About Bryan D. Hayes, PharmD, DABAT, FAACT, FASHP

Leadership Team, ALiEM
Creator and Lead Editor, Capsules and EM Pharm Pearls Series
Attending Pharmacist, EM and Toxicology, MGH
Associate Professor of EM, Division of Medical Toxicology, Harvard Medical School

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.

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.

Bupropion Overdose: Factors Associated with Seizures

Background

Bupropion ingestions are one of the scarier poisonings due to a relatively narrow therapeutic index and the numerous adverse effects that may occur. Medical toxicologist Dr. Dan Rusyniak details his hatred of this drug in overdose in a Tox & Hound blog post aptly-titled Illbutrin. When bupropion was first approved in the 1980s, the max dose was 600 mg/day [1]. However, reports of seizures, particularly in patients with bulimia, caused its temporary removal from the market [2]. It was reintroduced a few years later with a max dose of 450 mg/day [3]. Common signs and symptoms noted in overdose include seizures, agitation, sinus tachycardia, and QRS/QTc prolongation. Seizures occur in up to 40% of overdose cases, are often refractory to initial therapy, and can happen as long as 24 hours after an overdose with extended release formulations [4, 5].

Evidence

A study of 256 patients from the Toxicology Investigators Consortium (ToxIC) Registry identified three factors associated with seizure development after bupropion overdose [6, 7].

  1. QTc prolongation > 500 msec (OR = 3.4, 95% CI: 1.3-8.8)
  2. Tachycardia (heart rate > 140) (OR = 1.9, 95% CI: 1-3.6)
  3. Age 13–18 years (OR = 2.4, 95% CI: 1.3-4.3)

Agitation and tremors are more common in patients who develop seizures with bupropion compared to those who do not [4]. Additionally, presence of tachycardia (heart rate >100 bpm) has a sensitivity of 91% and a negative predictive value of 93% for development of seizures [4].

Bottom Line

  • Seizures are common following bupropion overdose and patients who seize are generally tachycardic.
  • Patients should be observed at least 24 hours after a extended release bupropion overdose, as seizures can be significantly delayed.

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. Davidson J. Seizures and bupropion: a review. J Clin Psychiatry. 1989;50(7):256-261. PMID: 2500425.
  2. Horne RL, Ferguson JM, Pope HG, et al. Treatment of bulimia with bupropion: a multicenter controlled trial. J Clin Psychiatry. 1988;49(7):262-266. PMID: 3134343.
  3. Huecker MR, Smiley A, Saadabadi A. Bupropion. In: StatPearls. StatPearls Publishing; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470212/.
  4. Starr P, Klein-Schwartz W, Spiller H, Kern P, Ekleberry SE, Kunkel S. Incidence and onset of delayed seizures after overdoses of extended-release bupropion. Am J Emerg Med. 2009;27(8):911-915. doi: 10.1016/j.ajem.2008.07.004. PMID: 19857406.
  5. Al-Abri SA, Orengo JP, Hayashi S, Thoren KL, Benowitz NL, Olson KR. Delayed bupropion cardiotoxicity associated with elevated serum concentrations of bupropion but not hydroxybupropion. Clin Toxicol (Phila). 2013;51(10):1230-1234. doi: 10.3109/15563650.2013.849349. PMID: 24131328.
  6. Wax PM, Kleinschmidt KC, Brent J, ACMT ToxIC Case Registry Investigators. The toxicology investigators consortium (Toxic) registry. J Med Toxicol. 2011;7(4):259-265. doi: 10.1007/s13181-011-0177-z. PMID: 21956161.
  7. Rianprakaisang TN, Prather CT, Lin AL, Murray BP, Hendrickson RG, Toxicology Investigators Consortium (ToxIC). Factors associated with seizure development after bupropion overdose: a review of the toxicology investigators consortium. Clin Toxicol (Phila). Published online April 21, 2021:1-5. doi: 10.1080/15563650.2021.1913180. PMID: 33878992.

One-Time Vancomycin Doses in the Emergency Department

Background

A previous ALiEM post from 2013 by an EM pharmacist colleague argued the case against one-time vancomycin doses in the ED prior to discharge. The take-home points from this post were:

    1. No evidence that a one-time vancomycin has any benefit
    2. This practice is not recommended by the Infectious Diseases Society of America (IDSA)
    3. May extend the patient’s ED stay by at least an hour for the IV infusion, depending on the dose
    4. Increases the cost of the ED visit (e.g., IV line, medication, RN time)
    5. Pharmacokinetically 1 dose of vancomycin doesn’t make sense
      • Vancomycin 1 gm IV x1 provides sub-therapeutic levels for patients with normal renal function
      • Efficacy is based on overall exposure (e.g., AUC/MIC) achieved with repeated dosing over several days
    6. Subtherapeutic vancomycin concentrations lead to development of resistance

Despite the above points, a one-time dose of vancomycin prior to the patient being discharged on an oral regimen is a common practice [1].

Evidence

As stated above, a single dose of vancomycin is unlikely to provide a therapeutic benefit and may only serve to reassure clinicians. The 2020 consensus guidelines regarding vancomycin monitoring for serious MRSA infections reinforce the recommendation of achieving an AUC0-24/MIC ratio of ≥400, as a ratio <400 increases resistance and has inferior efficacy [2]. Since the AUC is dependent on overall time of exposure plus concentration, a single dose for an average patient with normal renal function is not adequate (Figure 1). The graph below also demonstrates how long it generally takes for vancomycin to reach steady state when patients receive a dose every 8 hours.

 

*The estimated AUC above assumes a 30 yo male that weights 70kg and is 6′ tall with a serum creatinine of 1.0 mg/dL.

A randomized trial conducted at Christiane Care Health System compared patients who received a vancomycin loading dose of 30 mg/kg or 15 mg/kg [3]. Just twelve hours after this initial dose, 34.6% of patients who received 30 mg/kg had vancomycin levels in the therapeutic range (trough >15 mg/L) vs. 3% of patients who received 15 mg/kg (p < 0.01).

Bottom Line

Even large vancomycin loading doses rarely achieve therapeutic levels after one dose. Therefore, if the plan is to discharge, skip the one-time dose altogether and choose an antimicrobial regimen that will be continued in the outpatient setting (e.g., doxycycline or sulfamethoxazole/trimethoprim if concerned for MRSA or cephalexin for most other patients).

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. Mueller K, McCammon C, Skrupky L, Fuller BM. Vancomycin use in patients discharged from the emergency department: a retrospective observational cohort study. J Emerg Med. 2015;49(1):50-57. doi: 10.1016/j.jemermed.2015.01.001. PMID: 25802166.
  2. Rybak MJ, Le J, Lodise TP, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant staphylococcus aureus infections: a revised consensus guideline and review by the american society of health-system pharmacists, the infectious diseases society of america, the pediatric infectious diseases society, and the society of infectious diseases pharmacists. Am J Health Syst Pharm. 2020;77(11):835-864. doi: 10.1093/ajhp/zxaa036. PMID: 32191793.
  3. Rosini JM, Laughner J, Levine BJ, Papas MA, Reinhardt JF, Jasani NB. A randomized trial of loading vancomycin in the emergency department. Ann Pharmacother. 2015;49(1):6-13. doi: 10.1177/1060028014556813. PMID: 25358330.
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