Correcting Acidosis or Just adding CO2?: On Sodium Bicarbonate for Metabolic Acidosis

Clinical Scenario:
You are working in the emergency department when an elderly male is brought in by EMS after being found unresponsive at home with an unknown downtime.  The paramedics report a possible seizure.  His finger stick glucose registers as critical high.  Post-intubation for poor GCS,  his initial labs reveal an ABG of  6.8/20/90 and a lactate of 18.   As you are signing out the patient to the ICU the ICU team requests a sodium bicarbonate infusion.  You wonder, will sodium bicarbonate administration improve outcomes or correct acidosis faster when compared to normal saline?

Physiology & Literature Review:
Other than well-defined indications for sodium bicarbonate administration (such as treatment of Na-channel blockade in TCA overdose or to induce alkalinization in salicylate toxicity), one should be skeptical about administering sodium bicarbonate simply for acidosis. On the one hand if a patient is acidotic, it makes intuitive sense that you should try to alkalinize them, which is why sodium bicarbonate has been used so often in the past.  On the other hand, there is evidence to show that administration of sodium bicarbonate shifts the oxygen dissociation curve, increasing hemoglobin affinity to oxygen,  and resulting in paradoxical tissue hypoxia and causes an increase in lactate production. In addition, it causes an intracellular acidosis.  Despite this,  because it tends to be part of the "code cocktail",  it is often administered anyway. 

Rise in EtC02 after bicarb (Dr. Sacchetti video)
The effect of administration of Sodium bicarbonate on the end-tidal CO2 in an intubated patient with severe metabolic acidosis is well demonstrated by  this video by Dr. Alfred Sacchetti. While we disagree in giving a bicarb drip as mentioned in the video, it does demonstrate the acid-base physiology in real time. 

A small randomized-controlled trial published in Critical Care Medicine more than 20 years ago gave either a blinded bolus of saline or sodium bicarbonate to patients with lactic acidosis vasopressor support [1].  They then checked ABGs one hour later.   While sodium bicarbonate did increase the venous bicarb level, improved pH, it did not improve hemodynamics.

Regarding two common metabolic acidosis scenarios seen in the emergency department, Diabetic ketoacidosis, the evidence suggests that sodium bicarbonate has the potential to cause harm:
     1. Diabetic ketoacidosis: A recent retrospective observational cohort study examined the effect of sodium bicarbonate on 86 patients in DKA with a pH less than 7.044 patients received sodium bicarbonate and 42 did not.  There was no difference in time to resolution of acidosis (pH greater than 7.2) or hospital length of stay between the two groups. However, there was a significant increase in insulin and fluid requirements in the sodium bicarbonate group. With regard to pediatrics, the PECARN study examining DKA in the pediatric population found that one of the only risk factors for cerebral edema (once again a retrospective analysis) was administration of sodium bicarbonate [3].

    2. Lactic Acidosis: Regarding lactic acidosis, an article from Korea retrospectively looked at 103 patients with acidosis (CO2 less than 20) and lactate greater than 3.3 mmol and compared those that got bicarb (69) to those that did not (34) [4].  Patients who received sodium bicarbonate had increased mortality, but this was confounded by the fact that these patients had lower initial pH, higher initial lactate, and higher APACHE 2 scoresWhen they ran their regression analysis, the only two things that were independently associated with mortality were Sequential Organ Failure Assessment (SOFA) and bicarb administration (95% CI 1-251).   When the authors did a subgroup analysis by excluding less ill patients (SOFA less than 8), they found again that administration of sodium bicarbonate was  associated with death.  They also found that those that received sodium bicarbonate cleared their lactate more slowly. 

Take home points:
Sodium bicarbonate may increase serum pH, but may worsen rather than improve prognosis.  Other than indications where sodium bicarbonate is the treatment for the acidosis (such as TCA overdose), the treatment for metabolic acidosis is to correct the underlying cause, whatever it may be.

