancy, hyperlipoproteinemia / seronegative: AS, psoriatic, IBD

Other: fibromyalgia, multiple bursitis/tendonitis, soft tissue abnormalities,

hypothyroidism, neuropathic pain, metabolic bone disease, depression, serum sickness

Infectious: lyme, endocarditis, viral (see above), gonococcal, Tb, other

Post-infectious or reactive: Reiter’s, rheumatic fever, enteric infection

HOA and clubbing

Primary HOA (pachydermoperiostosis)

AD / childhood / remits in 10-20 yrs

Secondary HOA

Causes: associated with intrathoracic malignancies, suppurative lung disease, congenital heart disease, and more / without clubbing (vascular grafting)

bronchogenic CA (usu. non-small cell) à RA-like picture (with effusions/arthralgia) can develop even before onset of clubbing

Mechanism: megakaryocyte shunting with R to L arteriolar trapping à release of PDGF à proliferation [doesn’t seem to explain the classic pattern of progressive development of clubbing from feet to hands seen with congenital heart disease]

Treatment: after lung tumor resection (or even just radiation of mets) or lung abscess drainage, symptoms and signs of arthropathy often subside rapidly; radiographic changes remit during weeks and months / NSAID’s, ASA, bisphosphonates, even trial of low-dose steroids may relieve bone pain in some pts

Diagnosis: clinical? / bone scan will show periosteal deposition [pic], plain films may reveal changes also

Periarticular disorders:

bursitis, rotator cuff tendonitis and impingement syndrome, calcific tendonitis, bicipital tendonitis and rupture, adhesive capsulitis, lateral epicondylitis (tennis elbow), medial epicondylitis

General Points about OA, RA, gout

· OA à affects many vertebrae, RA particularly C1/C2 (because there’s a bursa there)

· RA causes destruction and osteoporosis; gout causes destruction but not osteoporosis

Osteoarthritis (OA) most common joint disease

Causes: primary (80% of population > 70 yrs) or secondary 5% (previously damaged joints, weight-bearing joints, endocrinopathy, metabolic disease, neuropathy, avascular necrosis, Paget’s); 34% of patients presenting with acute knee pain

Clinical: age > 50 yrs, morning stiffness < 30 mins, crepitus, bony enlargement or tenderness; no inflammation (no heat), slow progression / normally pain worse with weigh-bearing, motion, but can progress to point where causes pain at rest, at night

ACR: osteophytes on XR + at least one of above signs is 90% sensitive, specific for OA

Findings:

Affected Joints: DIP > PIP > CMC, knee, hip, feet

Spared Joints: hands (except DIP/PIP/CMC), wrist, elbow, shoulder, spine

· Heberden’s nodes (DIP) and Bouchard’s (PIP) seen more in post-menopausal women with genetic predisposition [pic] / only wrist joint involved is 1^st CMC [pic]

· Knees: medial >> lateral involvement / may develop popliteal cysts

Radiographic (weight-bearing): osteophytes (77% sensitivity/83% specificity), subchondral sclerosis, subchondral cysts, joint space narrowing (erosions), malalignment, may see soft-tissue swelling

· Spondylosis is the formation of osteophytes in response to degenerative disc disease / thick and often project laterally (unlike in AS) / spinal stenosis can also occur from hypertrophy of posterior facet joints, spondylolisthesis, synovial cysts, Paget’s disease, epidural lipomatosis, and congenitally small spinal canal

· Schmorl’s nodes (invasion of disc into vertebral body) are common (often associated with Scheuermann’s disease, osteopenia and degenerative disc disease) / bony margin may be visible on roentgenogram

· Forestier’s disease (diffuse hyperostosis) can occur (usu. elderly) and may form “flowing ossification” (usu. on right side, thoracic vertebrae, but also can occur on ligamentous, tendinous attachments anywhere)

Labs: ESR < 40, RF < 1:40, non-inflammatory synovial fluid (< 2000/mm³)

Treatment: NSAIDs (some say glucosamine works in patients who cannot tolerate NSAIDs), when it’s bad enough, only treatment is joint replacement (knee/hip) (~95% 10 yr success rate) / chondroitin sulfate under investigation / multiple, short periods of rest throughout day better than one large period of rest / intraarticular steroids occasionally helpful (esp. in joint “lock up”)

Nodal OA DIP/PIP / runs in families

Rheumatoid Arthritis

females 4:1 / any age / mildly shortened life span

Findings: swollen, painful, warm joints (PIP, MCP, not DIP), ulnar deviation of MCP [pic], radial deviation of wrists, swan-neck fingers [pic], Boutonnière or button-hole deformities [pic][pic]

Joints: inflamed synovium (pannus) / penetrates to cause erosions, subchondral cysts / fibrin aggregates in joint space (rice bodies) / synovium eventually bridges and ossifies opposing surfaces

Skin: 25% have rheumatoid nodules (firm, oval, non-tender, fibrinoid necrosis, inflammation)

Vasculitis: rheumatoid vasculitis, ulcers, gangrene, splinter hemorrhages, raynaud’s

Neuro

· peripheral neuropathy (10%; ½ are slowly progressive, distal symmetrical sensory or sensory-motor polyneuropathy)

· mononeuritis multiplex

· entrapment neuropathy à carpal tunnel

Renal: early (drug-induced nephropathies), late (amyloid-like renal disease)

Lungs (almost always RF positive): [NEJM]

· pleuritis/pleurisy, effusion

· pulmonary nodules (CT will show them if CXR doesn’t)

· ILD

· alveolar hemorrhage

Heart: pericarditis > myocarditis, valves / conduction abnormalities

Eyes: (1^st dry eyes or keratoconjunctivitis sicca (Sjögren’s), 2^nd episcleritis – may be severe, perforate)

Heme: anemia of chronic disease

Diagnosis: r/o TB (also has RF)

Criteria: 4 of 7 required

morning stiffness > 1 hr

swelling of 3 or more joints

swelling of hand joints (PIP, MCP, wrist)

symmetrical swelling

rheumatoid nodules

positive RF

erosions of hand joints (X-ray)

Labs: 80% have RF (IgM to Fc of IgG), ANA / HLA DR4, HLA DR1 / anti-CCP (worse prognosis; ⅓ with negative RF will have positive anti-citric citrullinated peptide)

Radiography: early X-ray changes in feet (MTPs, very specific for RA), ulnar styloid changes (late becomes piano key sign), C1-2 subluxation (can be very serious and damage spinal cord, but if seen incidentally on lateral flexion c-spine at < 5 mm, can observe)

Course: usually insidious course

Treatment: aggressive therapy is the rule / immunosuppressive drugs from day one

· Steroids

· TNF-a inhibitors

· Others: Immuran

· Old school: gold, MTX, penicillamine

· New school (example of regimens): initial tapered high-dose prednisone + MTX and sulfasalazine or infliximab + MTX

Prognosis: more nodules, DR4, anti-CCP, more systemic Sx, are worse indicators

Palindromic RA

waxing and waning course / usually resolves within 24-48 hrs / joint involvement atypical compared to classic RA

Felty’s syndrome

neutropenia, splenomegaly, leg ulcers, polyarticular arthritis (RA~) or SLE

More: nodules (75%), weight loss (70%), Sjögren’s (55%), LAD (35%), leg ulcers (25%), pleuritis (20%), skin pigmentation (15%), neuropathy (15%), episcleritis (10%)

caused by autoantibodies and cytokine/T cell suppression of granulocytopoesis / more common in elderly patients with RA (especially if untreated) / may also have vasculitis etc.

Large Granular Lymphocytes (LGL)

Usually polyclonal, 20% have RA (the rest are considered neoplastic) / usually associated with Felty’s / course is variable

Juvenile Rheumatoid Arthritis (JRA) (Still’s disease)

children under 16

Presentation: fever, rash (transient, macular), hepatosplenomegaly, serositis

Findings: RF and nodules usually absent (only in older, more severe cases)

Complications: pericarditis, myocarditis, pulmonary fibrosis, glomerulonephritis, growth retardation, iridocyclitis (anterior uveitis – main systemic symptom in up to 25% of girls with mono/pauciarticular RA, insidious yet may lead to blindness), 40% incidence of myopia / 70% recover, 10% with severe deformities

Adult Onset Still’s Disease (AOSD)

Presents with fever, transient rash, joint inflammation / notable for persistent plaques and linear pigmentation

Labs: over 2/3 will have elevated AST/ALT (2-5x) and AST/GGT / (-) RF, ANA / often extremely elevated ferritin

Cogan’s syndrome

Still’s + hearing loss / Treatment: high-dose steroids and pulse Cytoxan

Infectious Arthritis

Infectious Monoarthritis

Neonates: group B strep, H. influenza

Children: S.aureus (45%), Strep A (25%), GNR (20%), Gonococcus (5%), Tb (1%)

Adults: Neisseria (50%), S. aureus (35%), Strep A (10%), GNR (5%), Tb (1%)

Other causes: Pseudomonas (IV drugs, wounds), Klebsiella/E. Coli (IV users, GU infections), lyme disease, Salmonella in sickle cell patients, syphilis (2^nd stage and Charcot’s joints) / HACEK organisms

Pathology: usually hematogenous spread / polymicrobial from surgical implantation or elderly with peripheral vascular disease / usually monostotic (except newborns and sickle cell pts)

Neonates: metaphyses, epiphyses

Children: usually metaphyseal only as growth plate prevents spread into joint

Adults: growth plate closed, vessels reunite, bacteria can go everywhere

Clinical symptoms:

early: fever, skin, arthralgias / knee is hot, tender (pain on active AND passive movement; joint movement that is NOT limited by passive motion suggests soft-tissue problem, e.g. bursitis))

Gonococcal: hand and feet lesions (erythematous, +/- pustular)

Non-gonococcal: another focus / debilitating illness / other? / pre-existing joint abnormality

Synovial fluid from joint aspiration or arthrocentesis of knee [video]

· WBC is a helpful value:

< 200 is normal ( < 25% WBC)

200-2000 is non-inflammatory ( < 25% WBC; PMNs)

2000-100,000 is inflammatory ( > 50% WBC)

> 80,000 is purulent/septic ( > 75% WBC)

Fungal: 10-40 WBC, 70% neutrophils Syphilis: 10-40 WBC in 2^nd

· glucose: 25% less than fasting blood glucose indicates infection

· culture and gram stain (60-80% sensitive)

· wet prep (not always used, many false negatives by non-expert labs)

· synovial biopsy (may be needed to diagnose Tb or hemochromatosis)

XR shows pale bone necrosis (sequestrum) / surrounding deposition of new bone (involucrum)

Treatment: empiric antibiotics / joint drainage

Tuberculous arthritis (see TB)

Usually knees / most common is chronic granulomatous monoarthritis / 1% of Tb / 10% of extrapulmonary Tb / onset is months/years / systemic symptoms only in ½ / Synovial fluid: 20 WBC 50% neutrophils, culture positive in 80%, gram stain positive in 1/3 / Pott’s (spine) / scrofula (TB of neck)

Poncet’s disease

reactive arthritis from Tb / bilateral, no organisms found in joints

Lyme arthritis (see Lyme Disease)

large joints, weeks to months duration, periods of remission, permanent deformities in 10%

Viral Arthritis (from systemic infection)

Parvovirus B19, rubella, HBV, HCV

Gout

usually not before 30 yrs / many are asymptomatic / asymptomatic intervals get shorter over time (severe cases can mimic RA)

Pathology: tophi may occur in joints, ligaments, tendons, soft tissue, earlobes, palms, soles, kidney (uric acid > 8 à causes gout, > 20 à causes renal damage (due to very rapid cell turnover)

· Hyperuricemia (10%) ( > 750 mg/dl)

?HGPRT deficiency

Increased turnover: myeloproliferative disorders, hemolytic anemias, lymphoproliferative malignancy, psoriasis, glycogen storage diseases

· Impaired renal excretion of uric acid (90%) ( < 700 mg/dl)

polygenic inheritance

hypovolemia (adrenal insufficiency, diabetes insipidus)

Toxins: heavy alcohol use / lead toxicity / ASA interferes with tubular secretion / organic acids compete for secretion (ketones, LA)

Other drugs: thiazide, radiocontrast agents, allopurinol/probenecid (if given during attack)

Presentation:

Some classify in stages:

I – asymptomatic hyperuricemia

II – acute gouty arthritis

more at night, last hours to weeks, 1^st attack usually only in one joint / Podagra (90%) – 1^st MTP (great toe)

III – intercritical gout

most patients have next attack within 1-2 years

IV – chronic tophaceous gout

erosion of underlying bone from chronic inflammation

Precipitation: dietary excess, alcohol, acute medical illness, surgical procedures, joint trauma

Renal complications: urate crystals in medullary interstitium (pyelonephritis, obstruction) / 20% of chronic gout die of renal failure (typical to have mild albuminuria, not glomerulonephritis)

Diagnosis: needle-shaped urate crystals in synovial fluid - yellow, parallel to polarizing light

Note: don’t rule out infection just because you see crystals as infection frequently coexists with hyperuricemia

Treatment:

Acute attack:

colchicine (0.6 mg bid or until diarrhea, unless renal impairment)

NSAIDs (indocin and tolectin thought to work best)

steroids (prednisone 40 mg qd x 2-3d with rapid taper)

Prevention: low purine diet / weight loss / avoid alcohol / colchicine (low dose daily)

Probenecid: frequent attacks / stones / tophi / do not use with renal insufficiency

Allopurinol: diminishes uric acid production (do not start during acute attack)

Pseudogout (CPPD) far less common than gout

elderly man/woman (over 85) / calcium pyrophosphate dihydrate in synovial membranes et al / usually asymptomatic rhomboid crystals / familial form chr 8q and chr 5p

Labs: mildly elevated ESR / chondrocalcinosis (+ / -) / CPPD crystals - coffin-shaped, weakly (+) positive birefringence (blue when parallel)

Presentation: warmth, erythema, tenderness, swelling, may have fever, leukocytosis / self-limited to several days / usually knee (50% of acute attacks) / pseudopodagra is almost impossible

Radiography: calcific deposits (chondrocalcinosis present in 26% of asymptomatic adults > 60 yrs) / hook-like osteophytes/subchondral cysts (similar to OA)

Associated metabolic conditions:

Hyperparathyroidism (primary or secondary)

Hemochromatosis (perform basic Fe studies), maybe Wilson’s, A1AT

Hypothyroidism

Gout

Hypomagnesemia (mild hypomagnesemia potentiates PTH action)

Hypophosphatemia

Amyloidosis

Neuropathic joints, aging, trauma/surgery

Note: urate gout and rheumatoid arthritis have a strong negative association (10x)

Work-up for newly diagnosed CPPD: Ca, Mg, PO4, Alk Phosphate, ferritin, Fe, TIBC, TSH (less Mg and PO4 in over 60 yrs?)

Treatment: symptomatic relief from NSAIDs (indomethacin), steroids (injection or PO), joint aspiration, joint immobilization, IV or PO colchicines (only if you can use high doses) /

correction of underlying metabolic problem does not always stop progression

Pseudogout (Type A) (25% of CPPD)

Almost never causes podagra / males / asymptomatic between attacks / usually have radiographic evidence (such as chondrocalcinosis seen in AP pelvis, PA wrists)

20% with hyperuricemia, 5% with urate gout

HC associated shows 2^nd/3^rd MCP enlargement and/or attacks of pseudogout

Pseudorheumatoid arthritis (Type B)

10% with low titre RF / joints inflamed “out of phase” (like gout, not like RA), osteophytes, CPPD, lack of typical erosion patterns on X-ray

can mimic sepsis in elderly patients (fever, WBCs, mental status, polyarthritis)

Hydroxyapatite (HA)

secondary to many systemic disease states (apparently, mostly with elevated Ca²⁺) / crystals so small, a special stain is required to detect / anti-inflammatory treatment may shorten duration of attacks, long-term changes cannot be undone?

Calcium oxalate (CaOx)

strong positive (+) birefringence

Primary: rare genetic disorder, death < 20 yrs

Secondary: renal failure or vitamin C abuse

Fibromyalgia

usu. middle-aged women / hypersensitivity to physical stimulation causing pain, fatigue, poor sleep(mechanism poorly understood)

Diagnosis: diagnosis by exclusion of other disorders and demonstrating ≥ 11 of 18 trigger points

Labs: no specific lab abnormalities

Treatment: no good treatment, but TCA’s might provide some relief

Relapsing polychondritis

Inflammation of cartilage (breakdown of chondroitin sulfate)

Findings: saddle-nose deformity, scleral thinning (scleromalacia), floppy ear, aneurysms, valvular insufficiency (AR, MR, TR), tracheal narrowing (steeple sign)

Liquid lipid microspherules?

Other Bone Disorders

Scoliosis

adolescent females > males / 20% with positive family history

slipped capital femoral epiphyses

20% with referred knee pain (can be misleading) / occurs in pubescent males, happens gradually, can be bilateral / Treatment: surgical with pinning

Villonodular synovitis (benign neoplasms)

aggregates of polyhedral cells, hemosiderin, foam cells, giant cells, zones of sclerosis

Treatment: surgery if possible, usually difficult to excise

pigmented villonodular synovitis (PVNS)

single or multiple, diffuse involvement, red-brown projections

giant cell tumor of tendon sheath (localized tenosynovitis)

small, discrete nodule

Bone Cancer

mets most common form: BLT2KP lung > breast (lytic) > prostate (blastic) > testes, kidney

primary malignant: OS, malignant fibrous histiocytoma, adamantinoma, chordoma

Osteochondroma

most common primary bone lesion / young males / sessile or stalked / cartilage cap / usually stops growing as bones mature

Chondroma

single or multiple (Olier’s Disease, Maffucci’s syndrome) / short bones of hands, feet / radiolucent [XR] / lobulated, hypercellular, disorganized / focal calcification w/in lesion / self-limited disease

Chondrosarcoma - good prognosis

proliferation of malignant cartilage / older males / axial skeleton / surgery only useful option

Osteoid osteoma

very common / young males / < 2 cm growth / appendicular skeleton / produces pain at night (relieved by aspirin) / radiolucent lesion surround by reactive bone formation / surgical removal / 25% relapse due to poor nidus locating by surgeon

Osteosarcoma (OS) - poor prognosis

pre-op and post-op chemotherapy / arm, leg bones / produces bone, cartilage, spindle cells usually have mets / cortical destruction w/ extension in soft tissues (Codman’s triangle)

Parosteal osteosarcoma (POS) - excellent prognosis

young, early middle age, women / long bones / radiolucent ‘string sign’ along cortex / spindle cells produce well-formed bone

Ewing’s sarcoma (variable prognosis)

small cell neoplasia / unknown histiogenesis / very young, males, lower extremities / XR: moth-eaten intramedullary pattern, ‘onion skin’ periosteal reactive bone / diaphysis to metaphysis / PAS+ cytoplasm / therapy evolving

Fibrous cortical defect

very common / young, males, long bones / XR: metaphysis, sub-cortical, soap bubbles, sclerosis at interface spindle cells, foamy macrophages, hemosiderin, chronic infiltrate / self-limiting at skeletal maturity

Fibrous dysplasia

very common / single, multiple / young, localization random / XR: radiopaque, ‘shepherd’s crook’ of proximal femur / spindle, cells, woven bone, lack of osteoblastic rimming, Chinese character appearance / no treatment unless symptomatic / excellent prognosis

Malignant fibrous histiocytoma (poor prognosis)

similar demographics to OS / XR: metaphysis, destructive, radiolucent / anaplastic spindle cells, storiform pattern / treatment same and prognosis slightly worse than OS

Giant cell tumor of bone

benign but aggressive local tumor / young, wide distribution / hemorrhage / surgery when possible / extended curettage (experimental) or resection / prosthesis / 98% monostotic / radiation contraindicated (secondary sarcomas)

Adamantinoma (good prognosis)

primary malignant bone tumor / young males, tibia/fibula / XR: may be multifocal (observe carefully) / epithelial or endothelial proliferation / complete surgical extirpation

Chordoma

malignant bone tumor arising from notochord / 40s to 60s / males / physaliferous cells in acid mucoid background / surgery and post-op radiation

survival: sacral 60% (fair) 5 yr, cervical (horrible) 50% 5 yr 0% 8 yr

Myositis ossificans

athletic adolescents, history of trauma (50%) / central fibroblast proliferation, intermediate zone of osteoid formation, peripheral shell of organized bone / Treatment: usually cured by excision

Connective Tissue Diseases

Rheumatoid arthritis (see bone)

Systemic Lupus Erythematosis (SLE)

1 in 300 black women / HLA-DR3 / HLA-DR2

Differential: psoriasis (i.e. avoid UV light therapy), lyme disease, drug reactions, tinea

Diagnosis: must meet 4 of 11 criteria (malar rash, discoid rash, photosensitivity, mucosal

ulcers, arthritis, serositis, renal, neurologic, hematologic, positive ANA, positive LE or anti-ds or anti-Sm)

Complications:

General: fatigue, weight loss, fever

Skin: malar rash (fixed erythema, flat or raised over malar area, tends to spare nasolabial folds), discoid rash (erythematous raised patches with adherent keratotic scaling and follicular plugging), photosensitivity, periungual telangiectasia, alopecia

Renal: many forms possible / note: 80-90% of SLE becomes dormant when ESRD occurs

· mesangial (earliest: may remit or transition to other forms)

· focal proliferative (50%)

· membranous (50%)

· diffuse proliferative (20%, worst)

Cardiovascular:

· endocarditis (Libman-Sacks/caused by APA syndrome)

· pericarditis

· hypercoagulability

· Raynaud’s (20-30%)

· purpuric lesions (see hematologic)

Hematologic:

· hypercoagulable state (in addition, there is arterial-specific hypercoagulability in SLE patients due to variant mannose-binding lectin genes)

· leukopenia (<4000/mm³), lymphopenia (<1500/mm³), thrombocytopenia (<100,000/mm³), hemolytic anemia

Pulmonary:

More common à pleuritis (LE cells are very specific, WBC’s with pushed aside nucleus, very characteristic appearance, but make sure pathologist looks for them), pleural effusion (mildly exudative, unilateral or bilateral)

Less common à ILD (including pneumonitis)

PE (from APA)

pulmonary HTN

diffuse alveolar hemorrhage (rare): 90% will have concurrent nephritis, abrupt onset, young women, association with pneumonia)

malignancy: ↑ risk of lung cancer > lymphoma

other: BOOP, shrinking-lung syndrome, lymphadenopathy, infections

GI: painless oral or vaginal ulcers, non-specific abdominal complaints / GI vasculitis (less common, serious)

Musculoskeletal: arthralgias (symmetric/peripheral, two or more joints, swelling, effusion,

tenderness but NOT erosive; only small percentage actually get joint deforming arthritis as in RA)

CNS: diffuse psychosis, depression or focal neurological deficits (including seizures) [Ddx] / 50% experience some degree of neuropsychiatric problems / may see cystoid bodies in fundus

Other: hepatosplenomegaly (functional hyposplenism), LAD

Labs:

decreased C3/C4 (can be marker of active disease, either can be depressed first depending on if classical or alternate pathway is activated, can also be decreased from poor synthesis such as in liver disease)

thrombocytopenia, anemia

schistocytes generally not seen without active vasculitis or major HTN

anticardiolipin Ab (30-50% have it, fewer actually have APA syndrome)

false positive VDRL

anti-nuclear antibodies (ANA) (labs)

98% sensitivity, often high titre (1:80 happens in many people is non-specific) / 10% of SLE in whites may be ANA only (no other positive Abs), this is rare in non-whites

Specific Patterns

Peripheral à active disease, renal involvement

Diffuse à SLE, RA, discoid lupus, normal elderly (rare) / can mask speckled or peripheral pattern

Speckled à RA, SLE, MCTD, chronic discoid lupus, chronic lung disease, scleroderma, normal elderly (rare)

Nucleolar pattern à scleroderma (occasionally SLE, RA, Sjogren’s)

anti-ds DNA specific for SLE, can fluctuate with treatment

RPGN, rash, pneumonitis

anti-Sm very specific

anti-Ro (SSA) Sjogren’s, SLE, myositis, etc.

anti-La (SSB) cannot have La without Ro

anti-U1-RNP/nRNP

SLE, PSS, myositis / cytoplasmic Ab, thus can be negative ANA / very strong correlation with blacks + Raynaud’s and/or myositis and primary pulmonary HTN (uncommon)

anti-ribosomal P

specific for SLE, can be sole antibody with ANA negative SLE

ANA to histone (diffuse pattern)

suggests drug-induced (90% sensitive, but not so specific in that 20-30% of idiopathic SLE will have anti-histone Abs)

Note: each patient has there own idiosyncratic pattern of lab markers to follow (compliment, platelets, WBC?, Anti-DS)

Drug-induced SLE

SLE-like syndrome / (+) ANA to histone / (+) genetic predisposition, ANA may remain positive for years

Course: usually much less severe, resolves within 6 months of stopping drug

Drugs: procainamide, INH, hydralazine, chlorpromazine, methyldopa

Cutaneous lupus erythematosus

Pathology: interface dermatitis and granular deposition of IgG along the dermal-epidermal junction

Chronic Discoid Lupus

Chilblain’s Lupus – rare

violaceous digital plaques, nodules develop after cold exposure / anti-Ro (SSA), Raynaud’s, changes in nail-fold capillaries / lesions contain papillary and deep dermal T-cells

Pregnancy and SLE

antibodies DO cross placenta and affect infant up to 6 months after birth / can cause irreversible congenital heart block (anti-Ro/SSA) (often before mother is diagnosed)

Treatment: education! If disease is controlled (and < 10 mg prednisone), then it is okay to proceed with pregnancy

Sjögren’s syndrome (Keratoconjunctivitis Sicca) [NEJM]

females (usu. peri-menopause) / HLA-DR3 / can have primary or secondary (with SLE/RA)

Mechanism: lymphocytic infiltration and destruction of lacrimal and salivary glands

Presentation: dry eyes, dry mouth, dry skin, enlarged parotid, enlarged lacrimal gland / patient avoids sour foods

Findings: dry skin, GI, GU, arthritis (more synovitis), bronchitis

Complications:

· Peripheral neuropathies (50-60%) / usu. pure sensory, asymmetric chronic neuropathy (may precede other symptoms by many years)

· GERD

· increased risk of B-cell lymphoma (1-5%)

· association with decreased PFTs (lung disease)

Diagnosis: eye exam (Schirmer test), lip biopsy (salivary gland) in uncertain cases, SSA (anti-Ro), SSB (anti-La) occur in only 3% of cases [note, one does not have anti-SSB without anti-SSA], often have elevated RF, ESR

Treatment: symptomatic (fake tears, benzodiazepines for anxiety, etc.), pro-cholinergic agents, steroids for severe systemic complications

Polymyositis/Dermatomyositis

Antibodies

Many with (-) Ab’s, but if (+) à very specific for autoimmune myositis

· anti-Jo1 (his-tRNA synthetase) – moderate prognosis

30% of PM, 20% of DM

arthritis, interstitial lung disease, fever, Raynaud’s, mechanics hands

all patients with Jo-1 are DR52, whites may also have DR3 or DR6

· anti-SRP (signal recognition particle) – poor prognosis

cardiac (with palpitations), myalgias, mostly blacks / DR5

· Anti-Mi-2 – good prognosis

8% PM/DM, 20% of DM

classic DM picture / 7, DRW53

Polymyositis

Onset usually > 50 yrs

Genetics: HLA-DR3, DQA1*0501 (whites and blacks), 0401 (blacks)

Mechanism: CD8 T-cell mediated destruction

Muscle: inflammatory myopathy

Lungs: pulmonary inflammation / mostly CD8, some CD4

Heart: can get cardiomyopathy (even heart block)

Diagnosis: clinical, EMG, biopsy

Presentation: proximal muscle weakness, up to 30% with esophageal dysphagia, Raynaud’s (30%); eyes are spared; unlike myasthenia gravis; up to 50% will have additional connective tissue disease at same time

Diagnosis: electromyography, biopsy (not always conclusive) / often confused with other forms of myopathy

Labs:

· elevated plasma CK

· ESR may be elevated (but a super-high ESR may hint that something else instead or along with myositis is happening)

Antibodies

· Anti-Jo-1 associated ILD responds more to steroids than other ILD (scleroderma, RA)

· Anti-Ku à SCL/PM overlap (mostly in Japanese) / association with Graves, pulmonary HTN, and RNAP-II

Course: less prolonged than muscular dystrophies / mortality usually from aspiration (pharyngeal weakness)

Malignancy: risk ~2.0 x (no particular types, usually occur after PM diagnosis)

Treatment: high-dose steroids (up to ~100 mg/day IV then PO) / improvement should occur with first few weeks with continued improvement over 3 to 6 months / continue initial dose until strength and CK normalizes for 4-8 weeks / CK can remain elevated due to leaky membranes and strength can remain low with normal CK due to steroid myopathy (i.e. steroid myopathy does not cause elevated CK) / reduce steroids by 10 mg/month, then qod dosing / 90% will improve at least partially / 50-75% will enter remission / can try MTX, azathioprine or even both together after 6 weeks of non-response to steroids / Plaquenil can help with skin manifestations of DM / others like cyclosporin and Cytoxan have been used / IVIG is useful for DM, and is being tried for IBM

Dermatomyositis

bimodal age peaks [15-20] and [45-55]

Mechanism: CD4 T-cell and B-cell mediated destruction / humoral response more important

Skin changes without muscle involvement occurs in ~10% of cases

Skin/Joints: heliotrope rash on face (Shawl sign) [pic], V-sign, mechanic’s hands, cuticle

Changes (capillary engorgement, capillary dropout), periungual telangiectasia [pic], calcinosis [pic] [dermis], Gotron’s papules over finger joints, knuckles, elbows, patella

Lungs: can have bad lung disease (usu. w/ anti-Jo1)

Vasculitis of the gastrointestinal tract, kidneys, lungs, and eyes can complicate dermatomyositis (but not polymyositis), particularly in children

Malignancy: relative risk 6.2 (about 20%, no particular type) / DM often diagnosed after or at same time as cancer, then risk decreases to 1.6 after 5 yrs

Biopsy: classically different pattern than PM / ?can it look like SLE

Treatment: similar to PM (with exception that IVIG can be particularly useful) / newly diagnosed cancer patients should have basic workup for malignancy

Juvenile Dermatomyositis (JDM)

ANA negative / disease usually lasts about 2 years / diagnosis often suggested by

calcinosis on plain films [pic]

Scleroderma

Sarcoidosis

more common in women, African-Americans

Presentation: various protean manifestations / adults: CNS, lungs > heart >> renal

· Lungs: restrictive lung disease, pleurisy (with effusion) / actually does not produce rales (too much fibrosis)

· Liver: hepatomegaly (20-30%)

· Skin: both acute and chronic changes / lupus pernio (violaceous indurated lesions with a predilection for the nose, ears, lips, and face), skin plaques [dermis], maculopapular/papules (red-brown, waxy), subcutaneous nodules, and erythema nodosum, vitiligo (hypo or hyperpigmented), alopecia, old cars

Ddx (for skin changes): Tb, berylliosis, leprosy, leischmaniasis, syphilis, deep fungal infection / other panniculitis (Behçet’s, superficial thrombophlebitis, cutaneous vasculitides)

· CNS: can present with only CNS problems (peripheral neuropathy, aseptic meningitis) or focal (cranial nerves, hypothalamus, pituitary)

Ddx (for CNS): cancer with mets, fungal or Tb, lymphoma, Langerhans histiocytosis, other

· Joints: knees, ankles, elbows, wrists, small joints of the hands / swollen, warm, tender, painful

Complications:

· Lungs: hilar lymphadenopathy, pleural effusion

· Eye: variety of conditions / uveitis / others (20% incidence)

· ENT: parotitis / nasal involvement

· CNS: Bell’s palsy, diabetes insipidus (posterior pituitary > anterior), cranial nerves, basal meninges, hypothalamus, seizures, etc. / [MRI] / elevated ACE in CSF (66%)

· Heart: restrictive cardiomyopathy

· Liver: very common, but usually no symptoms, can be good biopsy site

· Renal: very uncommon

Diagnosis: can be diagnosis of exclusion when biopsies inconclusive, often first recognized from CXR in asymptomatic patients (60-70% will have some abnormality on chest CT)

· Biopsy (of involved lesions): widespread non-caseating granulomas with Schaumann and asteroid bodies / may look like Tb / any one of following has 50-80% sensitivity (all three combined have 99% sensitivity) / note: granulomas in scalene, liver nodes are not (by themselves) sufficient for diagnosis (because granulomas are so frequent in these nodes)

· Transbronchial biopsy (TBLB)

· Transbronchial needle aspiration (TBNA)

· BAL showing lymphocyte predominance ( > 12%), high CD4:CD8 ratio (should not have high neutrophils or eosinophils at same time; ratio > 3.5 has 90% specificity, 50% sensitivity)

Labs:

· Hypercalcemia (10%) (elevated 1-hydroxylase produces 1,25-OH D₃) (hypercalciuria in 33%)

· serum ACE elevated in 66% (many false positives including Mycobacteria and malignancy)

· lysozyme

· elevated d-dimer (correlates with disease activity)

Course: often asymptomatic and self-limiting

Children under 5: skin rash, eyes (uveitis), arthritis (worse prognosis)

Older children: lungs (usu. bilateral, hilar lymphadenopathy), lymph nodes, eyes

Treatment: for stage I (asymptomatic), observation only, may regress / for stage II-III or with any serious organ involvement, corticosteroids (40 mg/day), other DMARDs

Prognosis: earlier onset tends to mean better prognosis

Lofgren’s syndrome

acute sarcoidosis / usually with symmetric, periarticular ankle inflammation / may have erythema nodosum

Systemic vasculitides

Complement levels

all have normal complement levels except variable in PAN, leukocytoclastic, connective tissue disease, endocarditis / decreased in urticarial vasculitis

Vasculitis Associations

PAN and hairy cell leukemia

Wegener’s and Hodgkin’s disease

Granulomatous angiitis of CNS and lymphoma

GCA and lymphoma

HSP and lymphoma

grouped by vessel-size

Large

giant-cell arteritis

Takayasu’s arteritis

primary CNS vasculitis

Medium (with or w/out involvement of small)

Small

leukocytoclastic (HSP, cryoglobulinemia, infectious)

connective tissue diseases

paraneoplastic

microscopic PAN

urticarial vasculitis

Any size (pseudovasculitis)

APAS

endocarditis (bacterial/marantic)

other embolic

cholesterol embolism

drugs (amphetamines and rarely cocaine)

Infectious Vasculitis Ddx

Bacterial agents

Acute septic meningitis agents

Mycobacteria

Spirochetes

Treponema, Borrelia sp., Leptospira

Other agents

Brucella species

Bartonella henselae

Rickettsiae

Mycoplasma

Viral agents

HSV, VZV, CMV, EBV, B19, HBV, HCV, HIV, HTLV

More: hantavirus, California encephalitis virus, EEE encephalitis virus, influenza, rubella

Fungus

Aspergillus, Coccidoides, Candida

Mucormycetes

Parasites

Cysticercosis

CNS vasculitis

Ddx: reversible cerebral vasoconstriction syndromes (RCVS)

PAN – classic, microscopic/HBV, HIV

Wegener’s

Takayasu’s

hypersensitivity angiitis – drug-induced, HSP

neoplasia (many)

infection (see below)

CTD: SLE, RA, GCA

primary angiitis of CNS (PACNS) – CNS angiography, brain biopsy

Diagnosis: start with MRI, then CNS angiography à vessel wall irregularities, focal dilations, supraclinoid internal carotid artery narrowing, and distal branch occlusions [MRI][MRI][MRI][MRI]

