Over at the Pulmcrit blog, Dr. Josh Farkas has proposed the use of phenobarbital monotherapy for the treatment of ethanol withdrawal. He argues that phenobarbital has the following advantages:
Reliable – some patients will be resistant to benzos but this does not happen as much with phenobarbital
We cover alcohol withdrawal using Rosen’s Emergency Medicine (9th ed) Chapter 142 , Tintinalli’s Emergency Medicine (8th ed) Chapter 292, and Goldfrank’s Toxicologic Emergencies (10th ed) Chapter 81 as guides.
A 49-year-old man presents to the Emergency Department complaining of sweating and tremors. The patient drinks a bottle of liquor per day and stopped suddenly because of a pending court case. His last alcoholic drink was 3 days ago. On physical examination, his blood pressure is 168/105 mm Hg, pulse rate is 106/minute, respirations are 22/minute, and temperature is 99.3°F. The patient appears agitated and restless with a visible tremor of bilateral hands. The triage team ordered folic acid, thiamine, and a multivitamin. Which of the following is the most appropriate disposition?
A. Admit the patient and start diazepam
B.Admit the patient and start disulfiram
C.Discharge the patient with a prescription for diazepam
D.Discharge the patient with a prescription for disulfiram
A. Admit the patient and start diazepam is the correct disposition because this patient is suffering from alcohol withdrawal, which potentially can be fatal. Withdrawal symptoms occur when a patient has alcohol use disorder and has developed a tolerance to alcohol, where an increased amount of alcohol is needed to achieve the desired effect. When tolerance has developed, cessation leads to withdrawal. Early symptoms of alcohol withdrawal include anxiety, irritability, headache, tremor, tachycardia, hypertension, hyperthermia, and hyperactive reflexes. Seizures (usually grand mal) can develop between 12-24 hours after withdrawal starts. After 24-72 hours, life-threatening delirium tremens may occur, which manifests with signs of altered mental status, hallucinations and marked autonomic instability. Treatment of alcohol withdrawal involves giving a benzodiazepine (e.g. diazepam) until symptoms lessen and then tapering the dosage over days to weeks. Thiamine, folic acid, and vitamin B12 are also administered and any electrolyte abnormalities are corrected (typically low potassium and magnesium). Following withdrawal, the patient should be referred to support groups. Long term medication used to deter use of alcohol include naltrexone, disulfiram, and acamprosate.
Admit the patient and start disulfiram (A) is incorrect because the patient needs a benzodiazepine medication to prevent delirium tremens and potentially fatal consequences. Disulfiram is a medication used in some patients for long-term adherence to alcohol abstinence. Ingestion of alcohol while taking disulfiram causes copious vomiting and potentially more severe reactions. Discharge the patient with a prescription for diazepam (C) or disulfiram(D) is incorrect because alcohol withdrawal is potentially lethal and this patient should be admitted.
A 27-year-old man is brought to the ED by EMS after being found wandering in the street. His BP is 155/70, HR 115, T 37.5°C, RR 16, pulse ox 99% on room air, and finger stick glucose 98. On exam, the patient is confused with mumbling speech. His pupils are 7 mm and nonreactive. His face is flushed. Mucous membranes and skin are dry. Which of the following toxidromes is this patient exhibiting?
A. Anticholinergic Toxidrome refers to a constellation of physical findings that can provide important clues in a toxic ingestion. This patient exhibits an anticholinergic toxidrome. Anticholinergics are widely available as over-the-counter cold preparations and sleep aids (diphenhydramine, chlorpheniramine, doxylamine). They also are the basis of the toxicity of jimsonweed. Anticholinergics competitively inhibit acetylcholine in the central and peripheral nervous systems. This classic toxidrome is often described by the phrase “mad as a hatter (altered mental status), blind as a bat (mydriasis), red as a beet (flushed skin), hot as a hare (dry skin due to inability to sweat), dry as a bone (dry mucous membranes).” Other findings include tachycardia, delirium, seizures, and hallucinations. Treatment is mainly supportive with benzodiazepines for agitation and seizures, and cooling for temperature reduction. Gastric decontamination (whole-bowel irrigation or gastric lavage) is often recommended due to the delay in gastric emptying caused by anticholinergics. The use of physostigmine, a reversible cholinesterase inhibitor that will increase synaptic acetylcholine, is controversial and should be administered only in consultation with a toxicologist.
The cholinergic toxidrome (B) is characterized by the mnemonics SLUDGE (salivation, lacrimation, urination, defecation, GI upset, emesis) or DUMBBELS (defecation, urination, miosis, bronchospasm, bronchorrhea, emesis, lacrimation, salivation) and occurs after exposure to organophosphates or carbamates. The sedative-hypnotic toxidrome (C) is seen with benzodiazepines and barbiturates. Clinically, patients exhibit central nervous system and respiratory depression. The sympathomimetic toxidromes (D) can occur after ingestion of cocaine, amphetamines, or decongestants. It typically presents with delirium, paranoia, tachycardia, hypertension, hyperpyrexia, diaphoresis, mydriasis, seizures, and hyperactive bowel sounds. Sympathomimetic and anticholinergic toxidromes are frequently difficult to distinguish. The key difference is that sympathomimetics are associated with diaphoresis, whereas anticholinergics cause dry skin.
A 22-year-old man is brought into the Emergency Department by Emergency Medical Services with altered mental status. He is an agitated man and mumbling incoherent words. His pupils are 6 mm and reactive to light. His axillae are dry. His heart rate is 115 beats/minute and temperature is 101.6 oF. Which of the following is a complication of the antidote used in the treatment of this condition?