Submitted by Wes Watkins, PGY-4
Edited by Louis Jamtgaard, PGY-3 @Lgaard
Faculty reviewed by Evan Schwarz @TheSchwarziee

1. Mathieu D, Neviere R, Billard V, Fleyfel M, Wattel F (1991) Effects of
bicarbonate therapy on hemodynamics and tissue oxygenation in patients with lactic-acidosis: a prospective, controlled clinical study. Crit Care Med 19: 1352– 1356.
2. Adeva-Andany, M. M., Fernández-Fernández, C., Mouriño-Bayolo, D., Castro-Quintela, E., & Domínguez-Montero, A. (2014). Sodium Bicarbonate Therapy in Patients with Metabolic Acidosis. The Scientific World Journal, 2014.
3. Glaser N, Barnett P, McCaslin I, et al; Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics: Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. N Engl J Med 2001; 344:264–269

4. Kim, H. J., Son, Y. K., & An, W. S. (2013). Effect of Sodium Bicarbonate Administration on Mortality in Patients with Lactic Acidosis: A Retrospective Analysis. PloS one, 8(6), e65283.

Hitting the bottle hard, beyond benzos for AWS.

Clinical Scenario:
It’s the age old story, chronic alcoholic evaluated for an unrelated issue, cleared from that issue only to now have developed alcohol withdrawal. The patient in question is a middle aged male with heavy alcohol use history who was transferred from another center for specialist evaluation. After being cleared by the consultant, he is now 24 hours from his last drink and looks decidedly not well. He is tremulous, tachycardic, anxious, and vomiting. You recognize his alcohol withdrawal, but despite treatment, he rapidly worsens requiring very high doses of benzodiazepines and an ICU admission. What adjunct therapies are available for severe alcohol withdrawal?

Synapse in AWS (© 2015 Cynthia Turner
Alcohol abuse is an exceedingly common problem and alcohol-related ED visits are encountered daily across the country.  Annually, around 500,000 episodes of acute alcohol withdrawal require treatment. The symptoms typically begin to manifest within hours to days after cessation of alcohol and typically peak at 2 – 3 days.  The clinical course of alcohol withdrawal varies widely among patients.  Chronic alcohol use leads to down-regulation of GABA receptors and up-regulation of NMDA glutamate receptors. Additionally, GABA receptor expression is suppressed. In the active drinker, this allows patients to maintain a normal level of consciousness despite blood alcohol levels that would incapacitate a nondrinker. Withdrawal is therefore, associated with a decrease in GABAergic activity and an increase in glutaminergic activity. The increase in excitatory activity and loss of inhibitory activity results in the symptom complex of alcohol withdrawal. Symptoms include autonomic hyperactivity, tremor, insomnia, nausea/vomiting, hallucinations (commonly visual or tactile in addition to auditory), psychomotor agitation, anxiety, generalized tonic-clonic seizures. Benzodiazepines are the standard of care for alcohol withdrawal. Adjunct therapies of old have targeted adrenergic symptoms, not so much the underlying disease. These include beta-blockers and calcium channel blockers. Other more targeted therapies like gabapentin are hindered by prolonged onset of action. Adjuncts that make a bit more sense pharmacologically and are gaining popularity include barbiturates, ketamine, and dexmedotomidine.  Let’s look at some of that data.

Literature Review:

Phenobarbital?! What is this the dark ages? Phenobarbital has a rapid onset and long duration of action, with a half-life of 80 – 120 hours. Barbiturates stimulate the GABA receptor and may augment the efficacy of benzodiazepines – so it makes sense.  A retrospective cohort study by J. Gold et al at Bellevue described success with an alcohol withdrawal treatment protocol that used phenobarbital as the primary adjunct. In this protocol, increasing bolus doses of benzodiazepines (in their case primarily diazepam) were given in a symptom-based manner. If symptoms were not controlled with these measures, phenobarbital was added to the mix. All of their patients were admitted to the ICU specifically for alcohol withdrawal. They found that their 24hour diazepam dose, maximum individual dose and use of phenobarbital increased after protocol initiation. With these increases, they also observed a reduction in the need for mechanical ventilation and non-significant trends towards improved ICU length of stay and nosocomial infections.

What about everyone’s favorite drug of the moment, ketamine? Well, it might be good for this too! (Is there anything it can’t do?) Ketamine is an NMDA antagonist. Remember that this is the other system that has been screwed up by chronic alcohol use. A pharm paper by Wong et al out of UPMC describes a retrospective review of patients treated in their ICU for alcohol withdrawal with ketamine. In their 23 cases, they found that after initiation of ketamine infusions, patients’ benzodiazepine requirement at 12 and 24 hours decreased. Sedation scores and alcohol withdrawal scores were stable despite the decrease in benzodiazepine administration. Their median infusion dose was 0.2mg/kg/hr and on average, was continued for just over 2 days. They do note that ketamine does increase heart rate and blood pressure, which can pose challenges in treatment titration.