Infectious Causes of Vasculitis

Bacterial agents

Acute septic meningitis agents

Mycobacteria (5%)

Spirochetes

Treponema, Borrelia sp., Leptospira (Weil syndrome)

Brucella species

Bartonella henselae

Rickettsiae

Mycoplasma

Viral agents

HSV, VZV, CMV, HBV, HCV, HIV, HTLV

Fungus

Aspergillus, Coccidoides, Candida

Mucormycetes

Parasites

Cysticercosis

BACTERIAL AGENTS

Neonate (<1 month)

Streptococcus agalactiae (44%)

Escherichia coli (26%)

Gram-negative bacilli (10%-22%)

Listeria species (5%-10%)

Children (1 mo to 15 yrs)

Neisseria meningitidis (25%-40%)

Streptococcus pneumoniae (10%-20%)

Haemophilus influenzae (8%-12%)

Adults (>15 years)

Streptococcus pneumoniae (30%-50%)

Neisseria meningitidis (10-25%)

Staphylococci (1%-15%)

Gram-negative bacilli (1%-10%)

Listeria species (5%)

Streptococci (5%)

Head trauma, surgery

Staphylococci

Gram-negative bacilli

Immunocompromise

Listeria monocytogenes

Respirator support

Proteus species

Pseudomonas

Serratia

Flavobacterium

Ruptured brain abscess

Gram-negative bacilli

Anaerobes

Neonates get arteritis/thrombophlebitis (larger, +/- hemorrhagic infarcts, +/- secondary abscess formation) / venous thrombosis and hemorrhagic necrosis (associated with Pseudomonas, Proteus, Enterobacter, and Serratia)

Septic venous sinus thrombosis/thrombophlebitis (up to 5%, usu. < 1 or 2 weeks)

Note: sinus, middle ear, skull infection can beget cerebral vasculitis without detectable meningitis / also, basilar infection can causes vasculitis of ascending arteries

Peripheral Nervous System

Lyme disease à multifocal axonal radiculoneuropathy

HIV-1 à multiple mononeuropathies

CMV

HCV à cryoglobulinemia

HSV, VZV à sensory ganglia, radicular syndrome

Giant Cell Arteritis (GCA) (temporal arteritis)

Not uncommon (1 in 5000) / usually > 50 yrs / women > men (2:1) / whites, Scandinavians / HLA-DRB1*04 and DRB1*01

Presentation: gradual > abrupt / 15% fever / headache (66%, unilateral >> bilateral, dull and boring, superimposed sharp pain), jaw claudication (50%), temporary blindness, fever, weight loss, myalgias/arthralgia, malaise, cough/hoarseness (10%), neuropathies (10%), TIA, polymyalgia rheumatica (50%)

Complications: blindness (can occur early on, retinal changes like edema of optic disk, cotton-wool patches, small hemorrhages, usu. occur after blindness, usu. from nerve ischemia), eye exam can be helpful / thoracic aortic aneurysm (17x) normal incidence

Associations: lymphoma (vasculitis may precede lymphoma) /

Pathology: mainly external carotids and vertebral / can hit central retinal artery (but intracranial arteries are NOT involved)

Diagnosis: biopsy temporal artery, try to get affected site (if cannot localize on exam, then get larger piece, 3-5 cm), can do bilateral biopsy to increase yield, yield of biopsy decreases with each day of steroids but can still be positive even at 1-2 wks post-steroid (lymphocytes, plasma cells, giant cells) / high ESR (over 50, often > 100, can be expected to decrease within days of

treatment, ~20% have normal ESR) / CRP is more sensitive / NOTE: careful exam may reveal findings prior to onset of symptoms

Treatment:

· prednisone (1 mg/kg qd 1-2 months then taper by 5-10% q 1-2 wks) / usually see improvement within days (if not, question diagnosis) / can use 100 mg qd for optic nerve involvement / can begin cyclophosphamide (maybe other DMARDS) if necessary / can begin to think about tapering after 1-2 months (10-20% every 2 weeks), but must continue to treat for a long time (1-4 yrs to reduce recurrence) / qod therapy thought to be less effective but open question of whether some patients can start at lower doses (20-30 mg qd) / ½ of patients have serious complication of extended steroid use

· ASA also thought to decrease risk of occlusions

Recurrence: 30-50% have spontaneous exacerbations independent of steroid regimen / most often, recurrence involves PMR Sx and can be treated by increasing steroids by 2 to 5 mg/qd

Takayasu’s Arteritis

Granulomatous inflammation of large arteries / young women (>Asian) / complications may develop over months to years / affects aorta and branches (subclavian), pulmonary arteries (up to 50%), renal artery

Presentation: weak pulse in upper extremities (arm claudication), ocular disturbances, HTN (renal artery ) / Raynaud’s / systemic: fever, weight loss

Diagnosis: CT may reveal circumferential thickening / MRI may show enhancement on T1

Labs: increased ESR

Kawasaki’s

Mostly children (4-5/years) / medium-sized arteries

5 diagnostic criteria: more than 5 days of fever, bilateral conjunctival injections, oral mucosa and pharynx (infected and dry fissured lips, strawberry tongue), peripheral extremities (edema, erythema, desquamation – rash, primarily truncal), cervical adenopathy

Complications: hydrops of gallbladder, more -

Treatment:

restrict activity 3-4 wks

Anti-inflammatory

Immunoglobulin 2 gm/kg single / 400 mg/kg/day x 4 days

MMR should be delayed 6 months

Aspirin – 80-100 mg/kg/day QID until afebrile

Anti-platelet agents

Treat for 3 months, but indefinitely and add more agents? if coronary involvement

ANCA Associated Vasculitides (AAV)

Polyarteritis Nodosum (PAN)

rare / occlusion (infarct) of medium to small arteries (NOT capillaries) / type III hypersensitivity

Presentation: usually present with constitutional symptoms

Associations: HBV, hairy cell leukemia

Findings: cotton-wool patches, pericarditis, myocarditis, palpable purpura aneurysm (hemorrhage)

Diagnosis: 3 or more of 10 criteria (sensitivity 80%, specificity 85%)

Weight loss > 4 kg
livedo reticularis
testicular pain	testicular biopsy useful if involved
myalgias/arthritis	CK usually normal
mono/polyneuropathy	50-80% (only 15% in MPA) good chance of recovery within 1 yr
diastolic ( > 90) elevated BUN/Cr	Renal vasculitis (not RPGN) Renal failure may occur later
HBV positive	Not in MPA
GI aneurysms by MRA	GI pain in 30% (risk of perforation)
positive biopsy

Labs: elevated ESR (~85), CRP, WBC, eosinophils, normochromic anemia, HBsAg found in 10-30%, HCV rarely associated, 20% have positive p-ANCA to myeloperoxidase (MPO), RF (+) in 20%

Treatment: steroids, cyclophosphamide, plasma exchange (2^nd line)

HBV-PAN

More HTN than classic PAN

Remember to treat both HBV and PAN

Treatment: plasmapheresis and lamivudine

Microscopic Polyangiitis (MPA)

May have capillary involvement in addition to small/medium arteries (unlike classic PAN)

Glomerulonephritis (usu. RPGN) common (not in PAN), alveolar hemorrhage (not in PAN)

Presentation: can have arthralgias, hemoptysis et al for months/yrs!!! before explosive onset

(longer prodrome than with PAN) / most with constitutional symptoms before diagnosis

Labs: almost always have p-ANCA (+) and MPO (+) / rarely c-ANCA will be (+) / other P-ANCA (but not MPO): Felty’s, UC (directed against different proteins)

Course: relapse in MPA (35%) > HBV-PAN and c-PAN (10%)

Treatment: ?similar to classic PAN

Wegener’s Granulomatosis

medium to small arteries / type IV DTH

Presentation: chronic sinusitis, epistaxis, mucosal ulcers, cough (45%), hemoptysis (30%), fever, night sweats, arthritis, myalgia, skin nodules, renal failure / mean interval from symptoms

to diagnosis 15 months

Affected: nose, throat, bronchi, kidneys

Complications: renal failure (hematuria, RBC casts, RPGN) / saddle-nose deformities, sepsis, hemorrhage, DIC / usu. does not lead to respiratory failure

Associations: Hodgkin’s lymphoma

Diagnosis: cANCA (confirm with anti-proteinase 3) (90% sensitivity, few false positives) / ~10%

with p-ANCA / ~10% with anti-GBM / biopsy of ENT likely to show only necrosis, biopsy of kidney likely to show only non-specific RPGN, you can’t stain for IF (that’s why it’s called pauci-immune!!!), biopsy of lung most likely to confirm diagnosis

Chest CT [CT] [CT] [CT] pulmonary infiltrates or nodules (up to 85%) / not pleural

effusions

Labs: elevated ESR

Course:

Prognosis: higher ESR, older age gives worse prognosis / ENT involvement gives better prognosis

Treatment: cyclophosphamide (1^st), steroids (2^nd or 1^st for pulmonary hemorrhage) / bactrim is

sometimes helpful (prevention of infection may avoid a potential trigger) / not MTX

Hypertrophic pachymeningitis (HP)

pANCA positive CNS disease, which some think of as Wegener’s limited to CNS/cranial nerves /

treat as Wegener’s

Buerger’s (Thromboangiitis Obliterans) [NEJM]

male, smokers / medium to small arteries AND veins

Presentation: hypercoagulability, claudication, pain, Raynaud’s, gangrene

Exam: Allen’s test

Treatment: perhaps ca-blockers, stopping smoking will hopefully stop progression of disease

Churg-Straus Angiitis [NEJM]

3 stages (order can vary) / asthma, eosinophilia, vasculitis

Asthma may occur up to 30 yrs (mean 3) before vasculitis, onset with vasculitis in 10%, after in 2%) / sinusitis, allergic rhinitis, nasal polyps

Eosinophilia can mimic chronic eosinophilic pneumonia

Vasculitis mononeuritis multiplex (72%), weight loss (>50%), fever, myalgia, skin lesions (60%) > GI (50%) > spleen > heart (myocarditis, infarction) > kidneys (FSGN)

Diagnosis: angiitis and extravascular necrotizing granulomas with eosinophils

Labs: P-ANCA (50%, usu. anti-MPO), RF, elevated ESR (80% of cases), eosinophilia (over 10% in 90% of cases)

Often seen in asthma patients being tapered from PO or inhaled steroids (may be associated with leukotriene antagonists)

Treatment:

Hypersensitivity Angiitis

adverse drug reaction

HSP (Henoch Schönlein Purpura) (see renal)

small vessel vasculitis

Behçet’s Disease (Behcets) [NEJM]

mostly in people of Middle East, Japanese descent / onset in 20 to 30s

Course: chronic, relapsing acute attacks / manifestations (except uveitis) usually self-limited

Presentation:

Mouth: aphthous oral [pic] / genital ulcers [pic]

Eye: uveitis, retinitis (can cause blindness), hypopyon

Skin: superficialmigratory thrombophlebitis, erythema nodosum (including pseudofolliculitis and acneiformnodules / pathergy

Joints: mono/polyarthritis (50%, knees > wrist, elbows, ankles) (non-deforming)

Coagulopathy: vasculitis/ hypercoagulability (major concern is retino-occlusive disease), venous 7 times more than arterial (however, can get aneurysms, stenoses), 25% will have at least superficial venous thromboembolism

Less common: GI, CNS (early onset males 10-20%), large vessels / may have

Diagnosis: oral ulcers + 2 other criteria / can look for HLA-B51 (not in S. American, N. American), elevated IgD levels

CSF: elevated IgG (not oligoclonal), pleocytosis

MRI: multiple high-intensityfocal lesions in brain stem, basal ganglia, and cerebralwhite matter are typical on T₂-weighted MRI

Ddx: chronic oral aphthosis, Sweet’s, HSV, AS / GI (IBD), CNS (MS), pathergy (Sweet’s, pyoderma gangrenosum), retinitis (sarcoid, viral retinitis)

Treatment:

Skin: topical steroids, thalidomide, colchicines, oral steroids

Ocular, GI, CNS: oral steroids / other immunosuppressives (Cytoxan, Immuran, others) / note: cyclosporin may worsen CNS symptoms (it’s not a first line agent) / IFN-a, IVIG under investigation

Arthritis: steroids, NSAIDS, colchicines, sulfasalazine, IFN-a (highly effective)

Vasculitis: steroids / be careful with anticoagulation for venous thrombosis (can get big time hemoptysis with arteritis) / treatment of vascular complications is very tricky in this disease since mechanisms are multiple and unclear / CV surgery for complications

HLA Associations [HLA genetics diagram]

Disease	HLA allele	Relative risk factor
DR5	Hashimoto’s thyroiditis	3
DR4	Rheumatoid arthritis	6
DR3	Dermatitis herpetiformis SLE (esp. subacute cutaneous, neonatal) Sjogren’s PM	56
DR2	Goodpasture’s Multiple sclerosis	13 5
B27	Ankylosing spondylitis Reiter’s Postgonococcal arthritis	87 37 14
C6	Psoriasis vulgaris	13
B8	Myasthenia gravis	4
B51	Behçet’s

Reversible cerebral vasoconstriction syndromes (RCVS) (or Call-Fleming Syndrome or Migraine Angiitis [AIM]

must be distinguished from classical cerebral angiitis (using CNS imaging)

Associated conditions (many) [table] / unlike migraine, no aura, presentation is hyperacute

Causes: vasoactive drugs, diet pills, stimulants, some antidepressants, decongestants, illicit drugs (amphetamines, cocaine, ecstasy)

Treatment: calcium channel blockers, steroids (mechanisms and treatments being worked out 1/07)

Spondylarthropathies AS, psoriasis, Reiter’s and Reactive, IBD

(1) spondylitis

(2) sacroiliitis

(3) enthesopathy

(4) asymmetric oligoarthritis

Other: inflammatory eye disease, urethritis, and mucocutaneous lesions

Labs: all have negative RF

Ankylosing spondylitis (AS) (Marie-Stumpell Disease)

inflammation and ossification of the joints and ligaments of the spine and of the sacroiliac joints

Epidemiology: young people (~24 yrs) / males=females / HLA B27 (90%) / may occur in association with IBD

Pathology: chronic, progressive (insidious) inflammatory disease of axial joints (hips, shoulders, sacroiliac) / asymmetrical, oligoarticular (1-4 joints) / inflammation at site of insertion / autoantibodies to joint elements following infection

Complications: kyphosis and eventually complete fusion or “bamboo spine” / aortic insufficiency / peripheral joint involvement / pulmonary fibrosis / uveitis (25%) (can lead to glaucoma and blindness)

Diagnosis: do sacral XR 1^st reveals squaring, syndesmophytes,

Presentation: morning stiffness (“gel”) / pace floor at night / improves with exercise / pain may move from one joint to another

Treatment: therapeutic goal is to maximize the likelihood that fusion will occur in a straight line physical therapy / avoid smoking (pulmonary compromise)

· NSAIDS (for symptomatic relief)

· Anti-TNF-alpha (showing some real benefits on slowing disease progression)

· methotrexate and sulfasalazine (were tried before TNF-alpha available)

· surgical procedures to correct some spine and hip deformities may be used in select cases

Course: only 6% die from actual disease; most commonly (cervical fracture, heart block, amyloidosis), and more rarely from the restrictive lung disease

Psoriatic arthritis (see skin psoriasis)

hereditary, 20 to 40 yrs / 7-40% of psoriasis patients get arthritis (may precede skin findings) / also has sporadic form presenting later on in life

4 major forms of arthritis

1. most have peripheral, asymmetric oligoarticular arthritis

2. DIP with nail disease

3. 25% have symmetric polyarthritis similar to RA

4. spondylitis/sacroiliitis less common

Findings: DIP swelling, sausage digits [pic] / nail problems (onychodystrophy, onycholysis, nail pitting, and subungual keratosis, onychauxis) [pic] / psoriatic lesions on extensor surfaces

Diagnosis: must have skin or nail changes for definitive diagnosis

Labs: mildly elevated ESR / hyperuricemia in severe cases

Synovial fluid: 2 to 15 WBCs / Radiography: distal interphalangeal erosions or telescoping joints, asymmetric sacroiliitis, isolated axial syndesmophytes

Treatment:

· TNF-alpha blockers now shown to slow progression of arthritis and skin complications

· NSAIDs (indomethacin) and intra-articular steroids (avoid injections through psoriatic plaques) for symptomatic relief / 2^nd line: MTX, penicillamine, gold, hydroxychloroquine

Reiter’s syndrome (see reactive arthritis)

HLA B27 / males, 20-30s / HIV patients

Presentation: asymmetric oligoarthritis, (non G-C) urethritis, conjunctivitis, uveitis, characteristic skin and mucous membrane lesions low back pain

Onset: 2-4 weeks after inciting GI or GU infection( Chlamydia)

Common complications:

· lower extremities: ankles, knees, feet, heels (enthesitis of Achilles tendon)

· oligoarticular

· sausage digits (dactylitis)

Other complications:

· transient conjunctivitis (40%) / may need urgent opthalmological referral (topical or systemic steroids) for (3-5%) disabling iritis, uveitis (can be difficult to treat), corneal ulceration

· oral ulcers and glans penis (circinate balanitis; 25-40%; painless, red rash)

· keratoderma blennorrhagicum (mollusk shell skin lesions on palms and soles, may have severe desquamation; similar appearing to papular psoriasis

· nail changes

· myocarditis: heart block (<5%), aortic insufficiency

Note: many people have single reactive arthritis symptoms without multiple findings

Causative organisms: chlamydia trachomatis (decreasing), Neisseria (culture-negative), GI: Shigella, Salmonella, Campylobacter jejuni, Yersinia enterocolitica

Labs: elevated ESR and leukocytosis / 0.5 to 75 WBC’s in synovial fluid / bacterial antigens present in joints (chlamydia is dormant) / ANA and RF usu. negative

Radiography: asymmetric syndesmophytes along spine (ankylosing spondylitis has symmetric and contiguous)

Course: most recover (one to several months), 50% recurrence (varying degrees of disability)

Prevention: must take antibiotics (doxycycline) prior to travel / even with HLA B27 – 20% risk of reactive arthritis with proper infection

Treatment: symptomatic relief with NSAIDs (2^nd line sulfasalazine) and intra-articular steroids / topical steroids for skin complications / prolonged doxycycline may be useful in cases with chlamydia infection

Reactive arthritis

may follow GI infection (Shigella flexneri, Salmonella species, or Yersinia enterocolitica infections / same joint problems as Reiter’s / extra-articular symptoms tend to be mild / treatment will be similar to Reiter’s (doxy?)

HLA B27

Ankylosing Spondylitis (90%)

Reiter’s Syndrome (75%)

Psoriatic arthritis (20%) / with sacroiliitis/spondylitis (50%)

Enteropathic arthritis (IBD) (8%) / with sacroiliitis/spondylitis (50%)

Arthritis of inflammatory bowel disease

Crohn’s or UC (10-20%) / similar to that of AS

spondylitis, sacroiliitis, and peripheral arthritis ( > knee / ankle)

peripheral arthritis may correlate with colitis activity (spinal disease does not)

antibiotics not effective, but still must rule out septic joints

Treatment: NSAIDS (not salicylates) / GI intolerance more likely in these patients, misoprostol may cause unacceptable diarrhea / sulfasalazine may also be effective / local steroid injection / PT

Myopathy

Drugs causing myositis (by mechanism)

Inflammatory

L-dopa, procainamide, cimetidine, D-penicillamine, L-tryptophan,

Non-inflammatory necrotizing or vacuolar

cholesterol-lowering agents, chloroquine, colchicine, emetine, aminocaproic acid, labetalol, cyclosporine and tacrolimus, isoretinoic acid (vitamin A analog), vincristine, alcohol

Rhabdomyolysis and myoglobinuria

cholesterol-lowering drugs, alcohol, heroin, amphetamine, toluene, cocaine, aminocaproic acid, pentazocine, phencyclidine

Malignant hyperthermia

halothane, ethylene, diethyl ether, methoxyflurane, ethyl chloride, trichloroethylene, gallamine, succinylcholine

Mitochondrial

Zidovudine (AZT)

Myotonia

2,4- d-chlorophenoxyacetic acid, anthracene-9-carboxycyclic acid, cholesterol-lowering drugs, chloroquine, cyclosporine

Myosin loss

non-depolarizing neuromuscular blocking agents, IV steroids

Drugs causing myopathy (painful vs. painless)

Painless

Alcohol (chronic), steroids

Myoglobinuria

CNS depressants, CNS stimulants, CO, cyanide, arsenic, snake venom

Hypokalemia

Diuretics, laxatives, licorice, carbenoxolone, ampho B, toluene, alcohol

Painful

Inflammatory

Procainamide, phenytoin, levodopa, interferon alpha, cimetidine, leuprolide, PTU, penicillamine

Mitochondrial

AZT, germanium

Drugs of abuse

Alcohol, cocaine, heroin, PCP, volatile chemicals

Focal myopathy

IM injections, IVDA, cephalothin, lidocaine, diazepam, pethidine, pentazocine, meperidine, antibiotics in children

Other

Alcohol (acute), NMJ blockers (vecuronium, pancuronium), lovastatin < simvastatin, clofibrate, gemfibrozil, aminocaproic acid, excess vitamin E, etritinate, ipecac, emetine (overuse), organophosphates (acute poisoning), toxic oil syndrome, eosinophilia myalgias syndrome, snake venom (peak at 24-48 hrs)

Chronic Alcohol Myopathy

Painless, progressive proximal muscle weakness / ½ of alcoholics / damage is cumulative, but strength often restored after cessation

Histology: type 2b fiber atrophy, no necrosis

Acute Alcohol Myopathy

Weak, painful, swollen muscles and cramps / may be limited to only one limb or muscle

in most cases, cramps resolve in 1-2 days, pain and swelling takes 1-2 weeks, strength normal in 10-14 days / can develop rhabdomyolysis / lag time between alcohol consumption and elevated CK (several indirect mechanisms proposed)

Labs: CK, LDH, myoglobin elevated

Histology: necrosis and myofibrillar disorganization (inflammation is debatable)

Hypokalemia

Severe, painless proximal muscle weakness (no cramps, no swelling) / develops over hours/days / serum K between 1.4 – 2.5 / can cause rhabdomyolysis / complete reversal with K replacement

Labs: CK, AST, aldolase elevated

Histology: vacuolar changes, macrophages, +/- necrosis, regeneration

Steroids (esp. dexamethasone, triamcinolone)

Symmetrical, proximal muscle weakness / lower > upper / occasionally myalgias / may have generalized weakness, atrophy (severe cases) / very unlikely with < 10 mg/day or alternate day dosing

Chronic Steroids

Usually > 3 weeks / usually with other stigmata of steroids use

Labs: CK usually normal / EMG shows normal rest activity, short-duration, low-amplitude motor units / Histology: type II atrophy, increased glycogen in type II fibers, lipid droplets in Type I fibers / EM shows sarcolemmal projections, vesicular bodies

High-dose steroids

Can occur 1-2 days after treatment / often seen when treating severe asthma / may be generalized / may involve respiratory muscles / additional risk factors such as NMJ blockers, sepsis / near total recovery in weeks

Histology: changes in both fiber types, vacuolar changes, regenerating fibers / normal EMG

Licorice, carbenoxolone

Pseudo-hyperaldosteronism / Na retention, edema, hypokalemia

Chloroquine

Usually starts in legs / takes 6 months to occur / may also have neuropathy

EMG shows fibrillations, positive waves, occasionally myotonic discharges

Histology: degeneration and acid phosphatase positive vacuoles in up to 50% of fibers / type I fibers predominantly affected / EM shows myeloid bodies and curvilinear bodies similar to neuronal ceroid lipofuscinosis

Hydroxychloroquine (Plaquenil) is supposed to be safer, but I suspect the findings are similar

Amiodarone

May occur as early as 1 month / also get peripheral neuropathy, tremor, ataxia

Perhexilene

Anti-anginal agent / myopathy usually with long-term use only (reported as soon as 2 weeks, associated with rash, resolved with discontinuation

Other side effects include weight loss, hypoglycemia, hepatic dysfunction, peripheral neuropathy

Colchicines

Note: sometimes misdiagnosed for polymyositis

Sensory or motor nerve conduction is low-amplitude or absent

EMG shows fibrillations, positive waves, myopathic motor units

Histology: vacuolar myopathy

Vincristine

Histology: segmental necrosis, phagocytosis, spheromembranous degeneration / probably can have myopathy without neuropathy

Zidovudine (AZT)

Mechanism: ?false substrate for mitochondrial DNA polymerase

Dose-related proximal muscle weakness and myalgias with pronounced wasting / elevated CK / usually improves with discontinuation

Histology: ragged RED fibers / rod-body formation, necrosis, microvacuolization / EM has various changes

Cannot always distinguish from HIV myositis

Lovastatin

Rapidly progressive, necrotizing myopathy / weakness, myalgias, CK 8000-30,000 / can lead to rhabdomyolysis / incidence of 0.5% (compare to incidence of elevated LFT of 2%) / risk increased with combination of lovastatin, gemfibrozil, niacin, immunosuppressive agents

Histology: necrosis

Much less common with Simvastatin

Aminocaproic acid

usu. > 4 wks, can occur as early as several days

Etritinate (dermatology drug)

mild-transient myalgias occur in 15%, do not require discontinuation / occasionally, can be more severe

Synovial fluid analysis

Characteristics	RA	Gout/Pseudogout	Reiter’s/Psoriatic	Septic	OA/Trauma
color	yellow
clarity	cloudy			pus
viscosity	poor
Mucin clot	poor
WBC	3-50 K			> 50 K
% poly	> 70
glucose	10-25% less than serum
protein	> 3.0 g/dl
complement	low
microscopic	RA cells
culture	negative

	WBC (% Poly)	glucose	other
early RA
chronic/subsiding crystal
osteonecrosis
SLE
Scleroderma
Vasculitis
sickle cell
amyloidosis
Hypothyroid
Osteochondritis dessicans
Group II
RA
Reiter’s
Psoriasis
IBD
AS
Acute crystal
Viral
ARF
JRA
Behçet’s
Infection
Group III
Bacterial
Fungal
Mycobacterial
Acute crystal
Group M
Trauma
Neuropathy
Bleeding Disorders (hemophilia, vWF, anticoagulation, scurvy, TCP, thrombocytosis)

Tumor, VNS, hemangioma
Prosthesis, post-op aneurysm
Sickle cell

Cardiovascular

[a bunch of images]

General Circulatory HTN, Edema, Thrombosis, PE, DIC, Shock, CHF , Cor Pulmonale

General Metabolic hyperlipidemia, atherosclerosis (PVD )

Ischemic ANGINA, MI (myocardial infarction)

Cardiomyopathies dilated, restrictive, HOCM

Arrhythmias bradycardia, heart block, atrial fibrillation, atrial flutter, SVT

MAT, VT, prolonged QT, torsades de pointes

Valvular AS, MS, AR, MR, TR, Rheumatic Fever

antibiotic prophylaxis

Aortic Aneurysm Aortic Dissection Endocarditis Myocarditis

Pericardial Disease pericardial effusions, acute pericarditis, infectious pericarditis, Dressler’s, uremic,

restrictive pericarditis, cardiac tamponade

Cardiac Tumors, Cardiac Malformations

[cardiac pre-op][cardiac physiology][cardiac physical exam][EKG reading] [cardiac labs]

Cardiac Physiology

Single Cardiac Cycle [see diagram]

Jugular Venous Pulses [see diagram]

Swan-Ganz catheter [interpretation of values]

· Radiology of the Heart in Cecil’s at MDconsult (great pictures)

Fick equation CO = (O2 consumption) / (AO2% - VO2%)(Hg)(1.36)(10)

Cardiac Physical Exam

Systolic murmurs [see diagram]

Diastolic murmurs [see diagram]

Low-Pitched Sounds à Bell à S3, S4, MS, AR (Austin-Flint)

High-Pitched Sounds à Diaphragm à everything else

Sound	Best Heard
S2	2^nd/3^rd LICS
S3	3^rd/4^th LPS and apex / increased with inspiration
S4	3^rd/4^th LPS and apex
PDA	1^st/2^nd LICS mid-clavicular
MR
AR
MS
AS
MS
MR	can radiate to various places
AR
AS
ASD	“pulmonic area” of the chest / may radiate to back as with pulmonary stenosis
VSD

S1 increased (↑)

LVH (muscle), MS

S1 decreased (↓)

LVH (collagen), LV dilatation/dysfunction, some MR, AR, prolonged PR, LBBB

Note: mechanisms can be way too complex and you’ll make yourself crazy; just refer to this

S2 (normally S₂ splitting increases with inspiration due to increase venous return and RVEF; it follows that inspiration will increase most right-sided murmurs/gallops)

· abnormally increased split S₂

Delayed RV (electrical): incomplete RBB, pacemaker, PVC

Delayed RV (mechanical): VSD (if LàR flow), pulmonic stenosis, severe pulmonary edema (↑ impedance)

Shortened LV ejection time:, MR

· fixed split S₂

ASD

(explanation; why not variable? RV already ~max overloaded; and L/R atrial pressures equalized so no net Δ in LV/RV output with inspiration—unlike VSD)

mild pulmonary HTN

RVF

· paradoxically split S₂ (decreases with expiration)

usually from delayed A2 due to electrical (complete LBB (1^st), RV PVC) or mechanical (AS, HOCM, acute ischemia, myocarditis, CHF)

S3 AR, TR, MR / don’t confuse with “tumor plop”

S4 stiff ventricle (various causes) / it can’t happen during Afib

Jugular Venous Pulsations (JVP) [diagram]

“dip and plateau” or “square root” sign à constrictive pericarditis

Kussmaul’s sign à constrictive pericarditis

Prominent y descent à constrictive pericarditis

Large V wave à TR

Canon a wave à AV dissociation

Pericardial effusion

r/o tamponade (pulsus paradoxus, undulating pulses)

elevated venous pressure

Borderline – expiration/inspiration 105/94

Electrical alternans or alternating voltage

big pericardial effusions from TB and tumor [< 5 mm leads 1-aVF] / can also be from AV fistula in lungs/coronary vessels

Treatment: pericardial window / can also obliterate pericardial space with nitrogen mustards, talc, tetracycline to prevent recurrence

Pulsus paradoxus

> 10 mmHg fall in SBP during inspiration / occurs in 95% of cardiac tamponade (as well as disorders involving intrathoracic pressure changes, such as COPD) / 4 mechanisms

1) septal shift/pressure, RV enlargement (prevents filling of LV)

2) tensing of pericardium (impairs cardiac output)

3) increased capacitance of pulmonary capillary bed (decreases LV filling)

4) decreased afterload (negative intrathoracic pressure, this is normal)

Tilt Table Testing

Decreased preload stimulates Bezal Jarisch reflex / catecholamines can be used to

enhance this reflex / hold vasoactive drugs for 5 half-lives before / endpoint is

pre-syncope w/ hypotension or bradycardia

Reading EKG’s [Vectorial diagram of Limb Leads]

· EKGs of the Major Arrhythmias [tutorial with pictures]

Method for EKG reading: heart rate / heart rhythm / intervals / axis deviation / hypertrophy

EKG reading in myocardial ischemia

For ECG changes associated with electrolyte disturbances (see lytes) [potassium ECG]

Definitions:

If the QRS complex begins with a negative deflection, it is called a Q wave

1^st positive deflection is R wave

a negative deflection following an R wave is an S wave

T waves are positive because the ventricles repolarize from epicardium to endocardium (opposite of contraction)

Heart Rate

Each small box is 0.1 mV and 0.04 seconds / one large square is 0.2 seconds (5 small boxes of 0.04)

HR is 300/# of large boxes in RR interval [ex., 4 large boxes between R waves à 300/4 or 75 bpm or just count # of large squares from 1,2,3,4,5,6 corresponds to 300, 150, 100, 75, 60, 50

Heart Rhythm

Regular? Are P waves present?

In sinus rhythm, P waves should be upright in lead II (unless reversal of leads or dextracardia)

Are P waves related to QRS?

[sinus arrhythmia v. multifocal atrial tachycardia v. atrial fibrillation v. ventricular arrhythmias etc.]