B. Bladder retention
C. QT-interval prolongation
D. Respiratory depression
Asystole. The mnemonic for the anticholinergic toxidrome is blind as a bat (mydriasis), red as a beet (vasodilation leading to flushing), hot as a hare (hyperthermia), dry as a bone (dry skin and mucosa), mad as a hatter (visual or auditory hallucinations, agitation, and mumbling or incoherent speech), bloated as a toad (ileus and urinary retention), and the heart runs alone (tachycardia). Additionally, anticholinergic toxicity can cause orthostatic hypotension (especially in the elderly), picking behavior, and can lead to seizures, coma, and even death. There are multiple anticholinergic medications, including tricyclic antidepressants, antihistamines, antiparkinson medications, antipsychotics, antispasmodics, belladonna alkaloids, skeletal muscle relaxants, and mydriatics. Antihistamine overdose is the most common cause of anticholinergic toxicity. Treatment is supportive with IV hydration. If the ingestion occurred within one hour, GI decontamination with activated charcoal is reasonable. Benzodiazepines are used for significant agitation and seizures. Good temperature control should be achieved with antipyretics and active cooling is essential. For wide complex tachyarrhythmias, treatment is with sodium bicarbonate. The antidote is physostigmine, a reversible acetylcholinesterase inhibitor. There is, however, a risk of profound bradycardia, seizures, and asystole in patients with widened QRS complexes. This risk is minimal if there is a pure anticholinergic syndrome without concomitant sodium channel blockade, but this is unfortunately not always known. Since the most common cause of anticholinergic toxicity is from diphenhydramine overdose (which causes sodium channel blockade), physostigmine should only be used with the assistance of a medical toxicologist.
Arens AM, et al. Safety and effectiveness of physostigmine: a 10-year retrospective review. Clin Toxicol. 2017 Jul 13:1-7. [Epub ahead of print] PMID 28703024
We cover Free Open Access Medical Education on opioids.
The Poison Review podcast reviews papers on the opioid epidemic, including a paper by Rudd et al demonstrating an increase in opioid-related deaths over the past five years as well as the following paper by Shah and colleagues.
The American College of Medical Toxicology recently released a statement on fentanyl exposure, stating how absolutely unlikely it is that accidental dermal exposure would result in toxicity. ” If bilateral palmar surfaces were covered with fentanyl patches, it would take approximately 14 minutes to receive 100 mcg of fentanyl…This extreme example illustrates that even a high dose of fentanyl prepared for transdermal administration cannot rapidly deliver a high dose.”
We cover core content on opioid overdose and withdrawal using Rosen’s Emergency Medicine (9th ed) Chapter 156 and Tintinalli’s Emergency Medicine (8th ed), Chapter 186 as a guide.
We cover a post from Dr. Josh Farkas on PULMcrit on lithium toxicity. The key message from the post is: a single serum lithium level doesn’t necessitate dialysis, despite a recommendation from the EXTRIP working group to initiate dialysis in patients with a lithium level > 5 mEq/L . Dr. Farkas advocates for aggressive management in asymptomatic patients with chronic lithium toxicity and patients without impaired renal function.
Lithium neurotoxicity does not correlate with serum lithium levels; it depends on the concentration in the CNS.
The argument is that the neurologic effects, among the most worrisome sequelae of lithium toxicity, results from lithium crossing the blood-brain-barrier (BBB) into the central nervous system (CNS). Thus, in an acute ingestion, patients may have a higher serum lithium level, but given the acuity, the lithium may not cross into the CNS. Conversely, a patient with chronic toxicity may have a mildly elevated serum lithium level but the lithium has had time to cross the BBB into the CNS so more neurotoxicity can result from lower serum lithium concentrations.
Differentiating between acute, chronic, and acute on chronic toxicity is important in management.
Acute – expect the levels will rise rapidly as the bolus of lithium is absorbed.
Chronic – expect the levels will not rise rapidly given a lack of lithium bolus.
Acute on chronic – again, expect levels to rise rapidly and may see more neurotoxicity as some lithium may have passed through the BBB into the CNS.
We review rhabdomyolysis using Rosen’s Emergency Medicine (8e) Chapter 160 and Tintinalli’s Emergency Medicine (8e), Chapter 181.
A 17-year-old man presents to the ED from a correctional facility complaining of general malaise with nausea and vomiting one day after a weightlifting competition. Vital signs are T 37.2°C, BP 100/65 mm Hg, HR 125, and RR 22. Physical exam reveals an uncomfortable, fatigued male who has diffuse muscle soreness. Urinalysis shows 3+ blood without red blood cells. What is the most important next test to direct the acute management of this patient?
A. Creatine kinase assay
C. Electrolyte panel with blood urea nitrogen and creatinine
B. Electrocardiogram. The patient presents with exercised-induced rhabdomyolysis. Although the causes of rhabdomyolysis are manifold, potential complications are independent of etiology. Of all the complications, hyperkalemia is the most concerning and, undiagnosed, can lead to sudden cardiac death. ECG changes indicative of hyperkalemia are thus critical to identify early in the course of management. Hyperkalemia results from impaired calcium transport with increased intracellular calcium accumulation, cellular necrosis, and expulsion of intracellular contents (including potassium) into the bloodstream. Rhabdomyolysis can also lead to acute tubular necrosis and kidney failure, which will exacerbate developing hyperkalemia by decreasing renal potassium clearance. Hyperkalemia is an immediate life-threatening condition that develops shortly after muscle injury. Absent point-of-care electrolyte analyzers, the most rapid way to screen for hyperkalemia is through an electrocardiogram.