Dexmedetomidine, a cousin to clonidine, has anesthetic, anxiolytic, analgesic and sympatholytic effects. A case series of 10 patients with severe alcohol withdrawal treated in the ICU with dexmedetomidine (J DeMuro et al) described improvements in vital signs but these improvements did not reach statistical significance. They noted no change in the rate of adverse events despite addition of dexmedetomidine to multiple other agents including bolus dose benzodiazepines, beta-blockers, antipyschotics and propofol. They also noted that dexmedetomidine allowed lower doses of other agents, thereby reducing the risk of respiratory depression with large doses of benzodiazepines, argue their authors. Additionally, they add to the literature that documents safe use of dexmedetomidine far past the FDA approved 24 hour window. The decreased need for benzodiazepines with dexmedetomidine use was echoed by S. Mueller et al. They performed a randomized, double-blind placebo controll trial comparing high dose dexmedetomidine, low dose dexmedetomidine, and placebo. They noted no difference in sedation scores despite greater reduction in benzodiazepine requirements in the dexemedetomidine group.

An important eye in the sky point to take away from a lot of this literature is don’t be stingy with the benzos. These folks have seriously mucked up their brain chemistry and may need an alarming amount of medication. Just taking the literature we’ve reviewed here, DeMuro describes benzodiazepine dosing in the 10 cases used in his series as 2mg lorazepam Q6hrs or 1mg midazolam Q4 hours and reports an average ICU LOS of 9.3 days. Compare that to the 24 hour totals in the Gold paper of over 500mg diazepam (around 50mg lorazepam) with their average ICU LOS of 3.21 days. Far from an apples to apples comparison, but a striking point.

Take home points:
So we end with another age old story. This time we answered the question we asked in the beginning only to find ourselves with more. Yes there are adjuncts to benzodiazepines that may improve clinically important outcomes like intubation, ICU length of stay, and complication rate. However, each of these has it’s own appeal and downsides, and there is no clear winner. So the next time you approach that patient with severe alcohol withdrawal, think back to some of this literature. Use strategies that have been shown to improve outcomes – symptom based and aggressive early benzodiazepine dosing. Beyond that, use of adjuncts looks like a good idea. Choosing a particular adjunct will likely be a multifactorial decision and include factors like availability, cost, and your own comfort with a particular agent. Plus, if your alcohol withdrawal patient is this sick, it might be time to call your friendly, neighborhood toxicologist.

Submitted by Sara Manning, PGY-3@EM_SaraM
Edited by Louis Jamtgaard, PGY-3 @Lgaard
Faculty reviewed by Evan Schwarz @TheSchwarziee 

DeMuro, JP et al, “Use of dexmedetomidine for the treatment of alcohol withdrawal syndrome in critically ill patients: a retrospective case series” 2012. Journal of Anesthesia. Vol. 26(4); pp. 601-605.
Gold, JA et al, “A strategy of escalating doses of benzodiazepines and phenobarbital administration reduces the need for mechanical ventilation in delirium tremens.” 2007. Critical Care Medicine. Vol. 35(3); pp. 724 – 730.
Goldfrank et al, Goldfranks Toxicologic Emergencies, 8ed. 2006. McGraw-Hill.
Mueller, SW et al, “A Randomized, Double-Blind, Placebo-Controlled Dose Range Study of Dexmedetomidine as Adjunctive Therapy for Alcohol Withdrawal.” 2014. Vol. 42; pp – 1131 – 1139.
Wong, A et al, “Evaluation of adjunctive ketamine to benzodiazepines for management of alcohol withdrawal syndrome.” 2015, Vol. 49(1)pp 14 – 19.

Droperidol the psycho dropper or heart stopper?