Intervals

PR interval [0.12 to 0.21] becomes shorter as HR increases

QRS Axis

Extreme left axis (-90 to -180°)

Right-axis deviation in presence of LBBB (+90 to +180°)

QRS interval [0.04 to 0.1]

LBBB: >160 msec

RBBB: >140 msec

QRS Morphology

QT interval normal is less than ½ RR interval with HR < 100

Prolonged QT interval

QTc – corrected for heart rate / women > men / can be a sign of ischemia (lack of ATP and reduced inward K current) / can cause torsades de pointes

Prolonged QT: class Ia and III agents, sotalol, amiodarone, TCA’s, phenothiazines, ketoconazole, quinolones, erythromycin, clarithromycin, antiemetics, antipsychotics, pentamidine, hypomagnesemia, hypokalemia, hypocalcemia, hyperthyroid, hypothyroid, intracranial bleeds, congenital long QT

Shortened QT: hypercalcemia, digitalis (scooping)

Tip: regarding intracellular electrolytes (K, Ca, Mg)

· ↑ Elevations à shorten ↓ QT interval

· ↓ Depressions à prolong ↑ QT interval

Voltage

low voltage is any 3 limb leads < 15 mm or any one precordial lead < 10 mm

Causes: pericardial effusion/tamponade, emphysema, obesity

Axis [vectorial diagram of limb leads]

Calculate Axis

If lead I and II /aVF are both positive à 0 to 90 and normal axis (down and to the left)

If lead I is positive and II/aVF is negative à LAD

If lead I is negative and II/aVF is positive à RAD

Note: axis can also be determined by finding the isoelectric deflection (i.e., shortest QRS) (axis is perpendicular to that vector)

Frontal planes: axis deviation (I, II/AVF)

Horizontal planes: axis rotation (V_1-6)

· LAD à LVH, LBBB, LAFB

· RAD à RVH, RBBB, LPFB, RV strain (pulmonary HTN, PE), emphysema / may be normal in children, young adults

Note: mean QRS tends to point away from infarct, toward hypertrophy

Hypertrophy

· LVH

1. sum of deepest S in V₁ or V₂ and tallest R in V₅ or V₆ is > 35 mm (in patients > 35 yrs)

2. R in aVL > 12 mm (strain pattern)

3. R in V₆ > 25-35 mm

Note: may see asymmetrical or inverted T in V₅ or V₆ (strain pattern ~ ST ↓ with upward hump in middle)

Criteria for LVH (sensitivity/specificity)

RaVL + SV₃ > 28 mm (men) (40/95)

or RaVL + SV₃ > 20 mm (women)

SV₁ + RV₅ or RV₆ > 35 mm (30/95)

RV₅ or RV₆ >/= 25 mm (20/95)

RaVL > 11 mm (20/95)

· RVH

right atrial enlargement, right axis deviation, incomplete RBBB, low voltage, tall R wave in V1, persistent precordial S waves, right ventricular strain

Criteria for RVH (sensitivity/specificity)

Limb lead criteria R in I </= 0.2 mV (40/100)

S₂ S₂ S₃(45/75)

Precordial lead criteria R/S ratio in V₁ > 1 (30/100)

R wave height in V₁ > 0.7 mV (30/100)

S wave depth in V₁ < 0.2 mV (20/100)

R/S ratio in V₅ or V₆ < 1.0 (10/100)

QR in V₁(-/100)

QRS axis > + 90 degrees (15/100)

P wave amplitude > 0.25 mV in II, III, aVF, V₁ , or V₂(20/100)

· LAE (P-mitrale)

broad, notched (M-shaped) P waves in mitral leads (I, II, aVL) or deep terminal negative component to P in lead V₁ (biphasic V₁ is the most specific criterion)/ causes include MS, HTN

· RAE (P-pulmonale)

P waves are prominent V₁ or > 2.5 mm in any limb lead (tall, peaked in II)

EKG segments [anterior heart] [posterior heart]

· Q waves

Septal depolarization normally moves from R to L causing small downward deflection in V₆

Significant Q waves

> 1 mm wide or > ⅓ QRS amplitude (measured from top to bottom) / can start early in MI or in ensuing weeks

Small, insignificant Q waves

o normal is < 0.04 seconds in I, aVL and V_1-6 / < 0.025 in II and < 0.030 in aVF

o small “septal Q’s” commonly seen in lateral leads (I, aVL, V₄, V₅, or V₆)

o mid-septal depolarization (from LBB) moving L to R

o medium to large Q waves may be normal in aVR if not lead placement

o Q in V₂ could be lead placement, LVH, LBB, pulmonary disease

o downgoing delta waves in II, III, aVF can mimic Q waves

o large (deep, broad) Q’s in I and III may occur in HOCM

· R waves

o R in V₁, V₂ with posterior MI (see below)

o Intrinsicoid deflection > 50 mm with some LVH

o Delta wave with WPW, large R in I with LBBB and LAFB, large R in inferior leads with LPFB

R wave progression

transition should occur between V₂ and V₄; LVH may change vector of conduction such that R wave progression seems poor (yet not ischemic); poor R wave progression is c/w prior anteroseptal infarct; early R wave progression can be sign of prior inferior infarct

· S waves

o V₆ with RBBB

o Large S in inferior leads with LAFB

o Large S in lateral leads with LPFB

· T wave changes [diagram] – cannot definitively localize MI’s

o subepicardial ischemia (inverted, symmetric), subendocardial ischemia (peaked)

o hyperacute MI (tall, peaked, may have associated ST ↑ and/or Q’s)

o RBBB, LVH, RVH (septal leads), LBBB (lateral leads)

o hyperkalemia (peaked, also with widened QRS, prolonged PR, sine wave) [ECG]

o hypokalemia (may have flat, inverted T)

o pericarditis (inverted), intracranial hemorrhage (ICH)

Note: can be normal in limb leads, but usually pathological in V₂ to V₆

Wellen’s T waves – deep, symmetric TWI (usu. early precordial leads) may occur in significant left main or proximal LAD

· ST segment changes [diagram]

shape more important than size of changes / J point is the beginning of the ST segment / ST segment changes tell you where the injury is because the injured tissue remains depolarized when surrounding tissue is repolarized / diffuse ST elevations with chest pain [table]

· ventricular aneurysm: can produce baseline ST elevations

· pericarditis: ST elevations are flat or concave (often entire QT segment)

ST elevation

Diffuse: pericarditis, myocarditis, cerebral hemorrhage, others

Localized: transmural ischemia, MI, wall motion disorder (e.g. aneurysm), others

ST depressions – cannot definitively localize MI’s

o subendocardial ischemia (e.g. angina)

o ST ↓ V₁, V₂ with posterior MI (flip and invert EKG to see posterior ST ∆’s)

o reciprocal changes with ST elevation MI’s (note:)

o LVH, LV strain with repolarization (inverted T’s)

o hypokalemia

o digoxin toxicity

· U waves

o (+) > 1 mm / caused by class Ia drugs, hypokalemia [pic], hypomagnesemia, CNS disease (TU fusion waves) [pic], LQTS (+/-) [pic] / predisposes to torsades de pointes

o (-) HTN, AV valvular disease, RVH, major ischemia, 60% of anterior MI, 30% of inferior MI, 30% of angina

ECG changes suggestive of MI

ST changes: convex suggests infarction (concave could be pericarditis, other)

ST ↑ > 2 mm in 2 contiguous (by grouping) precordial leads

ST ↑ > 1 mm in 2 contiguous (by grouping) limb leads

> 1 mm ↓ in at least 2 contiguous leads suggests ongoing ischemia (subendothelial

infarct, positive stress test) or digoxin effect

In presence of LBBB: cannot exclude MI but MI very likely if:

1. ST ↑ > 1 mm concordant with QRS (in same direction as QRS)

2. ST ↑ > 5 mm discordant (not in same direction as QRS)

3. ST ↓ > 1 mm in V₁, V₂ or V₃

Indication for thrombolysis: > 2 mm ST elevation in 2 limb leads, new onset LBBB

Contraindications include SBP > 180 (at any time, despite what happens after BP meds)

Reciprocal changes suggest ischemia (where to look)

Inferior ST depression, T inversion à anterior leads
Anterior ST depression, T inversion à inferior lateral
Lateral ST depression, T inversion à inferior, anterior

Localization of infarct

· Which artery is/was occluded

I, aVL (high lateral) – L circumflex

V₁- V₄ (anteroseptal) – LAD (see below)

V₅- V₆ (lateral) – L circumflex

II, III, aVF (inferior) – RCA (85%), L circumflex (15%)

Note: minimal ST changes and inverted T waves in II, III, aVF à common with circumflex a. occlusion

· ⅓ of inferior MI involve right ventricle / get right sided ECG if inferior leads involved, because right ventricular MI requires much different treatment! (see treatment of MI and avoid nitrates)

· Anterior Vs. Posterior MI

· V₂ is most reliable for determining anterior vs. posterior (it lies in the A-P vectorial plane through LV)

· Don’t confuse anterior sub-endocardial MI with posterior MI

· acute posterior MI (would be mirror of anterior MI) à V₁-V₂ w/ large R wave, ST depression

· LAD occlusion

Scenario A (wrap-around LAD)

V₃ V₄ ST

II, III, AVF ST

Scenario B

V₁V₂ ST

II, III, AVF may be normal 2^o to cancellation of vectorial forces

I, AVL, ST if affecting high diagonal

Scenario C

ST I, AVL, V_1-6

ST ¯ II, II, AVF

Swan-Ganz Catheter – Interpretation of Values

Complications: dysrhythmias (75%), thrombosis (3%), sepsis (2%), pulmonary infarction (2%), pulmonary valve perforation (1%)

RAP [0 to 8 mm Hg]

PAP [systolic: 15-30, diastolic 5-12, mean 10-20 mm Hg]

PCWP [5 to 12 mm Hg] normally LVEDP = PCWP

o PCWP > LVEDP in MS, LA myxoma, pulmonary venous obstruction, patient on PEEP

o PCWP < LVEDP with “stiff” left ventricle ( > 25 mm Hg)

Cardiac output [3.5 to 7 L/min]

Cardiac index [2.4 to 4 L/m²]

SVR [900-1300 dynes/sec/cm^-5]

PVR [155-255 dynes/sec/cm^-5]

Echocardiography

Normal EF roughly 55%

McConnell’s sign: reduced RV function with apical sparing (suggestive of PE)

Detect intracardiac shunt with agitated saline bubbles

General Circulatory Disturbances

Edema Hypothermia

Hypovolemia

Shock

CHF

Hypertension Cor Pulmonale ACLS

Edema

Ddx: CHF, renal disease, inflammation, various drugs, hypothyroid, exogenous estrogen, thiamine (B1) deficiency

Effects: hypovolemia, hydrocephalus, pulmonary edema

anasarca (severe edema) / chronic passive congestion of lungs (hemosiderin, brown induration) / chronic passive congestion of liver (nutmeg liver) and spleen (splenomegaly)

Hypovolemia

Free Water Deficit:

0.6* • weight (kg) •| current Na

----------- - 1

140

*0.5 if female

Shock

stage I compensated

stage II tissue hypoperfusion / dilated arterioles, fall in urinary output, DIC ?

stage III cell and organ injury / decreased CO from hypoxia or pancreatic myocardial depressant

factor / ATN (kidney) / ischemic encephalopathy / hemorrhage, necrosis in heart (zonal lesions, bands) / Phases 1) brain and CVS changes 2) renal dysfunction (2-6 days) 3) diuretic phase (renal tubules recover fxn)

hypovolemic replace with saline/ringer’s

cardiogenic this is due to left ventricular failure (MI, cardiomyopathy, etc)

consider Swann-Ganz catheter to maintain wedge of ? 17

Consider ongoing occlusion: coronary reperfusion with PTCA

Pressors: dopamine, dobutamine, levafed

With LV failure: consider intraaortic balloon pump placement to increase coronary flow (increased diastolic pressure) and decrease afterload / can also use left-ventricular assist device (LVAD) (risk of infection, thrombosis, mechanical pump failure)

Septic shock decreased SVR / goal is to maintain preload of ?>higher than normal

consider Swann-Ganz catheter

IVF: saline or lactated ringer’s to maintain wedge

Pressors: dopamine, dobutamine, levafed

Course: Capillary leak combined with a catabolic state will decrease albumin and cause 3^rd spacing of fluid / pre-renal state will occur as renal arteries constrict as the body diverts blood to brain and other organs / after recovery, there will be a diuresis as fluid re-enters circulation and renal tubules are somewhat leaky

may be associated with DIC

Congestive Heart Failure (CHF) [NEJM]

· Systolic dysfunction (pump failure) à all systolic also has some diastolic failure

· Diastolic dysfunction (impaired filling) à can have isolated diastolic failure

Note: RHF usually from LHF or cor pulmonale (RHF alone can actually cause pulmonary edema from pleural venous drainage)

Causes: myocardial injury (see cardiomyopathies), chronic overload (AS, HTN), chronic volume overload (MR, other), infiltrative (amyloid, HC, other)

Systolic dysfunction

Framingham Criteria

Clinical diagnosis of CHF can be made with at least one major and two minor

Major: PND, neck vein distension, JVP, rales, cardiomegaly, acute pulmonary edema, S3 gallop, positive hepatojugular reflex, weight loss > 4.5 kg with 5 days treatment

Minor: peripheral edema, night cough, DOE, hepatomegaly, pleural effusion, reduced VC (↓ ⅓)

NYHA Functional Classification

I – no limitation during ordinary physical activity

II – slight limitation of physical activity. Develops fatigue or dyspnea with moderate exertion.

III – marked limitation of physical activity. Even light activity produces symptoms.

IV – symptoms at rest. Any activity causes worsening.

Exam Findings

· Elevated JVP

· Pulmonary edema (see other)

· Orthopnea

LV failure or inflow obstruction causes raised PCWP and dyspnea

· Paroxysmal nocturnal dyspnea (PND)

similar phenomenon that occurs after several hours of recumbency (similar findings with pulmonary disease)

· Leg Swelling

· Pulsus alternans

· S3

Treatment of CHF (stages I-IV):

I – ACE inhibitors

II – ACE inhibitors + salt restriction + diuretics +/- B-blockers (metoprolol, carvedilol)

III – add inotropic agents and vasodilators

IV – add aortic balloon pump or cardiac transplantation

Note: if cannot tolerate ACEI, isosorbide dinitrate + hydralazine has proven mortality benefit over placebo (Imdur alone has not been proven as of 3/07)

Plus:

· Anticoagulants with atrial fibrillation or other risk factors for thrombus formation (such as very low EF with severe hypokinesis)welling

· Anti-arrhythmia agents vs. AICD

§ Some patients may need anti-arrhythmia agents for chronic atrial fibrillation (B-blockers are safest and might be useful)

§ Some studies favor AICD’s (+/- sotalol) over anti-arrhythmia agents alone for severe CHF with high-risk of ventricular tachycardia

· Cardiac resynchronization therapy (CRT) or biventricular pacing may decrease mortality by decreasing sympathetic activation; consider for moderate to severe HF

The intra-aortic balloon pump (IABP) is positioned in the aorta with its tip distal to the left subclavian artery. Balloon inflation is synchronous with the cardiac cycle and occurs during diastole. The hemodynamic consequences of balloon counterpulsation are decreased myocardial oxygen demand and improved coronary blood flow. Additionally, significant preload and afterload reduction occurs, resulting in improved cardiac output. Severe aorto-iliac atherosclerosis and aortic valve insufficiency are relative contraindications to intra-aortic balloon pump placement.

Ventricular assist devices (VADs) require surgical implantation and are indicated for patients with severe HF after cardiac surgery, in patients who have intractable cardiogenic shock after acute MI, and in patients who deteriorate while awaiting cardiac transplantation. Currently available devices vary with regard to degree of mechanical hemolysis, intensity of anticoagulation required, and the difficulty of implantation. Therefore, the decision to institute VAD circulatory support must be made in consultation with a cardiac surgeon experienced in this procedure.

Prognosis:

· 75% five-year survival with transplant

· peak oxygen uptake of 20 mL/min/kg is associated with a good 1-year prognosis

Physiology of CHF

Vasoconstriction / Salt-retention

· Left ventricle, carotid sinus, aortic arch, renal afferent à increased ADH, renin

· Brain-derived natriuretic peptide (BNP) promotes diuresis

Sympathetic System

· B₁ and B₂ are uncoupled (B₁ ↑ HR, B₂ ↑ TPR)

· NE causes myocyte hypertrophy, direct myocyte toxicity / NE (over 4.7 nmol/L) carries poor prognosis

Treatment: B-blockers may ↑ survival by counteracting NE affects (may also have anti-oxidant properties), ↑ diastolic filling time (via slowing HR) / biventricular pacing

Renin-angiotensin system

· No escape from renal sodium retention / combination of NE and ATII stimulation increases Na transport in proximal tubule and decreases delivery to distal tubule (which helps explain lack of escape phenomenon in CHF, unlike Conn’s syndrome) / resistance to atrial natriuretic peptide may result from decreased distal delivery of Na

· ACE inhibitors and ATII blockers also reduce mitogenic effect on cardiac muscle (which would crowd capillaries and decrease blood delivery) / they may actually reverse LVH

· ATII receptors may stimulate thirst despite hyponatremia

Treatment: ACE inhibitors and spironolactone both reduce mortality

ADH (AVP) System

· ADH V₂ receptors in collecting duct principal cells à AC à aquaporin-2 translocation and production

· ADH V₁ receptors constrict vascular smooth muscle

· Baroreceptors override atrial receptors (Henry-Gauer atrial reflex)

Endothelial hormones

· Endothelin Prostacyclin and PGE2 counteracts (afferent?) renal vasoconstriction à NSAIDS can precipitate acute renal failure in severe CHF

· Endothelin receptor antagonist BQ-123 (in development) may also counteract vasoconstriction

Diastolic Dysfunction

Inadequate filling during diastole / can be due to variety of causes

Treatment depends on cause

· control heart rate and increase relaxation with B-blockers (1^st), Ca channel blockers (2^nd)

· normalize any arrhythmias (i.e. atrial fibrillation, atrial flutter)

Cor Pulmonale

Pulmonary HTN and RV dysfunction

· vasoconstriction (ex. CF)

· primary idiopathic

· part of autoimmune disease (scleroderma)

· chronic pulmonary embolism

· parenchymal (sarcoidosis, ILD)

· obesity hypoventilation syndrome

ECG: peaked P waves in II, III, aVF (RA enlargement), deep S in V₆ with ST changes (RVH), R-axis deviation, RBBB occurs in 15% of patients

CXR: edema (if pleural effusion, think more of LV failure instead)

Treatment: treat pulmonary HTN (see other)

Hypertension [see pulmonary hypertension]

Definitions

> 140/90 (stage I) >160/100 (stage II)

essential HT 90% of HTN / genetics, environment / older age, except blacks

malignant HT (5%) 50% essential, 50% secondary (10% renal, 40% endocrine, vascular, neurogenic (rare))

Secondary causes

Renal parenchymal (chronic pyelonephritis, glomerulonephritis, APKD)

Tubular interstitial (reflux and analgesic)

Endocrine: hyperthyroidism, primary aldosteronism, Cushing’s syndrome, pheochromocytoma, acromegaly, oral contraceptives

Other: pain!, hypervolemia (posttransfusion, renal failure), hypercalcemia, drugs (steroids, TCAs, sympathomimetics, NSAIDs, cocaine), coarctation of aorta, vasculitis, renovascular hypertension (RAS), fibromuscular dysplasia

Clues to renovascular HTN: epigastric or flank bruits, accelerated or malignant HTN, < 35 or > 55, sudden development or worsening, concomitant poor renal function, refractory to anti-HTN meds, extensive occlusive disease in peripheral circulation (including CAD/CVA)

Complications

cardiac hypertrophy à heart failure, MI

vascular à aortic dissection

à hyaline arteriolosclerosis: retinal, renal disease

à arteriolosclerosis: MI, CVA, renal failure

à fibroelastic hyperplasia

à retinal changes

grade III retinal changes (hemorrhages, cotton wool spots, hard exudates)

grade IV retinal changes (papilledema)

Other à 2x risk of renal cell carcinoma

Initial work-up: CBC, chemistries (K, Ca, PO4, BUN/Cr), UA (protein, blood, glucose, micro), consider TSH / lipid profile / fasting glucose / EKG / consider CXR, head CT, echo

Secondary: captopril-enhanced radionuclide renal scan, MRA, spiral CT / pheo labs /

Treatment:

Goal is to reduce BP by 10-15% or diastolic 110

Organ dysfunction usually at > 130 diastolic

Outpatient Treatment:

Clinical Trials

HOT showed 51% reduction in cardiovascular events with diastolic < 80 (not 90)

UKPD suggested systolic should be < 120

HOPE à ramipril ↓ MI (22%), ↓ CVA (33%), ↓ mortality (24%)

LIFER à losartan decreased mortality more than atenolol for DM with LVH

ACE inhibitors

B-blockers

Ca blocker

Diuretics (HCTZ)

Avoid B-blockers with asthma, CHF (depends), peripheral vascular disease, theoretical risk of increasing sugars with DM or hyperlipidemia (nobody really worries about that)

Avoid diuretics with gout (impairs urate excretion)

With pregnancy, ACE contraindicated (fetal kidney agenesis) and diuretics risky; use aldomet or hydralazine

HTN emergency – must lower BP in < 1 hr

Causes: malignant HTN, associated with MI, flash pulmonary edema, ARF, intracranial events, post-operative bleeding, eclampsia, pheochromocytoma) à SZ, coma, death

MRI: posterior leukoencephalopathy (parietooccipital regions) can be missed on CT

Cerebral blood flow autoregulation à maintains MAP 60-120 (curve shifts to right in chronic HTN; which is why BP must not be lowered > 25% over ~1 hr, especially in presence of neurological effects)

HTN urgency – must lower BP in < 24 hrs

Causes: accelerated HTN, associated with CHF, stable angina, TIA, peri-operative

Pre-eclampsia and Eclampsia (Toxemia of Pregnancy)

Presentation: headache, epigastric pain, visual disturbances, swelling

Criteria: hypertension (systolic > 140 or +30, diastolic > 90 or +15), proteinuria, edema

Complications: placental ischemia, hypertension, DIC, seizures (true eclampsia)

6% of pregnancies / often last trimester (20 wks to 6 wks post-partum) /

Risk factors: hydatidiform moles, age extremes

Mechanism: angiotensin hypersensitivity may result from decreased PGE synthesis

Treatment: IV MgSO4 or BZ for seizures

Screening: neurokinin B test under development / maternal serum inhibin A concentration is elevated in established preeclampsia (early indicator of risk?)

Treatment for HTN emergency/urgency

Hypertensive encephalopathy

Labetalol, nicardipine, fenoldopam, nicardipine

Avoid: b-blockers, clonidine, methyldopa

Subarachnoid Hemorrhage

Nimodipine, nitroprusside, fenoldopam, labetalol

Avoid: beta-Blockers, clonidine, methyldopa, diazoxide

Intracerebral Hemorrhage

No treatment, nitroprusside, fenoldopam, labetalol

Avoid: beta-Blockers, clonidine, methyldopa, diazoxide

Ischemic Stroke

Nitroprusside, labetalol, fenoldopam

Avoid: beta-Blockers, clonidine, methyldopa, diazoxide

Acute MI/unstable angina

b-blocker + nitroglycerin

Avoid: diltiazem, hydralazine, diazoxide

Acute LV failure

Nitroprusside, IV nitroglycerin

Avoid: diltiazem, b-lockers, labetalol

Acute pulmonary edema

1^st line Nitroprusside or fenoldopam + Lasix

2^nd line nitroglycerin (up to 200 mug/min)

Acute aortic dissection

(B-blocker then nitroprusside) or labetalol or trimethaphan

Avoid: Hydralazine, diazoxide

Acute renal failure

Fenoldopam, nitroprusside, nicardipine, labetalol

Avoid: beta-blockers, trimethaphan

Sympathetic Crisis (pheochromocytoma)

Phentolamine, labetalol, nitroprusside, clonidine (for clonidine withdrawal only)

Note: block a then b to avoid problems

Microangiopathic hemolytic anemia

Eclampsia

Magnesium sulfate, hydralazine, labetalol, calcium antagonists

Avoid: ACE inhibitors, diuretics, trimethaphan

Postoperative crisis

Labetalol, fenoldopam, nitroglycerin, nicardipine, nitroprusside

Avoid: trimethaphan

Arteriosclerosis

Pathological Types

Senile sclerosis insidious / aging

Monckeberg’s medial calcification / wear and tear lesion?

Atherosclerosis see below

Arteriolosclerosis

hyaline benign HT, DM / slow, stenosis / plasma proteins, thick BM

hyperplastic malignant HT / flea-bitten kidney

transplant accelerated 2 to 5-10 yrs

Atherosclerosis

abdominal aorta > coronary > popliteal > carotid

Pathology: diffuse intimal thickening (normal aging) / gelatinous lesions (focal edema) / microthrombi / fatty streaks (normal aging)

Causes: by hyperlipidemia (diet, DM, gout), chronic HTN, smoking, Fabry’s, elevated homocysteine

Markers: CRP is associated with increased risk / other markers are associated but not useful for screening: homocysteine, lipoprotein A, plasminogen activator factor 1 / C. pneumoniae and CMV also implicated

Coronary Artery Disease (see other)

Peripheral Vascular Disease [NEJM]

Presentation: < 20% report typical symptoms of intermittent claudication / leg fatigue, difficulty walking, other atypical leg pain

Exam findings: cyanosis (with dependent rubor), decreased temperature, atrophic changes (shiny skin, thick nails, absence of hair), decreased pulses / ulceration usu. toes, heels, anterior shin and extended over malleoli

Risk factors: smoking, diabetes, HTN, hyperhomocysteinemia, hyperlipidemia

Diagnosis: [table]

· ankle-brachial index (ABI) > 1.0 normal / 0.41 to 0.9 intermediate / < 0.40 critical

· ultrasound – limited compression of calcified vessels, operator dependent

· MRA/CTA – usual considerations

· angiography – good because could also do stenting at same time

Ddx [table]: Buerger’s disease, fibromuscular dysplasia, Takayasu’s, acute arterial occlusion, compartment syndrome, venous congestion, spinal stenosis

Treatment: reduce contributing factors (smoking, DM, etc) à smoking cessation reduces related/CAD mortality 50% / exercise (as tolerated re: possible CAD) actually helps

Medical therapy

· cilostazol – phosphodiesterase type 3 inhibitor à vasodilation + mild anti-platelet activity / shown to increase walking distance 50%

· pentoxifylline (Trental) à immunomodulator à people doubt efficacy

· ASA or plavix à more to prevent MI and CVA

Note: other vasodilators (CA blockers, a-blockers, hydralazine) may worsen symptoms by decreasing perfusion to affected area

Surgery: critical leg ischemia, persistent foot pain at rest, non-healing ulcers, disabling claudication

· PTA (PCI) versus bypass / must take several factors into decision [table]

Leriche syndrome

claudication in buttock, buttock atrophy and impotence in men due to aortoiliac occlusive disease / treat with bypass

Acute arterial occlusion

embolic or in situ / consider source / consider HIT Ab

Treatment: heparin (to prevent propagation), limb placed below horizontal plane without pressure, urgent vascular consult

Hyperlipidemia

diagnose based on FH, blood tests (cholesterol not changed by fasting, TG are decreased) Friedwald formula: LDL chol = total - (HDL chol + TG/5) / 100 - 139 (mild) / >139 (severe)

Note: very severe hyperlipidemia can affect platelets causing elevated ESR

CARE trial à no benefit shown for lowering LDL < 125 mg/dL in post-MI patients

HPS trials à simvastatin reduced coronary or vascular events by 33% (regardless of lipid levels)

SSSS trial à simvastatin reduced MI (55%), mortality (43%)

VA-HDLIT à 24% reduction in stroke/MI with gemfibrozil and LDL > 140 and HDL < 40

Combination of statin and fibrate is promising; fibrate alone probably not as good as statin alone

Current trend is treat CHD or CHD equivalents (DM, stroke, PVD) with goal of LDL < 100

Primary hyperlipidemias

FH AD / chol

Familial HTG AD / TG

combined AD / chol, TG

broad beta (rare disorder)

(85%) polygenic chol

sporadic TG

Secondary hyperlipidemia

elevated cholesterol

elevated TG (DM, other)

Hypolipoproteinemia

AR disorders

Diabetes Mellitus (see endocrine)

Drug-Induced: certain b-blockers, protease inhibitors

Coronary Artery Disease [chest pain Ddx] [angina] [MI]

1st COD in US / 90% of cardiac deaths

PDA to AV node – 90% L circumflex / 10% RCA

Risk Factors:

DM à extremely important risk factor [annals]

Family history (MI < 40 yrs)

Smoking

HIV

Male, post-menopausal

Age

Hypercholesterolemia (LDL > 100 / HDL < 50 / TG > 170)

Cocaine (vasospasm, promotes blood clotting)

Obesity (BMI > 27)

OCP/estrogens

HTN

LVH

Stress

Hyperthyroid

Initial testing guidelines:

Pt’s over 50 yrs old: LDL, smoking, fasting glucose

ankle-brachial index can be checked in patients over 55-60 yrs old

Second line tests (not part of any initial work-up)

· low serum folate (required for homocysteine à methionine)

· elevated CRP, homocysteine, ApoA, ApoB

Physical Exam

Retinal changes – AV nicking and/or copper-wire changes (HTN)

S4 (HTN)

Peripheral bruits

Absent/decreased peripheral pulses

Xanthomas (hyperlipidemia)

Common causes of chest pain (see Ddx)

Cardiac: aortic dissection, myocarditis, pericarditis, valvular heart disease (MVP, AS, HOCM, MS)

Lungs: pulmonary embolism, pleurisy, pneumonia, pneumothorax, pulmonary HTN

GI: cholelithiasis, cholecystitis, GERD , esophageal spasm, PUD, pancreatitis

Musculoskeletal: costochondritis, chest wall trauma, cervical arthritis with radiculopathy, muscle strain, myositis

Other: Herpes zoster

Diagnosis of CAD (sensitivity/specificity of various criteria)

Exercise electrocardiography

>1 mm ST depression (70/75)

>2 mm ST depression (33/97)

>3 mm ST depression (20/99)

Perfusion scintigraphy

Planar (83/88)

SPECT (87/65)

Echocardiography

Exercise (85/76)

Pharmacologic stress (86-96/66-95)

Stress Test

adenosine / sestamibi (MIBI) / dobutamine (less bronchoconstriction, better for COPD)

Pt unable to exercise: can use persantine (vasodilates normal but not diseased vessels, inducing ischemia)

Contraindications: severe AS, HOCM, unstable angina, severe arrhythmias, EKG suggesting ischemia, severe COPD, active CHF, endocarditis, severe AV block, aortic dissection, severe HTN, recent cerebral hemorrhage

Bruce (fast) vs. Naughton (slower)

Note: females tend to have less reliable results on graded stress tests (use of thallium/nuclear imaging improves specificity)

Angina pectoris (see chest pain Ddx) Stable / Unstable / Variant / Syndrome X / Stress Test

Stable angina

Presentation: substernal or epigastric, usually radiates (usually left side, can be right) to shoulder, neck, jaw/teeth, and arm (ulnar distribution—4^th/5^th digit) / can be from exertion, emotional upsets, cold, eating

Note: noncardiac disorders often trigger angina from real CAD

Symptomatic with occlusion of 50% diameter or 75% cross-sectional area

EKG: may show ST depression, T wave flattening or inversion

Diagnosis: stress test or other

Treatment:

o ASA and other newer anti-platelets to limit aggregation

o Nitroglycerin SL or spray should work in 5-7 mins (if not, could be MI or other)

1. coronary artery dilation improves blood flow to sub-endocardium

2. venodilation reduces preload and wall tension

Isosorbide dinitrate / mononitrate (Imdur) is taken during daytime / can use patch to protect against night time MI

Note: tolerance develops to nitrates

Side effects: hypotension, light-headedness, HA

o B-blockers

reduce myocardial oxygen demands (try to avoid worsening CHF)

o Calcium channel blockers (Verapamil, Diltiazem)

Coronary vasodilation, variable peripheral vasodilation

can be used instead of B-blocker to reduce HR, BP and vasodilate [except in heart block, bradycardia, severe CHF (due to negative ionotrope/chronotrope activity]

Unstable angina

pre-MI (80%) / thrombus persists 15-20 mins (> 20 mins is MI) / chest discomfort at rest / decreased O2 delivery because plaque ruptures, thrombus formation /

Biological factors: thromboxane, 5HT, ADP, platelet activating factor, tissue factor (endothelium/macrophage), endothelin (potent vasoconstrictor), free radicals – vasospasm, vasoconstriction

mitogen – residual fibroproliferation -

elevated troponin I or CRP is a poor prognostic sign

Treatment: B-blockers and nitrates +/- Ca blockers (not Ca blockers as single agent)

Variant or Prinzmetal’s Angina

coronary artery spasm (causes similar EKG changes as STEMI) / majority of cases do have CAD and spasm occurs within 1 cm from lesion / RCA most common location / usu. younger age, do not have preceding stable angina and usu. risk factors

Presentation: similar to ACS, often occurs in early morning (4-11am) / sudden cardiac death (30% of heart attacks, most common COD post-MI, V-fib)

Diagnosis: may see spasm if active in catheterization / can provoke using hyperventilation ergonovine, acetylcholine, other agents

Treatment: nitrates, calcium antagonists (nifedipine, verapamil, diltiazem) / do not give B-blocker (may increase frequency); ASA also thought to worsen spasm / viral, sheer stress, smoking, catecholamines excess

Microvascular Angina (Syndrome X)

Defect in coronary microcirculation / normal angiogram, abnormal stress test / excellent prognosis

Anxiety induced chest pain

neurocirculatory asthenia, Da Costa syndrome, soldier’s heart, cardiac neurosis / often after exertion, fleeting or prolonged, associated with hyperventilation syndrome

Inappropriate myocardial lactate production

rare, usually woman / typical angina +/- abnormal resting/stress ECGs (but normal arteriograms)

Chronic ischemic heart disease (CIHD)

calcification, lipofuscin, scarring, nodular stenosis of valves

Sympathetic Crisis

Withdrawal of short-acting anti-hypertensives (clonidine or propranolol), cocaine, amphetamines, phencyclidine, MAO + tyramine foods, pheochromocytoma, and ANS dysfunction (Guillain-Barré)

Treatment: anti-hypertensive medication / labetalol can cause paradoxical worsening

Alternatives: phentolamine and nitroprusside

Cocaine

Cocaine-associated chest pain à 25% ischemia, 75% be musculoskeletal or psychological

Cocaine use may reduce the sensitivity and specificity of CK-MB and myoglobin (80à50%) for infarction

Thrombosis (increased platelet action)
Vasospasm (acute)
Peripheral vasoconstriction (with prolonged adrenergic sensitization)
Increased heart rate (with prolonged adrenergic sensitization)
Accelerated atherosclerosis

Complications: endocarditis, hemorrhagic and ischemic stroke, aortic dissection, accelerated CAD, MI, sudden cardiac death

Treatment: debate à is it better to give metoprolol or labetalol for cocaine-assoc. chest pain?

