Polyuria

Today we had a discussion about polyuria, and how to differentiate its different causes.

Polyuria is defined as greater than 3L/d. Always get a urine specific gravity. 1.010 is equivalent to plasma osmolality (~300)


General approach:

1. Solute- mediated: glucose, mannitol, NaCl (saline infusion, diuretics, post-obstructive), urea from high protein feeds.
Labs for solute show urine osm over 300, 24h urine osmoles over 900.
2. Psychogenic- urine osmol less than 300, esp probable if serum Na less than 137
3. Central DI- hypothalamic or pituitary stalk disease- urine osm less than 300. Serum Na usu over 142. May see urine osm over 300 if it is partial central DI and pt is water deprived.
4. Nephrogenic DI- X-linked, Li-induced, hyperCa2+, HypoK+, amyloid, sjogren's. Urine osm less than 300, Serum Na usu over 142. May see urine osm over 300 if it is partial central DI and pt is water deprived.


A word about psychogenic polydipsia and beer potomania:

Minimum achievable urine osmolality is ~50mEq/L (i.e. no ADH). Metabolism of a normal diet yields ~600mOsm/d. This means maximum urine output is ~12L/d.

In primary polydipsia, maximum output is exceeded by free water intake, leading to dilutional hyponatremia despite minimally concentrated, high volume urine output. Result is low (below 100) urine osm, low serum osm, hyponatremia, high urine output.

In beer potomania, protein intake is low, and ~250mOsm/d are produced, leading to a theoretical maximum urine output of 5L/d. If free water intake exceeds this (i.e. in beer), the same situation develops, with low urine osmolality, low serum osmolality, and relatively lower urine output.


Water deprivation test: Used for diagnosis of diabetes insipidus.

Patient is admitted to hospital first thing in AM. Do hourly weights, urine vol, urine lytes, osmol, serum Na, serum osm, ADH. Stop the test if urine osm is over 600. This means psychogenic polydipsia (i.e. kidneys can concentrate urine)
Give DDAVP 2ug sc when 1 of:
over 3% of body wt lost
serum osm over 300 or serum Na over 145
serum osm increasing, but urine osm unchanged x 2-3h

After DDAVP give, collect urine and plasma for 2 more hours.


Results

Complete nephrogenic DI: urine osm lower than 300, no resp to DDAVP
Partial nephrogenic DI: urine osm over 300 pre DDAVP, then no response to DDAVP
Complete central: urine osm never over 300, then over 50% increase after DDAVP
Partial central: urine osm over 300, rises 10-50% post DDAVP


Nephrogenic- fix underlying, salt restrict, thiazides
Central- give ddAVP


Bonus:

Secondary causes of central DI

1) Infection - TB, Whipple's
2) Malignancy- Germ cell tumor, lymphoma
3) Infiltration- Hemochromatosis, amyloidosis
4) Autoimmune- Wegner's, sarcoidosis, lymphocytic infundibulitis
5) Histiocytoses- Langerhans' cell or non-langerhans' cell

Approach to renal failure

Today we discussed acute renal failure. Some important points:

The time-tested approach to acute renal failure (or 'acute kidney injury') is
Prerenal, renal, and post-renal

Prerenal:

Hypovolemia: low intake, GI, GU, or insensible losses, hemorrhage, vasodilation)
Low effective circulating volume: CHF, cirrhosis, 'third spacing')
Renal vasoconstrictors: GN sepsis, cyclosporine, NSAIDS, ACE-I/ARB (sort of; different mechanism), hepatorenal syndrome
Characterized by clinical signs of hypovolemia or above problems, bland urine, urine osmol over 450, low urine Na. Responds to fluid replacement

Renal parenchymal:

1) Glomerular
Look for nephritic syndrome: HTN, rbcs, rbc casts, sub-nephrotic proteinuria
or nephrotic syndrome: edema, dyslipidemia, heavy proteinuria (over 3 g/day), hypoalbuminemia, thrombosis
Rapidly Progressive GN AKA 'crescentic' GN: mainly present as nephritic, but sometimes nephrotic (or both!)
1. Immune complexes: (with decreased complement- post strep, endocarditis, SLE, cryoglobulinemia. With normal complement levels- endocarditis, IgA)
2. Linear (Goodpasture's, AGBM)
3. Pauci-immune (Wegener's, Churg-Strauss, microscopic polyangiitis)

Other mainly nephritic: IgA nephropathy (can also be nephrotic), membranoproliferative GN, focal proliferative GN

Mainly nephrotic: minimal change, FSGS, membranous, nodular

2) Tubulointerstitial:
AIN: Drugs: Abx (methicillin classic, also quinolones), NSAID, allopurinol. Infection- pyelo, CMV, legionella. Neoplastic: myeloma, amyloid. May see WBC casts (shown above), urine eosinophils (Sn ~70%. Sp ~80%)
ATN: ischemic (hypotension, sepsis), toxic: exogenous (meds- aminoglycosides, ampho, cisplatin, contrast) or endogenous (myoglobin, hemoglobin, uric acid eg. from tumor lysis, Ca2+). Hallmark is heme granular casts. Characterized by high urine Na, low osmolality.

3) Vascular:
Large vessel: RAS RA thrombosis vasculitisrenal v. thrombosis esp. in nephrotic syn
Small vessel: HTN nephrosclerosis, scleroderma renal crisis, cholesterol embolic (livedo reticularis, blue toes, dusky feet, eosinophilia) TTP/HUS, antiphospholipid syndrome, DIC

Postrenal:

Lower UT obstruction (prostate, mass, etc) or effective obstruction (e.g. retention from meds), neurogenic bladder, UTI, bladder stones, bilateral stones or stone with 1 kidney, retroperitoneal fibrosis (NB- may have no hydronephrosis here), lymphoma
Usually characterized by bland urine, imaging evidence of obstruction (but not always). Urine output is not always low.

General approach:

1. Previous creatinine
2. Hx: drugs, volume, systemic disease (lung, joint, skin, fever...)
3. Volume status assessment, assesment for dialysis indications
4. Urinalysis: blood, protein, casts, cells, eosinophils
5. Urine lytes, osmolality
6. U/S of abdo to r/o obstruction
7. Serology: ANA, anti-GBM, ANCA, C3, C4.

Link:

Click here for a NEJM CPC that goes over the approach to ARF

Pulmonary embolism

Today we discussed PE in the setting of malignancy. Some points about this common and serious disease:

Clinical presentation:
Notoriously unreliable. May see any or none of

SOB, pleuritic C/P, hemoptysis, palpitations
Tachypnea, tachycardia, desaturation, hypotension

Other possible findings:
ABG- hypoxia, resp alkalosis
CXR- atelectasis, effusion, Westermarks's (proximal pulm art dist with distal oligemia), Hampton's hump (peripheral density from infarct). This CXR signs are rare; most commonly normal CXR
ECG- RV strain (STD V1-V2, RBBB, RAE, RVH, R axis dev), S1Q3T3- massive. Usually just sinus tach
Echo- RV stress (hypokinesis, TR, dilation)

Clinical exam is of insufficient Sn/Sp to make diagnosis; it gives a pretest probability.
Non-invasive investigations are also not Sn or Sp alone, although a -ve CTA may be sufficient to withhold anticoagulation

Approach is to
1) Determine pretest probability
2) Determine whether pt has adequate cardiopulmonary reserve (i.e. will another PE kill this pt?)
3) Perform noninvasive or invasive investigations.

Risk stratification:
Clinical findings of DVT- 3
No other more likely dx- 3
Immobilized over 3d or major surgery within 1 mo- 1.5
HR over 100- 1.5
Previous DVT/PE- 1.5
Active Ca- 1
Hemoptysis- 1

Greater than 6: High PTP (78% have PE)
2-6: Int (28% have PE)
Lower than 2: Low (3% have PE)

Management:

DVT and PE are treated the same way:
Initially: LMWH (unless renal impairment or need ability to reverse, in which case UFH infusion. Start warfarin; adjust to INR 2-3, then d/c warfarin

Long term:
With reversible/treatable cause for DVT/PE:
Treat underlying, anticoag for 3-6 mo then stop.