Rhabdomyolysis is not defined by a specific creatine kinase (A) level. But, in general, a serum CK >5 times the upper limit of normal (a threshold that may differ by lab) is considered indicative of rhabdomyolysis. Although kidney injury can occur at any level, higher CKs correlate with an increased likelihood for the development of acute renal failure. In the absence of cerebral or myocardial infarction, a CK >5 times is diagnostic for serious muscle injury. Urinalysis (D) typically shows brownish discoloration with “large” blood on dipstick but few, if any, red blood cells on microscopic evaluation. This occurs because most dipstick tests cannot distinguish myoglobinuria from hematuria or hemoglobinuria. Protein, brown casts, and renal tubular epithelial cells may also be present. Measures of renal function and an electrolyte panel (C) should be obtained in all patients with suspected rhabdomyolysis. But, as mentioned, waiting for results may lead to a delay in the identification of life-threatening complications. In addition to hyperkalemia, hyperphosphatemia and hypocalcemia may also be seen. Additional (though less worrisome) laboratory abnormalities include elevated uric acid and low albumin.
One Step Further Question: What is the late complication of rhabdomyolysis associated with thrombocytopenia, hypofibrinogenemia, and an elevated D-dimer?
Disseminated intravascular coagulopathy may occur and is a result of muscle necrosis with liberation of activating substances from injured cells.
We delve into core content on cocaine and phencyclidine (PCP) using Rosen’s (8th edition), Chapter 154 and Tintinalli (8th edition)
Note: Beta-blockers are contra-indicated in cocaine induced hypertension and chest pain. Much of the ischemia induced by cocaine is thought to be due to vasospasm, predominantly from alpha-1 receptor effects. Beta-blockers block the relaxation provided by beta-2 stimulus on muscles, leaving alpha-1 constricting vessels, “unopposed.” This is largely theoretical/based on canine literature as there are only two human studies on this, (a) 10 humans given propranolol + cocaine with vasospasm and (b) 9 humans given labetalol + cocaine without vasospasm [4,5]. However, recent papers attempting to dispel this teaching don’t quite prove the point. One retrospective chart review looked at cocaine positive urine screens in patients with chest pain and found no worsened troponins. Cocaine stays positive in the urine for 3 days so it is not clear that these were patients presenting with cocaine associated chest pain .
Generously Donated Rosh Review Questions
An 18-year-old man is brought to the ED by the police after being found running around a parking lot, screaming at bystanders. He reportedly smoked phencyclidine (PCP) earlier that day. His vital signs are notable for a heart rate of 130 beats per minute and a blood pressure of 150/86 mm Hg. On physical exam, he is diaphoretic, with vertical nystagmus and equal pupils and appears acutely agitated.
A. Administer haloperidol for acute agitation
B. Administer IV fluids for presumed rhabdomyolysis and benzodiazepines for agitation
C. Apply physical restraints; this is adequate treatment for most cases
D. Monitor for traumatic injuries; they are the most common cause of morbidity and mortality with PCP use
E. Urinary acidification to increase PCP elimination
The most common cause of morbidity and mortality in patients with phencyclidine (PCP) intoxication is rhabdomyolysis. Fluid hydration with normal saline is the initial therapy for rhabdomyolysis. Creatinine kinase (CK) should be obtained in patients with PCP intoxication. If abnormal, serial levels should be obtained until a downward trend is noted. Serum creatinine should also be monitored for evidence of renal insufficiency. PCP is a dissociative anesthetic drug that works on the NMDA glutamate receptor. People who abuse PCP can have sensations of euphoria initially, but this can be followed by an emergence reaction that is characterized by dysphoria and psychosis. If initial calming measures such as placing the patient in a calm environment fail and chemical restraints are needed, benzodiazepines are the treatment of choice. Benzodiazepines are also the preferred medication for acute agitation. Haloperidol (A) may cause dysrhythmias and hypotension. It also lowers the seizure threshold and may precipitate PCP-induced movement disorders. PCP is a weak base and its excretion is increased in acidic urine. Physical restraints (C) may be required for patients with PCP intoxication, but they should be used in conjunction with chemical restraints (preferably benzodiazepines). An agitated patient fighting against physical restraints is at risk for worsening rhabdomyolysis, which, if unrecognized, can precipitate cardiac arrest. Traumatic injuries (D)frequently occur in PCP-intoxicated patients; however, rhabdomyolysis with subsequent renal insufficiency is the most common cause of associated morbidity and mortality. Patients with PCP intoxication should be evaluated for suspected trauma, and any injuries should be stabilized and treated. Acidification of the urine (E) can cause a metabolic acidosis, which is potentially harmful and has not demonstrated improved outcomes. For these reasons, urinary acidification is not routinely recommended.
2. A 39-year-old woman presents with chest pain and difficulty breathing that began shortly after smoking crack cocaine. Vital signs are BP 190/85 mm Hg, HR 105, RR 18, T 99.1℉. The ECG demonstrates ST segment depression and T wave inversions in the lateral leads.