Myocardial Infarction

[lab markers] [treatment][complications][prognosis][follow-up] [non-CAD causes]

Presentation:

intense pain / may radiate or present as chest, jaw/teeth, left arm (4^th 5^th digit), epigastrum /

Lavine’s sign à clenched fist over midchest / diabetics 20% or more have decreased sensation of pain from peripheral neuropathy / post-cardiac transplant patients also have a decreased sensation of pain

Ddx for MI

Pericarditis à ST elevations / echo

Myocarditis à ST elevations, Q waves / echo

Aortic dissection à ST elevation/depression, non-specific ST/T waves / TEE, chest CT, MRI, aortography

Pneumothorax à new, poor R-wave progression in V1-V6, acute QRS axis shift / CXR

PE à inferior ST elevation, ST shifts V1-V3

Cholecystitis à inferior ST elevation / U/S, radioisotope scan

Subendocardial (non-Q wave)

not occlusive (successful fibrinolysis occurs) / ST depression, flat T-wave

Transmural (Q wave)

90% occlusive / moves from inner wall, vertically outward / ST elevation, inverted T-wave, wide Q wave is pathognomonic for MI

only ischemic condition requiring thrombolytic therapy

Location of Infarction

Anterior vs. Septal vs. Posterior vs. Right Ventricle (determined by ECG)

Note: pre-existing BBB clouds evaluation of ischemia

Early R wave progression (V₁/V₂) suggests posterior MI

Lab markers for MI

Note: cardiac markers may also be elevated with myocardial strain (e.g. PE), CHF, myocarditis

CK (CPK) [more]	not selective / rises at 4-8 hrs, peaks at 16-24 hrs, normal by 2-5 days Note: if CK goes up in 7-15 hrs, could be early ‘washout’ (reperfusion)
CK-MB [more]	very selective / rises at 8 hrs, peaks at 16-24 hrs, normal by 3 days / cannot rule out MI when taken 24-48 hrs later CKMB [0-10] / CK-MB to CK fraction [0-2.5] increase within 3 hrs – peaks 10-12 hrs (reperfused infarct – later peak if you don’t reperfuse) – descend – [MM (skeletal > heart), BB (brain), MB (heart >)]
Troponin C	up in 3-5 hrs, normal by 10 days / 20 mins rapid test
Troponin I [< 0.3]	more specific 6-8 hrs after infarction – remains elevated 7-10 days Note: troponins can also be elevated (mildly) in renal failure Note: peak troponin levels 6 hrs after onset of chest pain in unstable angina and non Q MI can predict subsequent more severe MI within 30 days
Troponin T [< 0.1]	more specific 6-8 hrs after infarction – remains elevated 10-14 days
myoglobin	fast and sensitive (also from skeletal muscle damage) / leaks out within 1 hr / 4-6 hr peak normal by 24 hrs / used to monitor thrombolysis / urine myoglobin underestimates level
LD1 [30-80]	not specific, but sensitive / up at 24 hrs / peak at 3 days / normal by 1-2 wks
LD isozymes	LD1 > LD2 / LD flip is more selective

Other labs:

high WBC 12-24 hrs to 2 wks

AST up at 12 h, peak at day 2, normal by day 5 (over 200 means liver damage)

CRP mediator/marker of inflammation

cardiac myosin light chains under investigation

Management of LV Infarct

ASA, Plavix, GP IIb/IIIa inhibitors (see below)

Heparin (UFH or LMWH)

to prevent clot propagation / risk of major bleed is 2% (½ with subsequent CABG will bleed, but this can be controlled with transfusions)

Trends: AIM 10/6 current thinking is LMWH better than UFH for reducing risk of reinfarction (has not been shown yet to reduce mortality) at cost of slightly increased risk of bleed

GP IIb/IIIa inhibitors

give with ASA and heparin in pts in whom cath is planned; some cardiologist are more aggressive about giving IIb/IIIa agents (i.e. even if cath not necessarily planned, even if only NSTEMI, still not ruled in, etc)

Nitroglycerin

coronary artery dilation improves blood flow to sub-endocardium

venodilation reduces preload and wall tension

Morphine

Pain, anxiety, decreased work for heart

ACE inhibitors

benefits are seen with early initiation (< 24 hrs) for afterload reduction and to limit ventricular remodeling

B-blockers

shown to decrease mortality (but be careful to make sure patient is hemodynamically stable; overly aggressive b-blockade can worsen acute heart failure)

Statins

may have early benefit on vasodilatory tone (so give in early with ACS)

Other

Pacing: transvenous pacemaker for complete heart block from acute MI

Ca channel blockers are in general ?frowned upon for CAD patients (but I haven’t read the studies)

Avoid: steroids, NSAIDs – which impede healing, increase risk of myocardial rupture, increase size of resulting scar / isoproterenol (increases cardiac demand, ischemia)

Reperfusion

· Thrombolysis (see thrombolytics/contraindications)

benefit declines as one moves to 30-60 mins, 1-3 hours, and 3-6 hours after pain [by 12 hrs, risk of bleed outweighs benefit of thrombolysis]

(RPA + Reapro) slightly better outcome than (RPA alone)

tPA or rPA (increased half-life, action / studies ongoing)

expect idioventricular “reperfusion” rhythm (“accelerated idioventricular” rhythm) à don’t be alarmed if rate drops to 45~ (often 60-110 bpm; wide-complex escape rhythm)

reperfusion is almost assured with resolution of chest pain / 5% get acute re-occlusion

Prognosis: 30 day mortality only 2% with 60% post-thrombolysis reduction in ST segment elevation (7% otherwise) / mortality also better with flip T at 2 hrs post-MI

· PCA (with stenting) (cardiac cath)

Indications for cath: recurrent ischemia at rest, elevated troponins, new ST depressions, recurrent angina w/ CHF Sx, high-positive stress test, decreased LV systolic fxn (EF < 40%), hemodynamic instability, sustained VT, PCI w/in last 6 months, prior CABG

Indications for CABG: three vessel disease, significant left main disease, two vessel and diabetes (BARI trial), patients with CAD already needed other intracardiac surgery

Issues: pretreatment with Mucomyst for renal insufficiency, adequate pre-post hydration, stop metformin 48 hrs before, watch for dye allergy, how long to run IIb/IIIa inhibitors after procedure, which sealing method reduces risk of hematoma

Plavix:

CURE à add plavix along with ASA in pts w/ UA/NSTEMI in whom PTCA planned (duration from 1–9 months)

PCI-CURE à start plavix x 1 mo s/o PTCA

Note: hold plavix 5-7 d prior to surgery in planned CABG

SIRIUS study showing dramatic reduction in restenosis rates using drug-eluting stents (especially for DM patients)

General outcomes for elective stenting: 1% mortality, 2-5% incidence of nonfatal MI, 1-3% need for emergency CABG / clinical restenosis rate of 10-20% in discrete lesions

low-risk à ASA before, heparin during

mod-risk à ?

high-risk à 2b3a inhibitors before, during, after

TIMI risk score (0 to 14)

one point each for: ³ 3 CAD risk factors; prior angiographic evidence; ST

changes; ³ 2 anginal events last 24 hrs; use of ASA in last 7 days; increased

troponins, time to reperfusion therapy > 4 hrs

two points: age > 65, HR > 100, Killip class II to IV

three points: SBP < 100 mm Hg, age > 75 yrs

Risk of event increases linearly for TIMI 0/1 to 6/7 (4 to 41%)

30-day mortality (1 to 36%) / 1 yr mortality (those surviving 1^st 30 days) (1 to 17%)

Implications:

· TACTICS-TIMI 18 à TIMI ³ 3 benefited from early invasive

· PRISM-PLUS à TIMI ³ 4 benefited from 2b3a in addition to heparin

· TIMI 11B, ESSENCE à benefit of Lovenox over heparin for ³ 4 and ³ 5 respectively

Treatment of Right Ventricle Infarct

key is not to lose LV preload

give IVF as needed

avoid NTG, morphine (use with caution)

still give antiplatelet and anticoagulation agents

Complications of MI

Arrhythmias (1st COD post-MI; most often < 1 hr post-MI; must monitor closely first 24 hrs)

Atrial arrhythmias: sinus tachycardia, AF, paroxysmal SVT, junctional (inferior)

Ventricular arrhythmias (NSVT, sustained VT (> 30s requires treatment), VF)

Note: females with MI more likely to develop cardiac arrest or shock (males à VT)

Bradycardia/heart block

1^st degree AV block – every P followed by QRS

2^nd degree AV block

Mobitz I (inferior MI)

Mobitz II (large anterior MI, needs pacer)

3^rd degree AV block (needs pacer)

Indications for temporary AV pacing

Asystole, 3^rd degree block, Mobitz II AV block, sinus brady or Mobitz II w/

hypotension and refractory to atropine, new trifascicular block, alternating

BBB, 3^rd degree block w/ inferior MI complicated by RV infarction, incessant VT

CHF w/ pulmonary edema

Killip classification (pulmonary associations with MI)

I - no rales; clear – 90% survival

II - bibasilar rales – 80% survival

III - rales, low BP – 60%

IV - rales, low BP, poor perfusion – 20% (cardiogenic shock)

Shock
Acute pericarditis (3-5 days) vs. Dressler’s autoimmune pericarditis (weeks to months)
Mural thrombosis
Rupture of papillary muscle (1%; 2-7 days)
VSD (1 to 4%; 3-7 days)
Cardiac tamponade
Ventricular aneurysm (rupture of infarct) (5-10 days)

Other treatment concerns

Tight glucose control (see DIGI-AMI)

Prognosis

· Increased Risk of subsequent MI

post-MI angina, non-Q wave MI, CHF, EF < 40%, failed stress test by ECG or

scintigraphy, ventricular ectopy (> 10 PVCs/min)

Note: females have higher mortality in 30 days after MI (various theories)

Follow-up Care

· measure left ventricle EF / submaximal stress test before discharge (> 2 days post MI) /

maximal stress test 4-6 wks later

· return to work and resume sexual activity from 6-8 wks

· cardiac rehab improves functional status, exercise/activity tolerance / aerobic activity 20-30

mins 3 x week at 60-80% peak capacity or rate of perceived exertion of 13-15 on Borg Scale (can gradually build up if pt cannot start at this level)

Other Causes of MI (besides coronary artery disease)

Coronary emboli

aortic or mitral valve lesions, left atrial or ventricular thrombi, prosthetic valves, fat emboli, intracardiac neoplasms, infective endocarditis, and paradoxical emboli

Thrombotic coronary artery disease

oral contraceptive use, sickle cell anemia and other hemoglobinopathies, polycythemia vera, thrombocytosis, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, antithrombin III deficiency and other hypercoagulable states, macroglobulinemia and other hyperviscosity

states, multiple myeloma, leukemia, malaria, and fibrinolytic system shutdown secondary to impaired

plasminogen activation or excessive inhibition

Coronary vasculitis

Takayasu’s disease, Kawasaki’s disease, polyarteritis nodosa, lupus erythematosus, scleroderma, rheumatoid arthritis, and immune-mediated vascular degeneration in cardiac allografts

Coronary vasospasm

May be associated with variant angina, nitrate withdrawal, cocaine or amphetamine abuse, and angina with "normal" coronary arteries

Infiltrative and degenerative coronary vascular disease

amyloidosis, connective tissue disorders (such as pseudoxanthoma elasticum), lipid storage disorders and mucopolysaccharidoses, homocystinuria, diabetes mellitus, collagen vascular disease, muscular dystrophies, and Friedreich’s ataxia

Coronary ostial occlusion

aortic dissection, luetic aortitis, aortic stenosis, and ankylosing spondylitis syndromes

Congenital coronary anomalies

Bland-White-Garland syndrome of anomalous origin of the left coronary artery from the pulmonary artery, left coronary artery origin from the anterior sinus of Valsalva, coronary arteriovenous fistula or aneurysms, and myocardial bridging with secondary vascular degeneration

Trauma

coronary dissection, laceration, or thrombosis (with endothelial cell injury secondary to trauma such as angioplasty); radiation; and cardiac contusion

Augmented myocardial oxygen requirements exceeding oxygen delivery

aortic stenosis, aortic insufficiency, hypertension with severe left ventricular hypertrophy, pheochromocytoma, thyrotoxicosis, methemoglobinemia, carbon monoxide poisoning, shock, and hyperviscosity syndromes

Valvular Disease [NEJM]

Note: prophylactic antibiotics not needed for orthopedic procedures (board question) exceptions?

	AORTIC STENOSIS	MITRAL STENOSIS	MITRAL REGURGITATION	AORTIC REGURGITATION
	Idiopathic calcification of a bicuspid or tricuspid valve Congenital Rheumatic	Rheumatic fever Annular calcification	MVP Ruptured chordae Endocarditis Ischemic papillary muscle dysfunction or rupture CTD LV myocardial diseases	Annuloaortic ectasia Hypertension Endocarditis Marfan syndrome Ankylosing spondylitis Aortic dissection Syphilis CTD
Mechanism	Pressure overload upon the LV with compensation by LV hypertrophy. As disease advances, reduced coronary flow reserve causes angina. Hypertrophy and afterload excess lead to both systolic and diastolic LV dysfunction.	Obstruction to LV inflow increases left atrial pressure and limits cardiac output mimicking LV failure. Mitral valve obstruction increases the pressure work of the right ventricle. Right ventricular pressure overload is augmented further when pulmonary hypertension develops.	Places volume overload on the LV. Ventricle responds with eccentric hypertrophy and dilatation, which allow for increased ventricular stroke volume. Eventually, however, LV dysfunction develops if volume overload is uncorrected.	Chronic increased SV à hyperdynamic circulation, systolic HTN (pressure and volume overload) Compensation (concentric and eccentric hypertrophy) Acute Because cardiac dilation has not developed, hyperdynamic findings are absent. High diastolic LV pressure causes mitral valve preclosure and potentiates LV ischemia and failure.
Symptoms	Angina Syncope Heart failure	Dyspnea Orthopnea PND Hemoptysis Hoarseness Edema Ascites	Dyspnea Orthopnea PND	Dyspnea Orthopnea PND Angina Syncope
Findings	Systolic ejection murmur radiating to neck Delayed carotid upstroke S₄ , soft or paradoxic S₂	Diastolic rumble following an opening snap Loud S₁ RV lift Loud P₂	Holosystolic apical murmur radiates to axilla, S₃ Displaced PMI	Chronic Diastolic blowing Hyperdynamic circulation Displaced PMI Quincke et al Acute Short diastolic blowing Soft S₁
ECG	LAA LVH	LAA RVH	LAA LVH	LAA LVH
CXR	Boot-shaped heart Aortic valve calcification on lateral view	Straightening of left heart border Double density at right heart border Kerley B lines Enlarged pulmonary arteries	Cardiac enlargement	Chronic Cardiac enlargement Uncoiling of the aorta Acute Pulmonary congestion with normal heart size
Echo	Concentric LVH Reduced aortic valve cusp separation Doppler shows mean gradient > 50 mm Hg in most severe cases	Restricted mitral leaflet motion Valve area 1.0 cm² in most severe cases Tricuspid Doppler may reveal pulmonary hypertension	LV and left atrial enlargement in chronic severe disease Doppler: large regurgitant jet	Chronic LV enlargement Large Doppler jet PHT < 400 msec Acute Small LV, mitral valve preclosure
Cath	Increased LVEDP Transaortic gradient 50 mm Hg AVA < 0.7 in most severe cases	Elevated pulmonary capillary wedge pressure Transmitral gradient usually >10 mm Hg in severe cases MVA < 1.0 cm²	Elevated pulmonary capillary wedge pressure Ventriculography shows regurgitation of dye into left ventricle	Wide pulse pressure Aortography shows regurgitation of dye into LV Usually unnecessary
Medical Treatment	Avoid vasodilators Digitalis, diuretics, and nitroglycerin in inoperable cases	Diuretics for mild symptoms Anticoagulation in atrial fibrillation Digitalis, beta-blockers, verapamil or diltiazem for rate control	Vasodilators in acute disease No proven therapy in chronic disease (but vasodilators commonly used)	Chronic Vasodilators in chronic asymptomatic disease with normal left ventricular function Acute Vasodilators
Indications for Surgery	Appearance of symptoms in patients with severe disease (see text)	Appearance of more than mild symptoms Development of pulmonary hypertension Appearance of persistent atrial fibrillation	Appearance of symptoms EF < 0.60 ESD > 45 min	Chronic Appearance of symptoms EF < 0.55 ESD > 55 min Acute Even mild heart failure Mitral valve preclosure

Cardiac Maneuvers

· valsalva: decreases preload / ↑ HCM, ↓ AS

· sustained handgrip: increases afterload (but may enlarge LV cavity) / variable effect on HCM, AS / ↑ AR, MR, MS

· squatting: increases venous return and afterload / ↓ HCM / ↑ most murmurs

· inspiration: increases flow through right side of heart / ↑ TR

· leg raise (decreases HCM, increases AS)

Aortic Stenosis

Etiology:

· congenital AS (pediatrics/young adults)

· senile calcific AS (50s and older) – most common cause of AS in Western world

· bicuspid AS (30-40s)

· rheumatic AS (always associated with mitral valve disease) / 20% w/ mitral injury also

Pathology: concentric LVH, large pressure gradient (LV to aortic outflow) / > 50 mm Hg / AVA < 1.0 cm² / < 0.75 cm² is critical (can still have a soft murmur that is hard to hear)

Clinical symptoms: (up to 80% of patients with symptomatic AS are male)

Angina occurs in 35-50% / ½ die within 5 years without valve replacement / LVH impairs cardiac blood flow

Syncope: due to decreased TPR in exercise / due to A/V arrhythmias or heart block (conduction system calcification) / survival is 2-3 years without valve replacement

Heart failure: 1-2 year survival without correction

Physical signs:

Delayed carotid upstroke: most reliable for gauging severity of disease (except under 7?)

Systolic ejection murmur: harsh, late-peaking (crescendo, decrescendo) / heard in aortic area, transmitted to carotids / murmur decreases with valsalva / may be reflected in mitral area, producing false impression of mitral regurge (Gallavardin’s phenomenon)

Soft, single S2: aortic component is absent

S4 results from reduced LV compliance

Sustained, forceful apex beat (not displaced until heart failure occurs)

Labs: ECG shows LVH / fluoroscopy (absence of calcium indicates less severe AS) / echocardiography can rule out severe AS if valve motion is normal, but doppler more precisely measures pressure gradient / cardiac catheterization can be used

Treatment:

Note: DO NOT give too much afterload reducers at one, which can create a severe pressure gradient (serious hypotension) as the cardiac output cannot compensate for afterload reduction

Palliative:

Medical therapy useful but temporary improvement of heart failure / statins may actually slow progression of valve leaflet calcification

Balloon valvuloplasty only moderate, temporary improvement (used in children)

Aortic valve replacement:

May or may not be able to correct any resultant heart failure

Homograft: no anticoagulation required / donors hard to get

Heterograft (porcine): only lasts about 10 yrs

Mechanical: more durable, coagulation therapy required

Bicuspid Aortic Valve

1-5% overall incidence

Present with AR in 30-40s or AS in 50-70s / ejection click

Mitral Stenosis

Etiology: almost always due to rheumatic heart disease (mostly in women; over ⅔), thrombus, myxoma [similar to endocarditis with fever, chills, embolisms, but negative cultures]

Pathology: elevated LAP leads to pulmonary congestion / 3-5 fold elevated pulmonary arterial pressure leads to RH failure / jet lesions

Symptoms:

· Left heart failure: due to mitral stenosis itself, dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea

· Right heart failure: edema, ascites, anorexia, fatigue

o High risk of pulmonary hypertension during pregnancy

· Hemoptysis: rupture of small bronchial veins

· Hoarseness: enlarged left atrium impinges on left recurrent laryngeal nerve [pic]

Physical signs:

Atrial fibrillation usually irregularly irregular (may be present)

Carotid pulse is brisk but diminished

Pulmonary rales due to pulmonary hypertension

Increased S1: may become reduced late due to incomplete closure

Increased P2 component of S2: due to pulmonary hypertension

Opening snap follows S2: shorter interval from S2 ( < 0.1 sec) means higher LAP and more severe MS [very calcified MS may not have opening snap]

Diastolic rumble: low-pitched apical rumble begins after opening snap (pre-systolic accentuation occurs with atrial contraction when in NSR)

Sternal lift (enlargement of RV due to pulmonary hypertension)

Neck vein distension, edema, hepatic enlargement, ascites (if right heart failure occurs)

Data:

ECG shows atrial fibrillation, left atrial enlargement, RVH

CXR: straightened left heart border, double density of right heart border / Kerley B lines / loss of retrosternal space when RVH is present

Echocardiography: reduced excursion, thickened valve leaflets / can measure residual orifice, left atrial enlargement always present

Cardiac catheterization: used frequently for coronary arteriography in susceptible patients

Treatment: < 1.0 cm² is severe

· diuretics to control pulmonary congestion (but be careful because MS patients can be very preload dependent and hypovolemia can lead to cardiac collapse)

· B-blockers to decrease rate and increase LV filling

· if atrial fibrillation present, can use digitalis to control ventricular rate and anticoagulation (warfarin) to prevent systemic embolism

Balloon valvuloplasty: may be as effective as surgery for mild cases

Surgical: should be performed prior to pulmonary hypertension (usually regresses if surgery is successful)

Mitral commissurotomy: young patients without significant calcification or MR

Mitral valve replacement:

Aortic Regurge

Acute:

· infective endocarditis (see causes)

· aortic dissections (retrograde), aneurysm

· congenital bicuspid valve

Sub-Acute:

Idiopathic aortic root dilatation: frequently associated with hypertension and correlates with increasing age

Rheumatic heart disease: most severe manifestation

Secondary Syphilis

Collagen vascular diseases such as SLE, ankylosing spondylitis, relapsing polychondritis

Myxomatous degeneration / weight loss

Congenital: Marfan syndrome (proximal root dilatation or aortic root dissection), Ehlers-Danlos, osteogenesis imperfecta, elastica? something

AS: things that cause AS can also cause AR (e.g. bicuspid aortic valve)

Course: eccentric dilatation (ESV 40-50, normal 10-15), LVH, decreased ejection fraction, systemic blood pressure ↑↓

Symptoms:

· Left ventricular failure:

· Syncope:

· Angina:

Physical signs:

Left ventricular impulse displaced left and downward

Diastolic murmur (high pitched, blowing) (increased with squatting and handgrip)

S3 due to rapid filling – okay in young people / suggests surgical correction in older pts

Austin flint murmur – heard best with bell over PMI

Increased total stroke volume and pulse pressure (may be absent in acute AR)

Corrigan’s pulse

Hill’s sign

Pistol-shot femoral pulse

Durozier’s sign

De Musset’s sign

Quincke’s pulse

Labs:

ECG

CXR – enlarged LV (pic?)

Echocardiography

Cardiac catheterization

Treatment:

· afterload reduction if LV dilatation is present: ACE inhibitors / nifedipine

· periodic echo to evaluate LV function

· mildly elevated BP may be due to widened pulse pressure (may not need specific therapy)

· antibiotics as needed to prevent endocarditis

· valvuloplasty or valve replacement surgery

Mitral Regurge

Etiology:

CAD - myocardial infarction of LAD (see ruptured papillary muscle)

Dilated cardiomyopathy

MVP click-murmur syndrome

Rheumatic heart disease

Ruptured chordae tendinae – spontaneous (Marfan’s)

Endocarditis

myxomatous degeneration (including MVP)

Mechanism: LV initially remodels and enlarges eccentrically to compensate, but eventually muscle gives out

Physical signs:

· Murmur: holosystolic, apical, radiates to axilla, frequently has a thrill / increased with squatting (increase venous return and afterload) / high pitch, blowing SEM / murmur may be absent with severe MR / mid-systolic click with MVP / can have diastolic rumble from blood flowing? Shorter duration?

· S3 from rapid filling of LV by large volume of blood in LA

· PMI displaced down and to left, carotid upstroke brisk but diminished

Diagnosis: ECG w/ LVH/LAE, CXR w/ cardiac enlargement, cath w/ large V wave (full LA)

Treatment:

· afterload reduction (ACE, nitroprusside)

· digoxin for EF and Afib

· diuretics for volume overload

· anticoagulants for Afib and very low EF

Surgery: valve replacement best if done before EF too low (symptomatic or EF <60% or end-systolic cavity dimension > 45 mm; once EF < 30%, results less favorable); valve repair is better if possible (if chordal continuity can be preserved)

Rupture of (posterior) papillary muscle (must have high index of suspicion) [NEJM]

· new murmur after MI (acute MR is result of ischemia of posteromedial papillary muscle in 80% of cases; likely from PDA infarct)

· murmur peaks in mid-late systole, but usually not holosystolic or short ejection

Treatment: aortic balloon pump; nitroprusside; urgent surgical valve replacement / avoid dobutamine (often makes worse)

Mitral valve prolapse (MVP) and click-murmur syndrome (Barlow’s Syndrome)

redundant valve leaflets prolapse into left atrium during systole / most common cause of isolated severe MR in U.S. / females (14-30 yrs) / familial inheritance (could be AD)

Pathology:

· can be from connective tissue disorders such as OI, ED, Marfan’s) / redundant leaflets (post>ant) and chordae tendinae, calcifications and annular dilation can cause MR

· Others: rheumatic valve disease, cardiomyopathy, CAD, 20% of ostium secundum ASD pts

Presentation: variable chest pain (substernal, prolonged, atypical), palpitations / ?personality changes

Physical Exam: can have click w/ or w/o murmur or murmur w/ or w/o click

increasing LV size (squatting, B-blockers) delays click-murmur, decreasing LV size (valsalva, hand-grip), advances murmur (and also increases intensity of late systolic component)

EKG: usu. normal but can have biphasic or inverted T in II, III and aVF

Treatment: reassurance +/- B-blockers (empirical relief of CP), abx (for endocarditis prevention), anti-arrhythmics (if this is an issue)

Arrhythmias: VT, PVC and PSVT / can get ventricular arrhythmias from regional defects from papillary stress / very rarely causes sudden death

Endocarditis: may need abx prophylaxis if very thickened valves or MR present on echo

TIA: can occur in some pts as a result of endothelial defects (?) / treat accordingly

Tricuspid/Pulmonic

associated w/ other valve disease / drug use and infections of valve

Tricuspid Regurge

Infective endocarditis, RV failure, rheumatic heart disease, RV infarction

Presentation: similar as RV failure

Physical exam: RV lift, holosystolic murmur at LSB (increases with inspiration), large V wave in

JVP [diagram], pulsatile liver

Acute Rheumatic Fever (ARF)

Epidemiology: overcrowded, undernourished areas / occurs 3-4 weeks after Strep A

pharyngitis in a small percentage of untreated cases 3 yrs and up (average age ~8 yrs) / 20% of

patients have 1^st attack in adulthood (50% of 1^st attack involves heart)

Etiology: Strep (A-T) / Strep A has 80 types of M protein (determines if it causes ARF or PSGN)

Mechanism: molecular mimicry (autoimmune reaction) / familial predisposition: alloantigen on b cell (75% vs. 16% controls)

Note: impetigo causing strep do not cause rheumatic fever, but can cause renal disease

Valvular Involvement: (mitral >> aortic > tricuspid) / mitral only (65-70%) / mitral + aortic

(25%) / mitral – regurge then stenosis later / aortic – regurge but no stenosis

Presentation:

· Arthritis: transient migratory polyarthritis / large joints, hot, red, tender, limitation of movement – no residual deformity / symmetric

· Chorea (Sydeham’s): purposeless, involuntary, rapid, emotional lability / can happen 6 months later (as isolated symptom) and is usually transient

· Skin Lesions

o erythema marginatum: pea-sized, extensor surfaces, pink with clear centers, serpiginous margins change from morning to evening – trunk and proximal extremities (never on face)

o subcutaneous nodules: firm, painless, freely moving, extensor surfaces of elbows, knees, spine, occiput

· Acute Rheumatic Carditis (treat with steroids), focal interstitial, diffuse interstitial, direct injury / migratory polyarthritis, erythema marginatum

o Aschoff nodule: exudative, granulomatous with Aschoff (multinuclear) and

o caterpillar/owl-eye cells, (mononuclear), fibrous scar

o Verrucae – vegetations along lines of closure

o MacCallum’s plaques – sub-endocardial lesions, usually in left atrium

o Prolapse: myxoid replacement of leaflets, chordae tendinae may rupture à severe MR, apical systolic murmur MR, apical mid-diastolic murmur (?Corey-Coombs), basal diastolic murmur aortic regurge, change in previous murmur

Diagnosis: must have documented Strep A infection / must have 2 major / 1 major, 2 minor

Major criteria: carditis, arthritis, chorea, erythema marginatum, subcutaneous nodules

Minor criteria: arthralgia, fever, elevated acute phase reactants, ESR, prolonged PR, erythema nodosum other findings: malaise, anemia, epistaxis, precordial pain

Labs: high ESR, leukocytosis, prolonged PR interval, acute phase reactants / ASO positive in 80% (95% by 2 levels) / > 250 for adults / > 333 for children / positive throat culture (may give false positives due to colonization)

Treatment:

Initial: rest until afebrile (up to 2-3 months)

Heart failure: repair/replace valve once activity level impaired from MS; also put patients on coumadin because they are likely to have paroxysmal atrial fibrillation

Chorea: protect from injury / haldol (1^st), chlorpromazine, diazepam, barbiturates

Antibiotics: prophylaxis for 5 years (after 5 yrs secondary prevention on individual basis; indication for ongoing prevention are recurrence, rheumatic heart disease, occupation exposure) / benzathine penicillin G 1.2 IM every 3-4 weeks or penicillin V 250 mg bid / others: sulfadiazine, erythromycin, amoxicillin, cephalosporin, clindamycin

Suppression therapy:

aspirin 100 mg/kg/day QID (taper down with no heart symptoms)

prednisone 2 mg/kg/day for 2 weeks (taper for 2 weeks), then switch to aspirin with

good response (changes clinical course, but not long-term outcome)

Aortic Aneurysm

Causes (same list of causes for aortic dissection): HTN, hereditary fibrillinopathies (Marfan’s, Ehler’s Danlos), hereditary vascular (bicuspid, coarctation), vascular inflammation (GCA, Takayasu’s, RA, Behçet’s, Reiter’s, psoriasis, ankylosing spondylitis, syphilis, Tb, mycotic, Ormond’s), trauma (MVA, fall), iatrogenic (catheterization, aortic surgery)

Cystic medial necrosis: degeneration of collagen and elastic fibers in tunica media and medial layer of aorta / occurs in congenital syndromes (above) / also occurs in pregnant women, HTN, patients with valvular heart disease / predisposes to aortic dissection

Aortic Dissection

Presentation (based on location of dissection):

· sharp or tearing pain (often confused for MI), may radiate to back, may persist for long period of time

· may have unequal pulses in extremities: involves brachiocephalic artery

· AR: involves aortic root and/or pericardial tamponade:

· neurological deficits from cerebral compromise (type A à CVA) or acute peripheral neuropathies (type B à peripheral ischemia)

· hypotension from pericardial tamponade or exsanguination

· MI from coronary occlusion, bowel ischemia (SMA/IMA), ARF (renal arteries)

· Horner’s syndrome: compression of superior cervical ganglion

· SVC syndrome: compression of SVC

Findings: wide pulse pressure (aortic regurge, also seen with sepsis)

Mechanism: may occlude brachiocephalic trunk (right!), common carotid or subclavian (left!), renal arteries, celiac, SMA, IMA, etc [pic]

Classification: Debaky I (both), II (only ascending), III (descending +/- ascending) / Sanford A

(involves ascending), B (does not involve ascending)

Radiography:

CXR: widened aorta (mediastinum)

CT chest with contrast (85% are true medial and are visualized by CT)

MRI

TTE or TEE very important when type A suspected (15% are intimal (non-communicating) and are best diagnosed by TEE

Treatment: must reduce flow velocity as well as BP à 100-120 systolic or as tolerated (must avoid a reflex ↑ HR and flow increase)

· B-blocker then vasodilator (NP or even Ca blocker)

· Labetalol (as single agent)

· Trimethaphan camsylate (can be used without B-blocker à bad for COPD, bradycardia, CHF)

Ascending aorta à emergent surgical repair (90% mortality without surgery)

Descending aorta à observe, control BP (75% survival with medical then surgical management; some conditions like the congenital and inflammatory cases may be more likely to require surgical correction and more aggressive observation; also, if major artery branch occluded or impending occlusion such as spinal or renal arteries)

Ventricular aneurysm

Diskinetics à persistent ST elevation (indefinitely)

Heart failure

Clot à 10-40% of anterior MI develop clot (risk of embolism)

Sustained VT/VF

True aneurysm: rupture not the problem

False aneurysm: partial rupture of heart, lined by pericardium / echo, LV angiogram, MRI –show narrow discrete communication

Abdominal Aortic Aneurysm (AAA)

major cause of death / present in 1.5-3% of adults (5-10% of higher risk pts)

Presentation: abdominal pain, hemodynamic instability from rupture/bleed

Diagnosis: abdominal ultrasound, CT, MRI

Treatment: watch (scan at 3-12 mo intervals) if < 5.5 cm; if > 5.5 cm (or expanding > 0.5 cm/year), can do endovascular or surgical repair (risk of rupture is 5-10%/year > 6 cm but only 1-2% <5 cm)

Prognosis: mortality for elective repair 1-2% / emergent repair 50%

Screening: TNT and IDEAL suggest screening with abdominal all men between 65+ who have ever smoked (even briefly) or others considered at high risk (HTN, CAD/PVD, smoking)

Non -Bacterial Thrombotic Endocarditis (NBTE)

usually secondary to cancer, DIC, renal failure, sepsis / fibrin deposition, nidus / marantic

Infective Endocarditis [NEJM] [NEJM]

Incidence: 1 in 1000 hospital admissions / leading overall à S. aureus (½ of all cases are health-care related now 9/06)

Organisms:

Sub-acute: S. viridans (66%, indolent), HACEK (GNR’s, 5% in children), Candida non-albicans, Coxiella (Q fever), Brucella, Bartonella

Acute: S. aureus (20%), Enterococcus (15%), Pneumococcus (1-3%)

Post-surgical: S. epidermidis, S. aureus, pseudomonas, Candida (5-10%)

Neonates: Group B Strep

Elderly: Streptococcus bovis (5-10%) (clue to underlying GI disease, malignancy), Enterococcus (GU disease or instrumentation)

Immunocompromised, IV drug users (usually involves tricuspid): GNR’s

Others: E. rhusiopathae, Legionella, aspergillus, T. whippelii

Culture-negative endocarditis [table]

Mechanism: time from seeding to endocarditis < 2 wks in 80% of cases

Presentation: fever (90%), new or changing murmur (85%), chest pain, dyspnea, arthralgia, myalgia, headache, malaise

Other Findings: may have hematuria or TIA / commonly presents with acute renal failure from immune complex deposition / Osler nodes (vasculitis in fingers, toe pads) [pic][pic][pic][pic], Roth’s spots (flame shaped with white center, seen in retina [pic]; not directly in blood vessel), Janeway lesions (erythema of palms, soles), splinter hemorrhages, petechiae [pic], splenomegaly (sequestration) and hepatomegaly (congestion) after 2-3 weeks of infection / erythema nodosum is painful (different from rheumatic fever)

Complications: seeding of various organs (e.g., brain, kidney, eyes), vascular occlusion (e.g. myocardial infarction, CVA)

Presentation in children: fever (1^st), Osler and Janeway are rare in children

Diagnosis: [table]

Duke’s major criteria:

1. endocardial involvement: new murmur (not change in murmur) / positive echo

2. isolation of typical organisms from 2 separate cultures or persistently positive

Duke’s minor criteria: these are just some

1. predisposing valvular lesion or IVDA

2. fever

3. vascular or immune-mediated phenomenon (see above)

4. positive blood cultures (not meeting major criteria)

Echocardiography:

· TTE (50% sensitivity, but aorta often not seen well by TTE (you should always speak with the cardiologist who actually read the echo)

· TEE (95% sensitivity) (must not have ongoing upper GI problems, bleeding)

Large vegetations suggests Staph or fungus

Note: please consider TEE (as 1^st test) with high-suspicion of IE with fulminant-type organisms / also TEE can r/o abscesses

Blood cultures (3 in 24 hrs is 95% sensitive; best if each culture is > 2-3 hrs apart; but in interest of getting antibiotics started after cultures, can take 3 cultures over four hours)

Note: 50% of fungal cultures will be negative; lysis centrifugation blood tubes will increase yield with HACEK (usu. grow within 5 days), nutritionally deficient Strep, Histoplasma, Fusobacterium (Candida does not need the help), Bartonella and Proprionibacterium are very slow growing

Labs: elevated ESR, hematuria and anemia are most often seen

Elevated WBC with left shift may or may not be present

CBC, ESR, UA, 4 blood cultures over 48 hrs

Tends to cause false positive RPR, SLE and immune reactants in general

Treatment: always use high-dose antibiotics given IV (see below)

Duration: 4-6 weeks (6 if prolonged illness, relapse, prosthetic valve, other)

Long-term prophylaxis: PO amoxicillin or IV ampicillin/gentamicin

Procedural prophylaxis: PO amoxicillin or IV ampicillin/gentamicin or vanc/gent

Indications for surgery: severe heart failure (failed valve), abscess, fungus, multiple embolic phenomenon, uncontrolled infection (>7 days), prosthetic valve

Note: anticoagulation shown to increase mortality due to hemorrhagic stroke) / use only if necessary for PE/mechanical valve

Note: serial echo’s not helpful because vegetations organize and persists for months/years without late embolization

		Empiric Rx	Definitive Rx
Community	Strep viridans Enterococcus S. aureus S. pneumonia (1-3%)	amp nafcillin nafcillin/AG	Penicillin/ceftriaxone ampicillin/gentamicin nafcillin + 5 days gentamicin
IVDA	S. aureus (95%) S. non-aureus (5%) Pseudomonas	nafcillin/AG nafcillin/AG? nafcillin/AG +/- ceftazidime
Prosthetic valve (early)	S. epidermidis (50%) S. aureus (50%) Pseudomonas (10%) Fungal (5%)	vancomycin + ceftazidime or anti-pseudomonal AG
Prosthetic valve (late)	S. aureus or MRSA Enterococcus S. epidermidis GNR	vancomycin + gentamicin
Crohn’s	S. milleri
Colon Cancer	S. bovis

Austrian syndrome à pneumococcal pneumonia, meningitis, endocarditis (rapidly progressive)

Antibiotic prophylaxis for endocarditis (also see bone surgery)

Give prophylaxis for the following conditions (all are high-risk unless otherwise stated)

· all prosthetic cardiac valves

· previous endocarditis

· surgical systemic pulmonary shunts

· most congenital heart defects (including ductus arteriosis, coarctation, Marfan’s, others; complex defects are at high risk; except isolated secundum ASD and many of those which have been well surgically corrected)

· acquired valve dysfunction (moderate risk)

· hypertrophic cardiomyopathy (HCM) (moderate risk)

· mitral valve prolapse with regurgitation or thickened leaflets (moderate risk)

Low-risk: ASD, post-CABG, AICD or pacemakers, MVP without MR, (surgically repaired ASD, VSD, PDA)

Any procedure with high chance of transient bacteremia

· GI surgeries, biliary tract, ERCP, esophageal sclerotherapy or dilatation

· surgery involving respiratory mucosa or rigid bronchoscopy

· prostate surgery or cystoscopy

· any dental procedure likely to cause bleeding (e.g. dental extraction)

· tonsillectomy & adenoidectomy

Dental and upper respiratory tract:

· amoxicillin 2 g PO or cephalexin 2 g PO or clindamycin 600 mg PO or clarithromycin 500 mg PO 1 hour prior to procedure or ampicillin 2 g IV or clindamycin 600 mg IV (make sure infusion ends 30 minutes prior to procedure)

GI/GU:

· moderate risk à amoxicillin or ampicillin as above / vancomycin 1 g IV if PCN allergic

· high risk à give ampicillin 2 g IV + gentamicin 1.5 mg/kg (up to 120 mg) 30 minutes prior to procedure, followed in 6 hours by ampicillin 2 g IV or amoxicillin 2 g PO / if PCN allergic, give vancomycin 1 g IV + gentamicin 1.5 mg/kg (up to 120 mg)

Other Causes of Cardiac Damage

Tertiary Syphilis

tree barking vessels, aneurysms / valves

SLE

pericarditis, endocarditis / resembles rheumatoid type / Libman-Sachs

valves, granulomas

Ankylosing Spondylitis

fibrotic lesions of aorta

Carcinoid Heart Disease

caused by carcinoid tumors / endocardial thickening impairs tricuspid/pulmonic valves

Calcification of Mitral Ring

common over 70 yrs / may cause insufficiency

Cardiomyopathy [Dilated / Restrictive]

Dilated Cardiomyopathy

Alcohol (most common, reversible)

Coxsackie B

Cocaine (irreversible)

Doxorubicin (irreversible, perhaps glutathione might prevent)

CHF from garden-variety CAD

Post-partum cardiomyopathy (more)

Exposure: cobalt, mercury, lead

Endocrine: thyrotoxicosis, hypothyroid, acromegaly (usually reversible)

Metabolic: Fabry’s (hemi), hypophosphatemia, hypocalcemia, thiamine deficiency (wet Beri-beri),

Hemoglobinopathies: sickle cell, thalassemia

CXR: cardiothoracic ratio ( > 0.6 is abnormal) / heart looks wider on expiration (largest effect) and diastole (max 2 cm change)

Obliterative Cardiomyopathy

calcification, thrombi, macrophages

Restrictive Cardiomyopathy [see restrictive pericarditis]

sarcoidosis, amyloidosis, hemochromatosis, carcinoid, idiopathic eosinophilia, endocardial fibroelastosis, endomyocardial fibrosis (Loeffler’s) / also obliterative agents

Hypertrophic Obstructive (HOCM)

AD defect in contractile proteins leads to concentric hypertrophy of septum

Presentation: sudden death, dyspnea on exertion, syncope (usually occurs after exercise when venous return due to leg muscle contraction abates in the face of continued low TPR leading to woefully inadequate cardiac output)

Findings: bisferiens pulse, systolic ejection murmur

Maneuvers: conditions that shrink the size of the ventricle (valsalva) increase intensity of murmur; handgrip increases afterload and may increase LV volume which has variable effect (usu. decreases intensity of murmur)

Diagnosis: echo

Treatment:

· ß-blocker, Ca-blocker (to relax ventricle, slow HR and allow more filling)

· avoid afterload reducers (similar to AS)

· indications for AICD (multiple trials looked at this and decision is not really based on EP study)

· check all 1^st degree relatives with echo

Post-partum cardiomyopathy

may occur during last trimester or within 6 months of delivery (most often in 1 month before or after) / African-American, age > 30 / 50% will recovery completely (10-20% mortality)

Treatment: same as other cardiomyopathies (except avoid ACE in pregnancy) / avoid future pregnancy due to increased risk of recurrence

Cardiac tumors

Most are mets 10:1 from lung, breast, lymphoma, melanoma

Myxoma

ball valve obstruction of left atrium (tumor plop sound) / most common adult cardiac

tumor / can mimic PAN / can cause syncope

Rhabdomyoma

hamartoma / vacuolated myocytes / spider cells / most common childhood

Sarcoma

malignant / very poor prognosis

Arrhythmias

Bradycardia

Heart block LBBB, RBBB, Hemiblocks

Atrial atrial fibrillation, atrial flutter, SVT, MAT

Ventricular VT, prolonged QT, torsades de pointes

Bradycardia

Sinoatrial node dysfunction or SA nodal dysfunction

Intrinsic

Idiopathic degeneration (most common)

Infarction/ischemia

Infiltrative – sarcoid, amyloid, hemochromatosis

Connective tissue diseases – SLE, RA, scleroderma

Surgical, trauma

Infectious/infiltrative – Chagas, endocarditis

Extrinsic

Autonomic syndromes – neurocardiogenic, carotid sinus hypersensitivity, situational disturbances

Acute HTN

Drugs: B-blockers, ca-blockers, clonidine, digoxin, anti-arrhythmics

Hypothyroidism

Hypothermia (look for J-point elevation or Osborn waves)

Hypercapnia

Acidemia

Electrolyte disturbances

Advanced liver disease

Infectious/bradycariogenic – brucellosis, typhoid fever

Heart Block

Causes (most common) [Ddx]: drugs, CAD, degenerative process / congenital (in children) / others: increased vagal tone, surgery, electrolyte disturbances, myoendocarditis, tumors, rheumatoid nodules, calcific aortic stenosis, myxedema, polymyositis, infiltrative processes (such as amyloid, sarcoid, scleroderma), Chagas disease, lyme disease, many others

Note: there is type I and II for each of the 3 degrees of heart block

type I – above His / more likely to be inferior MI, transient, edema of AVN

type II – His and below / more likely to be anterior MI, permanent, QRS > 0.10

1^st degree heart block – PR interval > 0.21 seconds

Note: can have 1^st degree type II (Lev’s and ?Lenegre’s, which are degenerative diseases of His/Purkinje system that require pacing)

2^nd degree heart block – not all P waves followed by QRS complex

· Type I (Wencheback’s) – cycle (2 to 8) of PR lengthening until beat is dropped / can mimic group beating

· Type II – 2:1 (or 3:1 or 4:1) conduction block / here, the problem is in the bundle of His or branches, and therefore, type II is more likely to progress to 3^rd degree block

Note: new onset Mobitz II or BBB may signal impending MI (probably PDA from RCA)

3^rd degree heart block – complete block / severe bradycardia

not compatible with life in long term / don’t confuse with a non-conducted p wave / will get IJ (40-60) or IV (20-40) pacing / syncope from this is called Stokes-Adams syndrome

Ddx: ischemia, hyperkalemia, hypokalemia, Ca channel blockers, digitalis, B-blockers (rarely), a-blockers (SA node), sick sinus syndrome

Treatment: medication/pacemakers / asymptomatic, intermittent 3^rd degree heart black is class III indication of pacemaker (Lyme disease often reversible, some elderly have >3 sec pauses which are asymptomatic)

Pacemakers (treatment of heart block)

Atropine (½ amp is ½ mg) à start with 0.6 mg atropine

Epinephrine à 0.25 mg (do not give too much)

DA / isoproterenol (avoid with recent or ongoing ischemia)

Transthoracic pacing (A/P pads)

· Synchronous demand à sends pulse if no R wave is seen in time – may need to change sensitivity to avoid background impulses (big P waves)

· Asynchronous à do not do this if they have any inherent pacing (could give you R on T)

Start with rate < intrinsic rate

If no capture à increase current

Get capture then reduce to threshold and then go up to MA of 3 x threshold

DDD senses atrial/ventricular contraction and waits for set PR interval before firing

AV conduction delay

Hypervagotonia (often associated with sinus bradycardia or sinus arrhythmia)

Digitalis

B-Blockers

Ca Channel blockers

Class III antiarrhythmics

CAD

Lenegre’s disease (diffuse fibrosis of the conduction system)

Infiltrative heart disease

Aortic root disease (syphilis, spondylitis)

Calcification of the mitral and/or aortic annulus

Acute infectious disease

Myocarditis

LBBB or Left Bundle Branch Block

^^ in V5 and V6

· check limb leads / QRS > 0.12 / r/o artifactual QRS widening

· cannot rule out MI or LVH in presence of LBBB

· can rule in MI if ST changes > than 5 mm in synchronous leads (meaning T wave going same direction as R)

V1 broad R wave (>30 msec) / onset of R wave to nadir of S wave > 60 msec / notched downstroke in lead V1

V6 QR or QS complex

RBBB or Right Bundle Branch Block

^-^ in V1 and V2

V1 monophasic R wave / biphasic (qR or RS) / triphasic with R > R

V6 R/S ratio < 1

Common causes of BBB

Clinically normal individual

Lenegre’s disease (idiopathic fibrosis of the conduction tissue)

Lev’s disease (calcification of the cardiac skeleton)

Cardiomyopathy

Dilated, Hypertrophic (concentric or asymmetric)

Infiltrative

Tumor, Chagas’ disease, Myxedema, Amyloidosis

Ischemic heart disease

MI (acute/old), CAD

Aortic Stenosis (AS)

Infective endocarditis

Cardiac trauma

Hyperkalemia

Ventricular hypertrophy

Rapid heart rates

Massive PE

Hemiblocks

Watch for intermittent change in QRS axis and/or pattern

½ of LAD infarctions cause ant. hemiblock (also can get RBBB)

Anterior hemiblock

· QRS usu. 0.1 to 0.12

· Q₁S₃

· LAD from late depolarization (r/o inferior MI, LVH, horizontal heart)

Posterior hemiblock

· RAD (r/o lateral MI, RVH, lung disease)

· Normal or wide QRS

· S₁Q₃

Other slow (or no) rhythms

Asystole

PEA (pulseless electrical activity – many causes)

SSS (sick sinus syndrome)

BTS (SSS with intermittent tachycardia)

Tachyarrhythmias

Normal

Atrial foci à 60-80

Junctional foci à 40-60

Ventricular foci à 20-40

Atrial tachycardia à 150-250

Atrial flutter à 250-350

Atrial fibrillation à 350-450

Atrial flutter

Ventricular flutter – rapidly becomes V fib

Ventricular parasystole – simultaneous pacing of A and V

Types of Tachycardias

Regular narrow complex

Sinus, atrial, AV-reentrant, WPW, atrial flutter, junctional tachycardia

Irregular narrow complex

Atrial fibrillation, multifocal atrial tachycardia, atrial flutter with variable block

Wide complex

QRS > 0.12 with normal conduction or > 0.14 with RBB or > 0.16 with LBB

Ventricular tachycardia (VT), Torsades de Pointes (drugs that cause), supraventricular (SVT) with aberrant conduction, hyperkalemia, TCA toxicity

Note: hyperkalemia can cause complete AV block even without widened QRS

Diagnosis and Treatment

Synchronized countershock

Vagal maneuvers

Adenosine

P1 receptors in AV node / given as 6 then 12 mg IV / chest discomfort, transient hypotension / may terminate reentrant tachycardia / SVT may stop then recur / preexcitation tachycardia should not be affected

AV nodal agents

Lidocaine

1 mg/kg bolus, 1-4 mg/min / SE: confusion, seizures

Magnesium

torsades (especially drug-induced) / 1 g MgSO4 given IV

Calcium

membrane stabilization

Atrial Arrhythmias

Atrial Tachycardias (follow links for specifics)

Sinus tachycardia

Sinus node re-entry

Atrial tachycardia

Unifocal / Multifocal

Atrial flutter

Atrial fibrillation

AV Junctional Tachycardia

AV re-entry (WPW)

orthodromic / antidromic

AV nodal re-entry (common)

Non-paroxysmal Junctional (uncommon)

Automatic Junctional Tachycardia (uncommon)

General points

Causes of atrial/junctional irritability

epinephrine

caffeine, amphetamines, cocaine, other B1 agonists

digitalis, toxins, EtOH

hyperthyroidism (direct and sensitization to above)

low O₂ (to some extent)

Atrioventricular Relationship

atrioventricular dissociation

sinus capture beats

fusion beats

Regular atrial arrhythmias

sinus tachyarrhythmia

paroxysmal atrial tachycardia (PAT) (see other)

atrial flutter with constant conduction (see other)

Supraventricular Tachycardia (SVT)

Tachyarrhythmia originating above ventricle (includes PAT, AT, JT, etc.)

may have widened QRS (resembling PVT) – BBB or aberrancy

can try vagal maneuvers 1^st, then meds // Note: do not attempt carotid massage if there is a bruit!!!

Brugada’s Criteria (VT versus SVT with aberrancy)

· absence of RS complex in all precordial leads?

· interval from R to nadir of S > 100 msec in any precordial lead?

· AV dissociation?

· Are there morphology criteria for VT in both V1 & V6? (suggesting BBB)

If yes to any → VT
If no to all → SVT w/ aberrancy

Premature atrial beat (PAB)

P¹looks different / can merge with T-wave

SA pacing will be reset to P¹

Non-conducted PAB may resemble 3^rd degree heart block

Paroxysmal atrial tachycardia (PAT)

PAT with block is typical for digitalis toxicity

Note: Must have AV blocking when controlling SVT’s / do not use only a single class IC agent (e.g. flecainide) to control an atrial tachycardia because you might convert a 240 (A) 120 (V) to a 200/200

Atrial Fibrillation (AF) - Irregular

5% over 60 yrs / 10-15% over 80 yrs

Causes: mitral valve disease, thyrotoxicosis, HTN, CAD, MI, pulmonary embolism, pericarditis / stress, fever, excessive alcohol intake, volume depletion, idiopathic

Prognosis: 60% of new onset AF convert spontaneously within 24 hrs / atrium greater than 4.5 cm and long duration of Afib are more likely to have chronic/relapsing AF

Work-up: TSH, consider PE w/u, more…

Treatment:

Control ventricular response

Rate control: Digoxin, B-blockers, Amiodarone vs. His ablation and pacemaker

o B-blockers reduce relapse (60% à 40%) and when they do relapse, the HR will be lower (may also increase chance of conversion)

o Digoxin – good for rate control (not conversion) / peak action at 90 mins

o Ca channel blockers (verapamil, diltiazem) – for rate control (not conversion)

Cardioversion - immediate DC conversion if hemodynamically unstable

AFFIRM trial suggest no need to cardiovert most patients with chronic Afib; benefit may be seen more with younger, healthier women as well as patients whose heart failure is so severe that NSR would be of major benefit; some studies (PIAF/STAF/RACE) show that rhythm control may actually have worse outcome for elderly, CAD or non-CHF patients / for CHF patients, sometimes amiodarone is the best option (in spite of many side effects) [NEJM]

AF present > 48 hrs or unknown duration

· Plan 1: 10 days (some say 21) anticoagulation therapy à cardioversion à 4 weeks post-anticoagulation

· Plan 2: if no thrombus seen on TEE (85% of cases) à cardioversion 24-48 hrs later à 4 weeks post-anticoagulation [plan 2 has higher initial success rate and lower bleeding events due to shorter duration of anticoagulation, but chance of long-term NSR is same]

Spontaneous cardioversion (50% within 24 hrs)

Direct current (DC) conversion – success rate 90%, low rate of ventricular arrhythmia, premedication before DV conversion has no effect on short term maintenance of NSR

Chemical Cardioversion – variable success (ventricular arrhythmia rate 0-10%)

o Class III/Ia are more dangerous for hypertrophied hearts (prolonged QT and torsades)

o Class I are more dangerous for functionally (ischemic) and anatomically (fibrosis, infiltration) challenged hearts (ventricular tachyarrhythmias)

Examples of efficacy: amiodarone (30%/1 hr, 80%/24 hrs), procainamide (65%/1 hr), quinidine (?), propafenone (90%/1hr), digoxin (50%/1 hr)

If thrombus present (15% of cases): LA appendage > LA cavity (6:1) / 80% will resolve on repeat TEE within 2 months of anticoagulation

Anticoagulation: heparin in short term then coumadin long-term; by 2003, Lovenox still not officially recommended; older patients with chronic or paroxysmal AF without contraindications should receive long-term warfarin (INR 2 to 3). ASA 325 mg/day (20% risk reduction)

Risk of stroke: increased with diabetes, > 65 yrs, HTN, CHF, rheumatic heart disease, prior CVA or TIA, TEE showing spontaneous echo contrast in LA, left atrial atheroma, left atrial appendage velocity < 20 cm/s

Investigational: focal atrial ablation, atrial pacing/defibrillators

Atrial Flutter

saw tooth appearing p waves (look in V₁) with rate 200-350 / usually with 2:1 or 3:1 AV block / similar (but not identical) treatment as atrial fibrillation / atrial flutter is often curable with ablation / 40% with some tachyarrhythmia / also causes thrombus (needs to be anticoagulated like atrial fibrillation)

Wandering Pacemaker – benign

usually benign, mostly in young persons (athletes) / will have more than one p wave morphology

Multifocal atrial tachycardia (MAT)

Associated with COPD, digitalis, theophylline, severe hypokalemia, hypomagnesemia

Must have at least 3 different P wave morphologies on ECG / rate 100-130

can use adenosine to attempt to distinguish from coarse atrial fibrillation

Premature junctional beat (PJB)

May produce aberrant conduction

May produce retrograde (inverted) P¹(SA pacing will be reset to P¹)

Can get junctional bigeminy/trigeminy

Paroxysmal junctional tachycardia (PJT)

may have aberrant conduction (150-250)

Nonparoxysmal junctional tachycardia (NPJT)

may be treated with AV nodal agents, possibly including adenosine

AV nodal re-entrant tachycardia (AVNRT)

circus re-entry (normal impulse goes through AV node, but instead of terminating in ventricle, it goes back up into AV node and loops back around to stimulate ventricle again; hard to distinguish from JT)

Treatment: catheter ablation in young patients (90% success) / drug therapy: ß-blockers, Ca channel blockers, digoxin (be careful in WPW)

Wolf Parkinson White

AV muscle bridge (accessory pathway or Bundle of Kent)

Findings: short PR interval ( < .12 sec) and delta waves

· atrial arrhythmias may carry over to ventricles (loss of AV protection mechanism)

· ventricular tachyarrhythmias from re-entry

Treatment: for sustained VT or VT with hypotension, use DC cardioversion 1^st / avoid AV blocking agents like adenosine, ß-blockers, Ca channel blockers, digoxin which may only worsen arrhythmias by increasing conduction through accessory pathway / can use procainamide, lidocaine, some say ibutilide

Ventricular Arrhythmias

Causes of ventricular irritability

Low O₂

Low K

Adrenergic stimulation (to a lesser extent)

PVC or Premature Ventricular Contraction

· 6/min is pathological / > 3 PVC’s in a row is VT / > 30 seconds is sustained VT

· usually opposite polarity of QRS / enormous complex with QRS much longer than > .14 ms / long pause (does not disrupt sinus pacing, thus there is a punctual, but ineffective P wave)

· may occur in normal, healthy individuals (women > men) (usually disappear after exercise) in which case reassurance is treatment of choice and if needed, can try B-blockers / studies have shown reduction of PVCs (even in post-MI) patients cannot be used as an endpoint on its own (does not improve mortality)

R on T

During vulnerable period (after peak or during downslope of T) / vulnerable period extended by hypoxia / PVCs with R on T are more worrisome for triggering VT

Criteria for wide complex tachycardia

1. AV dissociation (may see fusion or capture beats)

2. QRS width > 0.14 s w/ RBBB, > 0.16 s w/ LBB

3. QRS axis: LAD w/ RBB morphology

4. concordance of QRS in precordial leads

SVT vs. VT

			fusion/capture	extreme RAD	Q in V6
VT	CAD	QRS > 0.14	yes	yes	yes
SVT	uncommon	QRS < 0.14	rare	rare	rare

Note: canon a waves in jugular venous pulsations occur from atria contracting against closed tricuspid valve (only seen with VT/AV dissociation)

Non-sustained ventricular tachycardia (NSVT)

Duration < 30 seconds / yes, it is a signal that something is not right

Treatment: B-blockers and type III drugs (lidocaine)

Ventricular tachycardia (VT)

150-250 bpm

Causes: ischemia, HOCM, AS, long QT

Treatment: ACLS measures (shock, medication), refractory cases (consider LVAD)

Polymorphic VT

Treatment: magnesium + other ACLS measures

Torsades de Pointes (twisting of the points)

ventricular arrhythmia associated with prolonged QT and characteristic EKG pattern / described by Dessertenne in 1966, related to 2 competing ventricular foci and abnormal electrolytes / whites > blacks / females > males

Causes: hypomagnesemia, hypocalcemia, intracranial events, bradyarrhythmias, many drugs (see below)

Course: TdP may either revert to normal or evolve into ventricular fibrillation

Treatment: give magnesium; cardioversion insufficient (must do external ventricular pacing; overdrive pacing will shorten QT interval)

Drugs associated with Torsades de Pointes:

Anti/Pro arrhythmics: amiodarone, sotalol, bretylium, procainamide, propafenone, flecainide, encainide, disopyramide

Antibiotics: fluoroquinolones, ganciclovir, pentamidine, macrolides (e.g. erythromycin, clarithromycin), amphotericin B, itraconazole, ketoconazole, ? fluconazole, co-trimoxazole, indapamide

Protease Inhibitors: amprenavir, indinavir, nelfinavir, ritonavir, saquinavir

Antipsychotics: droperidol, phenothiazines, chlorpromazine, thioridazine, moricizine, haldol

Antidepressants: doxepin, amitriptyline, imipramine

Other: tacrolimus, quinidine, quinine

drugs that I can’t remember what they are: terfenadine, terodiline, astemizole, bepridil, , maprotiline, ibutilide, ketanserin, perhexiline, prenylamine, probucol, sultopride

drugs not commonly prescribed: cocaine, arsenic

Prolonged QT syndromes

Jervell-Lange-Nielsen (JLN)

hereditary deafness and prolonged QT interval / syncope, sudden death

Treatment: B-blockers

Romano-Ward

prolonged QT interval / syncope, sudden death

Leopard syndrome [dermis]

ACLS Guidelines (will supply pic of algorithm here)

· For VF or hypotensive VT shock at 200 then 300 then 360 then 360 then amiodarone 150 mg IV x 1 or lidocaine 1-1.5 mg/kg/IV x 1 / may also be indications for magnesium sulfate or procainamide

Hypothermia

· EKG: J-point elevation or Osborn waves [pic] and QT prolongation

· occurs at temperatures below 30C

Pericardial Disease

[restrictive pericarditis] [cardiac tamponade]

Pericardial effusions

Acute pericarditis

Infectious pericarditis (viral, TB)

Dressler’s syndrome

Uremic pericarditis

Pericardial effusion

serous non-bacterial / some WBCs

fibrinous uremia, rheumatic heart disease

serofibrinous

purulent/suppurative infection

hemorrhagic blood, fibrin, pus, neoplasm

cholesterol rare

chronic adhesive result of fibrinous

constrictive result of purulent or hemorrhagic

Acute Pericarditis

Causes:

Infectious: (see below)

Cardiac: acute MI, post-radiation, postcardiac injury (postpericardiotomy, trauma, Dressler’s, chylopericardium), aortic dissection

Immune: sarcoidosis, SLE, RA, scleroderma (less), rheumatic fever, IBD

Other: uremia, myxedema

Drug induced: procainamide, hydralazine, INH, etc

Malignancy: primary (mesothelioma), metastatic malignancy (lung, breast, melanoma, lymphoma)

Presentation: fever (implies infection) occurs before pain (unlike MI where fever is after pain), 1-2 wks after viral illness / pain may resemble MI, radiate to back, shoulders, arms (less), pain may be pleuritic, altered by postural changes

Physical Exam:

o Pericardial friction rub (50%): monophasic, triphasic (early, late, diastolic) < biphasic / may decrease with onset and increased size of pericardial effusion (but can co-exist with effusion) / distinguish from pleural friction rub by having patient hold breath / rub changes w/ position

o Pericardial Effusion: elevated JVD, pulsus paradoxus, prominent x descent, reduced y descent, peripheral edema, and disproportionate ascites, Kussmaul’s sign (constrictive pericarditis)

Diagnosis:

o ECG: PR ↓, J-point ↑, characteristic ST ↑ à restated: diffuse ST elevation (concave) with T wave inversion occurring temporally after ST resolution (unlike MI), PR depression / also ST-elevation to T-wave amplitude in V₆ > 0.24 is very suggestive [pic]

o Radiographic: pleural effusion [pic] in constrictive pericarditis, calcified pericardium (50%), enlargement of cardiac silhouette (with pericardial effusion > 250 ml) [pic] / CT or MRI may reveal thickened pericardium / other studies include left/right heart catheterization and fluid challenge

Labs: mild elevated WBC, ESR

Complications: cardiac tamponade, arrhythmias (resting tachycardia, atrial fibrillation)

Treatment: avoid anticoagulation!!! (may bleed causing hemopericardium/tamponade) / NSAIDs 1^st line (e.g. indocin 25-50 tid until 1 week after Sx resolve) / steroids 2^nd line (20-60 mg P qd) / prolonged/relapse may require colchicine 1 mg/d and/or pericardiectomy to prevent constrictive pericarditis

Prognosis: most cases improve in 2-3 weeks

Infectious Pericarditis:

Viral: coxsackie A/B, echovirus, adenovirus, mumps, influenza, EBV, VZV, CMV, HSV,

HBV(really?)

Bacterial: 30% mortality / antibiotics and drainage, not steroids

Organisms: S. pneumo and other strep, S. aureus, N. meningitidis and gonorrhea, H.

influenzae, Enterobacteriaceae, Campylobacter, Brucella, Actinomyces, Nocardia, Listeria, M. pneumoniae, Legionella, Chlamydia, Borrelia, M. tuberculosis, MAI

1. contiguous spread from chest infection (outside heart or endocarditis) or (peri or post) trauma/surgery

2. bacterial pericarditis from contiguous pneumonia usually occurs only after prolonged, untreated infection

Fungus (most of them)

Parasites: Toxoplasma, E. histolytica, Schistosomes

Viral pericarditis

friction rub – LLS border / more w/ leaning forward / pain come and goes / diffuse ST elevation / normalized by 1-2 days, then T inversion

TB pericarditis

5 to 10% of acute pericarditis / 1% of pulmonary Tb / serous (20%) or serosanguinous (80%)

hematogenous or contiguous / granulomatous (Langerhans cells)

Effusate: high protein, high PMNs early, high lymphocytes later

Complications: constrictive pericarditis (may be predicted by elevated adenosine deaminase), pericardial calcification, myocarditis, dissemination

Treatment: HRZE for 8 weeks then INH/rifampin / some evidence favors steroids / pericardiectomy recommended for pericardial thickening (over ½ will have some procedure)

Note: 2.6:1 odds that patient will have AIDS, 6:1 if disseminated Tb

Dressler’s syndrome

Presentation: pleuritis, malaise, CP occurring 1-4 weeks to months after MI

Findings: pleural/pericardial effusions, fever (up to 40c), leukocytosis, elevated ESR

Note: may consider biopsy of heart muscle to rule out ongoing inflammation

Treatment: NSAIDs (1^st) / steroids (2^nd)

Course: autoimmune process which may relapse up to 2 yrs later

Uremic pericarditis

often hemorrhagic / avoid anticoagulation

Constrictive pericarditis

thickened, fibrotic adherent sac, impaired diastolic filling

Causes: radiation-induced pericarditis > cardiac surgery, any other acute pericarditis

Presentation: progressive weakness, fatigue, exertional dyspnea (all signs of right-sided heart failure, liver congestion) / often presents long after initial insult (~10 yrs)

Exam: Kussmaul’s sign (increase in JVP during inspiration; rather than decreased), pericardial knock (high-pitched early diastolic just after aortic valve closure), no pulsus paradoxus

Diagnosis:

· MRI is test of choice: show pericardial thickening (> 4 mm), to moderate biatrial enlargement, normal ventricular dimensions, dilated venae cavae

· CXR may show cardiomegaly and calcified pericardium

· cardiac catheterization confirms hemodynamic constriction

· echo with doppler may show constrictive flow pattern

· TEE may show pericardial thickening (not 1^st line test)

Treatment: pericardiotomy (outcome based on pericardial substrate and severity of heart failure)

Restrictive pericarditis

Presentation: similar to constrictive only now we’re talking about infiltration: amyloidosis > cardiac surgery, radiation therapy (in Africa, endomyocardial fibrosis with eosinophilia much more common)

Exam: Kussmaul’s sign absent (why?)

Diagnosis: as with constrictive, but MRI and/or endomyocardial biopsy may be needed to distinguish

Treatment: treat underlying disorder (as much as possible)

Cardiac Tamponade – life-threatening emergency

Definition: pericardial pressure ≥ RA pressure / equalization of pressure in the four chambers during diastole / pericardium can accommodate from 200 to 2000 mL depending on acuteness of situation

Presentation: SOB from reduced cardiac output, pleuritic CP from stretch of pericardium

· Beck’s Triad: hypotension, elevated JVP, small quiet heart

Exam: narrow pulse pressures, pulsus paradoxus (drop > 10 mmHg in systolic BP on inspiration; some is physiologic, but not > 10 mmHg) (LA unable to expand so blood pools in lungs as opposed to going into aorta where it would maintain BP), tachycardia, ↑ JVP (but Kussmaul’s sign usu. absent), ↓ carotid volume 2^o ↓ CO, lung exam clear (Eà A L mid lung 2^o compression of lung by heart), cannot palpate PMI, distant heart sounds

EKG: electrical alternans 2^o swinging heart during respiration

Treatment: relieve tamponade with paracardiocentesis

Note: preload is badly needed à preload reducers are contraindicated (diuretics, nitrates, etc.)

Myocarditis [NEJM] [NEJM]

Infections: [table]

Viral (10-30%) (Enterovirus > Adenovirus, HIV?)

Chagas disease (Trypanosoma cruzi) (20% develop CHF)

Drugs: Doxorubicin, Anthracyclines + anti-HER2, Cocaine

Autoimmune:

Idiopathic giant cell myocarditis (affects healthy, young people)

Allergic myocarditis (eosinophilia)

Other autoimmune: polymyositis, scleroderma, SLE

Diagnosis: EKG likely same as pericarditis (diffuse ST elevations) / Dallas criteria, endomyocardial biopsy (gold standard, but often inconclusive and carries 0.25% mortality) / cardiac MRI probably most helpful (90% specificity in diagnosing lymphocytic myocarditis) / echo DIP / cardiac markers non-specific and levels do not correlate with severity of inflammation

Treatment:

· Arrhythmias: probably good idea to push low dose b-block or stronger as needed / be careful with digoxin (only use low doses, may worsen inflammation)

o consider transfer to hospital equipped with LV assist devices in case of rapid heart failure

· bed rest (exercise shown to increase viral replication and worsen outcomes; rest for at least a week? 3^rd leading cause of sudden cardiac death in athletes), eliminate unnecessary meds (esp. with eosinophilia)

· avoid anticoagulation (as much as can in case of hemorrhage into pericardium)

· treat underlying cause / immunosuppression for autoimmune diseases (including giant cell myocarditis) but not helpful for infectious or post-infectious / INF-a currently under investigation for viral myocarditis

Fiedler’s (young adults)

Vascular Diseases (see other)

Berry aneurysms

A/V fistula (circoid aneurysm)

Subclavian steal syndrome

Occluded subclavian artery (usually on the left) leads to collateral perfusion of shoulder joint from vertebral artery / symptoms are intermittent arm claudication and syncope and/or ataxia, confusion, vertigo, dysarthria from exercise-induced decreased vertebrobasilar perfusion leading to Treatment: bypass

Cervical rib

May impair blood flow through subclavian artery / Treatment is resection of rib

Cardiac Transplant

survival 76% at 3 yrs / transplant half-life ~9.3 yrs / chronic cardiac transplant rejection manifests as CAD with characteristic long, diffuse, concentric stenosis / only definitive therapy is retransplant

Oncology

General: markers, associations, tumor biology, patterns of spread, BMT, neutropenic fever

Leukemia / Lymphoma

Lung Liver GI Endocrine Skin Renal Brain

Male (Prostate) / Female (Breast, Ovary)

· Huge list of chemotherapy protocols

Tumor markers

CA-125 ovarian

CA-15-3

CEA colon, pancreas, gastric, breast

CA-19-9 pancreas

Bombesin neuroblastoma, small cell carcinoma, gastric, pancreas

S-100 melanoma, neural tumors

A-FP HCC, yolk sac tumor (NSGCT) / also B-hCG, a1-AT

B-hCG choriocarcinoma

PSA prostate

Tumor Associations

Visceral malignancy [dermis]

acanthosis nigricans, dermatomyositis, flushing, acquired icthyosis, thrombophlebitis migrans

Intrathoracic tumors (lung cancer)

clubbing of fingers

Hamartomas

Cowden’s, breast, intestinal, TS, skin, cardiac

Lymphoma

minimal change disease, HSP, GCA, granulomatous angiitis of CNS

HBV, HCV – HCC

PAN – hairy cell leukemia

Wegener’s – Hodgkin’s disease

Specific Syndromes

Tuberous sclerosis

astrocytoma, cardiac rhabdomyoma (facial angiofibroma, SZ, retardation)

Plummer-Vinson Syndrome

SCC of esophagus (atrophic glossitis, upper esophageal webs, iron deficiency anemia, women)

Muir-Torre syndrome

Sebaceous tumors associated with visceral neoplasms

AD / Colon CA / Increased risk for breast/thyroid CA

Cowden Disease (Multiple Hamartoma Syndrome) [pic][pic]

AD / cobblestoning of oral mucosa (trichilemmomas) / breast, thyroid, uterine, brain tumors / also have multiple small hamartomatous polyps in GI tract (not considered premalignant)

Peutz-Jeghers, FAP

Paraneoplastic Pemphigus Syndrome (see derm)

Lynch syndrome includes hereditary nonpolyposis colon cancer syndrome

Tumor Biology invasion/growth factors, tumor suppressors, carcinogens, radiation, viral

Tumor Invasion

use plasmin, type IV collagenase, etc.

growth factors, angiogenics

cleavage products PDGF, V-sis, EGF, CSF-1

protein kinases

membrane receptors c-erb-B2 (breast, ovarian, gastric), c-neu, c-fms

cytoplasmic receptors c-src, v-src / tyrosine kinase P-vinculin

G-proteins h-ras, k-ras, n-ras

nuclear proteins c-jun, c-fos, c-myb (transcription factors), c-myc (many cancers), l-myc (SCC lung), bcl-2 (lymphomas), ret (MEN)

BM type IV collagen, laminin / bind to and secrete laminin

ECM type I collagen, fibronectin / bind to fibronectin

platelet covered tumor thrombi / NK cells may destroy tumor cells

activation

point mutation (ras) / translocation (c-myc)

gene amplification (n-myc - neuroblastoma, c-neu - breast cancer)

Tumor Suppressors

Rb retinoblastoma

p53 colon, liver, breast

Wt Wilm’s tumor (children)

VHL renal cell carcinoma

APC colon

BRCA-2 breast

BRCA-1 breast, ovarian

NF-1 neurofibroma

NF-2 neurofibroma type II (acoustic)

DCC colon, stomach

DPC pancreatic

Carcinogens

alkylating agents

polycyclic aromatic hydrocarbons (tobacco combustion, smoked meats)

· tobacco increases risk of lung, bladder, esophageal and head and neck cancer

aromatic amines, azo dyes (butter, cherries)

natural (aspergillus flavus in grains, peanuts)

nitrosamines, amides (GI cancer)

asbestos, vinyl chloride, arsenic, insecticides

Radiation

UV UVB (xeroderma pigmentosum)

ionizing leukemia, thyroid, breast, lung, salivary (NOT skin, bone, GI) / ataxia telangiectasia

DNA repair XP, AT, Fanconi’s anemia, Bloom’s syndrome

Viral

HPV, EBV (nasopharyngeal, Burkitt’s), HBV (HCC), HTLV-1 (RNA gives T-cell leukemia), HHV-8 (Kaposi’s sarcoma)

Patterns of Tumor Spread

Elevated LDH or B2-microglobulin levels in lymphomas increase likelihood of CNS mets

Solid Tumors that spread to bone (including spinal mets)

thyroid, prostate, breast, melanoma, lung / (multiple myeloma, leukemias, etc.)