Idiopathic:
Anticoag for 6/12, then decide whether to continue based on:
bleeding risk, pregnancy plans, pt's preference.

Underlying unmodifiable reason:
Lifelong anticoag recommended

EBM points:

VTE in cancer

CLOT trial compared the efficacy and complications of the use of LMWH vs. warfarin in treatment of DVT/PE in cancer pts.
Intervention: Dalteparin 200u/kg SC OD x 5d, followed by coumadin for INR 2.5 or dalteparin alone, 200u/kg for 1 month and 150u/kg for 5 months.
Outcomes: recurrent DVT in 6 months, mortality, bleeding
Results: Recurrent DVT: 17% vs. 9% on LMWH (ARR 8%, NNT 13). Significant bleeding: 4% warf, 6% LMWH. Mortality in 6/12: 39% LMWH, 41% warfarin. Subgroup analysis showed decreased mortality on LMWH in pts presenting with VTE and metastatic ca.

Thrombolysis in PE

Only RCT evidence comes from 2002 NEJM paper comparing alteplase vs. placebo in patients with acute PE and RV dysfunction or pulmonary hypertension. Endpoint was mortality or "clinical deterioration requiring escalation of treatment"; this might include pressors/inotropes, CPR, surgery, intubation, or thrombolysis. There was no mortality difference, but the alteplase group had significantly lower "escalation of care". This is a criticized paper because some argue that it essentially gives the "escalation of care" outcome to 1 group to begin with (i.e. thrombolysis as both an intervention and an outcome is a bit strange).

Hemolytic anemia

Today we discussed hemolysis. These cases are relatively rare, but can cause impressive anema and can be very challenging to manage (and blog about!). A few points:

Hemolytic anemias account for less than 5% of cases of anemia, and have over 200 causes.


Traditional approach to differential is

1) Intracorpuscular 2) Membrane 3) Extracorpuscular


Intracorpuscular- think of what an RBC contains: Hgb, enzymes.

Inherited hemoglobinopathies:
alpha and beta thalassemia, sickle cell disease (SS and SC), unstable hemoglobins

RBC enzymopathies:
Pyruvate kinase def (N.Europe; shows echinocytes)
G6PD def- in males mainly. Inducers of G6PD deficiency related hemolysis:
dapsone, primaquine, sulfamethoxazole (many other obscure drugs), fava beans

Membrane

Hereditary spherocytosis: N europe (1/2000). 75% AD. Has spherocytosis, osmotic fragility
Hereditary elliptocytosis

Extracorpuscular

Inherited RBC antigen abnormalities

Immune-mediated hemolysis: Shown in above picture
Autoimm- warm (IgG), cold (IgM or IgG). Associated with autoimmune conditions, immunodeficiency, lymphoproliferative disorders, malignancy, infection (For cold, mycoplasma, EBV, HSV. For warm, CMV).
Alloimmune- active (e.g. transfusion, transplant), passive (e.g. in newborns)

Metabolic:
Renal failure- esp echinocytes
Hepatic failure- esp acanthocytes
Hypophosphatemia
Osmotic hemolysis (dialysis)

Toxins/physical:
aresnic, lead, Wilson's
valvular disease, vegetations
LVAD, intraaortic balloon pump, cardiac bypass, dehisced mechanical valves,
burns, radiation, trauma (e.g. march hemoglobinuria in soldiers)
Venoms (snake, spider)

Drug- induced hemolysis :
May be hapten, innocent bystader (RBCs adsorbed to IC's), or induce warm autoimmune (bad because remains after drug goes)
Drugs (many!)- Classics are alphamethyldopa, cephalosporins, penicillin, quinine, sulfonamides.

Infections:
clostridial sepsis
DIC
Mycoplasma, EBV, CMV
HSV, syphillis
Parasitic: malaria, babesiosis

Thrombotic microangiopathy
DIC, TTP, HUS, HELLP, acute fatty liver of pregnancy, ticlopidine, plavix, calcineurin inh


Some points on a "hemolysis history"

Age, ethnicity, malaria endemicity
temporal onset (for acquired vs congenital cause)
anemia symptoms
hemolysis symptoms (flank pain, hemoglobinuria, biliary colic)
PMHx (autoimm, rheum, malignancy, infectious, thrombosis)
FHx (hemolysis, splenectomy, pigment stones)
Meds/foods: Drug induced (or 'DIHA' as hematologists call it), TTP instigators, G6PD triggers
Transfusion hx


Focused physical

fever, tachycardia, hypotension
scleral icterus, pallor, jaundice
SLE features
lymphadenopathy
organomegaly, Murphy's sign

Lab:

1) For hemolysis itself:

Reticulocytosis, blood film changes (fragments, spherocytes, etc), plasma hemoglobinemia, high unfractionated bili, high LDH (nb- AST may be high, not ALT), low haptoglobin (both intra and extravascular). If all RBC production stops, expect Hgb fall of ~10/wk. If faster, probably destruction (e.g. hemolysis) happening

2) For potential causes

CBC, retics, blood film, DIC testing, ABO type and screen (i.e. indirect AT), DAT, cold agglutinin testing
Others: PNH, HB electrophoresis, osmotic fragility, sickle testing, 02 affinity testing, HIT, blood cultures, viral titres.


Management:

Depends on reason for hemolysis. If autoimmune, general principles are

1) avoid transfusion unless absolutely necessary, but involve the blood bank . transfusion medicine early- may be extremely difficult or impossible to find appropriate units
2) If cold autoimmune: warm extremities, warm IV fluids, steroids, plasmapheresis
3) If warm autoimmune: steroids, IVIG, plasmapheresis. Splenectomy in refractory cases
4) Try to reverse underlying cause if possible


Some links:

Click here for interesting NEJM case and image on cold agglutinin disease
For the serious connaisseur, click here for a review of autoimmune hemolytic anemias

HIV- CNS manifestations

Today we discussed the approach to neurological symptomatology in the setting of HIV.

As a general rule, whenever faced with a new (or worsened) problem in the setting of a pre-existing disease, a useful dichotomy is whether this new problem is related or unrelated to the underlying disease.


A useful way of subdividing this problem is whether or not there are imaging abnormalities (may require enhanced MRI to see), and if so, whether there is mass effect.

CNS lesion with mass effect:
1) Toxoplasma (in CD4 <100). Reactivation from prior infection. Toxo antibodies are supportive. Lesions are multiple, and localized to frontal or parietal lobes, thalamus, basal ganglia. Ring enhancement in 90%. Shown in the above picture. May be mimicked by lymphoma- MRI is best test.
2) Primary CNS lymphoma. May see neuro sx or wasting sx. Solitary and multiple lesions are equally frequent. Corpus callosum lesions or periependymal lesions are more likely lymphoma.
3) Brain abscess (staph, strep, salmonella, aspergillus, listeria, 'gumma' from syphillis) Rarely, tuberculoma or cysticercosis

CNS lesion without mass effect:
1) PML- demyeliniting disease from JC virus (acquired in childhood by 90% of population). Seen in severe immunosuppression. Rapidly progressive focal deficits inc. hemiparesis, field deficits, ataxia, aphasia, cognitive changes. Multifocal demyelination.
2) CMV encephalitis- need CD4<50. delirium, confusion, neurological abnormalities.
3) HSV encephalitis- increased risk in HIV; may see temporal lobe changes on MRI
4) HIV encephalopathy: memory and psychomotor slowing, depression, movement disorders- may see symmetric MRI lesions

No CNS lesion on imaging:
1) Bacterial meningitis- esp S. pneumo, listeria
2) TB meningitis
3) Cryptococcal meningitis- need to send CSF and serum crypto antigen.
4) Neurosyphillis

Brain biopsy is gold standard, and is sometimes required to differentiate above possibilities (esp. lymphoma vs. toxoplasmosis)

Some tests you might order from a lumbar pucture in this setting in addition to routine:
Fungal cultures, AFB staining
PCR for JC virus, HSV, EBV, TB ('AMTD')
Cryptococcal antigen
VDRL
Check opening pressure; may be high in cryptococcal meningitis. High OP in cryptococcal meningitis carries a poor prognosis, and may require a lumbar drain or shunt.