Diazepam, a benzodiazepine, should be administered to this patient who is hyperadrenergic from cocaine intoxication. Signs and symptoms of cocaine intoxication include, dilated pupils, diaphoresis, tachycardia, hypertension and hyperthermia. Many patients experience euphoria, though some will develop acute psychosis. Benzodiazepines decrease the cocaine-induced hyperadrenergic state. Reduction of sympathetic tone induces coronary and peripheral vasodilation. Coronary artery dilation directly improves myocardial blood flow. Peripheral vasodilation reduces preload and afterload. Reductions in preload and afterload decrease blood pressure and improve myocardial oxygen demand. Several factors, including, excess sympathetic stimulation, dehydration, hyperthermia, and cocaine-induced cardiac sodium channel blockade, may cause patients with cocaine intoxication to develop dysrhythmias. These contributing factors should be treated with benzodiazepines, IV fluid resuscitation and temperature management. In some patients, cocaine-induced cardiac sodium channel blockade may cause wide complex tachycardia that should be treated with sodium bicarbonate. Hyperthermia should be managed aggressively with a target temperature of less than or equal to 102.0℉. Severe agitation, aggression or psychosis should be initially managed with benzodiazepines. Most antipsychotic agents have pronounced anticholinergic side effects. This may worsen dysrhythmias.and decrease sweating, further complicating temperature management
Rao R, Hoffman RS. Cocaine and other Sympathomimetics. Rosen’s Emergency Medicine (8e). Chapter 154, 1999-2006.e2
“Cocaine and Amphetamines.” Tintinalli’s Emergency Medicine: A Comprehensive Study Guide (8e). Chapter 187
“Prison Medicine.” Tintinalli’s Emergency Medicine: A Comprehensive Study Guide (8e). Chapter 301
Lange RA, Cigarroa RG, Flores ED, et al. Potentiation of cocaine, induced coronary vasoconstriction by beta adrenergic blockade. Ann Intern Med. 1990;112:897–90
Boehrer JD, Moliterno DJ, Willard JE, Hillis LD, Lange RA. Influence of labetalol on cocaine-induced coronary vasoconstriction in humans. Am J Med. 1993;94(6):608–610
Ibrahim M, Maselli DJ, Hasan R, Hamilton A. Safety of β-blockers in the acute management of cocaine-associated chest pain. The American Journal of Emergency Medicine. 31(3):613-616.
Intervention – Nasal inhalation of an isopropyl alcohol pad for ~ 60 seconds (time 0 and, if still nauseated, at 2 minutes and 4 minutes)
Comparison – Nasal inhalation of an identical pad soaked in saline.
Outcome -Nausea score at 10 minutes post treatment using an 11-point verbal numeric response scale (0:“no nausea”; 10:“worst nausea imaginable”)
Lower in the isopropyl group (Median score of 3 vs. 6 on an 11 point scale, p<0.001). This gave an effect size of 3 (95% CI 2 to 4).
Limitations – single center, convenience sample, unclear blinding as isopropyl likely has a particular smell to it, outcome nausea score, not vomiting
Eagerton-Warburton et al conducted an RCT of intravenous ondansetron 4mg, metoclopramide 20mg, or saline (placebo) of adult patients with nausea and found no significant difference in nausea scores on a visual analog scale between groups (n=270).
We delve into core content on vertigo using Rosen’s Medicine (8e), Chapter 155 “Toxic Alcohols”and Tintinalli’s Emergency Medicine: A Comprehensive Study Guide(7e) Chapter 179“Alcohols.”
Any alcohol can be “toxic,” the ramifications depend on the dose. Toxic alcohols typically refer to ethylene glycol (EG) and methanol. In these cases, the parent compound (EG or methanol) is inebriating but not particularly toxic. These compounds are metabolized, like any alcohol, but unfortunately the metabolites (oxalic acid – EG, formic acid – methanol) have unique toxic properties. For example, the oxalic acid produced from EG metabolism combines with calcium. These deposit into tissues causing renal failure and neurologic sympotms. The formic acid has a predilection for the retina, causing visual symptoms.
Osmolal Gap (calculator) – One of the touted features of toxic alcohols is the elevated anion gap, that is, the difference between the measured serum osmolality and the calculated osmolarity.
Calculated Osmolarity: 2[Sodium] + [Glucose]/18 + [BUN]/2.8 + [ETOH]/4.6 (Note: Some references use ETOH/3.7)
Problems: A normal osm gap does not exclude the presence of toxic alcohols as the osm gap decreases as the alcohol is metabolized. Also, other disease processes can increase the osm gap, including shock, diabetic ketoacidosis, etc [2,3].
A common pearl exists that urine can be placed under a Wood’s lamp for fluorescence due to the fluorescein in ethylene glycol antifreeze (to detect leaks). Unfortunately this is neither sensitive nor specific [4,5].
Rosh Review Questions
Question 1. [polldaddy poll=9311166]
Question 2. [polldaddy poll=9311159]
1. A. Hypocalcemia. Most laboratories do not have the capability to measure serum levels of toxic alcohols in a timely fashion. As a result, physicians must use other clinical markers to determine the presence of these unmeasured toxins. The classic laboratory abnormality is an elevated serum osmolality with an osmolar gap since the actual toxic alcohol is not measured in its own quantity but contributes to the osmolality of the blood. When calculating the osmolar gap, it is important to have a measured serum ethanol level as this is a large contributor to the final osmolality.Ethylene glycol ingestion leads to the formation of calcium oxalate crystals. As a result, serum calcium levels will decrease and hypocalcemia is a surrogate marker for ethylene glycol toxicity.Hypoglycemia (B) is not characteristic of a toxic alcohol ingestion. Hypoglycemia is often seen in chronic alcoholics due to poor nutritional intake. In children, ethanol may induce hypoglycemia. Other toxic ingestions which may lead to hypoglycemia include beta-blockers, sulfonylureas and insulin. Hypokalemia (C) is not associated with any toxic alcohol ingestions. As patients become more acidemic from alcohol ingestions, hyperkalemia may develop. Hyponatremia (D) is not associated with toxic alcohol ingestions. Evidence of hyponatremia on laboratory analysis should prompt further investigation for other underlying causes.
