Is Lactated Ringer’s Solution Safe for Hyperkalemia Patients?

Is Lactated Ringer's Solution Safe for Hyperkalemia Patients?

Background

There are three primary fluids used for resuscitation, each contains varying amounts of potassium per liter (Table 1):

  • 0.9% Sodium Chloride (normal saline)
  • Lactated Ringer’s solution
  • Plasma-Lyte A

Additionally, these fluids contain markedly different amounts of other electrolytes, some of which directly influence their pH (Table 1).

SolutionNa*Cl*K*Ca*Lactate*Acetate*Osmolarity^pH
Sodium Chloride 0.9% (normal saline)1541543085.5
Lactated Ringer’s13010942.7282736.5
Plasma-Lyte A140985272947.4
Blood135-14596-1063.5-58.5-10.50-1NA275-2957.35-7.45

Table 1: Characteristics of IV fluids vs blood [1-3] (* = mEq/L; ^ = mOsmol/L); note: this is not an exhaustive list of fluid contents

A common question is if the balanced fluids containing potassium (Lactated Ringer’s and Plasma-Lyte A) are safe to use in hyperkalemia patients. The answer is YES! Despite containing potassium, these fluids will still decrease the serum potassium level of a hyperkalemic patient. This is because the potassium concentration in these fluids is lower relative to the patient’s serum potassium level and dramatically lower than the patient’s intracellular potassium concentration.

Evidence

A secondary analysis of the SMART trial did not find a difference in severe hyperkalemia (K ≥7 mEq/L) in hyperkalemic patients that received a balanced fluid (8.5%) vs those that received normal saline (14%) (p=0.24) [4]. The authors concluded that:

Our results suggest that the acid-base effects of isotonic crystalloids are more important for potassium homeostasis than the relatively small amount of potassium in these fluids.

A breakdown of the SMART Trial secondary analysis by Journal Feed summarizes other major findings and concludes, “It’s reasonable to choose LR to treat hyperkalemia over NS.” Lastly, Dr. Josh Farkas provides a succinct summary of this topic in a 2014 EMCrit/Pulmcrit post which is helpful in understanding the interplay between fluid balance and the different replacement options. Additionally, he discusses the potential for normal saline to cause a non-anion gap metabolic acidosis thereby leading to increased serum potassium levels.

Bottom Line

Balanced fluids (Lactated Ringer’s and Plasma-Lyte A) containing potassium can safely be used in patients with hyperkalemia. Given their more neutral pH, they may be preferred over normal saline in some 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. Sodium Chloride Injection. Package Insert. Baxter Healthcare Corporation; 2013.
  2. Lactated Ringers Injection. Package Insert. Baxter Healthcare Corporation; 2019.
  3. Plasma-Lyte A Injection. Package Insert. Baxter Healthcare Corporation; 2019.
  4. Toporek, A. H., Semler, M. W., Self, W. H., Bernard, G. R., Wang, L., Siew, E. D., Stollings, J. L., Wanderer, J. P., Rice, T. W., Casey, J. D., & SMART Investigators and the Pragmatic Critical Care Research Group. (2021). Balanced crystalloids versus saline in critically ill adults with hyperkalemia or acute kidney injury: Secondary analysis of a clinical trial. American Journal of Respiratory and Critical Care Medicine. doi: 10.1164/rccm.202011-4122LE. PMID: 33503391.

 

ACMT Toxicology Visual Pearls – In “Spore” Taste

puffball mushroom spore

A 15-year-old male presents symptomatic several hours after inhaling spores of this mushroom as a home remedy for epistaxis. What is the presentation and pathophysiology of the toxic syndrome associated with this mushroom?

For a video of this mushroom in action: https://youtu.be/G_DXTlvvsco

  1. Dyspnea and cough from hypersensitivity alveolitis
  2. Flushing, nausea and vomiting from acetaldehyde accumulation
  3. Nausea, vomiting and hepatoxicity from RNA synthetase inhibition
  4. Seizures from reduced GABA production in the central nervous system

(more…)

By |2021-04-10T10:23:37-07:00Apr 7, 2021|ACMT Visual Pearls, Tox & Medications|

Does the Combination of Parenteral Olanzapine with Benzodiazepines for Agitation in the ED Increase the Risk of Adverse Events?

A previous EM Pharm Pearl focused on the adverse events associated with the use of IV olanzapine for agitation. This pearl addresses concerns around using parenteral (IV or IM) olanzapine with parenteral benzodiazepines.

