Phenytoin (Dilantin) toxicity

Yesterday we discussed dilantin toxicity. Dilantin is an anticonvulsant that can cause a number of drug reactions of different types:

Pharmacology:
Phenytoin binds to and inhibits sodium channels in neurons and in cardiac tissue

It is cleared by the liver via the CYP450 system.

An important clinical point about phenytoin pharmacokinetics is that it exhibits "zero-order" kinetics. 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).

There are many drugs that can increase and decrease phenytoin levels via CYP450 interections. Click here for a complete list.

Phenytoin toxicity ("poisoning")
The earliest sign is nystagmus (usually horizontal) and unsteady gait. More severe toxicity causes slurred speech, lethargy, confusion, and eventually coma.
It can rarely cause cardiac arrhythmias (mainly bradycardia, AV blocks, sinus arrest)
There is no specific antidote for phenytoin; treatment is supportive.

Chronic effects/toxicity
Neurological involvement as above, gingival hyperplasia

Idiosyncratic reactions
These are non-dose related effects.

Drug hypersenitivity syndrome
Characterized by fever, rash (with or without mucosal involvement), and internal organ involvement. Sometimes also called "DRESS" or "drug reaction with eosinophilia and systemic symptoms". Dilantin is a rare, but very well described culprit, along with sulfonamides, allopurinol, dapsone, and many others. Timeframe is 2-8 wks after initiation.

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. Dilantin is a well described culprit. Tx: supportive (inc. burn unit), possible role for steroids, IVIG.

Drug-induced lupus
Clinically, mainly arthritis, serositis, wt loss. 95% have anti-histone AB, negative anti dsDNA, normal complements.

Others
Isolated hepatitis
Leukopenia, thromboctyopenia, agranulocytosis

Lymphadenopathy
IV preparation can cause hypotension during infusion (treatment is fluid)

Links
Click here for a good overview of idiosyncratic drug reactions

Click here for a summary of phenytoin kinetics

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Hepatic encephalopathy

Today we discussed hepatic encephalopathy and its triggers. Some points that came up:

In the context of stable chronic liver disease, the triggers of hepatic encephalopathy are:
1) non-adherence to diuretics/lactulose/nadolol, etc.
2) psychoactive meds (narcotics, benzos)
3) volume overload (usu insufficient diuretics/NaCl excess)
4) new hepatic insult: hepatitis, HCC, PV thrombosis, Budd Chiari
5) infection: esp SBP
6) GI bleed/protein load
7) hypokalemia/alkalosis

Approach is to control encephalopathy and rule out/in precipitating causes:
1) All cirrhotics with ascites and worsening encephalopathy must be tapped. Also rule out other causes of infection
2) Lactulose 30cc BID, qid PRN for 2-3 loose BMs.
3) Diurese if needed, but consider holding if intravascularly depleted
4) D/C all meds that could contribute
5) Continue/start nadolol
6) Decide on ABx from clinical picture and preliminary tap cell count
7) Consider U/S with dopplers to r/o PV thrombosis, HCC, etc
8) If suspicion of GIB, possible OGD
9) Low salt diet. Fluid restrict.

Click here for the 2004 guidelines for cirrhosis managment from Hepatology

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Subclinical hyperthyroidism

Today we discussed subclinical hyperthyroidism

This is defined as
1) Low (usually undetectable) TSH
2) Normal T3 and T4
3) no symptoms of hyperthyroidism

The causes of subclinical hyperthyroidism mirror the causes of overt hyperthyroidism:
1) Exogenous T4
2) Toxic adenoma or multinodular goiter
3) Subacute thyroiditis
4) Graves' disease
5) Amiodarone
Others...

Differential of a low TSH with normal T3/T4 besides subclinical hyperthyroidism:
1) "Sick euthyroid"- stress causing decreased peripheral conversion to T3 (i.e. low), normal T4, low TSH.
2) Glucocorticoids, dopamine
3) Autonomous thyroid nodule producing enough T3/T4 to suppress TSH but not cause high T3/T4 levels

Workup consists of same as overt hyperthyroidism: radioactive iodine uptake and scan, possibly thyroid-stimulating antibodies.

Concerns in subclinical hyperthyroidism
1) Atrial fibrillation
2) Osteoporosis
3) Risk of progression to overt hyperthyroidism
4) Neuropsychiatric effects, diastolic dysfunction (softer evidence)

Natural history: Depends on underlying cause; ~2-5%/yr progress to overt hyperthyroidism

Whom to treat?

Controversial! Very little evidence.

This structured review from JAMA suggests considering treatment for patients who are older than 60 years and for those with or at increased risk for heart disease, osteopenia, or osteoporosis, or for those with subclinical Graves disease or nodular thyroid disease

Therapy consists of ablative therapy (i.e. radioactive iodine) with replacement or medications (PTU or methimazole) with goal to normalize TSH.

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Inhalational injury

Today we discussed inhalational injury.