Solid Tumors that spread to brain

bronchogenic carcinoma > breast > melanoma > renal cell carcinoma > colon, lymphoma

Tumors associated with hypercoagulability

lung, pancreas, stomach, colon > prostate, ovary >>> breast, brain, kidney, lymphoma

Trousseau’s syndrome usu. pancreatic or other GI

Hepatic or portal vein thrombosis myeloproliferative disorders (PNH, PRV, essential

thrombocythemia)

Tumors of fibrous tissue

Fibroma most common in ovaries

Fibrosarcoma lower extremities (45%) > upper extremities (15%) > trunk > head,

neck

benign fibrous histiocytoma cutis or subcutis / extremities

malignant fibrous histiocytoma

storiform/pleomorphic (worse) > myxoid, inflammatory / mets mostly to lungs (hematogenously)

Treatment: surgical +/- chemotherapy/radiation adjuvant or palliative

Fibromatoses

relapse but do not metastasize / palmer pattern causes Depuytren’s contracture (50% bilateral) / penile fibromatosis causes Peyronie’s disease (Bill Clinton)

Fibromuscular Dysplasia [pic]

can compress vasculature mimicking various vasculitides or vaso-occlusive diseases

Tumors of adipose tissue

lipoma most common soft tissue tumor / mostly subcutaneous, upper half of body

liposarcoma 2nd most common adult soft tissue sarcoma / well-differentiated, myxoid (low grade) / round cell, pleomorphic, dedifferentiated (high grade) / retroperitoneum, thigh, perirenal, mesenteric fat, shoulder

Tumors of smooth muscle

leiomyoma female genital tract / can occur elsewhere, can be painful

leiomyosarcoma larger, softer, hemorrhage, necrosis, metastases

Other tumors

synovial sarcoma may recur and metastasize

granular cell tumor benign

Cancer with Unknown Primary

· Usu. > 60 yrs / median survival 4-11 months (best hope is for cancer to be a nearby met from treatable solitary tumor)

· CUPS syndrome (biopsy proven malignancy with path not c/w primary tumor + unrevealing workup)

· adenocarcinoma > poorly differentiated carcinoma

· pancreas, breast, colon, prostate, lung

· 2% of all cancer diagnoses / 5% of newly diagnosed mets are unknown primary

· work-up based on findings, consideration of patient’s life-expectancy (usually 6 months), and then consider whether certain tests will change management / abdominal CT, CXR, occult blood (why do colonoscopy or ERCP if no symptoms), PSA (very different treatment), aFP, B-HCG

o extragonadal germ cell syndrome: < 50 yrs, midline structures, parenchymal lymph nodes, lung, elevated aFP or B-HCG, rapid growth / cisplatin-based chemotherapy offers 20% chance of cure

· PET scans may identify primary site but have not been shown to increase survival

Tumor Fever

can try NSAID’s (thought to reduce fever caused by many ?solid tumors) / often used as a diagnostic/therapeutic tool

Cancer Chemotherapy Theory

· Gompertzian kinetics suggests benefits of adjuvant chemotherapy to treat micromets

· Combination chemotherapy for maximum cell kill, broader range of kill, slows emergence of resistance

· Choose – some action as single agent / non-overlapping / optimal dose and schedule

NOTE: up to 25% of patients treated with chemotherapy will develop secondary chemo-related tumor by 25 years

alkylating agents leukemias with deletions of chromosome 5 or 7 (peak 4 to 6 years)

topoisomerase II leukemias with deletions (e.g. 11q23) (peak 1 to 3 years)

Irradiation

Many uses (find listed under various diseases)

Mediastinal irradiation: acute or chronic pericarditis (mean onset 9 months; can manifest years later), myocardial fibrosis, accelerated atherosclerosis

Renal

Renal Studies / Proteinuria / Hematuria [Electrolytes]

Acute Renal Failure (ARF)

drug-Induced, TLS, rhabdomyolysis, hepatorenal

Chronic Renal Failure (CRF)

Nephritic Glomerulopathies

PSGN, IgA nephropathy, RPGN, ANCA, GBM, Cryoglobulinemia

Nephrotic Glomerulopathies

minimal change, FSGS, MGN, MPGN

Renal-Systemic HTN, DM, amyloidosis, MM, Gout, SLE, PAN, Wegener’s, scleroderma

Tubular Disease ATN, RTA, Bartter’s

Renal Thromboembolic DIC, HUS, TTP, HSP, Endocarditis, CES, Alport’s

Interstitial Nephritis analgesic, acute, Balkan, xanthogranulomatis

Renal Other renal stones , hydronephrosis, mechanical, hypertension, RAS

Renal Malformations anomalies of position, differentiation, APKD

Renal Transplantation

Renal Neoplasms

Dialysis

Renal Physiology Tidbits [nephron]

Clearance and GFR

normal kidney can clear 20 L/day

FeNa – U_Na x Ser_Cr / Ser_Na x U_Cr

GFR = (U_Cr x Ur vol) / (P_Cr x time)

BUN can rise much faster than Cr [40/2 is pre-renal / 20/4 is renal]

Note: decreased flow in tubules allows back diffusion of urea (but not creatinine)

GFR = [(140 – Age)(Wt)] / [(Cr)(72) x 0.85 (for women)]

ATII constricts efferent arteriole à increases GFR and glomerular pressure

Afferent constriction (influx of extracellular Ca – affected by Ca channel blockers)

Efferent constriction (influx intracellular Ca – not affected by Ca channel blockers)

Normal protein loss:

Men – 15-20 mg/kg/day lean body mass – 50 +/- 2.3 x inches over/under 60

Women – 10-15 mg/kg/day lean body mass – 45.5 +/- inches over/under 60

Renal Studies

Renal Ultrasound

ARF: number, size, shape, hydronephrosis/hydroureter (10%-20% smaller by U/S than IVP), can sometimes detect renal stones, abdominal aneurysms, and renal vein thrombosis

Large kidneys: multiple myeloma, amyloidosis, early DM, HIV nephropathy, pyelonephritis

Evaluation of renal artery flow (can also get MRI/MRA of renal arteries)

Abdominal CT

Can diagnose hydronephrosis, 1^st line (after KUB) for evaluation of renal stones, determine if cystic masses (benign or malignant)

Intravenous Pyelography (IVP)

Can provide information about kidney ultrastructure (size, shape, mass) and function (obstruction) / CT can do most of the same things

Retrograde pyelography

inject contrast during cystoscopy (only perform after intravenous urography) / used when urography does not visualize kidneys and collecting system and obstruction is suspected

Isotopic flow scans (eh…)

ARF: marginally useful for renal perfusion (DTPA) and obstructive uropathy / hippurate for assessing tubular function

Useful for evaluating renal allograft function

Renal Biopsy

When cause of nephrotic syndrome is sought

acute inflammatory lesion requiring cytotoxic therapy

Note: wire-loop lesions or sub-endothelial deposits are not disease specific / huge sub-endothelial deposit may resemble a thrombus

Cystoscopy

For urethral obstruction (always) and ureteral obstruction (sometimes)

Urinalysis

Color

Blood

Glucose

Ketones

Protein

Bilirubin

Urine pH

Concentration

Sediment

Crystals

Cells [pic]

Bacteria

Casts RBC casts – glomerulonephritis [pic]

WBC casts – glomerulonephritis [pic]

Muddy brown casts – ATN

Hyaline casts [pic]

Fatty casts [pic]

24 Hr Urine

average daily Cr production in men is 16 to 25 mg/kg (women 15 to 20 mg/kg) / 24 hr sample should have this amount of creatinine (otherwise it is an inadequate sample)

Drugs that alter serum creatinine reading

Interfere with tubular secretion

Trimethoprim, cimetidine, probenecid, triamterene, amiloride, spironolactone

Interfere with lab measurement

ascorbic acid, cephalosporins, flucytosine, levodopa, methyldopa

Non-renal causes of elevated BUN

GI bleeding

catabolic effect: tetracycline, steroids

Proteinuria

> 30 mg/24 hrs albumin excretion is considered abnormal (microalbuminuria)
> 300 mg/24 hrs is nephrotic range proteinuria
urine dipstick can detect if more than 500 mg/day / > 90% sensitivity/specificity but doesn’t account for variations in urine creatinine
spot albumin/creatinine ratio > 30 mg/g creatinine is considered microalbuminuria / > 95% sensitive, specific

Transient increased proteinuria (albuminuria): exercise, short-term hyperglycemia, urinary tract infections, marked hypertension, heart failure, and acute febrile illness
False positive: menstrual bleeding in women
Note: dietary protein intake does not cause microalbuminuria, but patients with diabetic nephropathy are advised to take low protein diet (0.6g/kg/d)

Nephrotic Syndrome

Primary: ⅓ Secondary: ⅔ of cases

· Proteinuria (normally prevented by large size, net negative charge)

· Edema (from salt retention)

· Hypoalbuminemia

· Hyperlipidemia (decreased oncotic pressures triggers liver to produce lipoproteins)

↑ LDL, lipoprotein-A / causes atherosclerosis

· Hypercoagulable state (↓ATIII, protein C/S)

· Vitamin D deficiency (loss of Vitamin D binding protein)

· Iron deficiency anemia (loss of transferring)

· Hypogammaglobulinemia (increased susceptibility to bacterial infection)

Diagnosis:

· Urinalysis: urine dipsticks (albumin only) and sulfosalicylic acid precipitation (albumin, paraproteins, immunoglobulins, and amyloid)

· 24-hour urine for protein (better for low urine output) / urine protein electrophoresis / serum lipids / lipiduria is suggested by oval fat bodies on microscopic study

· Biopsy (if no obvious cause and significant proteinuria) / EM, IF, special stains (e.g., Congo red for amyloid)

Treatment:

· Control blood pressure: this is the most important thing, more than ACE even, goal is to use MAP of 80-100? (too low is also bad)

· ACE inhibitors or ARB’s (decrease proteinuria, reduce progression; also, low protein diet helps reduce amount and toxicity of proteinuria)

· Diuretics (for overload): reasonable goal is 0.5 – 1 L/day (usually need Lasix (+) to achieve; go slowly; do not volume deplete; note: because HCTZ and Lasix are highly protein bound, there is reduced delivery to kidneys and large doses are often required to get same effect)

· Control hyperlipidemia: dietary changes + statins / this is not optional, these patients must be on statins (note: lipoprotein-a elevations unresponsive to statins)

· Note: calcium channel blockers worsen proteinuria by decreasing afferent > efferent thus raising intraglomerular pressure

Prognosis: usually takes 5-10 to go from microalbuminuria to overt nephropathy; then 5-15 years to reach ESRD; once ESRD, dialysis patient have average life expectancy of 2 years.

Orthostatic proteinuria

Only happens when patient has been standing (so use nocturnal urine collection in patients who exercise vigorously) / remain constant at about 0.5-2.5 g/24 hr

Treatment: none required / excellent prognosis

Tubulointerstitial nephritis

Albumin, Tamm-Horsfall protein and B₂-microglobulin

drug-induced disease, chronic inflammatory disease (e.g., sarcoidosis), analgesic nephropathy

Treatment: remove offending agent / treat underlying disease

Renal Vein Thrombosis (RVT) (lots of proteinuria)

Causes:

· Nephrotic syndrome

· Renal cell carcinoma with renal vein invasion

· Pregnancy or estrogen therapy

· Volume depletion (especially in infants)

· Extrinsic compression (lymph nodes, tumor, retroperitoneal fibrosis, aortic aneurysm)

Presentation: nausea, vomiting, flank pain, hematuria, leukocytosis, renal function compromise, and an increase in renal size

Note: adult nephrotic patients (chronic RVT) can be more subtle (big increase in proteinuria or tubular dysfunction such as glycosuria, aminoaciduria, phosphaturia, and impaired urinary acidification)

Diagnosis: MRI/MRV (1^st) or CT or selective renal venography (U/S and IVP are sometimes okay)

Treatment: 1 yr anticoagulation (some advocate thrombolysis if very acute)

Hematuria

Normal excretion of 500,000-2,000,000 RBC/24 hr (< 3 RBC per HPF)

Isolated Hematuria à stones, trauma, prostate > tumor (15%), Tb

Causes and microscopic findings:

Intrarenal

trauma, renal stones, GN, infection (pyelonephritis), neoplasia (RCC), vascular (renal thrombosis)

Extrarenal

trauma (Foley), infection (urethritis, prostatitis, cystitis), ureteral stones, neoplasia (prostate, bladder)

Glomerulonephritis	Gross or microscopic hematuria, abnormal proteinuria, red blood cell casts / dysmorphic red cells on phase-contrast LM
Diffuse (SLE, vasculitis) Focal (IgA nephritis)	gross or microscopic hematuria without proteinuria, thin basement membrane / dysmorphic red cells
Vascular disease	Gross or microscopic hematuria without proteinuria isomorphic red cells
Tumors (hypernephroma)	Isomorphic red cells
Trauma, kidney stones, systemic coagulopathies	Isomorphic red cells

Diagnosis:

· Dipstick (hemoglobinuria vs. myoglobinuria) / positive heme (orthotolidine test) and no RBC’s suggests pigmenturia / red urine without hemoglobin or RBC’s is rare (beeturia, porphyria)

· Urine culture

· IVP for renal masses, cysts, AVM, papillary necrosis, ureteral stricture or obstruction by calculus, bladder tumor, and ureteral deviation / other: angiography and nuclear scans (rarely used to delineate mass lesions)

· MRI/CT (mass effects, surrounding structures)

· Cystoscopy (when other tests non revealing)

· Biopsy (sometimes needed)

Complications: iron deficiency anemia (only with chronic, significant hematuria) / obstruction from lower urinary tract clots

Treatment: identify/treat underlying disorder / maintain urine volume to prevent clots/obstructions in the lower urinary tract

Acute Renal Failure (ARF) (see drug-induced ARF) (ARF in AIDS)

Incidence: 5% of all hospitalized patients / 10-30% in patients in critical care units

General: sudden, rapid, potentially reversible renal failure causing nitrogenous waste accumulation

GFR of 10-15% /Cr not always reliable marker for GFR / usually 0.5 to 1.0 mg/dl/day increase in Ser Cr, > 1 mg/dl/day suggests obstruction or rhabdo/tumor lysis syndrome

Pre-Renal (30-60%)

volume depletion, ↓ perfusion, renal artery obstruction

· FeNa <1%, U_Na <20 mEq/L (this is the most useful of these in that if elevated, pre-renal is unlikely)

Renal Parenchyma (20-40%)

ATN: ischemia, toxins, pigments

Nephrotoxicity

Intrinsic: GN, TIN, vasculitis (HUS/TTP)

Systemic: atheroembolic syndrome, scleroderma, malignant HTN

· ATN, TIN à FeNa >1%, U_Na >20 mEq/L (tubules broken, so can’t retain Na)

· GN à FeNa <1% (unreliable), U_Na variable (kidneys try to retain Na)

Post Renal (1-10%)

Obstruction: tubular, pelvic, ureteropelvic, ureteral, bladder

Drugs: antihistamines, TCA

· Early à FeNa <1%, U_Na <20 mEq/L (due to intense vasoconstriction)

· Late à / FeNa >1%, U_Na >20 mEq/L

Diagnosis:

Azotemia

Rising BUN and serum creatinine (can be asymptomatic) / BUN reflects dietary intake, protein breakdown and resorption of GI or soft-tissue hemorrhage / creatinine reflects muscle breakdown (rhabdomyolysis, steroids, tetracycline), renal secretion (blocked by drugs like cimetidine and trimethoprim), chromogens (usually drugs) can cause measurement errors.

Urine Output

Anuria (< 100 ml/day) usually worse prognosis

Oliguria (< 400 ml/day) (most ARF patients)

Polyuria (> 800 ml/day) (25%-50%) (common with partial obstruction)

H/P

surgical, IV contrast, meds, allergies, chronic disease, FHx, signs of volume depletion, CHF

acute allergic interstitial nephritis: periorbital edema, eosinophilia, maculopapular rash, and wheezing

obstruction: suprapubic or flank mass, symptoms of bladder dysfunction

Uremic syndrome: nausea, lethargy, pruritis, pericarditis, uremic frost (skin), asterixis, uremic fetor (breath), platelet dysfunction

Note: uremic pruritis responds well to UVB radiation

Urinalysis

Only hyaline casts: pre-renal or post-renal

RBC: calculi, trauma, infection, or tumor

WBC: infection, immune-mediated inflammation, or allergic reaction

Eosinophiluria: 95% of acute allergic interstitial nephritis (Hansel’s stain tells E from PMN)

Pigmented casts and > tubular epithelial cells in 75% of ATN (casts without RBC’s à hemoglobinuria or myoglobinuria)

RBC casts: acute glomerulonephritis

Urine culture

Chemistries: FeNa < 1 suggests not ATN more than it actually proves pre-renal (exceptions: ARF from rhabdomyolysis and IV contrast are notably associated with FeNa < 1) / BUN/Cr > 20

Radiography:

Most useful: renal U/S >> AXR, cystoscopy

Less useful: isotopic flow scans, abdominal CT, biopsy

Course: azotemic, diuretic, recovery

Oliguric (50% mortality): more GI bleeds, sepsis, metabolic acidosis and CNS abnormalities

Nonoliguric: 26% mortality

Prognosis

60% mortality when surgery/trauma, 30% when medical illness, 10%-15% when pregnancy

Ischemic ATN has two times higher mortality over nephrotoxic ATN

Complete recovery in 90% if no complications

Treatment:

Correct: obstruction, nephrotoxic drugs, infections, electrolytes

Optimize intravascular volume and cardiac performance (can maintain output with Lasix)

Note: mannitol does not help, Lasix may increase urine output (but is more likely to decrease renal perfusion than help kidney recovery, it merely indicates less severe ARF)

Investigational: selective D1 agonists (renal dose dopamine is BS), Ca channel blockers (to increase renal perfusion), IGF-1 (may speed recovery of renal function)

Fluid/Electrolytes

I/O’s sensible losses (urine, stool, NG, other tubes) and insensible (400-500 ml/day)

sodium and potassium

Sodium bicarbonate if serum bicarbonate < 16 mEq/L

Oral phosphate-binding antacids (Al³⁺OH₃) if serum phosphate > 6.0 mg/dl

No Mg containing drugs

Diet: lose 300 mg body weight daily with ARF, wt gain or stability usually means Na and water retention / give 40-60 g/day total protein and 35-50 kcal/kg lean body weight / up to 1.25 g of protein/kg with severe catabolism

Drugs: careful adjustment of drug doses (serum creatinine cannot be used to calculate doses because ARF causes a 1.0 mg/dl/day increase in serum creatinine, so cannot calculate appropriate drug doses)

Dialysis, CAVH, CVVH

Complications:

volume overload

hyperkalemia ( > 6.5 or EKG changes is an emergency)

hyponatremia, hyperphosphatemia, acidemia, hyperuricemia

hypocalcemia (decreased D-1,25, hyperphosphatemia, hypoalbuminemia)

hypercalcemia (rarely follows rhabdomyolysis)

bleeding (uremia/DIC), seizures (uremia)

chronic renal failure (10% show decreased renal function for months, pre-existing renal disease will likely progress to CRF)

ARF in AIDS patients (one study)

Causes: ATN/Sepsis, HUS/TTP (TMA-like) > HIV meds (indinavir) > rhabdomyolysis (from IVDA) > lymphoma > HIVAN (13:1 M:F, avg. 8 months of HIV) > HBV/HCV > SLE-like

Tumor Lysis Syndrome

esp. important with lymphoproliferative malignancies; usually 1-3 after starting chemo but may occur spontaneously (Burkitt’s, acute B-cell lymphoblastic leukemia)

Risk factors: large tumor burden, high LDH, not being on allopurinol

Mechanism: CaPO₄ deposition (see rhabdomyolysis) / uric acid damages renal tubules

Labs:

· urinary uric acid:urinary creatinine ratio > 1 (normal < 0.60-0.75) supports uric acid nephropathy (higher than in rhabdo where urate is elevated but itself does not cause nephropathy)

· PO₄usu. elevated but may not be in spontaneous TLS (because tumor cells can incorporate it)

· ↑ lactic acid, ↑K, ↓Ca

Treatment: volume repletion / consider dialysis when uric acid reaches 15-20 / can also give uricase to metabolize uric acid to allantoins (should have already given allopurinol) / phosphate binders can be given / alkalinization of urine not proven to prevent tubular damage from urate crystals (may increase CaPO₄ precipitation as well and further decrease Ca levels)

Rhabdomyolysis (see other)

Atheroembolic Syndrome (see cardiac)

cause of renal failure

Hepatorenal failure (see liver)

Note: almost never see without CNS signs

Drug-Induced Nephrotoxicity

Prerenal

Renal

Postrenal

Drug-induced acid/base abnormalities

20% of ARF is drug-related

Prerenal (due to drug effect)

↑ serum Cr at least 0.5 mg/dL over 24 hours / FeNa < 1%, Uosm > 500, benign sediment

Causes:

diuretics, NSAIDs, ACE inhibitors, IV contrast, tacrolimus à vasoconstriction

IL-2 à volume depletion from capillary leak

cyclosporine à vasoconstriction of afferent/efferent arterioles decreases GFR

mannitol > 300 g can cause prerenal failure

Treatment: discontinuing offending agents often returns renal function to baseline

General Renal Toxicity

FENA >2%, Uosm < 350, urinary sediment shows granular/dark brown casts and tubular epithelial cells / nonoliguric renal failure / hypomagnesemia (urinary magnesium wasting and ADH resistance) / can occur despite appropriate serum levels and after drug discontinuation

IV contrast

Antibiotics: aminoglycosides, amphotericin B, cephaloridine, streptozocin, pentamidine, mithramycin, quinolones, foscarnet, tetracyclines (made before 1950?)

Chemo: cisplatin, ifosfamide, mithramycin, vincristine, methotrexate, cyclophosphamide (rare)

Other: methoxyflurane, tacrolimus, carbamazepine, IVIG

IV contrast

CRF, DM, volume depletion, and MM predispose to IV contrast toxicity

Renal protection protocol: Mucomyst (600 mg bid prior to administration) and IV fluids plus aminophylline 5 mg/kg during contrast administration

Aminoglycosides

reabsorption by pinocytosis can increase half-life over 100 hours (normal 3 hours) / Treatment is primarily supportive

Amphotericin B

1) decreases renal blood flow because of acute renal vasoconstriction in a dose-dependent manner (causes ATN)

2) direct tubular injury in cumulative doses exceeding 2 to 3 g / classic distal RTA, concentrating defects (it punches holes in the membrane), and potassium wasting / usually nonoliguric and reversible on discontinuation

Cisplatin

up to 50% get enzymuria, Mg and K wasting (Medstudy says only K, not Mg), and ATN /

urine output of at least 100 mL/hr decreases risk

Rhabdomyolysis

lovastatin, ethanol, codeine, barbiturates, diazepam (elevated CPK, brown casts)

Severe hemolysis

quinine, quinidine, sulfonamides, hydralazine, triamterene, nitrofurantoin, mephenytoin

Acute interstitial nephritis (AIN)

penicillins, cephalosporins, rifampin, sulfonamides, thiazide, cimetidine, phenytoin, allopurinol, cytosine arabinoside, furosemide, interferon, NSAIDs, ciprofloxacin

Findings: fever, rash, arthralgias, eosinophilia, renal failure (may be absent in 30%)

UA shows pyuria, WBC casts, eosinophiluria / nephrotic range/proteinuria with NSAIDs

Note: above findings Treatment: steroids may* speed recovery in aggressive AIN

NSAID nephritis

(esp. fenoprofen and mefenamate) / nephrotic range proteinuria (80%), minimal change disease (10%), membranous nephropathy (rare) / signs of hypersensitivity often absent due to anti-inflammatory action, FeNa often < 1%, *steroids are not beneficial for NSAID nephritis (and some say not for other AIN either)

HUS (see other)

afferent arteriolar thrombosis

Cyclosporine, mitomycin C, cocaine, tacrolimus, conjugated estrogens, quinine, 5-fluorouracil

Note: plasmapheresis less useful HUS from mitomycin C

Glomerulopathy (membranous)

Causes: gold, penicillamine, captopril, NSAIDs, mercury

Findings: edema, moderate to severe proteinuria, hematuria, RBC casts (sometimes) / nephrotic range proteinuria esp. in penicillamine, gold and captopril (rare) / complete resolution may take up to several years (esp. gold)

Intratubular obstruction due to precipitation

Acyclovir ( > 500 mg/m²), MTX, sulfonamides (only at super high doses), ethylene glycol, high-dose vitamin C

Findings: urine sediment can be benign, or if severe can cause an ATN-like sediment

Chronic interstitial fibrosis with or without papillary necrosis (see other)

Phenacetin, NSAIDs, acetaminophen, aspirin, cyclosporine, FK-506, lithium

Findings: history of long-term medication use

Postrenal Causes

Ureteral obstruction due to retroperitoneal fibrosis

B-blockers (pindolol, atenolol), migraine meds (ergotamine, dihydroergotamine), methysergide, hydralazine, methyldopa

Findings: usually benign urine sediment, ultrasound reveals hydronephrosis

Chronic Renal Failure (CRF)

substantial ( < 20% normal) and irreversible reduction in renal function

Major causes: DM >> HTN (20%), tubulointerstitial (7%), APKD (5%)

Prerenal: severe, long-standing renal artery stenosis and bilateral renal arterial embolism

Renal: chronic glomerulonephritis, chronic TIN, Alport’s, SLE, diabetes, amyloidosis, HTN, cystic diseases, neoplasia, and radiation nephritis

Postrenal: chronic urinary obstruction

Complications: normochromic normocytic anemia, renal osteodystrophy (via PTH), metabolic acidosis, malnutrition, decreased immunity, HTN, dyslipidemia, LVH, neuropathy

· Electrolyte imbalances (hypocalcemia, hyperkalemia, hyperphosphatemia)

Treatment: provide supplemental 1,25-D3, CaCO3 (binds intestinal phosphate and provides Ca)

· Uremia

CNS: lethargy, somnolence, confusion, and neuromuscular irritability (gradual or abrupt)

CVS: HTN, CHF, pericarditis (can be abrupt)

GI: anorexia, N/V (very common)

Bones: pain from secondary hyperparathyroidism

Other: fatigue, pruritis, and sleep disturbances

· Uremic Immunodeficiency

T-cell abnormalities (lymphopenia), reduced response to vaccination

· Other Complications:

Hematologic: chronic anemia (from reduction in erythropoietin and mildly reduced red cell half-life) and bleeding

CVS: HTN, pericarditis, cardiomyopathy, arrhythmias, and CHF

CNS: generalized seizures, confusion, lethargy, emotional lability, myopathy, peripheral neuropathy, and syndromes related to nerve compression (carpal tunnel)

GI: ulcers, gastroduodenitis, colitis, angiomas

Endocrine: secondary hyperparathyroidism, euthyroid hypothyoxinemia, hyperprolactinemia, bad GnRH axis (amenorrhea, impotence), gynecomastia

Immune: lymphocytopenia, anergy, increased anticomplement activity, abnormal monocyte motility

Metabolic: renal osteodystrophy (osteitis fibrosa and osteomalacia) and altered drug-metabolism

Treatment:

· Meds

o ACE inhibitors: cause mild (10 ml/min) decrease in GFR but overwhelmingly proven effective by multiple mechanisms

o avoid peripheral calcium blockers: used alone may speed progression of renal failure

· Blood pressure control: MAP of 92 (not too low, too low actually does harm) / MDRD

study showed this is only helpful if proteinuria is 0.5 to 1 g/day

· restrict protein < 0.6 g/kg lean body weight

· restrict dietary sodium < 4 g/day (unless residual urine obligates greater daily losses)

· restrict K⁺, Mg²⁺, PO4³⁺ and fluid intake to match daily losses

· pregnancy can accelerate pre-existing renal disease

· give vitamin D early on to decrease PTH levels (which if unchecked, speed renal damage)

· correct acidosis (which also contributes to renal damage)

· correct lipid abnormalities (for usual reasons)

· correct anemia with erythropoietin (ideal target level still not determined; some evidence suggests overly aggressive correction can worsen heart failure; mechanisms not completely worked out 11/06)

Dialysis or transplant for clinical uremia, severe azotemia (GFR < 10 ml/min), intractable hyperkalemia or acidemia, intravascular volume overload

Nephritic Glomerulopathies

Findings: hematuria and/or RBC casts, variable proteinuria, oliguria, hypertension (fluid retention and disturbed renal homeostasis), azotemia, edema (salt and water retention)

Immune complex diseases (some of these overlap with nephrotic section)

· Primary: IgA nephropathy, Anti-GBM (C₃), membranoproliferative I and II (MPGN) (C₄), membranous (C₃) / mesangioproliferative (MSGN) / fibrillary glomerulonephritis

· Systemic: SLE, HCV/HBV-related cryoglobulinemia (C₄), post-infectious glomerulonephritis: PSGN (C₃), infective endocarditis, vasculitides (W, C-S, PAN, mPAN, HSP (IgA),)

Acute Poststreptococcal GN (PSGN)

follows Strep A infection (pharyngitis or skin) by 10 days (different strains from those causing RF; renal involvement not impacted by antibiotic)

Presentation: hematuria, edema, proteinuria, decreased urine output, possible HTN

Labs: acute phase with decreased complement (C3 more than C4) / may have (+) ASO titres

Pathology: diffuse proliferation / exudative PMN’s / crescents / coarse granular immune deposits by IF/EM (sub-epithelial > sub-endothelial > intramembranous)

Course: usually self-limiting / occasionally progress to RPGN or chronic latent stage (more common and less likely to produce chronic renal disease in younger patients)

Treatment: B-lactam, diuretics and antihypertensives as needed, rarely steroids

IgA Nephropathy or Mesangial Glomerulopathy or (Berger’s Disease) - good prognosis

most common GN in the world / 15-30 yrs

Presentation: similar to HSP / sore throat followed shortly with nephritic syndrome, hematuria

micro (older), macro (younger) / synpharyngitic

Pathology: mesangial proliferation / IgA and other deposition by IF / dense deposits in

mesangium by EM

Labs: elevated IgA (50%)

Prognosis: good in 80% cases, more proteinuria is worse

Treatment: fish oil, IVIG, CSA

Goodpasture’s Syndrome (Anti-GBM) (see other) – poor prognosis

Occurs in two forms

· young men, hemoptysis and hematuria

· older people (male=female) / RPGN with no lung involvement

Labs: C-ANCA (+) in up to 40%, this may improve prognosis / complement usually normal

Pathology: linear deposition of C3 and IgG by IF / no dense deposits by EM

Treatment: immunosuppressives, plasmapheresis

Cryoglobulinemia

Type I - usually asymptomatic

monoclonal Ig’s (usually IgM)

Causes: hematologic cancers (Waldenstrom’s, myeloma, lymphoma)

Manifestations: may cause MPGN

Type II

monoclonal IgM against polyclonal IgG (causes precipitation) / immune-complex

vasculitides (50% renal involvement)

Causes: HCV (most common), HBV, bacterial, parasite lymphoproliferative,

autoimmune (collagen), skin (PAN, PCT), essential mixed monoclonal/polyclonal

cryoglobulinemia

Manifestations:

Skin: raynaud’s – 40% mono / 25% poly

vascular purpura (almost always involves lower extremities)

leg ulcers – up to 8% mono / 30% poly

acrocyanosis/necrosis – 15-40%

urticaria – complement, mast cell

livedo reticularis (1% mono / < 5% poly)

Arthritis

60% poly, < 10% mono

Renal disease

monoclonal à endomembranous deposits of precipitate

polyclonal à proliferative glomerulonephritis

immune complex

azotemia (late)

Hemorrhagic

Liver poly (esp. AP)

GI 5-20% poly (acute abdominal pain)

CNS vasculitis of vasa vasorum – up to 40% symmetric, peripheral neuropathy secondary to associated disease (amyloid, vasculitis)

Sjögren’s (80% have cryoglobulinemia)

Diagnosis: quantitative cryoglobulins < 2 normal / cryocrit (% cryoIg’s/serum) / SPEP / low serum complement (C4 more than C3)

Treatment: avoid cold / bed rest – for ulcers / low-dose corticosteroids / IFN-alpha (60-70% response, 30% sustained) / cytotoxic agents

Type III - usually no clinical significance

mixed polyclonal (no monoclonal component)

Causes: infections, autoimmune (SLE), liver disease (HBV, HCV), renal disease

(proliferative GN), essential mixed polyclonal cryoglobulinemia

Crescentic Glomerulopathy (RPGN)

Immune Complex Deposition

Goodpasture’s

collagen vascular diseases

as a potential evolution of most any other forms of GN

Pauci-immune (ANCA) glomerulonephritis

Wegener’s (C-ANCA, proteinase 3)

microscopic polyangiitis (P-ANCA, MPO)

Churg-Strauss (asthma and eosinophilia)

Idiopathic RPGN (renal limited vasculitis)

50% of glomeruli involved / over weeks to months / non-specific symptoms

Pathology: epithelial proliferation and capillary necrosis / IF and EM depend on etiology

Course: rapidly fatal

Treatment: massive IV steroids, Cytoxan

Nephrotic Glomerulopathies (MCD, FSGS , MGN, MPGN)

Nephrotic syndrome (see proteinuria)

Minimal Change Disease (lipoid nephrosis, Nil disease)

most common cause of nephrotic syndrome in children peak at 2-3 yrs, 10-12 yrs

Pathology: effacement of podocytes / usually not hypertensive

Cause: usu. idiopathic

Drugs: NSAIDS, rifampin, IFN-a, heroin, iron dextran

Other: lymphoma, HIV, IgA, diabetes, Fabry’s, sialidosis

Treatment: if needed, steroids, cyclosporin, others / ?ACE inhibitors

Focal Segmental Glomerulosclerosis (FSGS)

25% of adult nephropathies / common in children, young black men, association with

obesity / HTN / most common idiopathic nephrotic GN in blacks

Primary: typical > collapsing (blacks) > glomerular tip

Secondary causes/associations: HIV, IVDA, obesity, sickle cell, congenital heart disease

Presentation: mild to massive proteinuria, hematuria (50%), HTN (33%), renal insufficiency

(33%) / collapsing variant: more proteinuria, more ARF, viral/URI Sx from days to weeks before nephrosis

Labs: low albumin (can be < 2), decreased immunoglobulins, increased lipids, normal compliment

Ultrasound: normal to large echogenic kidneys

Renal biopsy: shows FSGS / can be confused with hereditary nephritis, IgA nephropathy, Wegener’s / EM can diagnose these other causes

Treatment:

· steroids 60-80 4 wks then 40-60 mg 3d/wk 4 wks then taper / alternate steroid regimens used / late relapse, more steroids / early relapse, cyclosporine or Cytoxan

· ACE inhibitors (yes, yes and yes) / works by inhibition of TGF-B

Prognosis: variable (more proteinuria is worse), often refractory to therapy

HIV nephropathy – poor prognosis

20% of hospitalized AIDS patients develop ARF / often collapsing variant with same characteristics / black males with IVDA / more on East coast / no HTN (maybe)

Treatment: similar to idiopathic, ACE inhibitors may help, HIV meds ?

