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.

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 cynthiaturner.com)

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.

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.

EKG Challenge No. 6 Case Conclusion - Them Dirty Drugs

You are working the day shift at Children's Hospital when you get a medical control call from EMS.  They responded to a call for "altered behavior" at a house to find a partially-clothed and confused teenage boy who was discovered "talking nonsense" by his parents in the living room that morning.  They call you because the patient is somewhat "agitated" and just won't stop picking at every line and piece of equipment.  They want your okay to give him some versed to chill him out.  You agree to 2 mg of IV versed and await his arrival in the emergency department.

On arrival, the patient has a dry mouth, dilated pupils, and speaks some unclear, but seemingly pleasant gibberish.  Mom, through her tears, tells you the patient takes no medications but has "experimented with drugs" in the past.  There is radio silence when you listen for bowel sounds and your ungloved hand meets a dry axilla, confirming the clinical picture of an anticholingeric toxidrome.  Noting his heart rate in the 140's, you decide that it is prudent to get an EKG:

You carefully assess the EKG and review it systematically:
          Rate - tachycardic, regular
          Rhythm - sinus (clear p waves in the lateral leads)
          Axis - Right axis deviation
          Intervals - the QRS is wide (> 100 ms in toxicology), with normal QTc
          Other - Incomplete RBBB (see lead V1) with tall R' in avR

Together, these findings are indicative of Na-channel blockade, the hallmark of which is a widened QRS due to delay of phase 0 depolarization of the cardiac action potential:

Image source: Hollowell et. al. (2005)

Interestingly, the right heart seems to be more sensitive to Na-channel blockade as evidenced by the common finding of RBBB and Right axis deviation in Na-channel blocker toxicity [Ref 1].  This is corroborated by the association of RBBB with Brugada syndrome, which is due to a genetic defect in the SCN5a Na channel.

When you think of the toxicologic differential for anticholinergic toxicity with Na channel blockade, benadryl and TCAs are at the top of your list. Given the widened QRS and overall clinical picture, you administer Sodium bicarbonate and the patient's QRS narrows.  He is admitted to the hospital and has full resolution of all symptoms by morning.  Once awake, he admits to taking "a lot" of benadryl because he was having trouble sleeping.

While we use diphenhydramine for blockade of the histamine H1 receptor, it is a dirty drug that has  blocks both muskarinic acetylcholine receptors and voltage-gated Na channels as well [Ref 2].  This patient's clinical presentation - altered, dry, and tachycardic - is secondary to development of an anticholinergic toxidrome.  The abnormal EKG findings - right axis deviation, widened QRS, R' in avR - are due to Na-channel blockade.

It is important to be familiar with the EKG findings of pharmacologic Na-channel blockade because it is a property of many medications, including both cardiac and non-cardiac drugs.  See the table below from Kolecki & Curry  (1997) [Ref 3] for some common examples:

Because of the importance of Na influx at essentially every stage of  heart beat generation,  the cardiac effects of Na-channel blockade can have a number of manifestations, the unifying theme of which is a widened QRS [Ref 1, 3]:

(1) Intraventricular conduction defects - Na-channel blockade slows propagation of the action potential, which is manifested as a widened QRS, and occasionally this takes on the pattern of recognized bundle branch blocks. At extreme overdoses, the QRS can widen to a sine wave morphology.  If the action potential is completely blocked, this is manifested as asystole.

EKG for patient with cocaine overdose with 1st degree AV block, bradycardia, and markedly wide QRS; Source: Ref 7

With regard to the definition of widened QRS, it is important to note that unlike the standard definition of  > 120 ms, the QRS is considered wide in toxicology when it exceeds 100 ms.  This is rooted in part in a prospective study of 49 patients with TCA overdose that examined the correlation between QRS duration and risk of seizure and/or ventricular arrythmmia [Ref 4].  It was found that in acute tricyclic overdoses, seizures occurred "at any QRS duration of 0.10s or longer (p <.05) but ventricular arrythmmias were seen only with QRS duration of 0.16 seconds or longer (p < 0.0005)."  This finding for TCA overdose has been generalized to the management of all Na-channel blocker overdoses. Therefore, in our patient above, with an initial QRS of 117 ms, there may be cause for concern.

(2) Ventricular Arrythmmias - ventricular arrythmmias occur in Na-channel blockade by a variety of mechanisms. One proposed mechanism is that intraventricular conduction is slowed to a point at which unidirectional block and re-entry tachycardias can develop.  A second mechanism has to do with the fact that many Na channel blockers also block K channels (i.e. all group 1A anti-arrythmmics).  K blockade is associated with QT prolongation, thereby putting patients at risk for torsades.