Clinical Scenario:
You are working a typical EM-1 shift loaded full of psychiatric patients, EMS brings you another agitated male with a history of schizophrenia. He is shouting absurdities and threatening staff members.  The RN glances over at you, 5/2 doc? You're feeling a little different today and order 10mg of droperidol IM. The drug is administered and the patient calms down. With pride you present the patient to your attending. Your attending is alarmed and immediately requests an EKG and places the patient on a cardiac monitor and tells you the patient is in imminent danger of converting into torsades de pointes (TdP) secondary to prolonged QT.  You perform a rapid review of the literature.

Literature Review:
Droperidol is a butyrophenone that has been used since the mid 1970's primarily for acute agitation but it has also found a role in treating nausea, headaches, and abdominal pain. In 2001, droperidol received a black box warning by the FDA because of its association with QT prolongation and potential fatal arrhythmias.
FDA Black Box warning

There is no consensus as to what degree of QT prolongation is clinically significant, but several papers have cited QT longer than 500ms or delta QT of 60ms as at risk for TdP. (1) Mechanistically, in animal models Droperidol has been shown to both block efflux of myocardial potassium and induce early depolarization in cardiac fibers. Human studies have shown varied results, but lean towards droperidol causing some degree of prolonged QT without clinically significant arrhythmias. (2) 

 Lischke et al performed a randomized, double blind study on 40 patients undergoing cardiac surgery that were given either 7 mg,12.5 mg, or 17.5 mg of droperidol prior to surgery. Serial ECGs were obtained and QT prolongation ranged from 37 to 59ms in all groups in a dose dependent manner, however there were no recorded dysrhythmias or fatal events. (3) Again, Guy et al performed a prospective study in 55 patients who received 0.25mg/kg of droperidol prior to surgery, mean QT increased by 24ms, however no arrhythmias were noted. A 2014 prospective study by Calver involved continuous Holter monitoring for 24hrs in patients who had received 10-30mg IM of droperidol for acute agitation. Four out of 46 patients had abnormal QT greater than 480ms, but only one case was temporally associated with droperidol administration.  No arrhythmias were recorded. (4)  Kao et al reviewed decades of published literature including multiple systematic reviews and randomized controlled trials with outcome measures specifically observing for adverse effects of droperidol, and none cited any cases of fatal arrythmias. (1)

 Kao et al reviewed the FDA surveillance data cited by the FDA as cardiac events related to droperidol administrations, and found that the case reports were plagued by confounders and failed to show causation between droperidol administration and fatal arrhythmias.   Many of the European studies cited by FDA used doses of 50 -100mg IM, significantly higher than doses typically used in the US.  
Kao et al FDA surveillance data

Furthermore, similar case studies are described with haloperidol another commonly used antipsychotic.  

Take home points:
Bottom line is there are no randomized trials that demonstrate that droperidol causes fatal arrhythmias, there is data to show the droperidol prolongs QT in a likely clinically insignificant manner. There are rare case reports that suggest cardiac events might be associated with droperidol administration, but most cases involve confounders and cannot demonstrate causation.  Therefore it is likely reasonable to administer droperidol in most cases without any type of cardiac monitoring. However use of droperidol in this manner falls outside of FDA approval, therefore it is likely reasonable to take some precations (EKG or cardiac monitoring) in high risk groups (ESRD, severe cardiac disease) or consider alternative agents.  

Submitted by Louis Jamtgaard PGY-3 @Lgaard
Faculty reviewed by Evan Schwarz @TheSchwarziee

  1. Kao LW Droperidol, QT prolongation, and sudden death: what is the evidence? Ann Emerg Med. 2003 Apr;41(4):546-58.

  1. JM Guy, X Andre-Fouet, J Porte, et al. Torsades de pointes and prolongation of the duration of QT interval after injection of droperidol [in French] Ann Cardiol Angeiol (Paris), 40 (1991), pp. 541–545

  1. V Lischke, M Behne, P Doelken, et al. Droperidol causes a dose-dependent prolongation of the QT interval Anesth Analg, 79 (1994), pp. 983–986

  1. Calver LBr J Clin Pharmacol. 2014 May;77(5):880-6. doi: 10.1111/bcp.12272. High dose droperidol and QT prolongation: analysis of continuous 12-lead recordings.

Salicylate Toxicity with Normal Anion Gap Acidosis?

