ED Management of Cannabinoid Hyperemesis Syndrome: Breaking the Cycle

cannabis cannabinoid hyperemesis syndrome

What is cannabinoid hyperemesis syndrome?

Cannabinoid hyperemesis syndrome (CHS) is a condition in which patients who have been using cannabis or synthetic cannabinoids for a prolonged period of time develop a pattern of episodic, severe vomiting (usually accompanied by abdominal pain) interspersed with prolonged asymptomatic periods.

When should you consider cannabinoid hyperemesis syndrome as a diagnosis?

The diagnostic criteria for CHS require evidence of relief of symptoms with sustained cessation from cannabis, which makes them of limited utility in the Emergency Department (ED) [1]. However, a number of ED-based diagnostic criteria have been proposed with overlapping features [1,2]. There are 3 key components to assess for when making a presumed diagnosis:

  1. An episodic pattern of vomiting
    • Episodes of vomiting should last < 7 consecutive days
    • Asymptomatic periods often last > 1 month between episodes
  2. Prolonged cannabis use
    • Criteria vary: normally >1 time per week (often daily) for at least 1 year
    • Importantly, this is not an intoxication effect from a single large ingestion
  3. Exclusion of alternative diagnoses
    • Look for atypical features on history & exam including abnormal vital signs, diarrhea, focal abdominal pain, peritonitis, and jaundice
    • It is important to exclude pregnancy in all female patients
    • If a patient has never had an esophagogastroduodenoscopy (EGD), it is reasonable to refer newly diagnosed patients to gastroenterology for a non-emergent EGD to assess for a structural cause of the patient’s symptoms

What causes cannabinoid hyperemesis syndrome?

There is no singular theory that fully explains CHS. Importantly, the pattern of illness does not correlate well with the amount of cannabis consumed acutely, suggesting it is not related to a direct effect of the delta-9-tetrahydrocannabinol (THC) or a withdrawal effect. There are two prevailing theories related to changes in neuro-signaling and receptor expression with chronic THC exposure:

Theory #1: Downregulation of the cannabinoid receptor type 1 (CB-1) receptor which occurs with chronic THC use causing dysregulation of the hypothalamic-pituitary-adrenal stress axis. This theory supports why medications that have sedative or anxiolytic properties, such as haloperidol and benzodiazepines, have reported efficacy.

Theory #2: Changes in central nervous system dopamine signaling pathways with chronic THC exposure leading to a hypersensitive emesis response to dopamine. This theory is less well supported but has been used to explain the beneficial effects of dopamine antagonists such as haloperidol, droperidol, and olanzapine.

How should we treat cannabinoid hyperemesis syndrome in the ED?

Ondansetron, Metoclopramide, and Antihistamines

Traditional antiemetics have had low rates of success in treating CHS based on reported cases (ondansetron = 1.75%, metoclopramide = 4.35%) [3]. Antihistamines such as dimenhydrinate, diphenhydramine, and meclizine have no studies supporting their use, and the limited case reports available suggest they are ineffective [3]. While cases of treatment failure are more likely to be published which contributes to a reporting bias, clinical experience supports that CHS often does not respond well to these antiemetics. These medications may still have a role as an adjunct for patients who are refractory to other treatments, but given the evidence available supporting other agents, they can no longer be recommended as first-line therapy. Drawbacks to using a “traditional antiemetics first” strategies include a delay to effective treatment, prolonged ED length of stay, and prolongation of the QT interval.

Haloperidol

The HaVOC trial showed haloperidol was twice as effective as ondansetron at reducing nausea (change from baseline = -5.0 vs. -2.4) and abdominal pain (change from baseline = -4.3 vs. -2.1). Haloperidol also decreased rescue medication use (31% vs. 76%) and time from medication administration to ED discharge (3.1 hours vs. 5.6 hours) [4].

Lower doses of haloperidol were recommended (0.05 mg/kg) due to higher rates of adverse reactions with larger doses. Weight-band based dosing may be a more practical approach:

  • Haloperidol 2.5 mg IV for adults < 80 kg
  • Haloperidol 5 mg IV for adults > 80 kg

Olanzapine

There is very limited evidence supporting olanzapine specifically in CHS (6 reported cases) [3]. However, olanzapine has strong evidence supporting its antiemetic properties in oncology literature [5,6]. Unlike haloperidol, olanzapine does not prolong the QT interval and it has much lower rates of extrapyramidal side effects. Therefore, olanzapine may be a reasonable substitution for haloperidol in the following cases: documented allergy to haloperidol, prolonged QT interval, or previous extrapyramidal effects with haloperidol.