Background

Olanzapine has two FDA boxed warnings, one for increased mortality when used long-term in older adults with dementia-related psychosis and another pertaining to adverse effects of extended release IM olanzapine. However, there exists a potential risk of excess sedation and respiratory depression when IM/IV olanzapine is administered with parenteral benzodiazepines for agitation. The European Medicines Agency recommends separating the administration of IM/IV olanzapine and parenteral benzodiazepines by at least 60 minutes. The FDA does not have a specific recommendation regarding separation of the 2 medications, but cautions against co-administration citing a lack of data. Currently, IM olanzapine is the only second generation antipsychotic with a precaution listed in its FDA prescribing information. This advisory is the result of 160 post-marketing adverse events, including 29 fatalities, associated with IM olanzapine [1].

Literature

When the above cases submitted to the FDA are thoroughly investigated, the problem appears to be related to polypharmacy rather than an olanzapine/benzodiazepines alone [2, 3]. This FOAMcast podcast provides an excellent summary of the data (Table 1). Additionally, the timing of fatalities after the last dose of olanzapine is prolonged in many cases (Table 2) and many of the causes of death are unattributable to olanzapine [1]. Several ED studies have used IV/IM olanzapine in combination with parenteral benzodiazepines to treat agitated patients without an increased signal of airway compromise [4-6].

Table 1: Summary of Fatalities Associated with Olanzapine (n=29)
Olanzapine AloneOlanzapine

+ Benzodiazepines

Olanzapine

+ Benzodiazepines

+ Other Medications

3/291/2925/29

Adapted from FOAMcast podcast: Olanzapine + Benzodiazepines – What is the FDA warning about? [1]

 

 

Table 2: Timing of Fatalities Following Last Olanzapine Dose (n=29)
≤ 1 hour1-12 hours12-24 hours> 24 hoursUnknown
3/294/298/2911/293/29

Marder [1]

 

Bottom Line

Separating IV/IM olanzapine from parenteral benzodiazepines by 60 minutes is likely a safe practice, if co-administration of these medications is necessary or desired to treat agitated patients. Patients with ethanol on board are at a higher risk of adverse events [7, 8]. Monitoring should be commensurate with the patient situation and medication(s) chosen.

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. Marder SR, Sorsaburu S, Dunayevich E, et al. Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation. J Clin Psychiatry. 2010;71(4):433-441. doi: 10.4088/JCP.08m04411gry. PMID: 20156413
  2. Williams AM. Coadministration of intramuscular olanzapine and benzodiazepines in agitated patients with mental illness. Ment Health Clin. 2018;8(5):208-213. doi: 10.9740/mhc.2018.09.208. PMID: 30206503.
  3. Khorassani F, Saad M. Intravenous olanzapine for the management of agitation: review of the literature. Ann Pharmacother. 2019;53(8):853-859. doi: 10.1177/1060028019831634. PMID: 30758221.
  4. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DCM. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61(1):72-81. doi: 10.1016/j.annemergmed.2012.07.118. PMID: 22981685.
  5. Cole JB, Moore JC, Dolan BJ, et al. A prospective observational study of patients receiving intravenous and intramuscular olanzapine in the emergency department. Ann Emerg Med. 2017;69(3):327-336.e2. 10.1016/j.annemergmed.2016.08.008. PMID: 27823873.
  6. Martel ML, Klein LR, Rivard RL, Cole JB. A large retrospective cohort of patients receiving intravenous olanzapine in the emergency department. Acad Emerg Med. 2016;23(1):29-35. doi: 10.1111/acem.12842. PMID: 26720055.
  7. Wilson MP, MacDonald K, Vilke GM, Feifel D. Potential complications of combining intramuscular olanzapine with benzodiazepines in emergency department patients. J Emerg Med. 2012;43(5):889-896.
    doi: 10.1016/j.jemermed.2010.04.012. PMID: 20542400
  8. Wilson MP, MacDonald K, Vilke GM, Feifel D. A comparison of the safety of olanzapine and haloperidol in combination with benzodiazepines in emergency department patients with acute agitation. J Emerg Med. 2012;43(5):790-797. doi: 10.1016/j.jemermed.2011.01.024. PMID: 21601409.

Adverse Events from IV Olanzapine for Agitation in the ED

The ability to safely and effectively sedate agitated patients in the emergency department (ED) is paramount to provide prompt medical care and protect ED staff. Intravenous (IV) antipsychotics are frequently utilized, instead of other routes, given their more rapid onset of action. Similar to haloperidol, olanzapine can be used safely via the IV route despite both being FDA-approved for intramuscular (IM) administration only.

What is the adverse event profile for IV olanzapine when administered for agitation in the ED?

The table below summarizes the primary data evaluating IV olanzapine in the ED [1-5]. While IV olanzapine is a safe option for some agitated patients, some of these studies report a higher risk of respiratory complications or respiratory depression with the IV route compared to IM olanzapine or other IV treatment options. An Annals of Emergency Medicine commentary argues IV olanzapine might not be necessary for non-emergent cases of agitation or non-agitation indications and the IM route may suffice [6].