Link:
Click here for a good review of PML from the ID department

Diabetic ketoacidosis

Today we discussed DKA. This potentially life-threatening problem is a relatively common internal medicine referral, and although most cases are straightforward, there are a few points to keep in mind to ensure optimal management.

Pathophysiology:
Requires insulin deficiency and increased counterregulatory hormones. Often triggered by inadequate insulin dosing, surgery, infarction (e.g. MI, mesenteric, etc.), infection, steroids. Always search for the precipitant of DKA!

Points on history:
1) History of hyperglycemia: polydypsia, polyuria, polyphagia, visual blurring
2) History suggestive of DKA itself: abdominal pain is common, tachypnea, nausea
3) History of volume depletion: Presyncope, postural symptoms
4) Search for precipitant: Chest pain, abdominal pain, medications, intoxications, insulin use (ar lack thereof...)

Points on physical:
Physical examination may or may not demonstrate depressed sensorium. Typical findings include tachypnea with Kussmaul’s respiration, tachycardia, frank hypotension or orthostatic blood pressure changes, the odor of acetone on the breath, and signs of volume depletion.

Labs:
Ordered on most patients would be
Glucose, cbc+diff, lytes, ABGs, serum ketones, urine dipstick, Cr, BUN, tox screen, lactate, troponin, ECG, CXR
Monitors: 2 large bore IVs, ECG, foley, possibly art line.

3 Common errors in DKA management:
1) Mismanagement of K+ is the main reason for mortality in these patients. The K+ may be normal because of shifting out of cells from acidosis and lack of insulin, but patients are total body depleted because of urinary losses from polyuria and increased aldosterone. Starting with normal K+ is concerning, and starting with low K+ is very concerning, and that patient may need ICU for central line to deliver K+

2) The main problem in DKA is not hyperglycemia, it is ketoacidosis. The insulin drip is to treat the anion gap (i.e. the ketoacidosis), not the hyperglycemia. If the patient has a high anion gap and normal glucose, continue the insulin and add glucose.

3) Transition to SC insulin after infusion is an issue. Remember that the halflife of IV insulin is minutes, and you therefore need to overlap SC with IV, usually for several hours (until the effect of the SC insulin) before turning infusion off. Transition to SC when anion gap is normal, glucose is controlled, IV insulin dose is stable, and patient is eating. Remember that SC insulin is half as bioavailable as IV.

Management:

Major issues (not necessarily in this order; depends on specific situation) are:

1) volume 2) electrolytes (esp. K+) 3) insulin 4) acid/base status

1. IV fluids: Start with 1L NS wide open. Make sure urine output. General teaching is 1L in 30 min then 1L in 1h. When glucose reaches 12-14, change to D5W with 1/2 NS and decrease insulin to 0.05U/kg/h. Maintain glucose at this level until DKA is resolved and pt is alert. Avoid giving hypotonic solutions because of risk of brain edema (seen more in kids) which comes from shifts in glucose without accmpanying change in Na.

2. K, PO4: If K less than 3.3mM, hold insulin, give 40mM K per liter of IV fluid until K is greater than 3.3. If K is above 5.5, do not give K, but check level q2h. If K is between 3.3 and 5, give 20-40mM K in IV fluid to keep K at 4-5mM, possibly with additional K po. Give K before insulin anticipating fall if it is low to begin with. Remember that phosphate also gets shifted (like K) and if gets very low may cause rhabdo, severe muscle weakness, CHF, etc. Replace it.

3. Insulin (IV): Bolus 0.1u/kg, then 0.1U/kg/h. Check glucose hourly. If it does not fall by 3mM in 1st hour, double insulin dose hourly until steady drop of 3-4mM/h. See above for when glucose=12-14. After resolution, check glucose q4h and start SC insulin. Insulin continues until AG normalizes.

4. Acid/base: In general bicarb not required unless pH is less than 7.0. If so, may give amps or dilute 3 amps NaHCO3 in 850mL D5W, and infuse 150-200mL/h.
Control N/V with IV Gravol

Many people find it convenient to manage DKA by a flowchart updated ~hourly (although not everything needs to be checked hourly). You may want to record:
Time, Vitals, urine output, pH, HCO3, AG, Ket, Glu, K, PO4, IV fluid rate, insulin dose

A couple of extra points:
-Na for anion gap calculation is not adjusted for glucose.
-Expect to see non-anion gap metabolic acidosis after AGMA resolves, because of loss of ketone bodies without H+ (i.e. loss of anion alone)

Link:

Click here for a CMAJ review article on DKA that also compares and contrasts with diagnosis and management of HONK

Listeriosis

Today we discussed issues related to listeriosis. Some important points:

Listeria monocytogenes is an important cause of bacteremia and CNS infection in high risk groups. Listeria enters the body through the GI tract and then disseminates hematogenously; it is particularly "CNS-tropic"

Microbiology:
Aerobic gram positive bacillus that grows in cold temperatures, making it particularly suited to be a "refrigerator-proof" food-borne organism. Effectively cultured from normally sterile sites (e.g. blood, CSF), but not from stool samples.

Some of the implicated foods in outbreaks:
-Soft cheeses
-Coleslaw
-Deli meats
-Smoked fish
-Butter


Clinical syndromes
1) Self-limiting GI illness with foodborne ingestion in immunocompetent hosts
2) Bacteremia often without obvious focus. Non-specific presentation of fever, malaise, myalgias, back pain. This is the most common form to complicate pregnancy
3) Neonatal- early onset sepsis syndrome or late onset meningitis at 2 weeks
4) CNS infection (may follow bacteremia)- meningitis, encephalitis, brain abscess, brainstem involvement ("rhombencephalitis"; abrupt onset of asymmetric cranial nerve deficits, cerebellar signs, hemiparesis.
5) Others (rare): endocarditis, septic arthritis

Risk factors for listeriosis in adults
Deficits in cell-mediated immunity:
1) Pregnant women in 2nd or 3rd trimester- 30% of cases
2) HIV with low CD4 count (although Septra prophylaxis covers listeria)
3) Hematologic malignancy
4) Transplant
5) Steroids
6) Kidney or liver disease
7) Age over 60

Treatment:

Ampicillin is the drug of choice; this is why it is included in empiric meningitis treatment regimens in patients with risk factors.

Duration: Minimum 2 weeks IV for invasive infections (i.e. more than then self-limited GI illness); at least 3 weeks for CNS involvement

Link:

Click here for a recent CMAJ review of listeriosis

Rhabdomyolysis

Today we discussed rhabdomyolysis. Some important points:

There is a distinction between a CK elevation without other sequellae and rhabdomyolysis, which may involve consequences such as weakness, electrolyte disturbances, renal failure, acidosis, etc. True rhabdomyolysis is unlikely if the CK is below 10000.

Rhabdomyolysis is a syndrome of muscle necrosis and release of intracellular contents into circulation.

Clinical manifestations are myalgias, pigmenturia (positive supernatent for blood after spinning).

Weakness is only present in most severe cases with significant muscle necrosis.

Lab hallmark is increased CK; 10000 range, up to 100000. CK is the MM fraction. Myoglobin from muscle is released together with CK, but myoglobin is cleared before CK, so may see CK up, but not myoglobin

Renal failure- usually oliguric ATN, from tubular deposition of heme pigment casts and iron from myoglobin

Lytes- Disturbances in Na (sometimes high), K (high), PO4 (high), Ca (low), HCO3 (low), uric acid (high). Hypocalcemia may be extreme, from hyperphosphatemia and increased Ca/PO4 product from Ca salt deposition in necrotic muscle.

Can see hypernatremia because free water "3rd spaces" to muscle because of all of the metabolites.