Capsaicin

While capsaicin is often discussed as a treatment [ALiEM trick of the trade], the evidence supporting its use is limited to a small case series and a small RCT with some significant limitations. The small RCT published in support of capsaicin had large baseline differences between the capsaicin and placebo groups. The placebo group was “more sick”, having higher baseline nausea which was not corrected for in the analysis [7].

The trial reported a significant reduction in nausea scores with capsaicin (60-minute nausea score: Placebo = 6.4 vs. Capsaicin = 3.2, p = 0.007) which looks impressive, but the change in nausea from baseline was much less substantial (change in nausea: Placebo = -2.1 vs. Capsaicin = -2.8). Overall, the evidence supporting capsaicin is limited, so its use should be a shared decision.

Benzodiazepines

Lorazepam has no studies assessing its utility in CHS, but a summary of case reports suggests an efficacy of 58.3% in 19 patients [3]. Despite the lack of evidence, clinical experience has led to lorazepam being recommended as an adjunct in recent cyclic vomiting syndrome guidelines for patients who have an anxiety component to their presentation [8]. Since 40-50% of traditional cyclic vomiting syndrome patients were chronic cannabis users, it is reasonable to extrapolate these guidelines to CHS until more specific literature is published.

Overall Approach to Treatment

Based on the currently available research outlined above and clinical experience, the following is a reasonable approach to acute symptomatic management of CHS in the ED:

What should we be considering at the time of discharge?

Like other chronic episodic illnesses (eg. migraines) the long-term management of CHS can be conceptualized to have three components: avoidance of triggers, management of acute episodes, and episode prevention (prophylaxis).

Avoidance of Triggers

  • The only cure for CHS is the prolonged cessation of cannabis. It is important to emphasize that it may take 6 months of cannabis cessation before symptoms improve, and to recognize that the challenges in stopping cannabis use are often underestimated. Professional addictions support is encouraged.

Management of Acute Episodes

  • Medications at home to abort acute episodes are a logical management strategy and may be a safe option to reduce recurrent ED visits in some patients. This will depend on which medications work for the patient, their comorbidities, and the patient’s access to reliable follow-up.
  • There is no current evidence to guide outpatient treatment. Traditionally, many gastroenterologists have used a combination of sublingual lorazepam and ondansetron which may be reasonable if a patient has responded to these medications in the ED.
  • The use of oral haloperidol at home is currently being studied, but there are no good protocols published to guide practice.

Episode Prevention

  • There have been no studies on using medications to reduce the frequency of CHS episodes. However, amitriptyline is recommended as a first-line prophylactic treatment for adults with cyclic vomiting syndrome as it reduces subjective symptoms scores, episode frequency, and ED utilization [9,10].
  • Using amitriptyline for CHS would be considered experimental and amitriptyline has several well-recognized side effects, requires slow up-titrated, and necessitates close follow-up. It may be reasonable for a patient to discuss with their primary care provider.

 

References

  1. Venkatesan T, Levinthal DJ, Li BUK, et al. Role of chronic cannabis use: cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome. Neurogastroenterology & Motility. 2019 Jun;31(Suppl 2):e13606.
  2. Sorensen CJ, DeSanto K, Borgelt L, Phillips KT. Cannabinoid hyperemesis syndrome: diagnosis, pathophysiology, and treatment – a systematic review. Journal of Medical Toxicology. 2017;13:71-87.
  3. Richards JR, Gordon BK, Danielson AR, Moulin AK. Pharmacologic treatment of cannabinoid hyperemesis syndrome: a systematic review. Pharmacotherapy. 2017;37(6):725-34.
  4. Ruberto AJ, Sivilotti ML, Forrester S, et al. Intravenous haloperidol versus ondansetron for cannabis hyperemesis syndrome (HaVOC): a randomized, controlled trial. Annals of Emergency Medicine. 202 Nov;S0196-0644(20)30666-1.
  5. Hashimoto H, Abe M, Tokuyama O, Mizutani H, Uchitomi Y, Yamaguchi T, Hoshina Y, Sakata Y, Takahashi TY, Nakashima K, Nakao M, et al. Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncology. 2020;21:242-49.
  6. Naravi RM, Qin R, Ruddy KJ, et al. Olanzapine for the prevention of chemotherapy-induced nausea and vomiting. New England Journal of Medicine. 2016 Jul;375(2):134-42.
  7. Dean DJ, Sabagha N, Rose K, et al. A pilot trial of topical capsaicin cream for treatment of cannabinoid hyperemesis syndrome. Academic Emergency Medicine. 2020;27:1166-72.
  8. Venkatesan T, Levinthal DJ, Tarbell SE, et al. Guidelines on management of cyclic vomiting syndrome in adults by the American neurogastroenterology and motility society and the cyclic vomiting syndrome association. Neurogastroenterology & Motility. 2019;31(Supp 2):e13604.
  9. Hejazi RA, Reddymasu SC, Namin F, et al. Efficacy of tricyclic antidepressant therapy in adults with cyclic vomiting syndrome: a two year follow up study. Journal of Clinical Gastroenterology. 2010;44:18-21.
  10. Namin F, Patel J, Lin Z, et al. Clinical, psychiatric and manometric profile of cyclic vomiting syndrome in adults and response to tricyclic therapy. Neurogastroenterology & Motility. 2007;19:196-202.