Clinical Scenario:
A teenager with no significant past medical history presents to an outside hospital with tachypnea, nausea, vomiting, and altered mental status. There is no history of illness preceding today and the parents do not believe there was any ingestion.  The patient appears to be tiring from extreme tachypnea, so is intubated and transferred to your ED for further management, where new labs were drawn, including an ABG and BMP.  Sodium is 151, potassium 3.7, chloride 128, bicarbonate 8, which is an anion gap of 15. ABG shows pH 6.9, pCO2 44, pO2 268, bicarbonate 8. 

Clinical Questions:
In a patient with a normal or near normal anion gap metabolic acidosis, do you still have to worry about toxic ingestions?

Should a patient with suspected salicylate toxicity be intubated and placed on mechanical ventilation to prevent respiratory failure from fatigue?

Photo: Wiki Commons

Literature Review:
Traditional causes of non-gap metabolic acidosis can be summarized by the mnemonic HARDUP [1]:

H - Hyperalimentation (oversupply of certain nutrients, most commonly seen in initiation of TPN)
A - Acetazolamide use
R - Renal tubular acidosis (second most common)
D - Diarrhea (by far the most common)
U - Ureterosigmoid fistula
P - Pancreatic fistula

Diarrhea and RTA comprise >90% of cases of non-gap metabolic acidosis encountered clinically.

However, there have been several cases of patients with hyperchloremic, non-anion gap metabolic acidosis that are actually salicylate poisonings [2,3]. Some chloride analyzers can be confused by the overabundance of salicylate ions or the competition of salicylate with chloride ions for albumin binding. This can falsely elevate the reported chloride concentration and subsequently narrow the anion gap. This effect may be related to the manufacturer of the lab equipment, or the age of the chloride ion electrode.  Patients with a severe acidosis of unknown etiology with a normal anion gap should still be considered for salicylate ingestion.

The appearance of a severely tachypneic patient can prompt the urge to intubate. However, one must keep in mind that the organ of toxicity for aspirin is the brain. Aspirin has a pKa of 3.5 which means in acidic environments it is more likely to be non-ionized. This allows movement across membranes, including the blood-brain barrier. Aspirin causes a direct stimulation of the respiratory center inducing tachypnea. Frequently, salicylate-toxic patients will have a mixed metabolic acidosis with respiratory alkalosis. Intubation of these patients can remove the respiratory alkalosis component which causes blood pH to drop and allows more non-ionized aspirin to enter the brain [4]. Patients with salicylate toxicity may rapidly deteriorate or die if intubated because their minute ventilation on the ventilator often do not match their pre-intubation minute ventilation.

- Do not rule out salicylates based solely on an anion gap. 
- Patients with salicylate toxicity may rapidly deteriorate or die if intubated because it is difficult to match their pre-intubation minute ventilation once mechanically ventilated. 
- Almost all salicylate-toxic patients who require mechanical ventilation will need hemodialysis to remove salicylate and accumulated organic acids.

BONUS Crash Course in Salicylate Toxicity [5]:
Salicylate poisoning remains a frequently-encountered toxicity that can be easy to miss due to vague and nonspecific symptoms, especially in a chronic, unintentional overdose. However, missing the diagnosis may have dire consequences. One study found the in-hospital mortality of unrecognized aspirin poisoning was three times higher than if the toxicity was recognized in the ED. In another cohort, half of patients that died of salicylate toxicity arrived to the ED with normal mental status.

I. Pathophysiology
Aspirin uncouples oxidative phosphorylation, causing a severe metabolic lactic acidosis. The inefficiency of anaerobic metabolism often causes fever as a result, but lack of fever should not rule out salicylate toxicity. Glucose consumption increases, which may cause hypoglycemia.

Simultaneously, direct stimulation effects on the respiratory centers of the cerebral medulla, causing a respiratory alkalosis. This effect may not be as pronounced in pediatric patients.

The acid-base disturbances of salicylate toxicity advance in three phases:

Approx nl
Approx nl

II. Clinical Presentation
The classic triad of acute salicylism is hyperventilation, tinnitus, and GI irritation. Hyperventilation may take the form of increased respiratory rate and/or increase in tidal volume. Aspirin can form bezoars or concretions in the stomach, especially enteric coated (EC) formulations. Such a concretion should be suspected if a patient's clinical picture continues to worsen or serum salicylate levels continue to rise despite ongoing treatment.