May increase Cr out of proportion to GFR because creatine is broken down to creatinine


DDx of major causes: (for complete list see link below)

1) Trauma/compression
-crush injury
-struggle against restraint
-immobilization from coma, fracture
-compartment syndrome
-surgery; positioning and tourniquets

2) Non-traumatic "exertional"
-extreme exertion (RFs are unfit, hyperthermia, impaired sweating)
-hyperkinetic states: T-C Sz, DT, severe agitation, amphetamine OD

3) Drugs / poisonings
-Malignant hyperthermia: fever, rigidity, muscle contraction
-EtOH, narcotics, anything causing coma leads to compression
-Sympathomimmetics- cocaine, ecstasy, amphetamines
-CO poisoning
-Statins (esp with cyp inhibitors)
-NMS: fever, rigidity, autonomic instability, post-dopamine antagonist (antipsychotic), or withdrawal of anti-parkinsonians

4) Infections (do not usually cause 'rhabdo-level' CK elevations)
-generalized sepsis
-pyomyositis
-viral (HSV, HIV, EBV, Coxsackie, influenza, CMV)

5) Inflammatory (do not usually cause 'rhabdo-level' CK elevations)
-Dermatomyositis, polymyositis, other inflammatory myopathies

6) Metabolic
-hypokalemia, hypophosphatemia: normally, exercise causes shift of K out of cells, which is trigger for pathway leading to muscle hyperemia and increased O2 delivery. If total body K depleted, less shift, less hyperemia, necrosis.
-extreme hypothyroidism
-metabolic myopathies (suspect in recurrent; CPT deficiency most commonly- may present in adulthood)

Management:

1) HYDRATION!- even if euvolemic, lots of NS, or possibly 150mM HCO3 (i.e. "normal bicarb")- goal urine pH >6.5
2) Reverse underlying cause if possible
3) Mannitol for osmotic diuresis (this is controversial). Give 0.5-1g/kg then 0.25-0.5g/kg q4-6h, usu 20-200g/24h as 20% solution in D5. Possible alternative is loop diuretic (also controversial) Replace urine losses with appropriate IV solution- do urine lytes.
4) Correct lyte disturbances, except Ca, which is replaced only if clinically hypocalcemic (i.e. paresthesias, tetany, long QT) or hyperkalemic. NB- in extreme cases, may see profound hypernatremia acutely, from free water loss in muscle.

Link:

Click here for good review from Critical Care

Click here for a paper questioning the use of bicarb and mannitol

A hematology sampler

I couldn't find a unifying theme to morning report today other than all things hematologic. Many big topics were discussed, so to avoid a post that's 12 pages long, here are a few pearls that came up with a bit more detail...

"Leukoerythroblastic picture"
Neutrophilia, nucleated RBCs, few circulating blasts.
Ddx inc severe stress, infection, sepsis.
This with teardrop cells means "myelophthisic" picture
Ddx here includes tumor invasion of marrow, myelofibrosis, granulomatous disease

WBC morphology on blood film
-Normally less than 70% PMN, less than 30% lymphocytes
-PMNs should have no more than 3 lobes. More is megaloblastic (B12, folate, thyroid, valproate, AZT, hydroxyurea, folate antagonists). Bilobed seen in Pelger-Huet (congenital defect of PMN differentiation)
-Infection is suggested by a) toxic granulations, b) bands
-Atypical lymphocyes seen in EBV (means nuclei with nucleoli)
-Auer rod seen in AML. May also see eosinophils
-Eosinophils- drugs, parasites (esp filariasis), Churg-Strauss, HES, cholesterol emboli, many others
-Basophils- adrenal insuff, malignancy
-Monocytosis- seen in MDS
-Smudge cells- seen in CLL
-Marked L shift with preserved morphology- seen in CML before transformation

Myelodysplastic syndrome

Common feature: Ineffective production of normal mature red cells.
MDS implies risk of developing AML; 20-30% of MDS pts progress to AML

Dx is suspected if 1) sx of blood disorder 2) incidental finding of cardial MDS features: a) macrocytosis, b) monocytosis, c) cytopenias in any lineage - combination of these is highly suggestive.
~80% of pts are anemic at diagnosis; 50% have Hb <100. 40% are neutropenic at dx. TCP in 30-45%. Neutropenia or thrombocytopenia may occur without anemia.


Splenomegaly causes by etiology

Hematologic:
Massive (i.e. below or across the umbilicus): Thal major
Non-massive: RBC membrane defects, hemoglobinopathies, autoimmune hemolytic anemias

Rheumatologic:
Massive: none
Non-massive: RA (felty), SLE, sarcoidosis

Infectious:
Massive: leishmaniasis, malaria, MAC
Non-massive: viral, bacterial, mycobacterial, fungal, parasitic

Congestive:
Massive: none
Non-massive: cirrhosis, venous thrombosis (portal, hepatic, splenic)

Infiltrative:
Massive: lymphomas, myeloproliferative, Gaucher's
Non-massive: lymphoma, myeloproliferative, cancer, amyloidosis, Gaucher's, Niemann-Pick, glycogen storage diseases, hemophagocytic syndrome, histiocytosis

Links:

Click here for a good review of myelodysplastic syndromes
Click here for a good hematopathology slide site from the University of Utah

Click here for a NEJM CPC of massive splenomegaly

Splenomegaly

Today at physical exam rounds we discussed splenomegaly.

Some important points:

3 Percussion methods (Castell's is easiest and best):
1. Castell's: Pt supine, percuss lowest ICS L ant axillary line and full insp and exp. +ve is any dullness.
2. Traube's: Pt supine, L arm out of the way. Space is bordered by 6th rib superiorly, midax line laterally, L costal margin inferiorly. Pt breathes normally, and space is percussed. +ve is any dullness
3. Nixon's: Pt in RLD position. Percuss in midpoint of L costal margin (nipple line), and move perpendicular to margin. +ve is dullness over 8cm above costal margin.


3 Palpation methods:
1) Patient supine: Start in RLQ and move up to LUQ; Pt inspires, and feel for spleen tip meeting examiner's stationary hand. If not felt, move 2cm towards LUQ on expiration.
2) Patient in R decubitus: Examiner's L hand is across patient's thorax, lifting the L ribcage anteriorly and medially. R hand is just below costal margin. Pt takes deep breath, and feel for spleen tip. If not felt, move 2cm towards umbilicus to ensure massive spleen not missed.
3) Hooking: Pt lies flat with fist under CVA on L. Examiner is on pt's L side, facing pt's feet, with fingers of both hands under costal margin. Pt takes deep breath, and feel for tip.


Evidence:
In general, percussion is sensitive, and palpation is specific.
When the pre-test probability is low, physical exam cannot reliably rule out or rule in splenomegaly.
Examination is most useful in ruling in splenomegaly when the pre-test probability is high (i.e. if percussion and palpation are both positive, the diagnosis is established).
In high pre-test probability, no method is sensitive enough to exclude; need imaging.

Most sensitive signs (i.e. make it unlikely if not present):
1) Castell's sign (~80% range)
2) Traube's space palpation (~60%)
3) Nixon's method (~60%)
All palpation methods are insensitive (~50-60%)

Most specific signs (i.e. make it likely if present)
Any of the above palpation methods; (~90% specific)

Spleen vs. kidney:
1) upper pole never palpable in spleen
2) respiratory movement with spleen, not kidney
3) notch
4) kidney may be balotable
5) spleen expands towards RLQ; kidney expands vertically

Bonus:
Bruit: heard in splenic hemangioma
Rub: heard in splenic infarct

Link:
Click here for JAMA Rational Clinical Exam on splenomegaly (need log-in; ask me how to obtain)

Hypoglycemia

Today we discussed hypoglycemia. Outside context of medications, this is very rare, but must be investigated. Some important points that came up:


A framework for causes (loosely based on Harrison's):

1) Alimentary / postprandial

"Pseudo": normal glucose with symptoms. Possible role for 5h glucose tolerance test
"True": Occurs with rapid gastric emptying (gastrectomy, pyeloroplasty, refeeding, post-vagotomy)

2) Fasting

Decreased supply (i.e. not an insulin problem):

Hormone deficiency (pituitary or adrenal)
Liver failure (late)Starvation (late)
Enzyme deficiency (in childhood/neonate)
EtOH (from decreased NADH)
Medications (sulfa, salicylates, pentamidine, quinolones)

Increased demand (i.e. an insulin problem)

Low insulin- IgF-secreting tumor (sarcoma, RCC, HCC)

High insulin
Exogenous insulin
Insulin secretagogue (e.g. sulfonylurea)
Insulinoma
Insulin receptor antibodies (autoimmune)