Pre-Arrest Acidemia and the Effect of Sodium Bicarbonate on ROSC

Background

Sodium bicarbonate during a cardiac arrest is widely debated and used in many cases. In a 2018 PULMCrit post, Dr. Josh Farkas reviews much of the data and concludes that use of sodium bicarbonate is a “source of eternal disagreement.” A 2013 EMCrit article and podcast by Dr. Scott Weingart also details some of the controversy. The 2020 ACLS Guidelines state that routine use of sodium bicarbonate is not recommended in cardiac arrest [1]. Despite this recommendation, sodium bicarbonate is still often administered during resuscitations if a metabolic (or respiratory) acidosis is suspected or after a prolonged downtime. A recent study evaluated the effect of pre-arrest acid-base status on response to sodium bicarbonate and achievement of return of spontaneous circulation (ROSC) [2].

Evidence

This was a retrospective review of in-hospital cardiac arrests (IHCA) in patients with pre-arrest serum bicarbonate levels ≤21 mmol/L compared to >21 mmol/L. Pre-arrest bicarbonate levels were obtained <24 hours prior to the arrest. Similarly, post-arrest bicarb levels were obtained <24 hours following the arrest. Bicarbonate levels were recorded from basic chemistry panels rather than blood gases. All patients received a median sodium bicarbonate dose of 100 mEq. The groups were relatively well-matched, with the only major difference being the time to first bicarb administration was faster in the ‘acidotic’ group (6.9 vs. 9.2 minutes). Initial ECG rhythms were similar between the groups.

  • 102 patients in ‘acidotic’ group with a median pre-arrest bicarb level of 17 mmol/L
  • 123 patients in ‘non-acidotic’ group with a median pre-arrest bicarb level of 27 mmol/L
  • There was no difference in ROSC (53.9% vs 48.8%, p=0.44) or survival to discharge (8.8% vs 5.7%, p=0.36) between the acidotic group versus the nonacidotic group

Thoughts and Limitations

  • A meta-analysis found no difference in sustained ROSC or survival to discharge with sodium bicarbonate (Alshahrani 2021).
  • In the current study, prearrest bicarb levels could have resulted up to 24 hours prior to the arrest and the authors don’t comment on when exactly they were drawn. The timing limits the ability to know true acid-base status just prior to the arrest. And, that really limits applying this to out-of-hospital cardiac arrest where patients may have more significant acidemia if resuscitation is delayed.
  • A median bicarbonate concentration of 17 mmol/L isn’t really that low, relatively speaking, to indicate a potential impact from administering sodium bicarbonate.
  • Retrospective cardiac arrest studies are challenging. Many interventions happen around the same, making it impossible to connect any one of them with a specific outcome.
  • The study that would be more helpful is taking patients with metabolic/respiratory acidosis and giving have bicarb and the other placebo.

Bottom Line

  • In this cohort of IHCA patients, sodium bicarbonate administration did not improve the chances of ROSC or survival to hospital discharge, irrespective of pre-arrest acid-base status. In other words, attempting to correct ‘acidosis’ does not seem to change rate of ROSC.
  • Sodium bicarbonate use in cardiac arrest should be targeted (e.g., hyperkalemia with metabolic acidosis, sodium channel blockade secondary to an overdose).