Note: HIV patients also get RF from idiopathic, HCV, heroin, drugs, prerenal

C1Q nephropathy

Rare mimic of FSGS occurring mostly in young, black men

Membranous Glomerulopathy (MGN) – poor prognosis

most common adult idiopathic nephrotic syndrome in whites / 40-60 yrs/ men > women

Pathology: thickened BM matrix and vessel walls / more mesangial proliferation with systemic causes / sub-epithelial IgG and C3 granular deposits by IF (Heyman model) / spikes alternate with deposits

Secondary causes: HBV, syphilis, SLE, solid tumors (20% of MGN), thyroiditis, malaria, gold, d-penicillamine, PCN, captopril

Course: focal then global sclerosis / fairly responsive to steroids, cytoxic therapy / left untreated: ⅓ spontaneously regress, ⅓ stabilize, ⅓ slow progression to ESRD (women, children have better prognosis)

Membranoproliferative Glomerulopathy (MPGN) (nephrotic/nephritic) – very poor prognosis

primary or secondary forms / more in children, teenagers

Pathology: increased cellularity and mesangial matrix / mesangial proliferation with duplication of the glomerular basement membrane, splitting of capillary BM (silver stain) / immune deposits and low serum compliment (C3 more than C4)

types I subendothelial immune complexes (C3 and IgG)

type II dense deposit disease (alternate pathway of complement)

type III Burkholder subtype and Strife and Anders subtype

Hepatitis C Glomerulopathy

Findings: cryoglobulinemia, MPGN on biopsy, systemic manifestations (50%), abnormal LFT (70%), low complement (C4 more than C3) (80%), RF (70%)

Treatment: plasma exchange, treat the HCV (IFN-a, etc), cytotoxic agents

General Characterizations

Systemic diseases with secondary immune-mediated glomerulonephritis

· infection-related (including HBV, HCV, cryoglobulinemia types II or III, endocarditis, schistosomiasis, HIV-associated)

· autoimmune diseases (such as class IV lupus nephritis),

· dysproteinemia-associated (including light chain deposition disease, amyloidosis, cryoglobulinemia types I or II, fibrillary, and immunotactoid GN)

Membranoproliferative pattern but lack immune deposits

· diabetic nephropathy, hepatic glomerulopathy, and chronic TMA’s (HUS, TTP, APA), radiation nephritis, sickle cell nephropathy, eclampsia, and transplant glomerulopathy

Renal Other

hydronephrosis, mechanical, hypertension, renal artery stenosis, acid-base, RTA

Acute Hydronephrosis

takes 24 hrs to develop / 24 hrs to resolve

Diagnosis: decreased urine output, FeNa, ultrasound – not IVP (may see ascites)

Psychogenic polydipsia

Fluid builds up in bladder, it can’t keep up

Mechanical obstruction

Note: if one ureter is blocked, the other may go into spasm or intermittent spasm causing oliguria (10-20% of cases) [is this really true?]

Renal disease causing hypertension

Chronic Renal Failure (see other)

Renal Artery Stenosis (RAS)

Causes systemic HTN via renin-angiotensin pathway

Causes: idiopathic, fibromuscular dysplasia in young women

Diagnosis: U/S doppler renal artery, lab measurement of renin-angiotensin, captopril-based renal study

Treatment: ACE inhibitors useful to counter hyper-renin state seen in unilateral renal artery stenosis (this occurs at the expense of the GFR in the stenotic kidney). Obviously, this can be a problem with bilateral renal artery stenosis as the GFR in both kidneys may be too low.

Hypertension causing renal disease

benign nephrosclerosis hyaline arteriolosclerosis and focal atrophy

malignant nephrosclerosis tiny hemorrhages (flea-bitten) /infarcts / fibrinoid necrosis and

onion skin proliferation

Systemic Diseases Affecting Kidney

Diabetes Mellitus (see other)

most common cause of adult nephrotic syndrome

ACE inhibitors are beneficial even in normoalbuminuric patients (current thinking is that they should be used up to a Cr of ~ 4.5, at which point it’s too late)

Amyloidosis [NEJM]

primary or secondary (tumors, chronic skin disease such as ‘skin poppers’ or IVDA)

20% of cases are localized amyloidosis (½ involve lungs, benign course)

Presentation: weakness/fatigue, weight loss, autonomic disturbance (including GI tract), nerve dysfunction, hoarseness, tongue (macroglossia, tooth indentations, waxy deposits), edema, skin (bruising, waxy deposits)

Lymphadenopathy (> 33%): may present with stable pulmonary nodules
Neuropathy (35%), retinopathy [pic]
slowly progressive, distal, symmetric, dysautonomia, mechanisms unclear / may occur early, up to 4 yrs before diagnosis
mononeuritis multiplex
carpal tunnel syndrome (25%) (palmar cutaneous n. does not go through the tunnel)
Heart constrictive cardiomyopathy
Renal failure: deposits found anywhere in kidney / r/o fibrillary GN / kidneys first enlarge, then shrink / proteinuria and/or nephrotic syndrome

Diagnosis: SPEP (IgG kappa monoclonal protein (usu. < 2000), may have elevated ESR, EMG, MRI might reveal thickening in areas / echocardiogram may shows starry sky pattern

Biopsy of sural nerve, fat pad biopsy, lymph node, bone marrow

Pathology: acellular increase, sub-epi, sub-endo or spikes in BM, 8-10 nm fibrils by EM (random distribution) / stain with Congo red (apple-green birefringence), Gomori’s trichrome for myelin, crystal violet, thioflavin T / eosinophilic, glossy

Treatment: high-dose melphalan with autologous stem cell rescue may delay progression of disease / measure response at 3 months then yearly

Multiple Myeloma (see leukemias )

Gout (see rheum)

tophi deposition in kidney is relatively infrequent complication

Bacterial Endocarditis (see other)

embolic or immune complex deposits / MGN or MPGN

Systemic Lupus Erythematosis (see rheum)

anti-nuclear Ab (against snRPS) / anti-dsDNA factor

Membranoproliferative good prognosis

Focal GN okay, but may become diffuse later

Diffuse proliferative most common, bad prognosis, wire loop capillaries

Vasculitis

Interstitial nephritis

Membranous C3, Ig, C1q / indolent course

childhood lupus: prognosis determined by extent of renal involvement / immunosuppressive treatments often lead to opportunistic infection as the other major cause of death

Polyarteritis Nodosa (see vasculitides)

hypersensitivity angiitis (microscopic form) has glomerular involvement (focal or proliferative) classic PAN (infarcts in kidney)

Wegener’s Granulomatosis (see vasculitides)

most-common cause of RPGN / cANCA / similar to microscopic PAN

Scleroderma (see connective)

hyaluronic acid accumulation in medium and small arteries

similar lesions as malignant HT (may have normal BP)

Thrombotic Disease [hypercoagulability] [Ddx for hypercoagulable state]

Focal PE, DVT, PVT, fat embolism

Systemic DIC, HELLP, TTP, HUS, HSP

Focal Thrombosis [risk of thromboembolism]

Acute Arterial Occlusion (see other)

Superficial thrombophlebitis [pic]

Treatment: does not cause PE, so no anticoagulation; can do bedside thrombectomy or simply NSAIDS, applied heat; usually pain goes away within a few days

DVT

Cancers associated with DVT: lung, pancreas (Trousseau’s), stomach, colon > prostate, ovary >>> breast, brain, kidney, lymphoma

Other risk factors: late pregnancy (milk leg), OTC, smoking

Treatment: see PE / if confined to calf, consider withholding anticoagulation and re-imaging / treatment duration highly individualized (depends on cause and patient profile) / 1/07 current recommendations [annals][annals]

Pulmonary Embolism (see lungs)

Prosthetic Valve Thrombosis (PVT)

4% risk per patient/year without anticoagulation (0.016%/day), 2% with anti-platelet drugs, 1% with warfarin / mitral, caged-ball and multiple prostheses increases risk / known thrombus carries high risk of stroke (~10%) / consider operation for mobile thrombi or non-responders to medical therapy / consider thrombolysis (repeat TEE every few hours, continue 24-72 hrs) in high-risk surgical candidates with left-sided PVT / medical therapy is heparin à warfarin à ASA

Fat Embolism

Multiple cholesterol embolization (atheroembolic syndrome)

Risk Factors: vascular disease, catheterization, grafting, repair procedures, warfarin (mechanism unclear)

Findings: ecchymoses and necrosis similar to vasculitis: livedo reticularis (skin) [pic][dermis], Hollenhorst plaques (eyes), renal failure (progressive, step-wise) / note: peripheral pulses are preserved, despite marked peripheral ischemia

Bergman’s Triad: mental status changes, petechiae, dyspnea / complications: ARDS, DIC

Diagnosis: eosinophilia/eosinophiluria, renal biopsy is immediately diagnostic as ethanol preparation washes out cholesterol emboli leaving empty spaces

Treatment: steroid therapy may be harmful (unlike true vasculitides), if necessary, PEEP, treat any DIC

Prognosis: usu. severe but a significant number of patients have some recovery of renal function

Neutral Fat Embolism

12-36 h after bone trauma or fracture

Systemic Thrombosis

Disseminated Intravascular Coagulation (DIC) [NEJM]

Fulminant DIC

Intravascular hemolysis: hemolytic transfusion reaction, autoimmune diseases

Infection: sepsis (gram positive or gram negative), meningococcemia, viremia

Malignancy: mets, leukemia, other

Ob/Gyn: pre-eclampsia, amniotic fluid emboli, retained products of conception, HELLP

Burns/Crush/Trauma

Acute liver disease: obstructive jaundice, acute hepatic failure

Vascular disorders: giant hemangiomas, other

Prosthetic devices: LeVeen or Denver shunts, aortic balloon assist devices

Drugs: lamotrigine, penicillamine?

Low-grade DIC

cardiovascular, peripheral vascular, renal vascular, autoimmune disorders, hematologic disorders, inflammatory disorders

Labs: increased D-dimers, fibrinogen split products, decreased fibrinogen

Peripheral smear: RBC fragments [pic], schizocytes [pic]

Treatment:

· remove trigger / treat underlying problem

· Stop intravascular clotting process (this is complicated)

o activated protein C (promising new agent)

o use of heparin (early on) is debated

o ATIII concentrates / dose (given q 8 hrs) = (desired - initial level) × 0.6 × total body weight (kg)

o Other choices: IV heparin, LMWH, Hirudin, antiplatelet agents (less effective but sometimes a safer choice)

Note: ~75% will respond to above therapeutic steps / failure is probably component depletion / replace factors (try to leave out fibrinogen)

Components (as indicated): platelet concentrates, packed red cells (washed), ATIII concentrate, FFP, prothrombin complex, cryoprecipitate

Relatively Safe to Give: washed PRBC’s, platelets, ATIII concentrates (if available), and nonclotting protein containing volume expanders (plasma protein fraction, albumin, and hydroxyethyl starch)

Inhibit residual fibrinogenolysis

· Aminocaproic acid

given as initial 5 to 10 g by slow IV push then 2 to 4 g/hr for 24 hrs or until bleeding stops / may cause ventricular arrhythmias, severe hypotension, and severe hypokalemia

· Tranexamic acid (newer)

given as 1 to 2 g IV q 8 to 12 hrs / more potent, may have fewer side effects

HELLP (hemolysis, elevated LFT’s, low platelets) (see pre-eclampsia)

occurs in late 3^rd trimester in pregnancy (70% antepartum, 30% post-partum, usually < 48 hrs, almost always < 7 days)

Presentation: +/- elevated BP, fever (less common), may have proteinuria, severe renal failure, thrombocytopenia / 5-30% with DIC

Ddx: appendicitis, diabetes, gallbladder disease, gastroenteritis, PUD, glomerulonephritis, hepatic encephalopathy, ITP, renal stones, pyelonephritis, SLE, HUS, TTP, viral hepatitis

Course: delivery alone is not always curative, consider plasma exchange with FFP if not resolved by 72 hrs / recurrence risk for HELLP is 5-30%, for preeclampsia (40%)

Treatment: anti-platelet agents recommended by many for treatment and some say for prevention of recurrence

Thrombotic Thrombocytopenic Purpura (TTP)

1 in 1000 / female:male 10:1

Malignancy: gastric >> breast, colon, small cell lung

Drugs: tacrolimus, mitomycin C, cyclosporin, gemcitabine, bleomycin, cisplatin, plavix (rare, would happen in first 2 weeks of plavix therapy)

Infections: HIV, others

Presentation: fever, viral prodrome hemorrhage, pallor, CNS signs, jaundice, pulmonary edema / young women

Pentad: thrombocytopenia, microangiopathic hemolytic anemia, CNS, renal, fever

CNS (confusion, mental status, seizures et al)

Renal is often mild, but in 80-90% (proteinuria, hematuria, azotemia)

GI (N/V/diarrhea)

Heart: classically not, but may create subclinical damage

Prognosis: involvement of brain and kidney (50%) / mortality is 90% (10% with treatment but long-term problems arise from heavy use of blood products)

Labs: coagulation tests usually normal (unlike DIC), proteinuria, elevated BUN, elevated LDH (out of proportion), Coomb’s negative, fibrin split products (but not DIC levels), bone marrow Bx à megakaryocyte hyperplasia, schistocytes (should be plentiful)

Diagnosis: sometimes difficult, use labs, skin/gingival biopsy of petechiae, renal biopsy

Pathology: extra large forms of vWF circulate due to decreased activity of vWF degrading enzyme ADAMTS 13 (probably due to IgG inhibitors) / platelets stick too much à microangiopathic thrombi and hemolytic anemia (schistocytes from RBC’s being sheared in thrombi)

Treatment:

· plasmapheresis – follow platelet count and LDH

high dose steroids (possibly other immunosuppressives
antiplatelet drugs: ASA 325-1500 / dyprimamidole
avoid giving platelets (only aggravates the problem)
2^nd line: splenectomy (controversial), chemotherapy, IVIG

Prognosis: up to 85% remission with proper treatment

TTP-like syndrome (TMA) in HIV patients (~10% < 50CD4, ~3% < 100) (same treatment)

Association (50%) with CMV viremia

Evans’ syndrome

autoimmune hemolytic anemia and thrombocytopenia / positive Coombs’ test and by microspherocytes rather than schistocytes on peripheral smear / more common in children / idiopathic or related to hematologic malignancy

Hemolytic Uremic Syndrome (HUS)

similar findings as TTP but without neurological involvement / more severe renal disease

Mechanism: probably different than TTP

acute renal failure (mostly in children) associated with microangiopathic hemolytic anemia, thrombocytopenia and thrombosis, can lead to brain edema, seizures (give BZ or Dilantin) / some or all findings may be present / usually occurs after gastroenteritis, but can occur with just UTI / idiopathic form (AR and AD)

Other bacteria: has been associated with Pneumococcus, aeromonas, HIV

Drugs: cyclosporin A, tacrolimus, mitomycin C, OCP’s, OKT3, irradiation, gemcitabine, quinine, Ticlid

Children (90%): E. Coli 0157/H7, Shigella (verocytotoxins) cortical necrosis?,

Adults: HUS from infections, post-partum, systemic disease (cancers, etc) – worse prognosis

Note: in blacks, E. Coli toxin is an uncommon cause of HUS (unlike Shigella)

Treatment: life threatening condition that requires IVIG and/or plasmapheresis, steroids?, transfusions

as a sequelae of childhood pneumonia?

Henoch-Schönlein-Purpura (HSP)

Children 5-15 yrs (occasionally adults) / like IgA nephropathy plus GI problems

Presentation: palpable purpura (usu. lower extremities, buttocks) [pic], arthritis, arthralgia, abdominal (GI pain, bleed), renal (glomerulonephritis), CNS, hepatic are rare

Note: regular erythema blanches whereas true purpura does not

Complications:

abdominal intussusception (large > small); barium enema may be curative
renal: more in adults, nephritis (30%), may require hemodialysis (20%), chronic renal failure (2%)

Associations: lymphoma

Diagnosis: urinalysis, abdominal ultrasound,

Pathology: skin biopsy - IM shows around blood vessels and dermal zones / neutrophilic predominance around blood vessels / IgG deposition and some C3

Treatment: steroids may help GI manifestations but not renal / severe cases may require other immunosuppressives, plasma exchange, IVIG / dapsone can help skin, joints, GI manifestations / antihistamines for pruritis / follow up with urinalysis

Pyelonephritis

Acute pyelonephritis (see UTI)

50% have ureteric valve regurge / damage often localized to upper, lower poles (blunt calices), papillary necrosis, pyonephrosis, perinephric abscesses

coarse granular casts become fine granular casts

Chronic pyelonephritis

VUR / adherent capsule / U-shaped scar (late) / hyaline casts or thyroidization of tubules

glomerular fibrosis, atrophy (focal segmental) / account for 15% of renal transplants

Interstitial Nephritis higher risk of transitional cell carcinoma

Acute interstitial nephritis

Drugs: B-lactams, NSAIDS (nephrotic picture), diuretics, phenytoin, phenobarbital, cimetidine, sulfinpyrazone, methyl-dopa

Labs: eosinophils in urine (early in morning)

Chronic interstitial nephritis

Drugs: NSAIDs (nephrotic, decreased GFR, papillary necrosis, edema), analgesics, lithium (many mechanisms, also causes interstitial fibrosis and nephrogenic diabetes insipidus), gold

Toxins: cadmium, lead (Pb), copper (Cu), mercury (Hg)

Crystalline: uric acid, oxalate (primary, ethylene glycol, methoxyflurane)

Amyloid (nephrotic 75%)

Sarcoid (hypercalcemia from 1,25-OH +/- hyperglobulinemia causing distal RTA)

Analgesic abuse nephropathy

prolonged analgesic use including NSAIDs, acetaminophen, ASA (especially in combination)

2% of ESRD in US / > 2 to 3 kg cumulative dose

Pathology: chronic interstitial nephritis

bilateral papillary necrosis (25 to 40%) seen on IVP

patchy necrosis of the loop of Henle and medullary interstitium

Diagnosis: biopsy à tubular atrophy and interstitial fibrosis with occasional histiocytes

U/S à small-sized kidneys (50% to 65%) / middle-aged women

Balkan nephritis

causes fever, skin rash, renal failure

Xanthogranulomatous pyelonephritis

rare / foam cells / Proteus sp. / resembles renal cell carcinoma

Renal papillary necrosis

sort of like ATN on macroscopic scale / papillae can slough off causing obstruction

Causes: DM, obstruction, pyelonephritis, analgesic abuse, sickle cell (and sickle cell trait), hypoxia and volume depletion in infants, graft rejection

Renal Tubular Disease

· ATN, RTA, DI, Fanconi’s, etc.

Acute Tubular Necrosis (ATN)

most common pre-renal / decreased GFR / high recovery rate with proper management / 50% may not have oliguria

Causes: NSAIDS, aminoglycosides, IV contrast, rhabdomyolysis, thrombus

Diagnosis: FeNa (results are altered by diuretic use), muddy brown casts

Treatment: dialysis, fluid, diuretics, DOPA (increases output, but not GFR, will not lower creatinine level) / future: anti-endothelins, GF?

toxic nephrosis continuous damage in proximal tubule

ischemic tubular necrosis patchy damage

focal tubular necrosis

hydropic change

fatty change

hypokalemic nephropathy

chronic tubular disease

myeloma kidney (see mm) Bence-Jones light chain fragments combine with Tamm-Horsfall proteins, create tubular casts causing obstruction/inflammation

Acid-Base Metabolism

Anion gap

Anion Gap = [Na] – [Cl +HCO₃] normal: 8-12

MUDPILES

(methanol, uremia, DKA, Paraldehyde, isopropyl, lactate, ethano/ethelyne glycol, salicylates/starvation)

Increased acid production (noncarbonic acid)

Increased β-hydroxybutyric acid and acetoacetic acid production

Insulin deficiency (diabetic ketoacidosis).

Starvation or fasting.

Ethanol intoxication.

Increased lactic acid production

tissue hypoxia, sepsis, exercise, ethanol ingestion

Systemic diseases (e.g., leukemia, diabetes mellitus, cirrhosis, pancreatitis)

Inborn errors of metabolism (IEMs) (carbohydrates, urea cycle, amino acids, organic acids).

Increased short-chain fatty acids (acetate, propionate, butyrate, d-lactate) from colonic

fermentation

viral gastroenteritis

Other causes of carbohydrate malabsorption

Intoxications: methanol, ethylene glycol, paraldehyde, salicylate/NSAID,

Increased sulfuric acid

Decreased acid excretion: acute and chronic renal failure

Anion Gap Ethanol – no

Methanol – yes

Isopropyl – yes

Respiratory compensation for primary metabolic acidosis

For every 1 mEq decrease in HCO₃ the PCO₂ should decrease by 1-1.5 mmHg

Osmolality

Plasma osmolality (mOsm/kg) = 2([Na⁺] + [K⁺]) + [BUN]/2.8 + [glucose]/18 + ethanol/4.6 [pic]

Normal Osmolar Gap < 10 mOsm/kg

HCO3 metabolism

kidney increases serum bicarbonate via reabsorption and addition of new bicarbonate into serum via excretion of titratable acids and the formation of ammonia formation

HCO3 Deficit

HCO3 to replace (mEq) = Wt (kg) x (0.4)(15-measured HCO3)

or = (base deficit )(wt in kg)(0.4) / 2

Note: elevated AG may result from alkalosis freeing up negative charges on proteins (albumin), however, this cannot increase AG > 22

Lactic acidosis (see sepsis )

Severe metabolic and respiratory acidosis

pancreatitis, vomiting, hypokalemia, tissue necrosis, hypovolemia

Treatment: THAM (unproven)

Renal Tubular Acidosis (RTA)

All RTA’s associated with increased renal stones (calcium oxalate) from increased pH

Urine anion gap [Na + K] – Cl – ?HCO₃

If renal function intact, Ur AG will be negative due to excretion of ammonium chloride salts (high Cl) / Note: must consider unmeasured anions and cations (like Ca)

Urine – MM, hypoalbuminemia

TTKG (Ur_K / Pla_K) / (Ur_Osm / Pla_Osm)

> 8 à kidney is wasting K à suggests RTA

< 3 à kidney is not wasting K à suggest other cause for hypokalemia

Classic Distal RTA (Type I RTA) (hypokalemia)

Mechanism: H⁺ back leak, negative Urine AG

Drugs: cyclosporine, amphotericin B, vitamin D intoxication, lithium, analgesics, toluene,

cyclamate

Proximal RTA (Type II RTA) (normal or hypokalemia)

Mechanism: profound HCO₃ wasting from kidney / normal to low K (volume contraction causes increased aldosterone)

Drugs: carbonic anhydrase inhibitors (acetazolamide, sulfanilamide), mafenamide acetate, and 6-mercaptopurine, sulfanilamide, heavy metals

Note: difficult to correct with HCO₃, because you simply can’t give it fast enough

Type 4 RTA (hyperkalemia)

Mechanism: hypoaldosteronism, anti-aldosterone, or anti-adrenergic, or blocking Na⁺ channels (voltage effect)

Decreased aldosterone effect à hyperkalemia and acidosis¹ à more acidosis from hyperkalemia²

¹aldosterone also helps HTPase H⁺ secretion (requires luminal electronegativity)

²hyperkalemia also inhibits NH₃ secretion (proximal kidney), which reduces titratable acidity [thus promoting acidosis]

Findings: decreased urinary excretion of K⁺ despite high serum levels (low TTKG)

Drugs: NSAIDs (via PG inhibition)

ACE inhibitors, K-sparing diuretics (amiloride, triamterene)

Heparin (blocks production of aldosterone)

B-blockers, cyclosporine, pentamidine

Trimethoprim (bactrim) (block Na⁺ transporter, decreased tubular electronegativity à less K⁺ efflux)

Systemic diseases: Addison’s, SLE, sickle cell, amyloid, chronic partial obstruction, diabetes (especially older males with CHF; hyporeninemic hypoaldosteronism)

Treatment:

· Eliminate cause if possible

· Bicarbonate (rather than NaCl) – as the extra bicarbonate will help keep the tubule electronegative and help eliminate potassium

· Lasix may be used (↑ K washout and/or delivery of more Na to ↑ K excretion)

Drug-Induced Electrolyte and Acid/Base Abnormalities

hypokalemia/hypomagnesemia (increased urinary excretion)

gentamicin, cisplatin, diuretics, carboplatin

Findings: increased urinary excretion of K⁺ and Mg⁺⁺ despite low serum levels

hypomagnesemia or hypokalemia (increased urinary excretion)

aminoglycoside and cisplatin

hypomagnesemia, hypokalemia, metabolic alkalosis (increased K⁺ and H⁺ secretion)

thiazide and loop diuretics

hypokalemia and metabolic alkalosis

hypovolemia à hyperaldosteronism (increased K excretion) / volume depletion also causes increased HCO₃ reabsorption and prolongs metabolic alkalosis (e.g. NG suction)

hyponatremia (see lytes)

increased ADH secretion/sensitivity with decreased water excretion

NSAIDs potentiate ADH action (reduction of prostaglandins that inhibit ADH)

Findings: Uosm is less than maximally dilute in the face of low serum Na⁺

Thiazide diuretics (see below), chlorpropamide, vincristine, IV cyclophosphamide, Cytoxan, clofibrate, narcotics, haloperidol, thioridazine, amitriptyline, fluphenazine, NSAIDs, acetaminophen

Thiazide diuretics – no medullary washout àallows ADH-water resorption

Loop diuretics – medullary washout à less ADH-water resorption

Note: any diuretic can cause significant NaCl loss with hyponatremia from combination of volume depletion, salt restriction, continued free water intake

Cyclophosphamide and vincristine

direct antidiuretic effect in the distal tubule - impaired free water excretion

Nephrogenic diabetes insipidus (anti-ADH) (see central DI)

Mechanism: impaired response to ADH

Causes: lithium, cyclophosphamide, ifosfamide, vincristine, demeclocycline / ?hypokalemia and hypercalcemia >12 causes mild nephrogenic DI / rare congenital XLR form / metastatic breast cancer

Treatment: thiazides to prevent kidney from diluting urine too much, increase water intake, decreased salt intake

Meliturias, amino acidurias

Fanconi’s syndrome

inherited or acquired (see ARF drugs)

Mechanism: proximal RTA with tubular glucosuria (despite euglycemia), phosphaturia, aminoaciduria, bicarbonaturia, saluresis, kaliuresis, and decreased ammonium excretion

Presentation: rickets, short stature, uremia

Renal Stones

Presentation: unilateral flank pain, colicky, may radiate to groin

Ddx: appendicitis, PID, diverticulitis, abdominal aortic aneurysm, bladder cancer

Diagnosis: clinical and radiological

Radiography:

KUB à 75-90% of stones are radiopaque (non-opaque: cysteine, struvite, uric acid)

CT à sensitivity (96%) specificity (100%) [best study; non-contrast CT]

IVP à sensitivity (87%) specificity (96%)

U/S à sensitivity (15%) specificity (90%) [better for pregnancy]

Note: CT shows both opaque and non-opaque stones; can sometimes distinguish urate vs. struvite vs. calcium oxalate but get both studies because KUB will separate opaque from non-opaque

Types of stones: calcium oxalate (60%), calcium PO₄^3- (20%), NH₄⁺Mg²⁺PO₄^3- or NH₄⁺/Urate (Struvite) (10%), uric acid (5-10%), cysteine (1%)

Treatment: hydration (~2L/day urine output), pain control, strain urine to catch stone (can analyze to make specific diagnosis), intervention (see below)

Note: some advocate NSAIDs over narcotics in patients who are not obstructed and with normal renal function (avoid overhydration as NSAIDs reduce GFR)

Intervention: shock wave lithotripsy vs. surgical removal (e.g. endoscopic)

Urgent Intervention: obstructed, infected upper urinary tract, impending renal deterioration, intractable pain or vomiting, anuria, high-grade obstruction of solitary or transplant kidney

Course: most stones < 4-5 mm will pass w/out surgical intervention, if not passed after 4 weeks (complication rate 20%)

Note: infected renal stones must be considered as complicated UTI with regard to antibiotic treatment (duration)

Calcium stones

· hypercalcemia (hyper PTH, malignancy, other)

· GI diseases (small bowel bypass, inflammatory bowel diseases) often cause increased resorption of oxalate and increased CaOx stones

· renal tubular acidosis (increased urine pH, alkalinization of urine increases formation of CaPO₄ stones)

Struvite Stones (Staghorn calculi) – not opaque

often from UTI with Proteus, staph causing NH₄⁺Mg²⁺PO₄^3- stones / often gigantic (will not pass into ureter) / pH > 8

Urate Stones – not opaque

hyperuricemia (gout, leukemia, other malignancy), gout present in 20% of patients with urate stones, Lesch-Nyhan

Treatment: alkalization of urine helps prevent crystallization of urate stones (takes about 9 days to dissolve 2 cm urate stones) / urate is underexcreted in acid urine

· matrix stones (other urease-producing bacteria)

· indinavir stones (organic stones seen in pts taking indinavir)

Cysteine Stones (see other ) – lucent or opaque

1/7000 (rare) / hereditary defect in tubular amino acid transport of cysteine, ornithine, lysine, arginine (COLA) à homocystinuria à hexagonal-shaped stones

Treatment: diuresis (3L/day) and alkalization of urine (pH > 7) +/- D-penicillamine or tiopronin / moderate salt/protein restriction? / 50% may still require intervention

Course: start early in life and if untreated progress to ESRD

Renal malformations

Anomalies of urethra and bladder

ureteral valves kinks in dilated ureter / obstruction

vesicoureteral reflux common / serious / pyelonephritis

diverticulum congenital or acquired

exstrophy of the bladder very rare / abdominal wall defect

posterior urethral valves obstruction - oligohydramnios - pulmonary hypoplasia / males

Anomalies of position and formation

Renal agenesis

unilateral - always check before nephrectomy

bilateral (Potter’s) - facial, lower extremity deformations / not compatible w/ life

Renal hypoplasia

oligomeganephronia (Doll’s kidney) - small, reduced number of pyramids

Ask-Upmark kidney - transverse, linear scar from failed lobule

Duplication of renal pelvis, ureter

80% unilateral / common / asymptomatic or obstructive, infection

Simple ectopia

Crossed ectopia ureter crosses midline

Renal fusion horseshoe kidney / may lead to compression / 1/500

Anomalies of differentiation

Simple cysts

½ of population > 50 yrs

Acquired cystic disease

adults / hemodialysis / association with adenoma, carcinoma

Microcystic disease (with nephrotic syndrome)

~ maternal antibodies / rare / early death in infants

Dysplasia (cystic renal dysplasia)

most common cystic dysplasia in children / failure of differentiation of mesenchyme

Infantile PKD

rare AR, fatal, bilateral / many small cysts / hepatic fibrosis, bile duct proliferation

Adult Polycystic Kidney Disease (APKD)

age 40 / AD, APKD-1 (chromosome 16 del) / 70% have renal disease by 70 yrs (may have false negative or poorly recognized FH or sporadic mutation)

Presentation: flank pain, hematuria, low-grade proteinuria, systemic HTN (can have even with normal UA and serum creatinine), renal failure

Complications: hepatic cysts (33%), Berry aneurysms (12%, do MRI if FH of ICH), mitral valve prolapse (25%) or aortic/tricuspid insufficiency, colonic diverticulosis (most common extra-renal finding, more likely to perforate)

Medullary cystic disease (sponge kidney) – 2 types

1) non-uremic - normal renal function (normal urine sediment)

2) uremic - earlier onset, renal failure

Alport’s Syndrome

AD or XLR / defective GBM synthesis / onset age 5-20 yrs

progressive renal failure, CN VIII deafness and eye lesions / get a biopsy

Pathology: biochemical changes in BM, variation/layering, IF not useful

Renal Transplant

Hyperacute rejection – preformed cytotoxic antibodies destroy kidney within hours

Acute rejection – T cell mediated occurs over months / treat with steroids, antithymocyte antibodies and/or immunosuppression

Chronic rejection – gradual kidney decline, proteinuria, HTN / graft may survive several years

Immunosuppression: steroids, cyclosporine, azathioprine, ATG, OKT3, MMF

Note: 100x risk of malignancy due to chronic immunosuppression (often lymphoma), also increased risk of infection

Transplant glomerulopathy

most common cause of renal failure in transplant patients

Treatment: ACE inhibitors for chronic allograft nephropathy [article1] [article2] / post-transplant erythrocytosis (occurs in 10-20%) à consider using ACE inhibitors / 10-40% of patients with unilateral renal artery stenosis develop ARF (usu. 10-14 d and usu. reversible)

Membranous GN most common glomerulopathy

cyclosporin toxicity, tubular vacuolization (not specific), arteriolar hyalinization (may occur) Note: long-term cyclosporin and tacrolimus may induce chronic interstitial fibrosis / diagnosis can be confused with rejection / renal biopsy to distinguish interstitial fibrosis from acute or chronic rejection

Renal Cancer

Benign

· angiomyolipoma

· adenoma - from renal tubule

· oncocytoma -epithelial tumor

Renal Cell Carcinoma – poor prognosis

Males 2x > female; 50-70 yrs

Types: granular cell, tubular adenocarcinoma, Wilm’s, sarcoma

Pathology: clear cells rich in lipid or glycogen, distinct vascular pattern by arteriography

Presentation: hematuria, flank pain, palpable mass (classic triad occurs only in 10-20%)

Paraneoplastic syndromes: erythrocytosis, hypercalcemia, hepatic dysfunction, fever of unknown origin, amyloidosis

Diagnosis: IVP, CT

Treatment: nephrectomy (only potentially curative option); Il-2 and IFN-alpha is helpful in 10-20%; radiation can have some effect; metastatic disease carries dismal prognosis

Prognosis: poor / metastases ¼ have mets at presentation: lungs, bones, lymph nodes

Von-Hippel-Lindau (VHL deletion)

hemangioblastoma, pancreatic cysts or pancreatic cancer, cerebellum, medulla, multiple bilateral renal cysts or renal cell carcinoma / Hatfields and McCoys

Dialysis

Indications for: electrolytes (K, Mg), uremia, acidosis, volume overload, ingestions, severe ↑urate

Hemodialysis

Acute Complications

· risk of cardiac arrhythmias can last up to 5 hrs after HD (risk may be predicted by larger QTc dispersions > 65 ms bad (normal 40-50 ms) / typical pre-post HD values are 60 à 90

· Avoid overly aggressive dialysis – get relative hyperosmotic CNS (brain swelling)

· volume shifts may result in cardiac problems

· post-dialysis state of confusion, HA, nausea

· Increased Infections UTI most common (Candida, Enterococci for HD / Staph for non-HD patients)

Chronic Complications

· line sepsis from dialysis catheters, and infection of grafts >> fistulas

· dialysis amyloidosis occurs after many yrs of dialysis (50% by 13 yrs) due to buildup of amyloid protein (11-kDa b₂-microglobulin molecules too large to pass through membranes) / Only effective treatment is renal transplant

· Calciphylaxis [pic]

Presentation: plaque-like with dusky or purple discoloration / extremely painful / progression to ulceration and formation of eschars / occur in up to 4% of dialysis patients (male:female 1:3) / must distinguish from more common arterial, ocular, periarticular, soft-tissue calcifications / hyperparathyroidism (80%), hyperphosphatemia (70%), elevated calcium-phosphate product (30%) / note: lab abnormalities may not be present later on when disease presents

Diagnosis: biopsy (may want to avoid) / bone scan (can be useful)

Ddx: calcinosis cutis, dystrophic calcification (sites of injured tissue), medial calcific sclerosis (larger vessels)

Treatment: avoid vitamin D and calcium (use non-calcium aluminum binders; may give calcimetic agents (Cinacalcet) to help keep PTH levels down) / bisphosphonates, sodium thiosulfate, tPA, hyperbaric oxygen all have shown some success / role of parathyroidectomy debated

· Nephrogenic fibrosing dermopathy (NFD)

rare condition described in 90’s / may be caused by use of gadolinium dye in MRI

Hemofiltration – 12-16 L

Hemodialysis – 2 L

Peritoneal dialysis

May decrease risk of bleed/hypotension with CNS trauma and MI

1 infection per 30-40 patient months, is PD adequate?