Pts usually become symptomatic (neuroglycopenic or autonomic symptoms) at BG less than 2.5-3

Need to confirm hypoglycemia (with serum, not capillary glucose), that symptoms are caused by it, and that glucose reverses the symptoms (sometimes referred to as Whipple's triad)

Best test to rule in insulinoma or other neuroendocrine tumor after ruling out medications and adrenal insufficiency is 72h fast

Pts are admitted to hospital, and fasted for up to 72h, allowed to take calorie-free fluids only, and are active during waking hours. Blood for measurement of glucose (serum, not accucheck), insulin, c-peptide are taken q6h, with measurement of insulin and c-peptide when BG less than 3.3mM

Endpoints of the test are any of: 1) BG below 2.5, 2) neuroglycopenic symptoms, 3) 72h elapsed
-Also give 1mg glucagon and measure BG q 20min x 3
-Feed the pt
-Insulin level over 3uU/mL when BG is below 3.0 is highly suggestive of insulinoma.
-C-peptide is measured to differentiate endogenous vs. exogenous insulin (with exogenous insulin, insulin level is high, but c-peptide is undetectable since exogenous insulin does not have c-peptide)

If test is positive, imaging studies: CT/MRI/US

Therapy for insulinoma is surgery; medical management is octreotide or diazoxide.

NB- look for MEN1 if insulinoma (pancreatic endocrine tumors, pituitary tumors, primary hyperparathyroidism)

Link:

Click here for 2009 practice guideline for this problem from the Journal of Clinical Endocrinology and Metabolism

Asthma in inpatients

Acute asthma exacerbations are relatively common internal medicine referrals. Some points on managing this potentially life-threatening condition:

Indicators of severity:

Clinical- SILENT CHEST, pulsus paradoxus, acc muscle use, diaphoresis, inability to speak
Peak flow- less than 200 or less than 50% of baseline is severe attack
ABG- hypoxia is rare, and indicates very severe. Hypercapnia or even normal PCO2 is bad; indicates tiring.
CXR- unhelpful usually; may do to exclude pneumothorax (possible complication), pneumonia.

Very important to get a peak flow reading on presentation and then monitor closely q1-2h during therapy to assess progress.

Therapy

1) B-agonist: Mainstay of therapy
Salbutamol 4-6 puffs q1-2h iniitally. Outcomes with inhaler vs. nebulizer are essentially equal assuming proper technique. 1 NEB treatment generally equals 4-6 MDI puffs with a spacer.

2) Ipratroprium: Added if not initially responding or if severe.
Especially recommended for pts with COPD or B-Bl triggered asthma.
Ipratroprium 500mcg NEB q6-8h (can be given with 1st ventolin neb treatment) or MDI 2 puffs of 17mcg each q6h.

3) Steroids:
Consider if:
1) less than 10% increase in PF after 1st dose of B-ag
2) attack in pt on oral steroids before attack
3) PF less than 70% predicted after 1h of treatment
Only difference between PO and IV steroids is onset of action; within 1d for IV vs possibly 2d for PO. Otherwise equivalent. Dose of steroid is not clear. For severe, a commonly studied dose is Solumedrol 125mg IV q6h x 3d. For less severe, consider Solumedrol 30mg IV q8h x 3d then switch to oral.
PO: Prednisone 1-2mg/kg/d divided q 8-12h for 2-4d, then reduce. All pts who received steroids should get oral steroids on discharge; usually prednisone on tapering regimen for 8-10d, but also acceptable if steroid naive to keep on prednisone for 1 week, reassess, and d/c abruptly if less than 10d

4) MgSO4: Some evidence of benefit; blocks SM contraction. 2g IV over 20min. Little toxicity to this dose

5) Epinephrine: last resort; patient will probably need intubation.

6) Final step is rapid sequence induction and intubation by the most skilled person available (there may only be 1 chance), and initiation of inhaled anesthetics (which are bronchodilators). Ketamine is also a bronchodilator.

Little or no role for antibiotics, theophylline, montelukast

Consider admission if:
-peak flow less than 40% of predicted after bronchodilators or less than 25% on arrival
-any hypoxia, distress, etc.

Consider ICU or intubation if:
-Clinically tiring or in respiratory distress
-Hypercapnea or hypoxia
-Worsening on therapy
-PF less than 150

Links:

Click here for acute exacerbation guidelines from 2007

Click here for evidence for magnesium in acute exacerbation

Asthma in outpatients

We had a clerk teaching session on asthma, and I thought I would share some points with everyone:

Diagnosis

Relative increase in FEV1 of 12% post-bronchodil AND over 200cc change. More sensitive test is methylcholine challenge

Steps for therapy: With each, patient education, environmental control

1) SABA prn
2) low dose ICS
3) (low dose ICS + LABA) or medium dose ICS
4) medium dose ICS + LABA
5) high dose ICS + LABA and consider omalizumab for allergic asthma (eosinophilia or symptoms)
6) high dose ICS + LABA + oral steroid and consider omalizumab

Before stepping up treatment, check puffer technique, adherence, environmental control, comorbidity.

Note that LABAs are never used without inhaled steroids; LABA alone increased mortality in trials

Do not step down unless asthma is well controlled for 3 months.

Parameters of control
daytime sx less than 4x/wk night sx less than 1x/wk normal physical activity mild, infrequent exac, no absenteeism B2 agonist use less than 4x/wk peak flow or FEV1 over 90% of best

Some general differences between asthma and COPD

1) reversible vs fixed obstruction
2) steroid responsiveness higher in asthma than COPD
3) small role for anticholinergics in asthma
4) very rarely use abx for exacerbations in asthma
5) dyspnea, tightness, wheeze in asthma vs dyspnea, cough, sputum in copd
6) early vs. late onset

In the non-responding asthmatic, think about:
1) poor compliance
2) poor inhaler technique
3) environment
4) drugs- B-bl, ASA
5) comorbitites- GERD, sinusitis, allergies, CHF
6) complications- ABPA, churg-strauss, chronic eosinophilic pneumonia
7) psychosocial
8) wrong diagnosis- consider vocal cord dysfcn, airway obstruction, CF (adult)

Links:

Click here for the 2007 NIH asthma guidelines

Acknowledgement:

Some of the above is taken from the University of Toronto Department of Respirology resident handbook

Hyponatremia

Today we discussed a common internal medicine problem, hyponatremia.

Acute vs. chronic cutoff is 48h.

Hyponatremia relative excess of free H2O for a given total body Na or ECFV (whether it's hypo/eu/hyper).

Traditional first breakpoint is by serum osmolality:
1) Hyperosmolal: hyperglycemia (10:3 adjustment), mannitol (IV)
2) Euosmolal: hyperproteinemia, hyperlipidemia (both pseudo; not usually an issue with modern lab techniques), bladder irrigation (dilutional)
3) Hypo-osmolal: Most common

Within Hypo-osmolar, divide by volume status:
Hypo: vomiting, diarrhea, DKA, diuretics, hypercalcemia
Eu: post-op, pain, nausea, pregnancy, SIADH (paraneopl from lung/CNS/pancreas/HL/leukemia or non-neoplastic), beer potomania, psychogenic polydipsia, hypothyroidism, adrenal insufficiency
Hyper: CHF, cirrhosis, nephrotic syndrome, renal failure

A word on SIADH:

Drugs that cause it: The "C's":
cyclosporin, cyclophosphamide, carbamazepine, cisplatin, 1st gen sulfonylureas (like chlorpropramide), antipsychotics (like clozapine), SSRI (OK...not a "C")

SIADH criteria
serum osm less than 275
urine osm more than 100
urine na more than 40
euvolemia
no diuretics
normal thyroid and adrenal function

NB- 'SIADH' with low UNa is not inappropriate b/c hypovolemia should turn on ADH.

Rate of correction:

Be very careful with the hypovolemic, hyponatremic patient (which is very common!). Danger is to volume replete and turn off ADH, causing dilute urine excretion, and rapid increase in Na. Consider ddAVP here; e.g. 2-4mcg IV or SC, even possibly before volume resuscitation. Always monitor urine output and serum lytes closely in this setting.