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References

  1. Panchal AR, Bartos JA, Cabañas JG, et al. Part 3: adult basic and advanced life support: 2020 american heart association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2020;142(16_suppl_2):S366-S468. doi: 10.1161/CIR.0000000000000916. PMID: 33081529.
  2. Mclean H, Wells L, Marler J. The effect of prearrest acid-base status on response to sodium bicarbonate and achievement of return of spontaneous circulation. Ann Pharmacother. Published online August 5, 2021:10600280211038392. doi: 10.1177/10600280211038393. PMID: 34353142.

INR reduction with FFP – How low can you go?

Background

Bleeding patients or those undergoing procedures that are at high risk of bleeding may require correction of their INR. Multiple products can be used to achieve this, including fresh frozen plasma (FFP). FFP contains many substances, including clotting factors, fibrinogen, plasma proteins, electrolytes, and anticoagulant factors. It is sometimes said that the intrinsic INR of FFP is approximately 1.6-1.7 and that it’s not possible to achieve a lower INR. This pearl will further explore these concerns.

Evidence

  • What is the INR of FFP?
    • The mean INR of FFP appears to be ~1.1 (0.9-1.3) [1,2].
    • Reports that the intrinsic INR of FFP is 1.6-1.7 may be based on the clinical experience of not being able to achieve an INR <1.6-1.7 with FFP.
  • Is it possible to “normalize” the INR with FFP alone?
    • Several studies have found that it’s difficult to achieve an INR <1.7 with only FFP [3,4]. However, other studies were able to achieve lower average INR values [2,5,6]. 
    • Overall, these studies found that there was a significantly greater decrease in INR when the pre-FFP INR was higher, but there was a much smaller decrease when the INR was closer to the normal range.
  • Why does FFP appear to have diminishing returns when the pre-FFP INR is lower?
    • The relationship between the INR and percentage of clotting factors present in the blood is not linear (see figure) [7].
    • For example: An increase of ~5% in clotting factors may decrease the INR from 3 to 2.5 but the same amount of FFP may only reduce an INR of 1.7 to 1.6.

Figure 1: Adapted from Dzik  2012 [7].

    • Additionally, the table below also demonstrates that small volumes of FFP result in large changes when the initial INR is elevated, but very large amounts of FFP are required to achieve an INR of 1.3 no matter the initial INR (see table).
Amount of FFP to Achieve a Target INR Based on Pre-FFP INR
Target INR
1.31.73.0
Initial INRVolume (L)Dose (mL/kg)Factor (%)Volume (L)Dose (mL/kg)Factor (%)Volume (L)Dose (mL/kg)Factor (%)
6.04.564452.536251.52115
5.04.361432.332231.01410
4.04.057402.029200.575
3.03.550351.52115
2.02.536250.575

Table 1: Adapted from Holland 2006 [3]. Note: 1 unit of FFP is ~200-250 mL

    • Given the above data, the issue preventing the achievement of an INR <1.7 appears to be the dose/volume of FFP required and not the intrinsic INR of FFP.
  • Does the INR need to be <1.7 to achieve hemostasis?
    • Since the INR only provides limited information regarding a single aspect of anticoagulation status, complete normalization for the INR to control bleeding is usually not necessary [6].
    • An INR elevation alone does not indicate a patient is coagulopathic or at an increased risk of bleeding [7]. Additionally, an INR elevation in patients with liver dysfunction likely reflects an overall state of decreased factor production, both procoagulant and anticoagulant factors [8].
    • The target INR varies depending on multiple patient factors and planned interventions, but an INR of 1.0 is likely not necessary to prevent bleeding or achieve hemostasis.

Bottom Line

  • A unit of FFP has an INR of ~1.1, but this doesn’t mean it can easily normalize the INR.
  • There is a non-linear relationship between percentage of clotting factors and the INR, resulting in diminishing returns from each unit of FFP as the INR decreases.
  • Very large doses of FFP may be required to fully correct an elevated INR, which frequently precludes its use.
  • Complete normalization of the INR is not required to achieve hemostasis or prevent bleeding from a procedure.