This is suggested by:
-soot in the upper airway, including mouth and nares
-singed eyebrows, nares
-persistent cough, stridor, wheezing
-hoarseness

Some principles of managment:
1) Consider early intubation; peak of airway edema is 48-72h after injury, and may make intubation extremely difficult. ARDS is also common following thermal injury
2) Look for carbon monoxide poisoning (more below)
3) Bronchoscopy should be performed initially then frequently to assess the extent of the injury and to clear sloughed airway epithelium
4) Look for cyanide poisoning (from plastics and fabrics burning). This presents as a triad of altered mental status, cardiovascular collapse, and lactic acidosis
5) Ophthalmology should see patients with inhalational injuries to exclude ocular injury, since they often go together

A few points about carbon monoxide poisoning:
Presentation
-Notoriously difficult to diagnose
-Common presenting symptoms are altered mental status, headache
-Physical exam may show a "cherry red hue" but this is unreliable

Labs
-Oxygen saturation is normal! (oximeter reads carboxygemoglobin as oxygen-bound)
-ABG tends to be normal (PO2 is dissolved oxygen, which is not changed by CO)
-Need to do co-oximetry on ABG sample to detect carboxyhemoglobin (reported as a percentage)

Management
-100% oxygen by non-rebreather mask for everyone (decreases the halflife of carboxyHgb from 300 to 100 min)
-Hyperbaric oxygen therapy decreases the halflife to 30 min. Generally recommended for any of 1) Carboxyhemoglobin level over 25% (although some sources suggest 4o%) 2) Signs of ongoing organ ischemia (lactic acidosis, myocardial ischemia, etc) 3) Loss of consciousness, 4) Pregnancy with a level over 20% or fetal distress

Links
Click here for a Cochrane review of hyperbaric oxygen in CO poisoning by Toronto investigators (including this hospital!)
Click here for a website from the University of Utah outlining burn management

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Psychosis: medical causes

Today we discussed the approach to the psychotic patient from a medical standpoint (i.e. causes other than primary psychiatric disease)

See this post for a general approach to dementia.

In terms of psychosis (i.e. hallucinations or delusions) from a medical cause, things to think about include:

Delirium
Hallmark is attention problems. Also cognitive problems, simple hallucinations (often visual), fluctuating course, underlying medical condition
General causes:
Infection, intoxication (esp. anticholinergic; 'mad as a hatter'), medications (e.g. benzos, opiates), substance withdrawal (esp. alcohol), metabolic derangements (Na, Ca, hepatic encephalopathy, uremia), trauma, CNS pathology, hypoxia, deficiencies, endocrine (e.g. hyper or hypothyroidism, hypoglycemia), vascular (e.g. vasculitis, hypertensive emergencies)

With more elaborate hallucinations/delusions, other medical possibilities that are well known to present with psychosis include
-Seizures (especially temporal lobe)
-Encephalitis (especially HSV encephalitis)
-Brain tumor / bleed involving the temporal lobe
-Lewy Body dementia (classically non-bizzare delusions, worsens with neuroleptics)
-Neurosyphillis
-Wilson's disease
-Hyperthyroidism
-Neuropsychiatric lupus
-Carbon monoxide poisoning
-Charles Bonnet syndrome
(complex visual hallucinations with insight in pts with visual impairment that reverse with visual correction)
-"megaloblastic madness" from B12 or folate deficiency
-Porphyria

Link:
Click here for a summary of medical causes of psychosis to consider.

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Hypoglycemia practical management

Today we discussed hypoglycemia in the context of medications.

For a discussion of the differential diagnosis of hypoglycemia, see

this post

Some considerations for dealing with hypoglycemia on the wards:

2 issues: 1. Increase blood glucose. 2. Determine reason

Gucose is below 4: If patient is awake, not NPO,

1. Need 15g carbohydrate (in the form of glucose tabs, 3 packs table sugar in water, 3/4 cup of juice or regular soft drink, 6 life savers)If BG is below 2, need at least 20g glucose.

2. Check glucose q 15 min until above 5, and repeat 15g CHO as needed

3. If over 1h until next meal, snack (e.g. 1/2 sandwich)

4. Look for cause, address.

5. Do not stop insulin in a type 1 diabetic

Pt NPO:
1. 25g CHO in form of D50 (50mL amp) push or D10 500cc. May also give glucagon 1mg sc/im if delay.

2. Check glucose q15 min until it is over 5 and give more D50 or D10 as needed

3. Pt may need ongoing glucose infusion after (e.g. D5 or 2/3+1/3 or D10)

4. Look for cause

5. Do not stop insulin in a type 1 diabetic

Reasons: Insulin or sulfonylurea excess or decreased PO intake.

NB- in sulfonylurea-induced hypoglycemia, consider octreotide as reviewed

here

Pulmonary hypertension

Today we discussed pulmonary hypertension (or, we at least had a "tangent"... on it.)
This is an important clinical entitiy to have an approach to both in terms of physical findings and the workup required to determine the etiology. Some considerations:

Defined as mean PA pressure over 25mmHg at rest with mean LA or wedge pressure below 15 (i.e. no LV dysfunction)

May be primary (idiopathic) or secondary.