The progression of salicylism is marked by complications of extreme metabolic acidosis, including pulmonary and cerebral edema, myocardial depression and cardiovascular collapse, and CNS depression with seizures.

III. Management
Serum salicylate levels should be obtained liberally in suspected ingestions, particularly if there is any doubt as to what substances were ingested.  Levels should continued to be obtained until there is a clear downward trend given the ability of bezoars, as mentioned above, to continue to secrete salicylate.

Those with salicylism are often volume depleted due to hyperventilation and fever.  Patients should undergo resuscitation with fluids containing glucose as well as bicarbonate, which will increase the elimination of salicylate through urine.  Potassium supplementation should also be included since many patients are hypokalemic due to the body's attempt at bicarbonate reabsorption.  Gastric decontamination with active charcoal may be considered, however with many patients with altered mental status, it must be weighted against possible aspiration.

Hemodialysis is the definitive treatment and should be considered in those with severe acidosis, evidence of end-organ injury (seizures, rhabdomyolysis, pulmonary edema), renal failure, high serum aspirin concentrations (>100 mg/dL), and patients who require intubation.

[1] Hellman N. "Mnemonic for NON-anion gap metabolic acidosis. From: The Renal Fellow Network.
[2] Jacob J, Lavonas EJ. "Falsely normal anion gap in severe salicylate poisoning caused by laboratory interference." Ann Emer Med. 2011; 58:280-281.
[3] Kaul V, et al. "Negative anion gap metabolic acidosis in salicylate overdose--a zebra!" Am J Emerg Med. 2013;31(10):1536.e3-4.
[4] Greenberg MI, Hendrickson RG, Hofman M. “Deleterious effects of endotracheal intubation in salicylate poisoning." Ann Emerg Med. 2003 Apr;41(4):583-4.
[5] O'Malley GF. Emergency department management of the salicylate-poisoned patient. Emerg Med Clin North Am. 2007 May;25(2):333-46.

Submitted by Dave Liss, PGY-4.
Edited by C. Sam Smith (@CSamSmithMD), PGY-3 and Steven Hung, PGY-2.
Faculty reviewed by Evan Schwarz (@TheSchwarziee), MD FACEP.

Oh Shacka - Dantrolene for Neuroleptic Malignant Syndrome?

You are in a community emergency department when a middle-aged woman is brought in by her husband for worsening confusion over the last two days.  The charge nurse comes and asks if it should be a stroke page because the patient has “slurred speech”.   You rush into the room, NIHSS card in hand ready to wheel the patient off to CT and are confronted by a worrisome picture.  The patient is burning man re-incarnate - She is laid out on the stretcher with all 4 limbs stiff and outstretched, is febrile to 39.4 and tachycardic to the 140’s.  Her blood pressure is normal. She can answer some of your questions (says she has trouble “saying” words) but is definitely confused.  You think that this might be good old sepsis, but something about her sets your tox-sense tingling …. and you ask her husband immediately for a medication list which contains a number of pro-serotonergic anti-depressants and a single anti-psychotic. 

Could this be serotonin syndrome?  Could this be NMS?  You  send off a CK level (which comes back at > 1000), initiate a sepsis work-up, get a head CT and phone a friend.  Your tox expert by phone helps you with this by asking a single question:  Well, does she have myoclonus  (SS) or is she rigid (NMS)?  Rigid has it, and you create a mnemonic for future reference:

Oh SHACKA this patient might have NMS:

Now that you think that this is like NMS, how is it best treated?  You have memorized for your board exams that bromocriptine is the treatment for NMS, but your toxicology friend reminds you that bromocriptine can worsen the symptoms of serotonin syndrome [1], and given this patient’s med list and possible mixed-picture, may not be the best idea. What about dantrolene?  Well, what about it?

Clinical question:  What is the mechanism of action for dantrolene? Does dantrolene have any proven effectiveness in the treatment of neuroleptic malignant syndrome? 