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References

  1. Holland LL, Foster TM, Marlar RA, Brooks JP. Fresh frozen plasma is ineffective for correcting minimally elevated international normalized ratios. Transfusion. 2005;45(7):1234-1235. doi: 10.1111/j.1537-2995.2005.00184.x. PMID: 15987373.
  2. Only AJ, DeChristopher PJ, Iqal O, Fareed J. Restoration of normal prothrombin time/international normalized ratio with fresh frozen plasma in hypocoagulable patients. Clin Appl Thromb Hemost. 2016;22(1):85-91. doi: 10.1177/1076029614550819. PMID: 25294634.
  3. Holland LL, Brooks JP. Toward rational fresh frozen plasma transfusion: The effect of plasma transfusion on coagulation test results. Am J Clin Pathol. 2006;126(1):133-139. doi: 10.1309/NQXH-UG7H-ND78-LFFK. PMID: 16753596.
  4. Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion. 2006;46(8):1279-1285. doi: 10.1111/j.1537-2995.2006.00891.x. PMID: 16934060.
  5. Müller MCA, Straat M, Meijers JCM, et al. Fresh frozen plasma transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy. J Thromb Haemost. 2015;13(6):989-997. doi: 10.1111/jth.12908. PMID: 25809519.
  6. McCully SP, Fabricant LJ, Kunio NR, et al. The International Normalized Ratio overestimates coagulopathy in stable trauma and surgical patients. J Trauma Acute Care Surg. 2013;75(6):947-953. doi: 10.1097/TA.0b013e3182a9676c. PMID: 24256665.
  7. Dzik W “Sunny.” Reversal of drug-induced anticoagulation: old solutions and new problems. Transfusion. 2012;52(s1):45S-55S. doi: 10.1111/j.1537-2995.2012.03690.x. PMID: 22578371.
  8. Harrison MF. The misunderstood coagulopathy of liver disease: a review for the acute setting. West J Emerg Med. 2018;19(5):863-871. doi: 10.5811/westjem.2018.7.37893. PMID: 30202500.
By |2021-08-28T10:03:39-07:00Aug 21, 2021|EM Pharmacy Pearls, Heme-Oncology|

Succinylcholine and the Risk of Hyperkalemia

Succinylcholine and the Risk of Hyperkalemia

Background

Succinylcholine is frequently used in the ED to facilitate intubation, but it may be avoided in some cases due to the risk of hyperkalemia. The underlying physiology of this effect appears to be directly related to its therapeutic mechanism of action. When succinylcholine binds to and activates acetylcholine receptors, it leads to an influx of sodium and calcium and and an efflux of potassium into the extracellular space [1]. Additionally, when these acetylcholine receptors are immature or denervated, it seems that these channels may stay open significantly longer, allowing for an increased  amount of potassium to exit the cell, leading to an increased risk of hyperkalemia.

Evidence

Based on multiple studies that included patients with normal renal function, succinylcholine leads to a serum potassium increase of  ~0.5 mEq/L [2-4]. This is likely clinically insignificant in most patients. In fact, an ED-based study found a variable response with serum potassium increasing in 46 cases, decreasing in 46 cases, and not changing in 8 cases [3]. It seems that even patients on chronic dialysis are not at increased risk of developing clinically-significant hyperkalemia from succinylcholine [5].

So, when should succinylcholine potentially be avoided specifically due to hyperkalemia concerns [6]?

  • Hyperkalemia with ECG changes present prior to succinylcholine administration
  • Denervating, crush, or burn injuries after 72 hours
  • Rhabdomyolysis
  • Prolonged total body immobilization
  • Denervating diseases (e.g., multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS))
  • Inherited myopathies (e.g., Duchenne muscular dystrophy (DMD))

In patients for whom succinylcholine is determined to be not an option, non-depolarizing muscular blocking agents (NMBAs), such as rocuronium, are still safe and do not lead to hyperkalemia.

Bottom Line

  • Succinylcholine-induced hyperkalemia is more likely to occur in patients with predisposing conditions
  • Development of hyperkalemia following succinylcholine is variable and not always predictable
  • If succinylcholine is not an option due to potential risk of hyperkalemia, NBMAs (i.e., rocuronium) are still safe and effective