Aim for an increase of less than 8mEq per 24h (truly dangerous range is 12mEq/24h)
Highest CPM risk: malnourished, elderly, EtOH use (i.e. most people who get hyponatremic!)

Acute or severely symptomatic (e.g. sz, coma, cerebral edema):
3% saline at 1-2ml/kg/h
aim for 2mM/h increase
check Na q2h
d/c when symptoms improve

Othewise, fluid restrict and watch carefully.

Links:

Click here for a NEJM review of SIADH

Click here for the evidence for ddAVP in preventing overcorrection

Dementia

Today we discussed dementia, paricularly with a rapidly progressive course

General classification of dementias:

1) Alzheimer's disease: 60-70%- hallmark is early loss of anterograde memory, with loss of functioning. Late loss of languange function.


2) Non-AD: 30-40%

Vascular- hx of CV risk factors, hx of overt stroke. Imaging shows stroke, leukoencephalopathy, ischemic or degenerative changes. Classically step-wise, with steps overnight.


With Parkinsonism:
- Dementia with Lewy bodies and Parkinson's dementia. Difference is whether parkinsonism was present first for over 1yr, which means PDD. DLB is characterized by nonbizarre delusions, neuroleptic sensitivity, REM sleep behaviour disorder (i.e. no paralysis in sleep, acting out violent dreams), autonomic disturbance
- Progressive Supranuclear Palsy (PSP)- upward, then downward, then lateral gaze palsy. Prominent truncal parkinsonism, with severe postural instability. Very high fall risk. Increased tone. Minimal response to L-dopa.
- Cortico-basal degeneration (CBD)- marked laterality of movement disorder. Apraxia, alien limb possible. Minimal response to L-dopa


Frontotemporal dementia (FTD)
- Frontal: personality change, with executive dysfunction, disinhibition, and/or apathy
- Temporal: Memory loss in 25%, language deficits- all anomic, either fluent or non-fluent with circumlocution and word-finding difficulty.
NB- ALS may present this way


Rapidly progressive dementia- a long, but still incomplete list of potential causes

1) Atypical presentation of primary neurodegenerative dementias (FTD, AD, LBD, PSP, etc.)
2) Structural brain disease (tumors, bleeds, collections, NPH)
3) Medications- Li, serotonin syndrome
4) Seizures
5) Infections (HIV, PML, cryptococcal meningitis, syphillis, malaria, TB, bartonella, Whipple's)
6) Psychiatric illness
7) Prion disorder (CJD, vCJD)
8) Autoimmune (Hashimoto's encephalopathy, others)
9) Inflammation (MS, ADEM)
10) Paraneoplastic (limbic, brainstem, etc)
11) Vasculopathy (vasculitis, intravascular lymphoma, CADASIL)
12) Nutritional (B12, folate, niacin, thiamine)
13) Genetic- late presentation of genetic disorder (e.g. hereditary adrenoleukodystrophy, neuronal ceroid lipofuscinosis, etc.)
14) Toxin (cocaine, EtOH, amphetamines, heavy metals, solvents, chemotherapy)
15) Systemic disease (sarcoid, celiac, CNS lupus, Sjogren's, Behcet's)
16) Metabolic (hypothyroidism, hypercalcemia, etc.)

Investigations:

CBC, lytes, liver, renal, glucose, thyroid, B12. CT scan for subdural, NPH. Possible MRI with gadolinium, EEG.
In correct settings, consider HIV, syphillis, depression, CNS vasculitis (h/a, sz, dementia), prion disease

Links:

Click here for NEJM clinical conference on this topic
Click here for CMAJ review of dementia diagnosis

Idiosyncratic drug reactions

Today we discussed many types of drug reactions. Some important points:

These are immune-mediated, which is distinct from drug toxicity, which everyone will get at high enough level. Idiosyncratic drug reactions (IDRs) are not anaphylactic reactions

IDRs may be single-organ (e.g. hepatitis) or multi-system ("drug hypersensitivity syndrome")

1) Drug hypersensitivity syndrome
Characterized by fever, rash (with or without mucosal involvement), and internal organ involvement (failure). Occurs with incidence of 1 in 1000 to 10000 with these culprit drugs: anticonvulsants (almost all of them), sulfonamides, allopurinol, and dapsone. Timeframe is 2-8 wks after initiation. Sometimes also called "DRESS" or drug reaction with eosinophilia and systemic symptoms)
Most serious:
Stevens-Johnson's, Toxic Epidermal Necrolysis: desquamating skin and mucosal involvement; organ failure. Distinguished by surface area involved. Less than 30% BSA = SJS. More than 50% = TEN; overlap = between. Tx: supportive (inc. burn unit), possible role for steroids, IVIG.

2) Serum sickness-like reaction
Causes fever, arthritis, lymphadenopathy, rash. No internal organ involvement. Timeframe is 7-14d after initiation. Major culprits are cefaclor, minocycline, and bupropion.

3) Drug-induced lupus
Clinically, mainly arthritis, serositis, wt loss. 95% have anti-histone AB, negative anti dsDNA, normal complements.
Major culprits are procainamide, dilantin, INH, hydralazine, methyldopa, quinidine, chlorpromazine, minocycline.
Timeframe may be up to 1-2 years after initiation of therapy

General approach to treatment is to D/C drug, supportive therapy, steroids as dictated by severity.

Some specific drug-rash combinations:
Urticaria: codeine, ASA
Photosensitivity: hydroxychloroquine, chlorpromazine
Psoriasis: lithium, B-blockers
Serum sickness-like reaction: Cefaclor
Fixed drug eruption: Anticonvulsants, sulfonamides

Dilantin kinetics:

Remember that phenytoin exhibits zero-order kinetics after a certain level. This means that only a fixed amount (not proportion) of drug is metabolized after a certain point (which is unknown for a given patient). If this threshold is crossed, a very small increase in dose can cause a big increase in level and toxicity. Increase doses slowly and by small increments (e.g. 25-50mg/d at a time, checking levels).

Links:
Click here for a good overview of idiosyncratic drug reactions
Click here for a NEJM case conference which discusses severe drug reactions
Click here for study of anticonvulsant teratogenicity
Click here for a summary of phenytoin kinetics

Sickle cell anemia

Blood film showing many features of SCD: sickles (blue arrow), Howel-Jolly body (black arrow), targets (red arrow), and nucleated RBC (top left)





Today we discussed sickle cell anemia. Some important points:

Pathophysiology is point mutation on Beta globin gene. Results in Hb polymerization and rigid, elongated RBC.

Sickling is promoted by hypoxia, low temp, low pH, volume depletion.

Notes on diagnosis:
1) Hemoglobin electrophoresis- shows 40% HbS in carriers (~60-40 split), and 90%+ HbS in homozygotes.
2) "Sickledex" screening test does not distinguish carriers vs. homozygotes vs hemoglobin SC. Looks for presence of sickling on hypoxic conditions.
3) Blood film will often show no sickles in carriers, but there should always be some sickles in SS. If you see predominantly targets, ddx includes hyposplenism and SC disease (shows almost all targets)

Heterozygotes are usually asymptomatic, with occasional sickles on PBF, but normal Hb levels.

Homozygotes have moderate to severe hemolytic anemia, and have crises and complications

Crises and complications:

Vaso-occlusive crisis: in bone, muscle (very painful). Also at increased risk for stroke even in children (on ddx of stroke in young). May develop 'Moya Moya' (hypervascularity from chronic hypoxia- increased hemorrhage risk)
Resp- chest crisis- defined by infiltrates and hypoxemia (not due to CHF).
Renal- hematuria, tubular defects (acidic, hypoxic environment causes sickling).
Marrow- aplastic crisis- Keep close eye on Hgb in patients with low retics (can drop rapidly) Pts may get parvo and have severe aplastic crisis (can't keep up with increased baseline demand).
ID- hyposplenic- susceptible to encapsulated microorganisms. Risk of osteomyelitis (esp with Salmonella)
Others: priapism, retinopathy/retinal occlusion, leg ulcers

Crisis management:
1) O2 whether hypoxemic or not
2) Fluids
3) Correct precipitating factor (infection, volume depletion, etc)
4) Analgesia
5) Consider transfusion strategy

Transfusions in SCD:
In general be sparing with transfusions because these patients develop antibodies and it's difficult to find units when really needed. Fe overload is also a problem with frequent "sub-necessary" transfusions. Simple pain crisis does not require a transfusion.