May occur from disease anywhere in the following circuit:
PA, lungs, PV, LA, MV, LV

1) Pulmonary artery- luminal (PE), mural (PPH), extramural (tumor)
Clinically and patologically indistinguishible from primary pulm HTN are cases associated with the following: anorexigens (diet pills), cocaine, HIV, rheumatologic diseases (esp CREST/scleroderma), portal HTN

2) Lungs- chronic obstructive and restrictive diseases can cause PHTN through hypoxic vasoconstriction. Interstitial lung disease can also cause destructive changes to pulmonary vasculature, leading to PHTN and cor pulmonale.

3) PV- veno-occlusive disease

4) Cardiac- L CHF- usually causes relatively minor PHTN. Mitral stenosis can cause severe PHTN. Shunts (ASD, VSD) cause higher R-sided pressures. Increased PA flows cause changes in PA structure and subsequent reversal of flow (Eisenmenger's)

Clinical features:

Hx: Sx of heart or lung disease, HIV RFs, Sx suggestive of CTD, esp scleroderma, anorexigens, PE symptoms, Fhx (in 5% of pphtn), snoring/OSA, rheumatic heart disease

P: Loud P2, RV lift (L parasternal), R-sided S4, TR murmur (holosystolic, louder on inspiration), edema, high JVP. A murmur of pulmonic insufficiency called the "Graham Steell murmur" is described (early diastolic, decrescendo, increased on inspiration). Look for findings suggestive of secondary causes including scleroderma, HIV, primary lung disease, etc.

Investigations:
ECG- RAE, RVH with strain (i.e. tall R and small S with R/S over 1 in V1)
CXR- enlarged R hilum, dilated PA (over 14mm in females, over16mm in males)
Echo- RVSP (approximaes PA systolic). Should be less than 40.
PFT/ABG
High resolution CT +/- VQ scan
Possible R heart cath to determine pressures directly

Link:
Click here for an excellent JAMA "grand rounds" discussion on pulmonary HTN

Essential thrombocytosis

Today we discussed essential thrombocytosis (AKA essential thrombocythemia). Some points about this condition:

Thrombocytosis
Majority of cases are reactive. Common causes: Post-op, infection, post-splenectomy, Fe deficiency, malignancy (non-hematologic)

Non-reactive causes include ET, polycythemia vera, myelofibrosis, CML, MDS

ET:
Concerns are
1)Thrombosis risk
2)Bleeding risk (platelets are numerous, but often dysfunctional, and patients can have acquired von willebrand's disease)
3)Potential for transformation to AML

Epidemiology:
median age at dx is 60. F:M is 2:1.
Clinical: ~1/3 asymptomatic. ~1/3 have "vasomotor" sx: Syncope/presyncope, H/A, paresthesias, visual dist, non-exertional c/p. ~1/3 have sx consistent with thrombotic/bleeding events- major or minor

Diagnosis:
PLT consistently above 600, no explanation for reactive cause. May see megakaryocyte hyperplasia on BMBx if done, -ve BCR-ABL, iron replete, no evidence of MDS. JAK2 is a mutation found in over 95% of patients with polycythemia rubra vera, and 50-60% of patients with ET. It can be detected in peripheral blood

Bleeding risk
This paper by Tefferi et al from the Mayo Clinic found a 4% 10-year risk of major hemorrhage. Bleeding risk was directly proportional to PLT level, with over 1500 (i.e. 1.5 million) highest.

Thrombosis Risk
Arterial and venous thrombosis may occur. Typical events are similar to those in PRV: stroke, TIA, ACS, retinal art occ, digital ischemia, pregnancy loss. Less commonly, DVT/PE, PV thromb/Budd-Chiari.
Incidence of major events (MI, stroke, PE) is ~4% at 10 years. There is conflicting data on whether PLT level correlates with thrombosis risk

Antiplatelet therapy
The ECLAP study (RCT) looked at low dose ASA in patients with no other indication for ASA and PRV (which carries similar thrombosis risk)
RR of composite outcome of MI, stroke, PE, CV death was 0.4 on ASA 100mg. No significant mortality benefit. No significant difference in bleeding. It also has demonstrated effect on vasomotor sx of ET.

Cytoreductive therapy in high risk pts
In those meeting high risk criteria (i.e. over 60 or history of thrombosis). this RCT by Cortelazzo et al, evaluated the use of hydroxyurea to bring PLT count to below 600 vs. placebo in patients on antiplatelet therapy. 2 year risk of significant thrombosis was 3.6% on HU, 24% on placebo (NNT 5) Therefore, hydroxyurea to reduce the platelet count to below 600 should be considered in high risk patients. Specific platelet reducing agent (Anagrelide) was evaluated in RCT vs. HU, and showed much higher thrombosis risk



The risk of conversion to AML is reported at 2-5% at 15 years from dx. This is the lowest risk of any of the myeloproliferative disorders