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References

  1. Hovgaard HL, Juhl-Olsen P. Suxamethonium-induced hyperkalemia: a short review of causes and recommendations for clinical applications. Critical Care Research and Practice. 2021;2021:e6613118. doi: 10.1155/2021/6613118.
  2. Magee DA, Gallagher EG. “Self-taming” of suxamethonium and serum potassium concentration. Br J Anaesth. 1984;56(9):977-980. doi: 10.1093/bja/56.9.977. PMID: 6466531.
  3. Zink BJ, Snyder HS, Raccio-Robak N. Lack of a hyperkalemic response in emergency department patients receiving succinylcholine. Acad Emerg Med. 1995;2(11):974-978. doi: 10.1111/j.1553-2712.1995.tb03124.x. PMID: 8536123.
  4. Raman SK, San WM. Fasciculations, myalgia and biochemical changes following succinylcholine with atracurium and lidocaine pretreatment. Can J Anaesth. 1997;44(5 Pt 1):498-502. doi: 10.1007/BF03011938. PMID: 9161744.
  5. Thapa S, Brull SJ. Succinylcholine-induced hyperkalemia in patients with renal failure: an old question revisited. Anesth Analg. 2000;91(1):237-241. doi: 10.1097/00000539-200007000-00044 PMID: 10866919.
  6. Martyn JAJ, Richtsfeld M. Succinylcholine-induced hyperkalemia in acquired pathologic states: etiologic factors and molecular mechanisms. Anesthesiology. 2006;104(1):158-169. doi: 10.1097/00000542-200601000-00022. PMID: 16394702.

High-Dose Nitroglycerin for Sympathetic Crashing Acute Pulmonary Edema

Background

Nitroglycerin (NTG) is an important intervention to consider for patients with Sympathetic Crashing Acute Pulmonary Edema (SCAPE) as it significantly reduces preload, and even modestly reduces afterload with high doses. For acute pulmonary edema in the ED, NTG is often administered as an IV infusion and/or sublingual tablet. Starting the infusion at ≥ 100 mcg/min produces rapid effects in many patients and can be titrated higher as tolerated, with doses reaching 400 mcg/min or greater. Combined with noninvasive positive pressure ventilation (NIPPV) and in some cases IV enalaprilat, patients often turn around quickly, from the precipice of intubation to comfortably lying in bed [1, 2]. But what does the literature say about starting with a high-dose NTG IV bolus followed by an infusion?

Evidence

A 2021 prospective, pilot study of 25 SCAPE patients proposed a clear and systematic protocol (below) for treating these critically ill patients with a combination of high-dose NTG bolus (600 – 1000 mcg over 2 mins) followed by an infusion (100 mcg/min) and NIPPV [3].There were no cases of hypotension after the bolus and 24 of the 25 patients were able to avoid intubation. Additionally, an earlier PharmERToxGuy post summarizes some of the previous studies evaluating the use of a high-dose NTG IV bolus for acute pulmonary edema.

It is important to note that some institutions may not allow IV push NTG or may limit the use of NTG boluses. Providers may then opt to implement dosing strategies such as bolusing from an IV infusion pump or initiating the infusion at a high rate for a short period (e.g., NTG 300 mcg/min for 2-3 minutes) before reducing the rate to a more traditional infusion rate (e.g., 100 mcg/min).

Bottom Line

  • A few small ED studies support the use of an initial IV NTG bolus followed by an infusion compared to the infusion alone [1, 2]
  • There is a low risk of hypotension following a single IV NTG bolus
  • Consider using the following protocol to identify which doses may be best for specific patients based on initial systolic blood pressure

Click for full-sized version [3]

 

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References

  1. Wang K, Samai K. Role of high-dose intravenous nitrates in hypertensive acute heart failure. Am J Emerg Med. 2020;38(1):132-137. doi: 10.1016/j.ajem.2019.06.046. PMID: 31327485.
  2. Wilson SS, Kwiatkowski GM, Millis SR, Purakal JD, Mahajan AP, Levy PD. Use of nitroglycerin by bolus prevents intensive care unit admission in patients with acute hypertensive heart failure. Am J Emerg Med. 2017;35(1):126-131. doi: 10.1016/j.ajem.2016.10.038. PMID: 27825693.
  3. Mathew R, Kumar A, Sahu A, Wali S, Aggarwal P. High-dose nitroglycerin bolus for sympathetic crashing acute pulmonary edema: a prospective observational pilot study. The Journal of Emergency Medicine. Published online June 2021:S0736467921004674. doi: 10.1016/j.jemermed.2021.05.011.

Beta-Blockers for Inhalant-Induced Ventricular Dysrhythmias

Background

There are a few unique scenarios when beta-blockers may be indicated for patients in cardiac arrest. Use of esmolol for refractory ventricular fibrillation was summarized in a 2016 PharmERToxGuy post with an accompanying infographic. Another potential use for beta-blockers is in the rare case of a patient with inhalant-induced ventricular dysrhythmias. The term ‘sudden sniffing death’ refers to acute cardiotoxicity associated with inhaling hydrocarbons. Check out this ACMT Toxicology Visual Pearl for more information about the background and diagnosis of inhalant abuse.