Ultrafiltration (e.g. CVVH or continuous venovenous hemofiltration)

highly permeable membranes allow low hydrostatic pressures and flows so patient’s own BP is the driving force / advantage is can do in patients with very low blood pressures (who could not tolerate fluid fluids of regular HD) / best way to remove large amounts of volume in shortest time possible (much faster than regular HD)

Renal Physiology II

Acid/Base

Increase proximal tubule H+ secretion and HCO3 reabsorption (and vice versa)

Acidosis

Increased PCO2

Hypokalemia (decreased intracellular K favors HCO3 reabsorption)

Cl depletion as with volume depletion (H+ is exchanged for Na instead of Cl, this effect is NOT due to aldosterone)

The distal tubule and collecting duct sees the same influences with the addition of aldosterone effects

ABG

Renal response to respiratory acidosis

.1 acute (still takes 24-48 hrs)

.5 chronic

Renal response to respiratory alkalosis

.25 acute

.5 chronic

CO2 falls 1.25 mmHg per 1 mmol/L drop in HCO3

CO2 rises between .2 to .9 mmHg per 1 mmol/L drop in HCO3

Base excess – will be normal in acute situation – but changed in chronic?

Note: always check for combinations of respiratory and metabolic perturbations.

Electrolytes or Lytes

Sodium Potassium Calcium Magnesium Phosphate

Hyper Na⁺ Hyper K⁺ Hyper Ca²⁺ Hyper Mg²⁺ Hyper PO₄³⁺

Hypo Na⁺ Hypo K⁺ Hypo Ca²⁺ Hypo Mg²⁺ Hypo PO₄³⁺

· hypoglycemia

POTASSIUM [K⁺]

Normal range: 3.5 to 5.0 mmol/L (extracellular) and 150 mmol/L (intracellular)

Total body stores run 50 to 55 mEq/kg (3000-4000 mmol intracellular; 300-400 mmol extracellular)

Normal intake is ~100 mEq/day

Normal output is 50 to150 mEq/day (95% renal, 5% stool, sweat)

Increased cellular uptake: insulin, B2 agonists, alkalosis, alpha antagonists

Decreased cellular uptake: acidosis, hyperglycemia, increase in osmolality, exercise, B2 antagonists, alpha agonists

When aldosterone is constant, acidosis decreases K secretion and alkalosis increases K secretion (direct effects on tubular cells – of course,

alkalosis enhances potassium excretion in exchange for resorption of H+ and Na+ ions in the distal renal tubule

Acidosis enhances renal conservation of K⁺in the distal tubule

High concentrations of H+ ion also may displace intracellular K⁺, causing an apparent hyperkalemia

Renal Physiology

increased tubular Na⁺ delivery and subsequent reabsorption favors secretion K⁺, increased flow decreases luminal [K⁺] and favors secretion

Hypokalemia

Renal losses (U_K⁺ > 20 mEq/day)

Diuretics, osmotic diuresis (DKA, other)

antibiotics (AG, amphotericin, penicillins), type I classic distal RTA, hyperaldosteronism (Conn’s), glucocorticoid excess, magnesium deficiency, chronic metabolic alkalosis, Bartter’s, Fanconi’s, ureterosigmoidostomy

Extrarenal losses (U_K⁺ < 20 mEq/day)

Diarrhea, intestinal fistulas, inadequate potassium intake, strenuous exercise (shift out of cells and urinary loss)

Cellular shift

Acute alkalosis (hyperventilation, GI losses, intestinal fistulas), insulin, vitamin B12 therapy, hypokalemic periodic paralysis, medications (lithium and salbutamol)

Note: GI losses (vomiting and NG suctioning) is due acutely to alkalosis from H+ loss, but then from increased Tm for HCO3 with volume contraction (increased resorption of HCO3 in proximal tubule)

Findings:

CVS: PACs, PVCs, digoxin toxicity

ECG: [hypokalemia ECG] [potassium ECG]

prolonged QT interval

T wave flattening or inversion

prominent U waves

ST depression

MS: cramps, pain

Abd: paralytic ileus

Neuro: weakness, paresthesias, and depressed DTRs

ABG: Metabolic alkalosis

Serum Ca2+: hypokalemia and hypocalcemia may coexist

Serum Mg2+: hypokalemia and hypomagnesemia may coexist

Treatment:

think of 10 mEq for every 0.1 deficit (unless significant deficit exists)

be careful not to give more than 40 mEq IV at one time

DKA: careful not to drop the K too fast by giving insulin/fluids

Hyperkalemia

Excessive intake

Iatrogenic supplementation (IV or PO)

Salt substitutes

High-dose potassium penicillin

Blood transfusions

Decreased excretion

Renal failure (acute or chronic) (GFR < 10 to 15)

Drugs: spironolactone, amiloride, triamterene / lithium, cyclosporin, heparin, trimethoprim

Addison’s disease

Hypoaldosteronism

Distal tubular dysfunction

Cellular shift (0.6 mmol/L for each 0.1 decrease in pH)

Acidemia [except (ketones, lactic acid) because they cross membrane and do not create voltage gradient]

Insulin deficiency

Tissue destruction (hemolysis, crush injuries, rhabdomyolysis, burns, and tumor lysis)

Medications (arginine, B-blockers, digoxin, and succinylcholine)

Hyperkalemic familial periodic paralysis (rare)

Factitious

Prolonged tourniquet application before blood draw

Hemolysis of blood sample

Leukocytosis

Thrombocytosis

Findings:

CVS: Fatal arrhythmias

Neuro: Weakness, paresthesias, depressed DTRs

ECG: ECG changes progress relative to severity of hyperkalemia [potassium ECG]

Firstà Peaked T waves

Shortened QT intervals

Depressed ST segments

Decreased R wave amplitude

Prolonged PR interval

Small or absent P waves (flattened P waves)

Widened QRS complexes

Lastà Sine wave pattern

Complications:

Pancreatitis

More-rhabdo?

Transfusion, inflammatory -

Acidosis (b/c K⁺ decreases ability of tri-transporter to pump NH₃ into tubule thus restricting NH₄ excretion)

Iatrogenic

Renal failure

Hypomagnesemia

Hypoaldosteronism

Treatment:

start getting worried > 6.0, super worried > 7.0 / lack of EKG changes is reassuring

but does not mean you ignore it / [some renal patients are allowed to get into the 6’s prior to next dialysis treatment if you know you will be able to get dialysis soon]

· calcium (to stabilize cardiac membrane)

· kayexylate resin PO/enema (enema works faster)

· insulin/D₅₀(drives K into cells)

· β-agonists (drives K into cells)

· bicarbonate (especially with Type 4 RTA)

CALCIUM [Ca²⁺]

Increased renal Ca reabsorption: metabolic alkalosis, volume contraction

Decreased renal Ca reabsorption: phosphate depletion, metabolic acidosis, ECF volume expansion, loop diuretics

Note: ionized calcium decreases with dialysis due to decrease in acidity. Ionized calcium increases with increased acidity. Therefore, patients in renal failure might maintain normal Ca_i although the total calcium stores are decreased.

Hypercalcemia

Corrected calcium level: add 0.8 mg/dL for every 1 g/dL of albumin below 4 g/dL. [normal 8.8 to 10.4 mg/dL]

Younger, asymptomatic à hyperparathyroidism from parathyroid adenoma

Older, sicker à malignancy

Causes:

Increased intake or absorption of Ca²⁺

milk-alkali syndrome (taking twice normal dose for osteoporosis)

Vitamin D or A intoxication

sarcoidosis or other granulomatous disease (in addition to increased absorption from the GI tract, sarcoidosis increases conversion of 25-(OH) vitamin D to 1,25-(OH)2 vitamin D

Increased mobilization from bone

Primary hyperparathyroidism (likely parathyroid adenoma)

Primary hyperthyroidism (increased bone turnover)

Secondary hyperthyroidism associated with renal failure

Paget’s disease

Long-term immobilization

Malignancy (often when Ca level very high)

with bone invasion:

lung, breast, prostate total 80% / others: multiple myeloma, renal, thyroid, colon, lymphoma, bladder

· most combination blastic/lytic (lytic causes more ↑Ca, better seen on XR; prostate mostly blastic, better seen by bone scan)

without bone mets:

· PTHrp secreted by tumor (squamous cell carcinoma of lung, kidney, pancreatic, cervix, ovary, colon, head and neck tumors, esophagus, hypernephroma)

· lymphomas à 1,25-(OH)2 vitamin D

· increased bony resorption via prostaglandin E2

· osteoclast-stimulating factor (lymphoproliferative disorders)

Drugs: lithium, HCTZ, phosphate

Adrenal insufficiency

Acromegaly

Recovery from ARF following rhabdomyolysis

Decreased excretion

Familial hypocalciuric hypercalcemia

SLE

Findings:

< 12 g/dL (polyuria, dehydration)

> 13 (more symptoms: stones, bones, groans, moans, psychiatric overtones)

CVS: bradycardia, complete heart block, hypertension, and digoxin sensitivity

ECG: shortened QT_c interval

short or absent ST segment

prolonged PR interval

MS: insomnia, restlessness, delirium, dementia, lethargy , and coma

HEENT: corneal calcification

Abd: GI upset, anorexia, nausea, vomiting, constipation, ulcers, pancreatitis

GU: polyuria, polydipsia (nephrogenic DI) and nephrolithiasis

Neuro: muscle weakness, hyporeflexia, bone pain and pathologic fractures

Other:

ABG: may show hyperchlorhydric metabolic acidosis

PTH: If no known malignancy is found, a serum PTH should be drawn. A high PTH is indicative of hyperparathyroidism; a low PTH requires workup for occult malignancy

Diagnosis:

Ca²⁺ < 12 à real hyperparathyroid (elevated iPTH and urine cAMP) vs. paraneoplastic (iPLP and decreased iPTH)

band keratinopathy (corneal lesions)

Treatment:

moderate (2.9-3.2 mmol/L) à volume expansion and diuresis (UO > 2500 mL/day)

IV Fluids 500 ml NS bolus IV (careful with CHF)

Lasix 20 to 40 mg IV q 2 to 4 hrs to ensure UO > 2500 mL/day and increase renal calcium wasting (i.e. no thiazides)

severe (> 13 mg/dL or > 3.2 mmol/L or symptomatic)

· calcitonin [short-lived effect; can cause tachyphylaxis]

· bisphosphonates: disodium etidronate (EHDP) or pamidronate (5 to 10 mg/kg/day IV over 2 hours for 3 days; careful with renal insufficiency as rapid infusion of pamidronate may exacerbate renal failure), repeat in 7 days if needed; longer term (20 mg/kg/day PO for 30 days) [onset: 1-2 days; may cause ↓ PO₄, ↓ Mg, ↓ Ca, fever]

· hemodialysis for hypercalcemia ( > 4.5 mmol/L)

· plicamycin (Mithracin) inhibits bone resorption of Ca²⁺ (15 to 25 /kg in 1 L NS over 3 to 6 hours) (onset ~ 48 hrs) [only use in emergency situation, many side effects]

chronic: steroids, oral PO₄, NSAIDs (only in PG-induced hypercalcemia)

· prednisone decreases Ca²⁺ absorption in malignancy and may have antitumor effects (10 to 25 mg PO q 6 hrs) [onset: 2 to 3 days]

· PO₄causes Ca²⁺ causes CaPO₄ deposition / give if serum PO₄ < 1 mmol/L (with working kidneys (5 ml PO 3 to 4 times daily until serum PO₄- is 1.6 mmol/L)

Hypocalcemia

Causes:

Decreased intake or absorption

Malabsorption, intestinal bypass, short bowel syndrome

Vitamin D deficiency or chronic renal failure

(decreased production of 25-(OH) vitamin D or 1,25-(OH)₂ vitamin Dl)

Increased excretion

Medications (aminoglycosides, loop diuretics, renal failure)

Decreased production or mobilization from bone

Hypoparathyroidism (after subtotal thyroidectomy or parathyroidectomy)

Pseudohypoparathyroidism

Acute hyperphosphatemia (tumor lysis syndrome, ARF, and rhabdomyolysis)

Acute pancreatitis (deposition) and other necrosis

Sepsis (mechanism unclear)

Hypomagnesemia (see Mg²⁺)

Alkalosis (hyperventilation, GI losses, and intestinal fistulas)

Neoplasm

Paradoxical hypocalcemia from osteoblastic mets from lung, breast, or prostate

Medullary carcinoma of the thyroid à calcitonin

Tumor lysis syndrome

Drugs: protamine, heparin, glucagons, transfusions

Transient: hypoalbuminemia (0.8 mgCa/g albumin), alkalotic state, pancreatitis, sepsis, burns, ARF

Findings:

Cardiac: arrhythmias and dilated cardiomyopathy

ECG: prolonged QT interval without U waves

T wave flattening or inversion

MS: confusion, irritability, and depression

HEENT: papilledema and diplopia, stridor (laryngospasm)

Abd: abdominal cramping

Neuro: paresthesias of the fingers/toes, increased DTRs, carpopedal spasm, tetany, and seizures

Chvostek’s sign: facial muscle spasm elicited by light tapping on the facial nerve at the angle of the jaw; may be present in ~10% of the population with normal [Ca²⁺]

Trousseau’s sign: carpal spasm elicited by placement of a blood pressure cuff on the arm and inflation to above SBP for 3 to 5 minutes (often painful for the patient)

Chronic hypocalcemia: eye (increased ICP and papilledema), CNS (spasms of hand, face, respiratory muscles), mental status changes (irritability, depression, psychosis), cardiac arrhythmias, intestinal cramps, malabsorption

Treatment:

Replace calcium (calcitriol and oral calcium) (monitor quantity of Ca²⁺consumed, watch for symptoms of circumoral or fingertip tingling)

Long-term calcium supplementation rarely required

PHOSPHATE [PO4^3-]

Hyperphosphatemia

Causes: CaPO₄ deposition (conduction problems, calcification of blood vessels)

Findings:

hypocalcemia

CaPO₄deposition in tissues (can occur when Ca²⁺x PO₄ index > 60) / see tumor-lysis syndrome

Treatment: what can you do about it? HD doesn’t take off PO4 very well –

Hypophosphatemia

Causes:

Decreased intake, excess GI PO₄³⁺binders, vitamin D deficiency

Hyperventilation or sudden alkalinization of serum

Mechanism: increased intracellular pH à increased PFK action/glycolysis à shift of PO₄³⁺into cells (this effect can persist for a brief period even after normal

ventilation) / refeeding stage of severe malnutrition with administration of carbohydrate

Findings:

Presentation: confusion, weakness, anorexia, malaise, paresthesias

Severe hypophosphataemia (< 1)

respiratory muscle weakness, CNS dysfunction (EEG and EMG changes), rhabdomyolysis, dilated cardiomyopathy, hemolytic anemia

Mechanism: decreased intracellular ATP, decreased 2-3 DPG and altered hemoglobin O₂ affinity à tissue ischemia

MAGNESIUM [Mg²⁺]

Normal range: 1.3 to 2.1 mEq/L

Reabsorption: 25% proximal / 50-60% Loop of Henle / passive and active reabsorption (mechanism unclear) / Mg²⁺ competes with Ca²⁺ for reabsorption in TAL

· Magnesium is required for proper function of many cellular mechanisms including the Na+ / K⁺-

ATPase pump. Derangements in magnesium levels should be sought in conditions associated

with abnormalities in potassium or calcium concentrations.

· Mg²⁺, K⁺, PO₄³⁺ usually simultaneously decreased with poor dietary intake

· PO₄³⁺deficiency causes K and Mg deficiency via catabolic state

Hypermagnesemia

Causes:

Medications: lithium

Magnesium-containing drugs in settings of renal failure

Tumor metastases to bone

Hypothyroidism

Viral hepatitis

Acidosis

Findings: symptoms generally not apparent until the level is > 4 mEq/L

VS: Bradycardia

CVS: Hypotension

ECG: shortened QT

Shortened PR interval

Heart block

Peaked T waves

Increased QRS duration

Lung: respiratory depression

Abd: nausea and vomiting

Skin: flushing

Neuro: loss of DTRs, and muscular paralysis

Treatment:

Identify and eliminate source

calcium gluconate (100-200 mg IV over 5-10 minutes) effects are immediate but transient

Dialysis for severe hypermagnesemia (esp. with renal failure)

Hypomagnesemia

· Hypomagnesemia is most commonly due to urinary or GI losses

· RBC Mg²⁺ content decreases earlier than muscle Mg²⁺/N ratio

· Effects on Ca²⁺ metabolism

o 1.2-1.6 mg/dl increased PTH à ↑ Ca²⁺

o < 1 mg/dl decreased PTH (blocks release and action) à ↓ Ca²⁺

o reduced renal synthesis of 1,25(OH)₂D à ↓ Ca²⁺

· Effects on K⁺ metabolism (mechanism less well understood)

Difficult to correct K⁺ without correcting Mg²⁺ (somehow causes renal wasting of K⁺)

Causes:

Diminished PO intake

Malabsorption

Malnutrition (prolonged IV therapy, and alcoholism)

GI losses

Diarrhea (laxative abuse, gastroenteritis, and inflammatory bowel disease)

Fistulas and NG drainage

Vomiting

Renal: renal wasting syndromes, recovery from ATN

Drugs: cisplatin, cyclosporin A, G-CSF, digoxin, aminoglycosides, amphotericin B, diuretics

Endocrine

Cell uptake/redistribution (including alcohol intake and withdrawal)

Insensible losses

Findings: (early à GI, late à neuro)

Psych: confusion, mood alteration, psychosis, and coma

Neuro: nystagmus, paresthesias, tremors, weakness, vertigo, ataxia, and seizures

CVS: ventricular arrhythmias, increased digoxin toxicity

ECG: Atrial fibrillation

Prolonged PR interval

Prolonged QT / Torsades de pointes

T wave flattening

Abd: anorexia, vomiting, and difficulty swallowing

Treatment:

· Severe/acute magnesium deficiencies

MgSO₄ 2 g (8 mEq/g as a 20% solution) IV over 2 to 5 minutes, followed by 10 g IV over next 24 hrs, followed by 4-6 /day IV/PO x –5/d (if normal renal function)

Note: may take > 1 day to correct / may take 2-7 days to correct hypocalcemia

· Treat chronic magnesium deficiencies.

MgSO4 3 to 6 g/day IV or PO for 3 days (assuming normal renal function)

· Prevention

MgSO4 1 to 2 g/day may be added to IV fluids (assuming normal renal function)

SODIUM [Na⁺]

Pseudohyponatremia

100 glucose lowers Na by 1.4 to 1.6 (effects become apparent with glucose > 300)

Hypernatremia

Causes:

Diabetes insipidus (U_Na variable)

central/renal

Osmotic diuresis (U_Na > 20 mEq/L)

hyperglycemia, urea, and mannitol administration

Extrarenal water loss (U_Na < 10 mEq/L)

vomiting, NG suction, diarrhea, insensible losses

Excessive sodium gain (U_Na > 20 mEq/L)

iatrogenic (excessive sodium administration), primary hyperaldosteronism, Cushing’s, hypertonic dialysis

Findings: (from brain dehydration and volume depletion)

MS: lethargy, apathy, confusion (< 125), restlessness, irritability/agitation à obtundation/coma

Respiratory : respiratory paralysis

GU: polyuria, polydipsia

Neuro: muscular irritability, hyperreflexia, ataxia, and seizures ( usu. < 120)

Labs: Ser_Na, Ser_Osm, U_Na,

Hyponatremia

Hypovolemic

Renal (U_Na > 20 mmol/L): diuretics, hypoaldosteronism (also type IV RTA), type II RTA with metabolic acidosis, salt-losing nephritis, osmotic diuresis, (esp.), ketonuria, Bartter’s syndrome, diuretic phase of ATN

Extrarenal (U_Na < 20 mmol/L): GI losses (vomiting, diarrhea, NG), sequestration (pancreatitis, peritonitis), burns, damaged muscle, sweating

Hypervolemic

acute/chronic renal failure (U_Na > 20 mmol/L)

cirrhosis, CHF (U_Na < 20 mmol/L)

Euvolemic

SIADH

Tumors above diaphragm + pancreatic, duodenal, GI/GU

CNS disorders (tumor, trauma, meningitis, encephalitis)

Hypopituitary (loss of negative feedback exerted by cortisol on ADH release)

pulmonary (pneumonia, neoplasms)

Drugs (chlorpropamide, clofibrate, narcotics, neuroleptics, carbamazepine, TCAs, SSRIs, oral hypoglycemics, cyclophosphamide, vincristine, vinblastine) / NSAIDs and somatostatin potentiate ADH

normal response to surgery

increased SIADH usually lasts up to 3-5 days / resolves without any specific therapy along with a physiologic diuresis

Pseudohyponatremia

normal serum Osm: hyperlipidemia, hyperproteinemia

increased serum Osm: hyperglycemia (/18), urea (/2.8), mannitol, alcohol (ethanol, methanol, and isopropyl alcohol), ethylene glycol

Hypothyroidism

Pain, emotional stress

Addison’s or inadequate cortisol replacement (U_Na > 20 mmol/L)

Findings:

MS: lethargy, apathy, disorientation, agitation, coma

Neuro: weakness, ?decreased DTRs, seizures

Labs:

ser Na, ser Osm, serum protein, lipids, glucose (each 100 mg/dl above normal decreases ser Na by 0.4 mEq/L), urine Na

Treatment:

do not correct faster than 2 mEq/L/hr (cellular dehydration in CNS may cause central pontine myelinolysis and other brain damage)

Beer potomania, tea and toast syndrome

· Typical Na excretion ~ 100 mEq/day (2 L/day urine x 50 mEq/L of Na assuming a maximally dilute urine)

· Typical dietary Na intake is about 150 mEq/day

Normal kidneys can dilute urine to 50 mEq/L, thus 18 L (if you drank that much) would necessitate a 900 mEq loss / The patient becomes hyponatremic when the volume of fluid intake necessitates the excretion of more sodium than the dietary intake / But someone who takes in a low sodium diet need only drink say 5-6 L/day to become hyponatremic

Pulmonary [PFTs / Pulmonary Procedures / ABGs / PEEP]

Pulmonary Embolism, Pneumothorax, Lung Abscess, Alveolar Hemorrhage, ARDS

Pleurisy, Pleural Effusion, Pleural Fibrosis

Bronchitis, Bronchiectasis, Atelectasis,

Obstructive (COPD, Asthma , Emphysema), Restrictive Lung Disease

Sleep Apnea (OSA , CSA)

Lung Cancer

Pneumonia

Typical: Pneumococcus, Staphylococcus, Group A Strep, H influenza

Atypical: Mycoplasma, Chlamydia, Psittacosis, Legionella

Other: GNR, PCP, Compromised, Post-Op, Aspiration, Tuberculosis, fungus/parasites

Viral, Fungal, AIDS-related

ILD

Idiopathic Pulmonary Fibrosis (UIP, DIP, AIP, NSIP)

Lymphocytic IP, Histiocytoses (Langerhans IP)

RBAIL, BOOP, IPH

Occupational

Inorganic Dust, Organic Dust, Other chemicals

Other

Goodpasture’s, Hypersensitivity Pneumonitis , Eosinophilic Pneumonias, Allergic Aspergillus Pneumonia, Pulmonary Alveolar Proteinosis

Pulmonary Physiology

Upright paO₂ = 104 – (0.27 x age)

Supine paO₂ = 104 – (0.4 x age) [shunting of blood to apical lobes]

PO₂ from 60-80 – mild hypoxemia (lower than normal, but still may have O₂ of 90%)

PO₂ from 40-60 – hypoxemia (O₂ rapidly falls from 90% to 70%)

Increase T, CO₂, acidity – all shift hemoglobin dissociation curve to right – allows oxygen to be released to tissues

Arterial Blood Gases

Acid-Base Tricks

Acute: 0.08 pH for each deviation by 10 in CO₂(from ABG)

Chronic: 0.03 pH rule for chronic compensation

Note: a pH of 7.60 can lead to arrhythmias, seizures

Base Excess

HCO₃ changes with respiration, so BE is the measured HCO₃ compared to the normal HCO₃ corrected for CO₂

PAO₂ = FiO₂ (760 – PH₂0) – PaCO₂/RQ [usu. 0.8]

· A-a gradient is usually 10-20 in normal, young adult

· A-a gradient in normal person is caused by VQ mismatch / bronchial and left ventricular venous drainage

Pathological A-a gradient

· Shunting (R to L) – AV shunt (anywhere), PE (shunt in lungs)

· VQ mismatch – asthma, chronic bronchitis, emphysema, PE

· Diffusion defect – sarcoidosis, chronic interstitial pneumonia, fibrosis

ARDS

PaO₂/FiO₂ < 200 (corresponds to PaO₂ < 40), PWP < 18 mm Hg

Treatment: can give 0.6 FiO₂ for up to 24 hrs (too much O₂ can increase Atelectasis) / nasal cannula usually equates to .25 FiO₂ + 0.25 for each Liter

oxygen delivery = cardiac output x oxygen carrying capacity

oxygen carrying capacity = Hgb x O₂ x 1.34 + PaO₂ (0.003)

PFTs [diagram]

· spirometry, flow-volume loops, lung capacity, DLCO

General

ventilation respiratory center in the brain stem – influenced by input from carotid (Pa_O2) and central (Pa_CO2, [H⁺]) chemoreceptors; proprioceptive receptors in muscles, tendons, and joints; and impulses from the cerebral cortex.

Static Lung Volumes and Capacities

Vital capacity

(VC or "slow VC") is the maximum volume of air that can be expired slowly after a full inspiratory effort / decreases as a restrictive lung disorder (e.g., pulmonary edema, interstitial fibrosis) / VC also reflects the strength of the respiratory muscles and is often used to monitor the course of neuromuscular disorders

Forced vital capacity (FVC)

similar to VC, is the volume of air expired with maximal force. It is usually measured along with expiratory flow rates in simple spirometry

The VC can be considerably greater than the FVC in patients with airway obstruction. During the FVC maneuver, terminal airways can close prematurely (i.e., before the true residual volume is reached), trapping gas distally and preventing its measurement by the spirometer.

Total lung capacity (TLC)

total volume of air within the chest after a maximum inspiration.

Functional residual capacity (FRC)

volume of air in the lungs at the end of a normal expiration when all respiratory muscles are relaxed. Physiologically, it is the most important lung volume because it approximates the normal tidal breathing range. Outward elastic recoil forces of the chest wall tend to increase lung volume but are balanced by the inward elastic recoil of the lungs, which tends to reduce it; these forces are normally equal and opposite at about 40% of TLC. Loss of lung elastic recoil in emphysema increases FRC. Conversely, the increased lung stiffness in pulmonary edema, interstitial fibrosis, and other restrictive disorders decreases FRC. Kyphoscoliosis leads to a decrease in FRC and in other lung volumes because a stiff, noncompliant chest wall restricts lung expansion.

Inspiratory capacity (IC) difference between TLC and FRC

The FRC has two components: residual volume (RV), the volume of air remaining in the lungs at the end of a maximal expiration, and expiratory reserve volume (ERV); ERV = FRC - RV. The RV normally accounts for about 25% of TLC). Changes in RV parallel those in the FRC with two exceptions: In restrictive lung and chest wall disorders, RV decreases less than do the FRC and TLC and in small airways disease, premature closure during expiration leads to air trapping, so that the RV is elevated while the FRC and FEV₁ remain close to normal. In COPD and asthma, the RV increases more than the TLC does, resulting in some decrease in the VC

The characteristic abnormality seen in obesity is a decreased ERV, caused by a markedly decreased FRC with a relatively well-preserved RV.

Dynamic Lung Volumes and Flow Rates

Forced expiratory volume in 1 sec (FEV₁) is the volume of air forcefully expired during the first second after a full breath and normally accounts for > 75% of the FVC

FEF_25-75% is less effort-dependent than the FEV₁ and is a more sensitive indicator of early airway obstruction.

FEV₁ ↓ by bronchospasm (asthma), impacted secretions (bronchitis), loss of elastic recoil

(emphysema)

Fixed obstruction of upper airway à equal reduction of inspiratory and expiratory flow rates

FEV1↑ in restrictive lung disorders

Maximal voluntary ventilation (MVV)

Diffusing capacity (DLco)

Increased by ↑ contact with blood/red cells: CHF, polycythemia, alveolar hemorrhage

Decreased by: anemia, parenchymal lung disease, removal of lung tissue

often used to distinguish asthma (normal DLco) from COPD (abnormal DLco)

Note: VQ mismatch does not affect DLco because trapped air will not see the CO gas anyway

Use of positive pressure

· optimal Hb for most acutely ill patients with severe hypoxemia ~10-12 g/dL

· correcting acute alkalemia improves Hb performance

Note: for assessing hyperventilation, use CO₂ as a guide (not just air movement)

PEEP

can increase 2.5 every couple hours / must decrease more slowly (to avoid alveolar collapse, no more than 2.5 every 6-8 hrs and check)

PEEP helps get blood out of lungs (useful for pulmonary edema)

PEEP makes it easier for the heart to pump (useful for heart failure)

CPAP (continuous positive airway pressure)

useful for acute Atelectasis or pulmonary edema

BIPAP

indications: RR > 25, pH < 7.35, acute increase in pCO2

Pulmonary Procedures

Thoracentesis Thoracoscopy Tube Thoracostomy Thoracotomy

Bronchoscopy Mediastinoscopy Mediastinotomy

Percutaneous Needle Biopsy Of Pleura

Percutaneous Transthoracic Needle Aspiration

Thoracentesis – diagnostic (see pleural effusion) / therapeutic [video]

Contraindications include lack of patient cooperation; an uncorrected coagulopathy; respiratory insufficiency or instability (unless therapeutic thoracentesis is being performed to correct it); cardiac hemodynamic or rhythm instability; and unstable angina. Relative contraindications include mechanical ventilation and bullous lung disease. Local chest wall infection must be excluded before passing a needle into the pleural space.

Complications are uncommon, although the exact incidence is unknown. They include pneumothorax due to air leaking through the needle or due to trauma to underlying lung; hemorrhage into the pleural space or chest wall due to needle damage to the subcostal vessels; vasovagal or simple syncope; air embolism (rare but catastrophic); introduction of infection; puncture of the spleen or liver due to low or unusually deep needle insertion; and reexpansion pulmonary edema, usually associated with rapid removal of > 1 L of pleural fluid. Death is extremely rare.

Percutaneous Needle Biopsy Of Pleura

A needle biopsy of the pleura is performed when thoracentesis with pleural fluid cytology does not yield a specific diagnosis, usually for exudative effusions when TB, other granulomatous infections, or malignancy is suspected. The diagnostic yield of pleural biopsy depends on the cause of the effusion. In patients with TB, pleural biopsy is much more sensitive than thoracentesis and pleural fluid culture alone; 80% of cases are diagnosed with the first biopsy, and 10% more with a second biopsy. Of patients with pleural malignancy, 90% can be diagnosed with a combination of pleural fluid cytology and needle biopsy of the pleura.

Contraindications are the same as those of thoracentesis

Complications are similar to those of thoracentesis, but the incidence of pneumothorax and hemorrhage is slightly higher.

Thoracoscopy

Endoscopic examination of the pleural space after induced pneumothorax.

Note: Thoracoscopy must be distinguished from video-assisted thoracic surgery (VATS). Thoracoscopy is primarily used for diagnosis of pleural disease and for pleurodesis. It is most often performed by surgeons but may be performed by other trained physicians. In contrast, VATS is used exclusively by surgeons to perform minimally invasive thoracic surgery.

Contraindications are the same as those for thoracentesis. In addition, thoracoscopy cannot be used if a patient is unable to tolerate a general anesthetic or the unilateral lung collapse that occurs during the procedure. Extensive pleural adhesions greatly increase the risk of complications.

Complications are similar to those of thoracentesis plus those of a general anesthetic. Pleural tears, with bleeding and/or prolonged air leakage, can occur.

Tube Thoracostomy

Complications include hemorrhage from intercostal vessel injury, subcutaneous emphysema, injury due to a malpositioned tube (e.g., into the major fissure, and occasionally into the lung), and local infection or pain. Reexpansion pulmonary edema due to increased capillary permeability may occur in the reexpanded lung, especially after prolonged lung collapse and rapid reinflation. Tube insertion may be difficult because of adhesions or a very thick pleura. Other problems include inadequate drainage of the pleural space due to clots or gelatinous inflammatory material and plugging or kinking of the tube.

Bronchoscopy

Contraindications include lack of cooperation or combativeness in a patient; unstable cardiovascular status due to hypotension, low cardiac output, arrhythmias, or ischemic heart diseases; an uncorrected bleeding diathesis (thrombasthenia of uremia is especially troublesome); severe anemia; and hypersensitivity to lidocaine. Elective bronchoscopy should be deferred 6 wk in patients who have had an acute MI. If a patient who has unstable gas exchange, inadequate systemic O₂ transport, or active bronchospasm needs bronchoscopy, the patient can be intubated and ventilated to perform it safely.

Complications include morbidity in 8 to 15 and death in 1 to 4 of 10,000 patients. Patients at greatest risk include the elderly and patients with severe COPD, coronary artery disease, pneumonia with hypoxemia, advanced neoplasia, or mental dysfunction. Many of the complications--such as respiratory depression and, rarely, CNS toxicity or seizures due to lidocaine absorption--are related to the use of sedation or anesthetics. Other complications include pneumothorax (5% overall, with higher rates after transbronchial lung biopsy); hemorrhage (rare unless a biopsy is performed); cardiac arrhythmias (premature atrial contractions in 32% and premature ventricular contractions in 20%); postbronchoscopy fever (16%), with pneumonia rarely and no bacteremia; bronchospasm (unusual unless the patient has poorly controlled asthma); and laryngospasm (rare).

Bronchoalveolar lavage (BAL) accomplishes a "liquid biopsy" of the distal airways and alveoli. The tip of the bronchoscope is wedged in a 3rd- or 4th-generation bronchus; sterile saline is infused, then suctioned back, thus retrieving cells, protein, and microorganisms. Supernatant fluid and cell pellets obtained in this procedure are useful in the diagnosis of neoplastic diseases, infections (especially in immunocompromised hosts), and interstitial lung diseases. Yields are very high, and risks minimal.

Myeloperoxidase deficiency

Neutrophil-Specific Granule Deficiency

Drug Fever or Drug Rash

History

Pain

Stiffness

Swelling

Weakness

Constitutional

Arthritis Ddx by category

Palindromic RA

Pseudorheumatoid arthritis (Type B)

Antibodies

Vasculitis Associations

DR2

Drugs causing myositis (by mechanism)

Drugs causing myopathy (painful vs. painless)

Chronic Alcohol Myopathy

Acute Alcohol Myopathy

High-dose steroids

Colchicines

Group II

Group III

Echocardiography

Causes: myocardial injury (see cardiomyopathies), chronic overload (AS, HTN), chronic volume overload (MR, other), infiltrative (amyloid, HC, other)

Exam Findings

Anxiety induced chest pain

Inappropriate myocardial lactate production

Ddx for MI

Management of LV Infarct

Other treatment concerns

Other Causes of MI (besides coronary artery disease)

V1 monophasic R wave / biphasic (qR or RS) / triphasic with R > R

Premature atrial beat (PAB)

[restrictive pericarditis] [cardiac tamponade]

Diabetes Mellitus (see other)

Treatment:

Simple ectopia