2.C. Glycolic acid level greater than 8 mmol/L. A glycolic acid level greater than 8 mmol/L is an indication for emergent hemodialysis following an acute ethylene glycol overdose. Ethylene glycol is found in automobile coolants, antifreeze, hydraulic brake fluid, de-icing agents and industrial solvents. Symptoms progress through 4 stages: inebriation and intoxication, cardiopulmonary symptoms (tachycardia, hypertension, pulmonary edema), renal symptoms (acute renal failure), and delayed neurologic symptoms (cranial neuropathy). Treatment includes 1.) Alcohol dehydrogenase (ADH) enzyme blockade with fomepizole or ethanol to prevent toxic and acidic metabolite production, 2.) Correction of the metabolic acidosis with sodium bicarbonate, and 3.) Hemodialysis for removal of the parent compound and toxic metabolites. Although somewhat controversial with the advent of fomepizole other indications for hemodialysis following ethylene glycol ingestion include severe metabolic acidosis, renal failure, deterioration despite intensive care, and electrolyte disturbances.Other indications for emergent hemodialysis following an acute ethylene glycol overdose include: ethylene glycol level greater than 50 mg/dL (B), anion gap greater than 20 mmol/L (A)and initial pH less than 7.3 (D).
Beadle KL, Helbling AR, Love SL, April MD, Hunter CJ. Isopropyl Alcohol Nasal Inhalation for Nausea in the Emergency Department: A Randomized Controlled Trial. Annals of emergency medicine. 2015. [pubmed]
Chapter 179. Alcohols. In: Tintinalli JE, Stapczynski J, Ma O, Cline DM, Cydulka RK, Meckler GD, T. eds.Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7e.New York, NY: McGraw-Hill; 2011.
Tobe TJM, Braam GB, Meulenbelt J, et al: Ethylene glycol poisoning mimicking Snow White. Lancet 2002; 359: pp. 444
Wallace KL, Suchard JR, Curry SC, et al: Diagnostic use of physicians’ detection of urine fluorescence in a simulated ingestion of sodium fluorescein–containing antifreeze. Ann Emerg Med 2001; 38: pp. 49
Caution with calcium channel blockers – may lead to hyperkalemia or myocardial depression
Dantrolene has also been used in severe dinitrophenol (industrial chemical and weight loss supplement) toxicity – see this Poison Review post.
The Bread and Butter
We cover syndromes associated with psychiatric medications and polypharmacy including neuroleptic malignant syndrome (NMS), serotonin syndrome, and some extrapyramidal side effects. We do this based on Rosen’s Emergency and Tintinalli. But, don’t just take our word for it. Go enrich your fundamental understanding yourself.
Neuroleptic Malignant Syndrome
Caused by atypical antipsychotics, rare, idiosyncratic and may persist for 2+ weeks after discontinuation of the offending medication
Symptoms – Varied diagnostic criteria but requires temp >100.4F + muscle rigidity + at least two of the following (in rough order of frequency):
Elevated creatine kinase
Labile blood pressure
Treatment – remove offending agents, supportive care (intravenous fluids, cooling), benzodiazepines. Dantrolene, amantadine, and bromocriptine are not recommended.
(PV card from Academic Life in Emergency Medicine). Caution with the elderly as these symptoms may be attributed to infection or delirium (and vice versa).
Symptoms – Classical clinical triad of AMS + Autonomic instability (Hyperthermia, Tachycardia, diaphoresis) + Neuromuscular Abnormalities: Myoclonus, ocular clonus, rigidity, hyperreflexia, tremor. Yet like most clinical triads, this performs poorly. The Hunter Criteria are often used (Sensitivity ~84%):
Serotonergic agent plus 1 of the following:
Inducible clonus + agitation or diaphoresis
Ocular Clonus + agitation or diaphoresis
Tremor + hyperreflexia
Hypertonia + temp >38F AND ocular clonus or inducible clonus
Serotonin syndrome often begins with akathisia (restlessness) and body systems become increasingly “ramped up” with tremors, followed by altered mental status, and then incereasing amounts of rigidity (inducible clonus -> Sustained clonus (+/- ocular clonus) -> Muscular rigidity -> Hyperthermia -> Death)
Causes – While often associated with antidepressants, polypharmacy seems to be the culprit here. Serotonin syndrome is commonly associated with some of these medications
Question 1. A 35-year-old man presents with fever, hypertension and altered mental status. He was recently started on haloperidol for schizophrenia. Physical examination reveals a confused patient with muscle rigidity. [polldaddy poll=8842561]
1. C. FOAMcast editorial: This is an exercise in selecting the *best* answer, not the one that is most correct. You’ve probably noted that a benzodiazepine is not an option, the next best option is dantrolene.
This patient presents with signs and symptoms concerning for neuroleptic malignant syndrome (NMS) and should be treated with dantrolene. NMS is a life-threatening complication of neuroleptic drug treatment. It is rare and only effects 0.5 – 1% of patients receiving these drugs. Although it is more common with use of the typical neuroleptic medications, it can also be seen with the atypical agents. It usually occurs within the first few weeks of starting neuroleptic medications but can also be seen after an increase in dosage. NMS is characterized bymuscle rigidity, fever, altered mental status and autonomic instability. Muscle contraction leads to an elevated serum creatinine kinase. Due to similarities, the disease may be confused with serotonin syndrome. NMS can become complicated by respiratory, hepatic or renal failure, cardiovascular collapse, coagulopathy or gastrointestinal hemorrhage. Dantrolene is a direct acting muscle relaxant that can be beneficial in severe cases.