It is thought that inhalants causes myocardial sensitization via changes in various cardiac channels (e.g., sodium channels, potassium channels, calcium channels, or gap junctions) leading to prolonged repolarization and conduction [1, 2]. Additionally, chronic inhalant use can lead to structural heart damage. When the above alterations are combined with a sudden increase in catecholamines (e.g., exercise, caught sniffing), a dysrhythmia can develop which is often fatal [2-4].

Evidence

There are no case reports to support the use beta-blockers to treat inhalant-induced dysrhythmias. However, the case reports below include patients that ingested various hydrocarbons who developed ventricular dysrhythmias and improved following the initiation of beta-blockers. As the adverse cardiac effects should be similar between inhaled and ingested hydrocarbons, we can potentially extrapolate this data to patients with inhalant-induced dysrhythmias.

DemographicsAgent(s) Ingested Cardiac EffectsInterventionsResolution of dysrhythmia following BB?
39 yo M [5]TrichloroethylenepVT/VF arrestDefibrillation, Propranolol bolus and infusion

Y

70 yo F [6]TrichloroethyleneBigeminy, Junctional rhythmEsmolol bolus and infusion

Y

23 yo F [7]Chloral hydrateVF arrestEsmolol bolus and infusion

Y

27 yo M [8]Chloral hydrate, Loxapine, FluoxetineStable VTPropranolol bolus and infusion

Y

3 yo M [9]Chloral hydrateSinus tachycardia, Bigeminy, Trigeminy, NSVTEsmolol bolus and infusion

Y

44 yo M [10]Chloral hydrateStable VTPropranolol bolus, Labetalol infusion

Y

BB=beta-blocker; pVT=polymorphic ventricular tachycardia; VT=ventricular tachycardia; VF=ventricular fibrillation; NSVT=non-sustained ventricular tachycardia

Bottom Line

  • Patients presenting to the ED with cardiopulmonary manifestations of inhalant use should have routine electrolytes and an ECG to assess cardiac status
  • A quiet environment is important to decrease stimulation and minimize catecholamine surges
  • For both stable and non-perfusing dysrhythmias, propranolol or esmolol are reasonable choices to counteract the catecholamine effects, in addition to standard care [5-10]
    • Consider avoiding epinephrine and other catecholamines unless necessary, as they may worsen the dysrhythmia

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series and find previous pearls on the PharmERToxguy site.

References

  1. Nelson LS. Toxicologic myocardial sensitization. J Toxicol Clin Toxicol. 2002;40(7):867–79. doi: 10.1081/clt-120016958. PMID: 12507056.
  2. Tormoehlen LM, Tekulve KJ, Nañagas KA. Hydrocarbon toxicity: A review. Clin Toxicol (Phila). 2014 Jun;52(5):479–89. doi: 10.3109/15563650.2014.923904. PMID: 24911841.
  3. Bass M. Sudden sniffing death. JAMA. 1970 Jun 22;212(12):2075–9. PMID: 5467774.
  4. Baydala L. Inhalant abuse. Paediatr Child Health. 2010 Sep;15(7):443–54. doi: 10.1093/pch/15.7.443. PMID: 21886449.
  5. Gindre G, Le Gall S, Condat P, Bazin JE. [Late ventricular fibrillation after trichloroethylene poisoning]. Ann Fr Anesth Reanim. 1997;16(2):202–3. doi: 10.1016/s0750-7658(97)87204-8. PMID: 9686084.
  6. Mortiz F, de La Chapelle A, Bauer F, Leroy JP, Goullé JP, Bonmarchand G. Esmolol in the treatment of severe arrhythmia after acute trichloroethylene poisoning. Intensive Care Med. 2000 Feb;26(2):256. doi: 10.1007/s001340050062. PMID: 10784325.
  7. Shakeer SK, Kalapati B, Al Abri SA, Al Busaidi M. Chloral hydrate overdose survived after cardiac arrest with excellent response to intravenous β-blocker. Oman Med J. 2019 May;34(3):244–8. doi: 10.5001/omj.2019.46. PMID: 31110633.
  8. Zahedi A, Grant MH, Wong DT. Successful treatment of chloral hydrate cardiac toxicity with propranolol. Am J Emerg Med. 1999 Sep;17(5):490–1. doi: 10.1016/s0735-6757(99)90256-5. PMID: 10496517.
  9. Nordt SP, Rangan C, Hardmaslani M, Clark RF, Wendler C, Valente M. Pediatric chloral hydrate poisonings and death following outpatient procedural sedation. J Med Toxicol. 2014 Jun;10(2):219–22. doi: 10.1007/s13181-013-0358-z. PMID: 24532346.
  10. Wong O, Lam T, Fung H. Two cases of chloral hydrate overdose. Hong Kong Journal of Emergency Medicine. 2009 Jul;16(3):161–7. doi: 10.1177/102490790901600307.

