Rosen & Barkin's 5-Minute Emergency Medicine Consult (543 page)

• Differentiate phenytoin-induced altered mental status from other potentially serious causes:
  
  • Head trauma common in seizure population
    
• Collect/transport prescription bottles and medications to aid in identification and quantification of ingestion
  

• ABCs:
  
  • IV access
    
  • Cardiac monitor (with IV overdose)
    
• For altered mental status:
  
  • Accu-Chek.
    
  • Administer naloxone, dextrose, and thiamine as indicated.
    
• Treat hypotension with IV fluids and Trendelenburg position:
  
  • Dopamine for refractory hypotension
    
• Treat paradoxical seizures with diazepam.
  

• Provide supportive care
  
• Activated charcoal
  
  • Administer single dose.
    
  • Multiple-dose activated charcoal may increase the clearance of phenytoin; does not correlate with clinical improvement in patients with phenytoin toxicity.
    

• Activated charcoal slurry: 1–2 g/kg up to 90 g PO
  
• Dextrose: D50W 1 amp: 50 mL or 25 g (peds: D25W 2–4 mL/kg) IV
  
• Dopamine: 2–20 μg/kg/min IV titrated to desired BP
  
• Naloxone (Narcan): 2 mg (peds: 0.1 mg/kg) IV or IM initial dose
  
• Thiamine (vitamin B
  ₁
  ): 100 mg (peds: 50 mg) IV or IM
  

FOLLOW-UP

• Altered mental status, severe ataxia, increasing phenytoin level
  
• Level >25
  µ
  g/mL
  
• ICU admission with intoxication from IV phenytoin
  
• Fall precautions
  

• Level ≤25
  µ
  g/mL
  
• Ambulatory without ataxia
  

• Psychiatric referral for intentional ingestions/suicide attempts.
  
• Close primary care follow-up to check phenytoin levels.
  
• Anticipate altered pharmacokinetics and phenytoin levels with any change in manufacturer or dosage formulation
  

• Small incremental increases in dose of phenytoin can result in toxicity since phenytoin follows zero-order kinetics.
  
• Repeat phenytoin levels every 4 hr until declining.
  

• McCluggage LK, Voils SA, Bullock MR. Phenytoin toxicity due to genetic polymorphism.
  Neurocrit Care
  . 2009;10:222–224.
  
• Skinner CG, Chang AS, Matthews AR, et al. Randomized controlled study on the use of multiple-dose activated charcoal in patients with supratherapeutic phenytoin levels.
  Clin Toxicol (Phila).
  2012;50:764–769.
  
• Von Winckelmann SL, Spriet I, Willems L. Therapeutic drug monitoring of phenytoin in critically ill patients.
  Pharmacotherapy
  . 2008;28:1391–1400.
  

CODES

966.1 Poisoning by hydantoin derivatives

BASICS

• Pheochromocytoma (pheo) is a catecholamine-producing tumor arising from the chromaffin tissues of the sympathetic nervous system.
  
• Origin from the adrenal medulla or sympathetic ganglia:
  
  • 80% solitary adrenal (usually the right side)
    
  • 10% bilateral (usually inherited form)
    
  • 10% extra-adrenal in location:
    
    • Abdominal, within mesenteric ganglia (86%)
      
    • Thorax (10%), neck (3%), bladder (1%)
      
  • 10% malignant (usually inherited form)
    
• Incidence:
  
  • 0.2–0.4% of hypertensive patients, but higher proportion of patients with severe hypertension
    
  • 2–8/million population per year
    
  • Peaks in decades 3–5, 10% in children
    
  • Male = female
    
  • In about 1/2 of the cases, the diagnosis is made postmortem.
    
  • 10% asymptomatic, incidental on CT
    
• Genetics:
  
  • Inherited form 25%, autosomal dominant
    
  • Usually associated with multiple endocrine neoplasia (MEN) 2A, less so with MEN 2B or von Hippel–Lindau (VHL) disease:
    
    • MEN 2A (medullary thyroid carcinoma [CA], pheo, and hyperparathyroidism)
      
    • MEN 2B (medullary thyroid CA, pheo, oral mucosal neuromas, skeletal and bony abnormalities)
      
    • VHL (hemangioblastomas of retina and CNS, pancreas and renal cysts, and pheo
      
  • Other associated diseases: Neurofibromatosis, tuberous sclerosis, Sturge–Weber syndrome, paragangliomas of the neck
    

• The tumor synthesizes and stores catecholamines in the same manner as the normal adrenal medulla.
  