We review Dr. Rory Spiegel’s, A Case of Identity Part Two, post on EMNerd which is essentially a take down of dual antiplatelet therapy (DAT) in acute coronary syndrome (ACS). The bottom line? There’s no demonstrable and clinically significant benefit from DAT as demonstrated in the trials below.
CURE trial – composite endpoints of questionable clinical significance and an enormous sample size.
2.1% absolute decrease in cardiovascular death and myocardial infarction (MI), completely powered by the 1.5% absolute difference in MIs. Almost all of these MIs were Type IV and peri-procedural. Mortality between groups was identical at 30 days and end of follow up (1.0% vs 1.1% and 2.3% vs 2.4%, respectively).
ACCOAST – RCT of prasugrel or placebo prior to angiography
No difference in cardiovascular death, myocardial infarct, stroke, urgent revascularization or glycoprotein IIb/IIIa rescue therapy (10.8% vs 10.8%)
Approximately 1% increase in major bleeding
CREDO – RCT with placebo or clopidogrel 3-24 hours prior to urgent cardiac catheterization
No statistical difference in the rates of death, stroke or MI at 28 days
Statistical significance of a secondary endpoint of the 1-year outcomes with a 2% absolute reduction in the rate of death, MI, and stroke, largely the result of a 1.9% reduction of MIs.
In patients with non-ST elevation ACS, pretreatment with thienopyridines is not associated with reduced mortality but comes at a cost of a significant excess of major bleeding.
Composite endpoints are problematic (see this post, “Would You Rather“) and statistical significance claimed in these trials is largely a product of composite outcomes rather than patient oriented measures.
The Bread and Butter
We summarize some key topics from the following readings, Goldfrank (10th ed) Chapter 60, EMPractice October 2013 (there’s almost nothing in Rosenalli on this topic) but, the point isn’t to just take our word for it. Go enrich your fundamental understanding yourself!
Irreversibly inhibits platelets (for the duration of platelet’s life)
Reversibly inhibits platelets
Novel Oral Anticoagulants (NOACs)
NOACs have gained increased popularity and are slowly supplanting warfarin for common anticoagulation indications such as non-valvular atrial fibrillation (NVAF) as well as treatment of venous thromboembolisms such as pulmonary embolism (PE) and deep venous thrombosis (DVT).
Direct thrombin inhibitor – dabigatran (Pradaxa). This drug was the first to supplant warfarin for NVAF in the United States, billed as more patient friendly given the lack of purported need for routine monitoring. Recent investigations by Cohen et al, however, demonstrate that monitoring may, in fact, be safer. Further, in a real world, retrospective cohort of Medicare beneficiaries given either dabigatran or warfarin for atrial fibrillation, major bleeding of the dabigatran cohort was higher than in the warfarin cohort 9.0% (95% CI 7.8 – 10.2) versus 5.9% (95% CI 5.1 – 6.6) after propensity matching [Hernandez]. For more on the problems with dabigatran, check out Emergency Medicine Literature of Note.
Predominantly renal excretion
Caution with impaired renal function (can cause dabigatran to stick around longer)
Hemodialysis an option in acute overdose; however, most people would probably not want to put a dialysis catheter in a coagulopathic patient.
Half-life ~ 15 hours
Can elevate the PTT. If the PTT is normal, likely not coagulopathic secondary to dabigatran [Dager et al].
No reversal agent
Factor XA inhibitors – these have XA in the name….rivaroXAban, apiXAban, edoXAban.
Rivaroxaban – approved for NVAF and treatment of DVT/PE. Half life approximately 6-9 hours.
Apixaban – approved for NVAF and treatment of DVT/PE. Half life about 12 hours.
Edoxaban – approved for NVAF. Half life about 10-14 hours.
Cleared by liver and kidneys.
Can elevate the prothrombin time (PT), but not reliably. Specific assays exist but are not widely available and are expensive.
No specific reversal agent although andexanet alfa is in the pipeline. It’s a Factor Xa decoy (Andexanet Alfa) that binds up the F10A inhibitors like a sponge. Read more here.
In the setting of major bleeding, guidelines recommend 4 factor PCCs. A recent study demonstrates reduction in bleeding using 4 factor PCCs on healthy patients given edoxaban [Zahir et al, EMLitofNote]. The benefit of 4 factor PCCs is predominantly based on improvement in numbers, not patient oriented benefit and is discussed in these posts by Dr. Spiegel The Sign of Four, The Sign of Four Part 2.