Literature Review: 
    Neuroleptic malignant syndrome is a rare, and potentially life-threatening adverse reaction to anti-dopaminergic anti-psychotic medication.  There are multiple established diagnostic criteria - the Levenson Criteria and DSM-IV - that are largely described by the mnemonic above. 

from Guzofski et. al. [2]

The exact pathophysiology of NMS is unknown, but the muscle rigidity (which looks a lot like Parkinsonism) is thought to be secondary to inhibition of dopamine-mediated signalling (as such this can also occur in Parkinson's patients in the setting of dopamine withdrawal).  This muscle rigidity can cause muscle
damage and subsequent rhabdomyolysis.  The hyperthermia may be the result of either (or both) the muscle rigidity or by direct effects of dopamine D2-receptor blockade on the hypothalamus.  Hyperthermia can become life-threatening, and thus the treatment, in addition to cessation of the offending agent, is to pharmacologically relax and cool down the patient.

Bromocriptine, a dopamine agonist, is sometimes used.  But as discussed above, if there is a serotinergic component to the patient's presentation, this could worsen serotonin syndrome.  Benzodiazepines and IV fluids are the mainstay of supportive care. 

            Dantrolene, the mainstay of treatment for malignant hyperthermia, has also been proposed and has been used for the treatment of NMS.  Dantrolene acts as a direct skeletal muscle relaxant by blocking calcium release from the sarcoplasmic reticulum [3].  As such, the main side effect is muscle weakness, but no reports of respiratory or airway compromise have been reported (at least in healthy volunteers) [3].  Given this mechanism, it is unclear why it would be helpful for NMS.  Like most things in toxicology, the majority of data regarding the efficacy (or lack thereof) of dantrolene in the treatment of NMS comes from case series and case reports. In 2007, a study published in Critical Care attempted to pool the results of 271 Case Reports to assess the effectiveness of dantrolene for the treatment of NMS [4].  From these 271 case reports, the authors collected patient data including gender, age, diagnosis, triggering medication, dosage, time of incidence, diagnostic criteria met, other laboratory parameters and whether the patients received dantrolene therapy alone, dantrolene + other medications, only other medications, or only supportive care.  The "other medications" and the scope of "supportive care" was not specified (or necessarily the same) between case reports.  The outcomes of the study were the following: reported improvement within 24 hrs, complete time to remission and overall mortality.  The authors found that dantrolene monotherapy was associated with a higher likelihood of improvement within 24 hrs and shortest time (9.4 +/- 12.7 days) to complete remission than dantrolene+ other medication, other medication or supportive therapy alone.  If this was not confusing enough (for example, why would dantrolene alone be better than dantrolene+other medication), the dantrolene monotherapy also had an overall higher mortality (16.2% vs. 7.3% for d+other, 8.9% for "other", and 2% for supportive care).  Given the innumerable caveats to pooling the data only from case reports and the difficult to interpret results, it is unclear whether dantrolene therapy is effective, helpful or potentially harmful in the treatment of NMS.  It is possible that patients who received dantrolene who were either 1) not very sick and so got better quickly or 2) very sick, in which case they received other medications (therefore the longer time to remission) or mismanaged by giving dantrolene alone leading to higher overall mortality.

Clinical Takehome: Know your hyperthermic toxidromes because they are not made better with antibiotics.  Regarding NMS, dantrolene has unproven effectiveness but lack of rigorous evidence that it causes harm.  Benzodiazepines and fluids will be your mainstay of treatment, give bromocriptine if you are confident in your diagnosis. Boom shaka laka.

[1]Boyer, E. W., & Shannon, M. (2005). The serotonin syndrome. New England Journal of Medicine, 352(11), 1112-1120.

[2] Peralta, M. D. (2006). Neuroleptic malignant syndrome, with attention to its occurrence with atypical antipsychotic medication: a review. Jefferson Journal of Psychiatry, 20(1), 7.
[3] Krause, T., Gerbershagen, M. U., Fiege, M., Weisshorn, R., & Wappler, F. (2004). Dantrolene–a review of its pharmacology, therapeutic use and new developments. Anaesthesia, 59(4), 364-373.
[4]Reulbach, U., Dutsch, C., Biermann, T., Sperling, W., Thuerauf, N., Kornhuber, J., & Bleich, S. (2007). Managing an effective treatment for neuroleptic malignant syndrome. Crit Care, 11(1), R4.

Submitted by Maia Dorsett [@maiadorsett], PGY-3
Faculty Reviewed by Evan Schwarz [@TheSchwarziee]