• Tumors predominantly secrete norepinephrine, and to a lesser extent epinephrine (some tumors are epinephrine predominant, in which hypotensive episodes are characteristic)
  
• Paroxysmal release of catecholamines:
  
  • Spontaneously due to changes in blood flow or tumor necrosis
    
  • Direct pressure on the gland from external forces (trauma, exercise)
    
  • Precipitation of release (opiates, glucagon, metoclopramide, steroids, foods with tyramine, iodinated contrast media)
    
  • Augmentation of catecholamine effect (tricyclic antidepressants [TCAs], β-blockers, sympathomimetics)
    

DIAGNOSIS

• Hypertension, moderate to severe, refractory to treatment:
  
  • 40%: Paroxysms with normal BP between episodes
    
  • 30%: Sustained hypertension with paroxysms
    
  • 30%: Sustained hypertension without paroxysms
    
  • Sometimes normotensive in familial forms and small tumors: <5%
    
• Paroxysmal symptoms
  
  • Sudden onset, gradual resolution
    
  • Duration: Minutes to hours (average 20 min)
    
  • Intervals: Hours to months (average weekly)
    
  • Increasing frequency, duration, and severity with time
    
• Clinical characteristics of paroxysms
  
  • Hypertensive crisis or urgency
    
  • Headache – abrupt, throbbing, bilateral
    
  • Tachycardia/palpitations
    
  • Profuse diaphoresis/pallor
    
  • Apprehension/anxiety/tremulous
    
  • Shock associated with trauma, surgery, parturition, anesthesia
    
• Acute crisis
  
  • Prolonged (>24hr) severe paroxysm
    
  • Severe HTN or shock, hyperpyrexia
    
  • Multiorgan failure/lactic acidosis
    
  • Pulmonary edema due to cardiomyopathy (dilated, hypertrophic or Takotsubo)
    
  • Stroke (SAH, PRES, RCVS, embolic)
    
  • Severe headache/encephalopathy
    
  • Chest pain (MI/dissection)
    
  • Acute abdomen
    
    • Hemorrhagic tumor necrosis
      
    • Mesenteric infarction
      
• Chronic symptoms
  
  • Chest pains/palpitations
    
  • Orthostasis (decreased plasma volume and blunted sympathetic reflexes)
    
  • Constipation can be severe, leading to ileus or pseudo-obstruction (catecholamines inhibit peristalsis)
    
  • Weight loss/fevers (increased metabolism)
    
  • Lethargy, fatigue (catecholamine withdrawal))
    
  • Polydipsia, polyuria (glucose intolerance)
    
  • Anxiety, tremors, heat intolerance
    

• Moderate to severe hypertension, often with orthostatic changes
  
• Tachycardic, diaphoretic, evidence of weight loss, low-grade fever
  
• Pallor, cold hands and feet (flushing not seen, except rarely after a paroxysm)
  
• Tremor, anxiety
  
• Mydriasis, hypertensive retinopathy
  
• Café au lait spots, neurofibromas, thyroid nodule
  
• No palpable masses (tumors tend to be small)
  

• Accurate BP determination with orthostatic BPs
  
• ECG to exclude ischemia or dysrhythmias
  

• Overdiagnosis in >20% from misinterpretation of borderline biochemical tests and overzealous imaging
  
• Underdiagnosis is common from failure to consider the diagnosis or ignoring adrenal masses on CT.
  

• CBC:
  
  • Elevated hemoglobin due to diminished plasma volume
    
  • Elevated WBC from demargination
    
• Electrolytes, BUN, creatinine, glucose:
  
  • Lactic acidosis
    
  • Renal failure secondary to hypertensive nephropathy
    
  • Hyperglycemia due to impaired response to insulin and effect of catecholamines
    
  • Hypercalcemia due to excess parathyroid hormone
    
• Urinalysis: Proteinuria and hematuria
  
• Plasma-free metanephrine (fractionated):
  
  • 96% sensitive, 85% specific—best screening test. Normal level excludes diagnosis, but many false positives
    
  • Least likely to be interfered by medications or stress and no special prep for venipuncture
    
• 24 hr urine collection for free catecholamines and metanephrine (total and fractionated):
  
  • 99.7% combined specificity and 87.5% sensitivity (best test for confirmation)
    
  • Must include creatinine to verify adequate collection
    
  • Medications that interfere: Levodopa, methyldopa, monoamine oxidase inhibitors (MAOIs), labetalol, propranolol, radiographic contrast media, sympathomimetics, benzodiazepines, TCAs, caffeine, nicotine