Question 1. A 65-year-old man with a metal aortic valve presents with hematemesis. His vitals are BP 95/50 and HR 118. The patient is on warfarin and has an INR of 7.3. [polldaddy poll=8501352]
Question 2. A 66-year-old woman with atrial fibrillation on warfarin presents with dark stools for 2 days. Her vitals are T 37.7°C, HR 136, BP 81/43, RR 24, and oxygen saturation 94%. Her labs reveal a hematocrit of 19.4% (baseline 33.1%) and an INR of 6.1. [polldaddy poll=8505511]
1. D. The patient presents with life-threatening bleeding and an elevated INR from warfarin use requiring immediate anticoagulant reversal regardless of the indication for anticoagulation. Warfarin acts by inhibiting vitamin K recycling thus limiting the effectiveness of vitamin K dependant clotting factors (factors II, VII, IX and X). The effect of warfarin can be measured using the prothrombin time or the INR. Warfarin is indicated for anticoagulation for a number of disorders including the presence of a metal valve. Patients with metal valves are at a higher 1-year risk of clot formation around the valve and subsequent embolic stroke. The therapeutic goal of warfarin in a patient with a metallic valve is usually between 2.5 – 3.5 or 3.0 – 4.0. Despite the increased stroke risk, patients with life-threatening bleeding should always have their warfarin reversed by administration of vitamin K and fresh frozen plasma (FFP). Alternatively, prothrombin complex concentrates can be given instead of FFP.
Warfarin is not amenable to hemodialysis (A) for removal or reversal. Although patients with a mechanical valve are at an increased stroke risk (increased 1 year risk) reversal should not be delayed (B), as the patient is more likely to die in the immediate situation from their gastrointestinal bleed. Platelet transfusion (C) will not help, as warfarin does not inhibit platelet function.
2. C. The patient has a life-threatening gastrointestinal bleed in the setting of anticoagulation with warfarin, a vitamin K antagonist. Warfarin acts by inhibiting the synthesis of vitamin K-dependant factors in the coagulation cascade (II, VII, IX, X, protein C, and protein S). The anticoagulant effect of warfarin should be reversed as part of the patient’s emergent treatment. Fresh frozen plasma (FFP) contains all factors in the coagulation cascade and should be given in patients with major bleeding and elevated INR. Vitamin K should be given IV in critically ill patients with elevated INR because it shortens the time to effect.
Vitamin K should not be given intramuscularly (B) because absorption via this route is highly variable. Vitamin K should also not be given orally (D) in critically ill patients because the onset of action will be delayed. Additionally, absorption in patients with gastrointestinal bleeding may be variable. Vitamin K should be given along with FFP (A) because the factors inhibited rely on vitamin K for function.
We summarize some key topics from the following readings, Tintinalli (7e) Chapter ; Rosen’s 8(e) Chapter – but, the point isn’t to just take our word for it. Go enrich your fundamental understanding yourself!
Hypothermia starts at 35°C and then is categorized based on severity.
Ethanol + hypothermia = bad news. Ethanol is the most common cause of excessive heat loss in urban areas as people tend to not take warming measures, may be homeless or without heat, and have impaired thermoregulation. Hypothermia also slows alcohol metabolism, making people drunker for longer.
Elderly patients are more susceptible to hypothermia, particularly as they may not sense the cooler temperatures. Some may also have impaired thermoregulation.
Have a low threshold
Get a temperature, on all patients. This applies to patient’s “found down” as well as the chronic alcoholic who just seems really drunk.
If patients aren’t rewarming 1°C/hr and they’re above 32°C, consider: sepsis, cortisol deficiency, myxedema, ethanol.
The J wave or “Osborn” wave is found in many cases of hypothermia, often quoted at ~80%. However, it is not pathognomonic for hypothermia.
Treatment: Warm the patient. Don’t call the patient dead until they’re warm and dead, which means their temp is above 30-32°C.
Passive Rewarming – effective when the patient can still shiver (33-35°C).
Generates ~1.5°C of heat/hr
Active Rewarming – direct transfer of heat to the patient.
Indications: Cardiovascular instability, temp ≤30-32° C, inadequate rate of rewarming or failure to rewarm, endocrine problem, trauma, tox, secondary hypothermia impairing thermoregulation
Can be external or internal (which can be minimally invasive like IV fluids or quite invasive with things like bypass or pleural lavage).
Unlikely survival with a potassium > 12 mmol/L and recommendations are to terminate resuscitation for potassium >12 mmol/L and consider cessation for potassium between 10-12 mmol/L
Question 1. A 40-year-old man with a history of substance abuse is brought in by EMS after being found unconscious outside of a nightclub in the middle of winter. It is unclear how long he was outside. He is unresponsive http://www.mindanews.com/buy-topamax/ with a GCS of 3.[polldaddy poll=8469565]
Question 2. What is the most common cause of death in hypothermic patients after successful resuscitation?
Question 4. What abnormal rhythm is common with temperatures below 32°C?
Danzl DF, Zafren K. Accidental Hypothermia, in Marx JA, Hockberger RS, Walls RM, et al (eds): Rosen’s Emergency Medicine: Concepts and Clinical Practice, ed 7. St. Louis, Mosby, Inc., 2013, (Ch) 140: pp 1883-1885.
Brown D JA, Brugger H, et al. Accidental Hypothermia. N Engl J Med 2012;367:1930-1938.
Mair P, Kornberger E, et al. Prognostic markers in patients with severe accidental hypothermia and cardiocirculatory arrest. Resuscitation 1994;27:47-54.
1. D. When the serum potassium is greater than 12 mmol/Lresuscitative efforts should be halted as the patient is unlikely to survive and further efforts constitute futile care. Accidental hypothermia is not an uncommon occurrence particularly in colder climates. It may occur in conjunction with substance abuse when an individual becomes impaired and is subsequently exposed to the outdoors. It can also occur as a result of drowning, avalanche and other trauma. Bio-makers other than potassium have been studied including serum lactate (B), pH (C) and clotting time. None have been proven prognostically reliable and therefore should not be used as a guide to determine if resuscitation should be continued. Hypothermic patients that present in cardiac arrest should be warmed to a minimum of 32°C (A) preferably via ECMO or cardiopulmonary bypass. However, if a hypothermic patient is warmed to 32°C and remains in asystole, recovery is unlikely and resuscitative efforts should be terminated. Other indications to cease resuscitative efforts include: obvious signs of irreversible death (e.g. major trauma), valid DNR order, conditions that are unsafe for the rescuer or provider, and an avalanche burial > 35 minutes in which the airway is packed with snow and the patient is asystolic.