(3) Bradydysrhythmias - Bradydysrhythmias in the context of Na-channel overdose are thought to occur secondary to Na-blockade at the pacemaker cells.  Bradycardia is rare (but very ominous) in the context of overdose with agents, such as benadryl or TCAs, that also have tachycardia-inducing anticholingeric activity.  Propanolol, a beta-blocker with Na-channel blocking activity, causes bradycardia by beta-blockade as well.

                                                  Ionic currents underlying depolarization at the SA node
                                     Image source: http://www.nataliescasebook.com/tag/cardiac-action-potentials

With regard to treatment, the mainstay is sodium bicarbonate, which has been demonstrated to narrow the QRS in Na-channel blockade secondary to diphenhydramine overdose [Ref 1, 5].  Sodium bicarbonate should be titrated to effect on the QRS.  It is generally recommended that initial boluses of 1 Amp of Sodium bicarbonate at a time be administered until the QRS narrows. Following this, one can consider starting a drip (3 ampules of sodium bicarbonate in 1L D5W infusing at twice the patient's maintenance rate) with close attention paid to the patient's potassium to prevent development of hypokalemia [Ref 1].  As the antidote effects of Sodium bicarbonate have more to do with the Sodium hypertonicity than alkalinization, hypertonic saline can also be considered (and actually works better in a swine model of TCA toxicity) [Ref 6].  Administration of physostigmine can reverse the clinical findings of anticholinergic toxicity, but should be used with caution in patients with a widened QRS, as reversal of anticholingeric tachycardia can unmask Na channel blockade at the pacemaker cells, leading to bradycardia, heart block, and cardiovascular collapse.


Take Home Points -
- If the QRS is wide (> 100 ms) in your overdose patient, they may have Na-channel blockade and Sodium bicarbonate should be considered for treatment.
- All that electrophysiology you learned in medical school does have clinical relevance.
- Clinical syndrome + EKG will likely lead you to the right treatment pathway:

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Agent	Clinical Presentation	EKG effects	Treatment
Antihistamines	Anticholingeric toxidrome: Delirium, mydriasis, anhydrosis, urinary retention, reduced GI motility, tachycardia	Tachycardia, QRS widening, Right axis deviation, tall R' in avR; can progress to bradyarthmmia, heart block, and asystole in large overdose	Sodium bicarbonate;                                                     Consider physostigmine (use with caution with widened QRS)
TCAs	Anticholingeric toxidrome+ hypotension + seizure		Sodium bicarbonate
Cocaine	Sympathomimetic toxidrome: hypertension, tachycardia, agitation, diaphoresis	Wide complex dysrhthmmias, heart block,  ST elevation/depression [Ref 7]	Benzodiazepines; Sodium bicarbonate if widened QRS
Propanolol	Hypotension, bradycardia, seizures	Bradycardia, QRS complex widening	Intralipid

References

[1] Hollowell, H., Mattu, A., Perron, A. D., Holstege, C., & Brady, W. J. (2005). Wide-complex tachycardia: beyond the traditional differential diagnosis of ventricular tachycardia vs supraventricular tachycardia with aberrant conduction. The American journal of emergency medicine, 23(7), 876-889.
[2] Jang, D. H., Manini, A. F., Trueger, N. S., Duque, D., Nestor, N. B., Nelson, L. S., & Hoffman, R. S. (2010). Status epilepticus and wide-complex tachycardia secondary to diphenhydramine overdose. Clinical Toxicology, 48(9), 945-948.
[3] Kolecki, P. F., & Curry, S. C. (1997). Poisoning by sodium channel blocking agents. Critical care clinics, 13(4), 829-848.

[4]Boehnert, M. T., & Lovejoy Jr, F. H. (1985). Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. New England Journal of Medicine, 313(8), 474-479.
[5] Sharma, A. N., Hexdall, A. H., Chang, E. K., Nelson, L. S., & Hoffman, R. S. (2003). Diphenhydramine-induced wide complex dysrhythmia responds to treatment with sodium bicarbonate. The American journal of emergency medicine, 21(3), 212-215.
[6]McCabe, J. L., Cobaugh, D. J., Menegazzi, J. J., & Fata, J. (1998). Experimental tricyclic antidepressant toxicity: a randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation. Annals of emergency medicine, 32(3), 329-333.
[7] Kerns II, W., Garvey, L., & Owens, J. (1997). Cocaine-induced wide complex dysrhythmia. The Journal of emergency medicine, 15(3), 321-329.



Submitted by Maia Dorsett (@maiadorsett), PGY-3
Faculty Reviewed by  Evan Schwarz 

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

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.

References:
[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]