Conventional transfusion guidelines:
-aplastic crisis (i.e. below baseline hgb with low or inappropriately normal retics)
-Hb below 50 (may accept lower than usual because baseline may be low)
-active bleeding, etc
STOP TRANSFUSING WHEN hematocrit >0.35 (hyperviscosity and stroke risk)

When to exchange transfuse (i.e. ~14 units exchange)

1) Chest crisis (FiO2 over 40%, infiltrate, no pulmonary edema)
2) Stroke (ischemic or hemorrhagic)
3) Pre-operatively for major surgery to HGB S below 30%
4) Severe sepsis, multiorgan failure
5) Retinal occlusion
6) Fetal distress
7) Priapism (relative indication)

Hydroxyurea in sickle cell disease

Adults with 3 or more painful crises/year; increases proportion of HbF
reduces frequency of painful crises and chest crises. Also mortality benefit (secondary outcome).
Need to monitor hepatic fcn and counts carefully.


References:

Click here for BMJ review of sickle cell disease management

Click here for NEJM review of hydroxyurea in SS disease

Colitis

Today we discussed the approach to bloody diarrhea. Some things that came up:

Bloody diarrhea implies colitis (of some etiology)
Triad of fever, bloody diarrhea, lower abdo pain defines "dyssentry".

Differential diagnosis:
Infectious colitis: campylobacter, yersinia, samonella, shigella, E. Coli (enterohemorrhagic), C.diff. In immunocompromise: CMV.
Ischemic colitis: seen in patients with severe vascular disease, hypercoagulable states, A-fib
Inflammatory colitis: UC (bloody diarrhea and mucous are hallmark symptoms), Crohn's
Post-radiation colitis

Important history:
travel, food, others with same symptoms, medications, hospitalization, sexual contact, symptoms suggesting IBD (inc. extra-intestinal), fhx, constitutional symptoms, immunosuppression risk factors


Antibiotics in infectious diarrhea:

Most causes do not require (and sometimes are worsened by) antibiotics.

Exceptions where Abx are indicated:
C. Difficile
Shigella (to prevent transmission)
Enterotoxogenic E. coli (ETEC) = "traveller's diarrhea", not 0157 (that is enterohemorrhagic)
Entamoeba histolytica
Giardia
Only in severe cases of yersinia, campylobacter, salmonella

Abx are harmful in
Enterohemorrhagic E. coli (as in Walkerton)

Abx not usually needed for
salmonella, campylobacter (most common causes of infectious colitis). Note that campylobacter is not covered by ciprofloxacin (if need to treat, use macrolide)


Extraintestinal manifestations of IBD

Eyes- uveitis
Skin- eryhtema nodosum, pyoderma gangrenosum
GI- PSC (esp UC), stones
Renal (stones- IBD affects oxalate metabolism by unabsorbed bile salts binding calcium, allowing increased oxalate absorption)
Arthritis- Seronegative, large joint symmetric. Either peripheral, which parallels IBD activity, or axial, which is usually independent of IBD activity


Toxic megacolon

Non-obstructing dilation of the colon.
May occur from infectious etiology as well as IBD.
Clinical: tachycardia, hypotension, fever, volume depletion, altered sensorium.
AXR: greater than 6cm at transverse, thumbprinting (big haustra), pneumatosis coli.


Reference:

Click here for a NEJM review of infectious diarrhea

Syncope

Today we discussed an approach to syncope. Some important points:

Definition:
Abrupt loss of consciousness followed by rapid, complete recovery

Is it syncope?


All of dizziness, presyncope, drop attacks, and vertigo do not involve loss of consciousness.

Sz vs. syncope: features before, during, and after event:

1) Pre- aura in sz vs. pain, exercise, micturition, defecation, stress usually syncope
2) During- rhythmic movements, >5 min event suggest sz; sweating, nausea suggest syncope
3) Post- disorientation to event, slow to return to consciousness, Todd's paralysis suggest sz. Completely normal post-event suggests syncope.

Differential

1) Cardiac-
Arrhythmic: brady (blocks), tachy (VT, SVT).
Non-arrhythmic: HOCM, AoS. Less common: myxoma, pulm HTN, tamponade, massive MI, MS, Aortic dissection

2) Non-cardiac-
Neurocardiogenic (i.e. 'vasovagal'), neurological (carotid sinus hypersensitivity, subclavian steal, bilat carotid stenosis, posterior TIAs, migraine) orthostatic, psychogenic.
Metabolic: (hypoglycemia, hypoxia, hyperventilation)
"situational" (micturition, defecation)
menstrual

Prognosis

The presence of heart disease is the most important prognostic factor
Cardiac cause- 1 year mortality 18-33%
Non-cardiac cause 0-12%
Unknown cause 6%
NB- the high mortality from cardiac cause is driven by underlying cardiovascular disease, not arrhythmia per se. Data from 1980's.

Evaluation:

Initial: history, physical, orthostatic BP, ECG. If no confirmed or suspected cause, these pts fall under "unexplained" category. If suspected cause, confirm with appropriate testing.

Unexplained: Consider 2D echo, stress testing. If normal, neurally mediated syncope is likely. Consider tilt table testing for neurocardiogenic syncope if recurrent episodes.

Structural heart disease, abnormal ECG: Holter, EP study, loop recorder

Outpatient vs. inpatient management:
Admit when rapid evaluation is necessary because of concern about serious arrhythmia, sudden death, newly diagnosed serious cardiac disease. Pts with facial trauma, bleeding, PE, severe orthostatic hypotension should be admitted.

Reference:

Click here for good review of syncope from Circulation

Ascites

At physical exam rounds we discussed ascites and liver disease

Some key points:

Most sensitive findings (i.e. make it unlikely if not present):
1) flank dullness
2) bulging flanks
3) shifting dullness
4) peripheral edema
-history of increased girth, weight gain, ankle swelling

Most specific findings (i.e. make it likely if present)
1) fluid wave
2) shifting dullness

An approach to the examination in liver disease (besides examining the liver itself)

1) Signs of decompensated liver disease
-jaundice, scleral icterus, dark urine (high bilirubin)
-petechiae, ecchymoses (coagulopathy)
-edema (hypoalbuminemia)
-asterixis, level of consciousness (encephalopathy)

2) Signs of chronic liver disease / hyperestrogenemia signs
-nail and hand findings
-muscle wasting
-spider nevi
-gynecomastia
-testicular atrophy

3) Signs of portal hypertension
-ascites
-splenomegaly
-dilated abdominal veins (extreme of this is caput medusae)
-hemorrhoids

4) Signs suggesting the etiology of liver disease
-cardiac exam (liver + heart involved in "cardiac cirrhoisis", EtOH, hemochromatosis, amyloid, sarcoid)
-resp exam (liver + lungs involved in sarcoid, alpha-1 antitrypsin deficiency)
-CNS (liver + movement disorder in Wilson's)
Many more...