2. Pulmonary edema.
2. C. Hypothermia. The ECG demonstrates the presence of J waves or Osborn waves which are seen in hypothermia. One of the first cardiac effects of hypothermia is bradycardia secondary to decreased firing of the cardiac pacemaker cells in cold temperatures. Osborn waves may appear at any temperature below 32°C. The waves are an upward deflection at the terminal portion of the QRS complex. They may represent abnormal ion flux in cold temperatures along with delayed depolarization and early repolarization of the left ventricular wall. As temperatures continue to drop, the ECG will demonstrate prolonged intervals: PR, followed by QRS and then QTc. Both diabetic ketoacidosis (A) and digoxin toxicity (B) may lead to hyperkalemia. In diabetic ketoacidosis, hyperkalemia develops as a result of the acidic pH in the blood and the transport of hydrogen ions intracellularly in exchange for a potassium ion. Digoxin toxicity poisons the cellular Na+/K+ ATPase resulting in elevated extracellular levels of potassium. The ECG manifestations of hyperkalemia begin with peaked T waves. Multiple other findings eventually develop including a shortened QT interval, ST depression, bundle branch blocks, widened QRS, prolonged PR interval, flattened T wave and ultimately a sine wave. Hyperparathyroidism (D) may lead to hypercalcemia. In hypercalcemia, the ECG shows a shortened QT interval, flattened T waves and QRS widening at very high levels.
Welcome to FOAMcast, a podcast created by residents who love Free Open Access Medical education (FOAM). We are looking at cutting edge FOAM and distilling it down to the basics. We’re not doing this to replace reading and hard work but increase interest and direct listeners to linking sexy FOAM with core content. So listen, and go read it yourself.
Patient in extremis or arrest after a fire and burn size doesn’t correlate to severity of illness? Treat for cyanide toxicity.
Treatment: hydroxocobalamin 5g IV in ~250mL normal saline in adults or 70 mg/kg in pediatric patients.
Get labs, including lactate, carboxyhemoglobin level, and transaminases prior to giving hydroxocobalamin if possible because the drug turns everything red and interferes with these tests.
And the Basics of Chemical Asphyxiants?
If a patient presents after smoke exposure, consider cyanide and carbon monoxide toxicity (Case Quiz). These toxicities have many similarities such as: impaired oxygen delivery and utilization, metabolic acidosis with elevated lactate, and presence in patients with smoke inhalation.
Mechanism – Binds to the iron of the cytochrome a3 of complex IV in the mitochondria, the last step of oxidative phosphorylation, effectively shutting down the mitochondria and ATP production leading to tissue hypoperfusion.
Cyanide level is worthless in the acute setting. If suspicious, treat without waiting for labs.
Labs often demonstrate a metabolic acidosis and, in a fire victim, a lactate >10 mmol/L is suspicious for cyanide toxicity.
ABCs – 100% oxygen, crystalloids and vasopressors for hypotension
Hydroxocobalamin 5 g IV for adults or 70 mg/kg IV for pediatrics
Cyanide binds to hydroxocobalamin, forming cyanocobalamin (vitamin B12) which is renally excreted. It also turns everything red, which can interfere with labs and dialysis.
Note: Tintinalli cautions that there’s no good evidence on hydroxocobalamin over the traditional sodium nitrite kits.
There’s also the traditional cyanide antidotes which include: inhaled amyl nitrite, Sodium nitrite 3% – 300 mg IV (10 mL), and sodium thiosulfate.
Sodium nitrite forms methemoglobin from hemoglobin, for which cyanide has enormous affinity. Cyanide leaves the cytochrome, setting the mitochondria free, forming cyanmethemoglobin. This is transformed to thiocyanate by an enzyme (rhodanese) and renally excreted.
If using this approach in a patient with carbon monoxide poisoning, use only sodium thiosulfate given these patient already have impaired tissue oxygenation and methemoglobinemia only further exacerbates this.
Carbon monoxide poisoning is non-specific and may manifest as headache, flu like illness, or coma and death and occurs throughout the year, not just during heat/generator seasons.
Most well recognized – CO has a far greater affinity for hemoglobin than oxygen, leading to impaired delivery of oxygen to tissues.
Causes a left shift of the hemoglobin-oxygen dissociation curve (Right shift = Removal of oxygen from hemoglobin. Left shift = loaded hemoglobin).
Inhibits the cytochrome system in aerobic metabolism, akin to cyanide toxicity, leading to a shift toward anaerobic metabolism.
Clinical suspicion is key.
Labs may show a metabolic acidosis with elevated lactate.
Carboxyhemoglobin level is often available and for boards, remember that levels >15% in pregnant patients or >25% in other patients may be a trigger to think about hyperbaric oxygen therapy. These levels do not correlate with symptoms.
ABCs, including high inspired oxygen which reduces the half-life of CO from ~4 hrs to 90 minutes.
Hyperbaric oxygen (HBO) or “diving” patients in controversial but if a patient is near-dead, pregnant with significant toxicity (level >15), consider HBO, at least on the boards.