Utility of Nebulized Naloxone

Background

Naloxone can be administered via multiple routes, with nebulization gaining popularity in the past decade. A previous ALiEM Trick of the Trade presented this unique method of administration. In order for nebulized naloxone to be effective patients need to have some level of respiratory effort. It should not be used in patients in respiratory arrest or impending respiratory arrest. It may be a more gentle way to wake up patients to confirm the diagnosis of opioid toxicity and to gather a history. Theoretically, if the patient arouses enough to start experiencing mild withdrawal, they can ‘self-titrate’ and remove the nebulizer mask.

How is it prepared?

Mix 2 mg naloxone (5 mL of  naloxone 0.4 mg/mL) with 3 mL of 0.9% sodium chloride for inhalation in a nebulizer cup.

Evidence

Anecdotal reports tout the benefits of nebulized naloxone, but what does the literature say?

  • Case report of a 46 y/o female with an initial oxygen saturation of 61%. Naloxone 2 mg was administered via nebulization and within 5 mins her oxygen saturation was 100% and mental status was normal [1].
  • Retrospective analysis of prehospital administration in 105 patients with suspected opioid overdose. Following nebulized naloxone,  22% had a “complete response” and 59% had a “partial response.” It’s important to note that the initial respiratory rate was already 14 bpm with GCS of 12 for patients that responded to treatment [2].
  • Prospective analysis of 26 patients with suspected opioid intoxication treated at an inner-city, academic ED. Pre-naloxone the mean respiratory rate was 13 with a median GCS of 11. Following treatment, the mean respiratory rate improved to 16 with a median GCS of 13. Three patients (12%) experienced moderate-to-severe agitation and 2 (8%) became diaphoretic, suggesting precipitation of acute withdrawal [3].
  • Case report of a 20 y/o female with initial oxygen saturation of 62% (respiratory rate not reported). She improved following administration of nebulized naloxone and clinical efficacy corresponded with serum naloxone concentrations [4].

 

Importantly, aside from the two case reports, the above studies both primarily included patients without severe respiratory depression. As far as the safety of nebulized naloxone, Baumann et al. reported 5 patients (out of 26) who seemed to have mild-to-moderate symptoms of withdrawal following administration [3]. So this raises a question that must be answered on a patient specific basis: Does the benefit of this therapy outweigh the risk in patients who may not require naloxone to begin with? An alternative approach, if IV access is established, is to try low-dose diluted IV naloxone.

 

Bottom Line

Many of the studied patients may not have needed naloxone in the first place as they had an initial respiratory rate 13-14, with a few developing withdrawal symptoms. Nebulized naloxone may have a role in the “not-too-sick” opioid overdose in whom you want to prove your diagnosis and wake the patient up enough to obtain a history. It is not a therapy for an apneic patient with suspected opioid overdose.

 

References

  1. Mycyk MB, Szyszko AL, Aks SE. Nebulized naloxone gently and effectively reverses methadone intoxication. J Emerg Med. 2003;24(2):185-187. doi: 10.1016/s0736-4679(02)00723-0. PMID: 12609650.
  2. Weber JM, Tataris KL, Hoffman JD, Aks SE, Mycyk MB. Can nebulized naloxone be used safely and effectively by emergency medical services for suspected opioid overdose? Prehosp Emerg Care. 2012;16(2):289-292. doi: 10.3109/10903127.2011.640763. PMID: 22191727.
  3. Baumann BM, Patterson RA, Parone DA, et al. Use and efficacy of nebulized naloxone in patients with suspected opioid intoxication. Am J Emerg Med. 2013;31(3):585-588. doi: 10.1016/j.ajem.2012.10.004. PMID: 23347721.
  4. Minhaj FS, Schult RF, Fields A, Wiegand TJ. A case of nebulized naloxone use with confirmatory serum naloxone concentrations. Ann Pharmacother. 2018;52(5):495-496. doi: 10.1177/1060028017752428. PMID: 29319329.
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