Reference:

Click here for JAMA rational clinical exam on ascites

Hypercalcemia

Today we discussed hypercalcemia. Some issues that came up:


Vomiting

One of many possible approaches:

Intraperitoneal causes

Obstruction: pylorus (gastric outlet obstruction), SBO, LBO
Infection: viral gastroenteritis, bacterial
Inflammation: cholecystitis, pancreatitis, appendicitis, hepatitis
Motor: gastroparesis, GERD, esophageal spasm

Extraperitoneal causes

Cardiovascular: MI, CHF
CNS: cerebellar, brainstem, raised ICP (masses, bleed, hydrocephalus), migraine
Inner ear: labyrinthitis
Medications: post-op, chemotherapy, antibiotics, OCP, oral hypoglycemics
Metabolic: uremia, hepatic failure, calcium, sodium, DKA, adrenal insufficiency
Pregnancy

Clues:
Bilious suggests from distal to duodenum
Undigested food suggests gastric outlet obstruction, gastroparesis or Zenker's diverticulum
Feculent suggests colonic obstruction
Immediately after eating suggests gastritis, gastric outlet obstruction


Hypercalcemia

Symptoms: GI- anorexia, n/v, abdo pain, constipation. Renal: stones, polyuria. Neuro: weakness. Cardiac: arrhythmias

Etiology:
Useful first division is by PTH level

1) High PTH- expect high Ca, low PO4.
A) primary/secondary/teriary hyperparathydoidism, parathyroid hyperplasia
B) lithium
C) familial hypercalcemic hypocalciuria

2) Low PTH
PTHrP from malignancy (esp. SCC- lung, H+N)
hypervitaminosis D- expect high Ca and high PO4- from granulomatous disease, lymphoma)
OAF = IL6 (local paracrine effect; in breast and hematological cancers)
Direct effect of mets (e.g. prostate, lung, etc.)
Myeloma
Medications- HCTZ, Ca, vit. D
Milk alkali syndrome
Hyperthyroidism

As inpatient, #1 cause = malignancy
As outpatient, #1 cause = primary hyperpara


Tx: Fluids!. Consider bisphosphonate if malignancy-related or v. high (but takes days to work)
Calcitonin by nasal spray or subq. If hyper D from sarcoid or lymphoma, possible steroids. Avoid lasix since most patients are profoundly volume depleted. Last resort is dialysis


Milk-Alkali syndrome

Triad of hypercalcemia, met alk, renal failure assoc with ingestion of large amts calcium, alkali

Once common because of PUD treatement. Making resurgence b/c of calcium for osteoporosis, and prevention of secondary hyperparathyroidism in CKD

Sequence: hypercalcemia, dec GFR, met alkalosis ("contraction"). Hypercalcemia per se stimulates renal bicarb fomation.

Pts on vit D, thiazides, vol contraction, CKD are at higher risk


Some links:

Click here for NEJM clinical problem solving case on hypercalcemia

Click here for a review of calcium disorders in renal disease

Bronchiectasis

Defined as inflamed, easily collpsible airways, with obstruction on PFTs. Dx by chronic sputum, bronchial wall thickening, and luminal distension on CT.

Clinical features are cough, sputum for months to years. Dyspnea, wheeze, pleuritic c/p, hemoptysis also seen.

Pathophysiology is acquired disorder of bronchi and bronchioles; abnormal dilation of walls and scarring.

Causes:

Focal: Foreign body, TB, old infection (usually a serious pneumonia)

Global: cystic fibrosis, dysmotile cilia (Kartagener's), allergic bronchopulmonary aspergillosis, nontuberculous mycobacterial infection, alpha-1 anitrypsin deficiency, RA, IBD

NB- "Traction bronchiectasis" is common in pulmonary fibrosis.


Investigations:

1) CXR, high-resolution CT
2) PFTs when stable
3) ECG (for cor pulmonale)
4) CBC, immunoglobulins, Ig subclasses (esp for IgE- ABPA), RF, alpha-1 antitrypsin, HIV
5) Sputum for bacteria, AFB (NB- nontuberculous mycobacteria), fungi
6) Sweat Cl +/- genetic testing
7) TB skin test
8) Aspergillus precipitins (for allergic bronchopulmonary aspergillosis)
9) Ciliary studies (e.g. EM)

CXR- tram lines

CT- dilated airways (more than 1.5x accompanying vessel), thickened bronchial walls, cysts, 'signet ring sign'


Exacerbations

Heralded by increased sputum, SOB, pleuritic pain, hemoptysis. Rarely do you see a new infiltrate.

Organisms: H. Flu, pseudomonas, st. pneumo. Fluoroquinolone is reasonable 1st line.

Prevention: several variations on chronic Abx, possibly inhaled tobramycin.

Chest physio is vital; hydration, mucolytics, bronchodilators all have role.


Reference:

Click here for a review from Chest on bronchiectasis

Hemoptysis

"Vincenzo Grimaldi has tuberculosis. His physician and several female relatives tend to him in his home while a family member prays to the Martyred Saints Alfio, Cirino,and Filadelfo for his swift recovery" - from US National Library of Medicine website

Today we discussed hemoptysis. Some issues that came up:

"Massive" is defined as >600cc in 24h (100-600cc depending on source). In these cases, souce of bleeding in most cases is bronchial artery (not pumonary)

Differential

For non-massive, bronchitis, bronchogenic carcinoma, and bronchiectasis are most common in North America. Frequency of different causes depends on the population (i.e. high prevalence area for TB, etc.)

1) Infection
Bacterial- community or hospital-acquired pneumonia with blood-tinged sputum (as opposed to massive), lung abscess, necrotizing pneumonia (St. aureus, klebsiella, anaerobes)
Mycobacterial- TB
Fungal- aspergillosis, coccidiomycosis

2) Neoplastic
Primary- Endobronchial tumor (carcinoma, adenoma), carcinoid
Secondary - Note that hemoptysis in metastatic ca is rare

3) Bronchiectasis

4) Pulmonary vascular
PE, Pulmonary HTN, AVM (as in HHT)

5) Vasculitis
Goodpasture's, Wegener's, Microscopic polyangiitis

6) Cardiac
Mitral stenosis, severe LV failure

7) Others:
trauma, post-procedural, drugs

Management of massive hemoptysis:

-Hemodynamic support, reverse coagulopathy
-R/O epistaxis or UGIB
-Position with bleeding side down
-Call anesthesia, respirology, thoracic surgery
-Determine which side is source; anesthesia can do bronchial isolation
-Rigid bronchoscopy with suction catheter, lavage with cold epi-saline
-Bronchial artery embolization by interventional radiology

Links:
Click here for a good review of massive hemoptysis management from Thorax
Click here for NEJM clinical-pathological conference on hemoptysis

Renal failure in lupus

Glomerulus with thrombi in a case of thrombotic microangiopathy related to SLE


Today we discussed renal failure (or acute kidney injury) in the setting of lupus. This scenario raises many diagnostic possibilities. Some important points:

Whenever faced with a new (or worsened) problem in the setting of a pre-existing disease, a useful dichotomy is whether this new problem is related or unrelated to the underlying disease.

Directly related to SLE
1) Lupus nephritis
2) Renovascular disease
3) Thrombotic microangiopathy (TTP-like situation), especially in context of antiphospholipid antibodies
4) Libman-Sachs endocarditis embolizing to kidneys (very rare)

Indirectly related to SLE
1) Prerenal state from cardiovascular event / disease (note high risk of CV disease in SLE)
2) Tubulointerstitial disease from medications
3) Prerenal state from medications (e.g. NSAIDs)

Unrelated: Usual approach of prerenal, renal, postrenal.

As in any case of acute kidney injury, the evaluation must include

1) Clinical indications for dialysis (pulmonary edema, uremic pericarditis)
2) Clues to the etiology (BP, volume status, rashes, arthritis, etc)
3) Urinalysis (the "physical examination of the kidney")
4) Assessment of serum and urine electrolytes, osmolality, lab evaluation for secondary causes

Lupus Nephritis

Accumulation of immune complex deposits is the pathologic mechanism, esp. in glomeruli.

Abundance and intraglomerular distribution of IC's are correlated with severity of lupus
nephritis. This is the basis of the WHO classification:

I- no glomerular abnormalities or minimal mesangial.
II- mesangial lupus nephritis- mesangial immune deposits. Variable hypercellularity
III- focal, segmental lupus nephritis; scattered peripheral glomerular deposits, with focal necrotizing and proliferative changes in fewer than 50% of glomeruli
IV- diffuse proliferative GN; extensive subendothelial deposits and necrotizing changes
V- membranous- subendothelial deposits with few or no mesangial deposits. This is not a GN cause (i.e. not as 'nephritic'; more 'nephrotic')

Notes: there is overlap between classifications, and this does not represent a progression. There is a high proportion of pts who evolve from one form to another.

Thrombotic microangiopathy / TTP in SLE

It is well established that autoimmune disease is a risk factor for TTP; checking for hemolytic anemia and RBC fragments (schistocytes) is important to exclude this condition which has a 90% mortality untreated (i.e. without plasma exchange)

Links:
Click here for NEJM clinical-pathological conference on renal failure in SLE
Click here for a presentation I gave on the link between TTP and autoimmune disease (esp. SLE)