Episode 28 – Neuroleptic Malignant Syndrome, Serotonin Syndrome, & Malignant Hyperthermia

The Free Open Access Medical Education (FOAM)

We review a post from Dr. Charles Bruen from ResusReview on Malignant Hyperthermia and dantrolene.

Malignant hyperthermia – a rare condition typically associated with volatile anesthetics, so more often an OR/inpatient issue; however, has been associated with succinylcholine use.

Cause: most often a mutation of the ryanodine receptor which, in the presence of certain anesthetics or succinylcholine causes too much intracellular calcium. This leads to increased ATP production.

Signs/Symptoms: tachycardia, hypercarbia, muscle rigidity, hyperthermia

Treatment – Dantrolene.

Administer though a large vein
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.

Ref: Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352:(11)1112-20.

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):

Diaphoresis
Leukocytosis
AMS
Elevated creatine kinase
Labile blood pressure
Tachycardia
Tremor
Incontinence
Dysphagia
Mutism

Treatment – remove offending agents, supportive care (intravenous fluids, cooling), benzodiazepines. Dantrolene, amantadine, and bromocriptine are not recommended.

Serotonin Syndrome

(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:
- Spontaneous clonus
- 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

Antidepressants –
- SSRIs/SNRIs – sertraline, fluoxetine, paroxetine, citalopram, venlafaxine, etc
- Trazodone, Buspirone
- TCAs
- MAOIs
Analgesics – fentanyl and tramadol
Antibiotics – Linezolid (Poison Review post)
Antiemetics – ondansetron, metoclopramide
Anti-epileptics – depakote
Anti-tussive – dextromethorphan
Herbs – St. John’s wort, ginseng

Extrapyramidal Symptoms

Acute Dystonia – involuntary motor tics or muscle spasms classically including torticollis, tongue or lip protrusion, or oculogyric crisis

Akathisia – a feeling of restlessness often accompanied by tapping, pacing, rocking. Reversible.

~40% of patients given 10 mg of intravenous prochlorperazine developed akathisia within 1 hour.

Treatment: Benzodiazepines, Benadryl (diphenydramine), Benztropine

Generously Donated Rosh Review Questions

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]

Answers

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.

Episode 20 – Anticoagulation

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The Free Open Access Medical Education (FOAM)

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.
1% increase in major bleeding events

Thienopyridine Meta-Analysis

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!

Aspirin

Irreversibly inhibits platelets (for the duration of platelet’s life)

Ibuprofen

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.

More FOAM on Anticoagulation Reversal

ER Cast

Generously Donated Rosh Review Questions

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]

Answers.

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.

Episode 19 – Environment: Mushrooms and Hypothermia

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The Free Open Access Medical Education (FOAM)

We review the Tox Talk podcast, Episode 23 – Mushrooms. Our favorite pearls:

Clitocybe, Inocybe – contain muscarine which stimulates muscarinic receptors (acetylcholine/parasympathetic), causing a cholinergic toxidrome. Think SLUDGE (salivation, lacrimation, urination, defecation, gastric emptying/emesis) and the Killer B’s (bradycardia, bronchorrhea, bronchospasm) or DUMBELLS (diarrhea/diaphoresis, urination, miosis, bradycardia, emesis, lacrimation, lethargy, salivation). Basically, cholinergic toxidrome: SMALL, WET, SLOW.

Memory aid: these mushrooms end in -yBE, akin to the “killer B’s” that make cholinergic toxicity deadly.

Gyromitra – (false morel) contains gyromitrin which can cause seizures, in addition to gastrointestinal upset and liver failure. Treatment: pyridoxine (B6).

Memory aid: gyromitra named because they look like the gyri of the brain and, conveniently, make the brain seize through depletion of GABA.

Amanita phalloides – contains amatoxins which cause delayed gastrointestinal symptoms and liver failure., echoing acetaminophen toxicity.

Caution: this is different than the amanita muscaria ‘mushroom, which is tricky because that amanita muscaria has neither muscarinic properties nor the toxicity of amanita phalloides.

Bonus pearl: Coprinus species can cause a disulfiram like reaction.

FOAM article on mushrooms by Jo et al

The Bread and Butter

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.

Pearls:

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

Diagnostics:

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).

Outcomes –

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

FOAM Resources:

EBM Gone Wild on Prognostication

ScanCrit on ECMO in Accidental Hypothermia

EMCrit on Severe Accidental Hypothermia

Generously Donated Rosh Review Questions (Scroll for Answers)

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 3.

[polldaddy poll=8473489]

Question 4. What abnormal rhythm is common with temperatures below 32°C?

References:

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.

Answers:

1. D. When the serum potassium is greater than 12 mmol/L resuscitative 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.

4. Atrial fibrillation.

Episode #1: EMCrit Episode #122 – Cyanide and Carbon Monoxide Toxicity

Welcome

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.

What Did Weingart and Dr. Nelson say?

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.

Cyanide Toxicity – Tintinalli (7e) Ch 198; Rosen’s (8e) Ch 179

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.

Diagnostics-

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.

Treatment –

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 (CO) – Tintinalli (7e) Ch 217; Rosen’s (8e) Ch 159

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.

Mechanism –

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.

Diagnostics –

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.

Treatment –

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.

Questions generously donated by the Rosh Review

Question 1. [polldaddy poll=8074537]

Question 2. [polldaddy poll=8074535]

Episode 1: Cyanide and Carbon Monoxide Toxicity

(iTunes)

References:

Gresham C, LoVecchio F. Chapter 198. Inhaled Toxins. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: McGraw-Hill; 2011. p 1317-1320.

Nelson RS, Hoffman RS. Chapter 159. Inhaled Toxins. Rosen’s Emergency Medicine, 8e. 2014. p 2036-2043.

Maloney G. Chapter 217. Carbon Monoxide. Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7e. New York, NY: McGraw-Hill; 2011. p 1410-1413.

Answers. 1) A 2)A