StudyOlanzapine DoseAdverse Event Rate – OlanzapineAdverse Event Rate – ComparatorsNotes
Chang 2013
(N=336)
10 mg8.3% IV Droperidol: 10.7%
Placebo: 15.7 %
Martel 2016
(N=713)
1.25-20 mgMinor: 11.4%
Major: 2.6%
N/AAdverse events were respiratory complications; 7 patients intubated
Taylor 2017
(N=92)
5-10 mg20%IV Midazolam + Droperidol: 22%
IV Droperidol: 16.2%
Yap 2017
(N=92)
10 mg21.4% IV Midazolam + Droperidol: 20.6%
IV Droperidol: 6.7%
Methamphetamine-induced agitation
Cole 2017
(N=784)
1.25-20 mg3.7%IM olanzapine: 2.0%Adverse events were respiratory depression

Table: Adverse Events from IV Olanzapine for Agitation in the ED [1-5]

 

Treatment of agitated patients in the ED can be complex. Respiratory complications after medication administration may be related directly to the medication(s), the reduction of sympathetic drive, or both. All agitated patients should be monitored after receiving medications for sedation. The exact time course of this monitoring is not known and likely medication specific. Patients at high risk of neurologic, cardiovascular, or hemodynamic compromise should be monitored even more closely. This could include an ECG, pulse oxygenation, vital signs, and direct observation, as appropriate based on the patient-specific factors.

Bottom Line

Medication selection for treating agitation in the ED requires thoughtful consideration of factors such as onset time (read more about “Onset of IM Medications for Severe Agitation“), duration, adverse events, and patient-specific variables. IV olanzapine is an option and monitoring should be commensurate with the situation and medication(s) chosen.

For further information, please read this in-depth literature review of IV olanzapine for the management agitation [7].

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. Chan EW, Taylor DM, Knott JC, Phillips GA, Castle DJ, Kong DCM. Intravenous droperidol or olanzapine as an adjunct to midazolam for the acutely agitated patient: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Ann Emerg Med. 2013;61(1):72-81. doi: 10.1016/j.annemergmed.2012.07.118. PMID: 22981685.
  2. Martel ML, Klein LR, Rivard RL, Cole JB. A large retrospective cohort of patients receiving intravenous olanzapine in the emergency department. Acad Emerg Med. 2016;23(1):29-35. doi: 10.1111/acem.12842. PMID: 26720055.
  3. Taylor DM, Yap CYL, Knott JC, et al. Midazolam-droperidol, droperidol, or olanzapine for acute agitation: a randomized clinical trial. Ann Emerg Med. 2017;69(3):318-326.e1. doi: 10.1016/j.annemergmed.2016.07.033. PMID: 27745766.
  4. Yap CYL, Taylor DM, Knott JC, et al. Intravenous midazolam-droperidol combination, droperidol or olanzapine monotherapy for methamphetamine-related acute agitation: subgroup analysis of a randomized controlled trial. Addiction. 2017;112(7):1262-1269. doi: 10.1111/add.13780. PMID: 28160494
  5. Cole JB, Moore JC, Dolan BJ, et al. A prospective observational study of patients receiving intravenous and intramuscular olanzapine in the emergency department. Ann Emerg Med. 2017;69(3):327-336.e2. doi: 10.1016/j.annemergmed.2016.08.008. PMID: 27823873.
  6. Isbister GK. Droperidol or olanzapine, intramuscularly or intravenously, monotherapy or combination therapy for sedating acute behavioral disturbance. Ann Emerg Med. 2017;69(3):337-339. doi: 10.1016/j.annemergmed.2016.09.021. PMID: 27974168.
  7. Khorassani F, Saad M. Intravenous olanzapine for the management of agitation: review of the literature. Ann Pharmacother. 2019;53(8):853-859. doi: 10.1177/1060028019831634. PMID: 30758221

Colchicine Toxicity: A New Threat from COVID-19 Treatments

In the continued fight against COVID-19, a January 22, 2021 press release from the Montreal Heart Institute touted the potential of colchicine, citing results from the COLCORONA trial [1, 2]. We’ve learned to be especially skeptical of any study results reported only via press release before undergoing full peer-review and publication. Nevertheless, the authors claim a non-significant (p=0.08) relative risk reduction of 19% (absolute risk reduction 1.1%) in hospitalizations, mechanical ventilation, and death. Note that the pre-print of the study has still not been peer-reviewed [3]. This study comes on the heels of the much smaller GRECCO-19 study published in June 2020 [4].

Early in 2020, promising results on hydroxychloroquine for treatment of COVID-19 led to a large increase in its use in outpatients and inpatients. It is now known that there is virtually no role for hydroxychloroquine and that this spike in use led to serious toxicity both from therapeutic use and overdose [5, 6]. The same may be anticipated for colchicine. And, if there is a drug that toxicologists fear more than hydroxychloroquine in overdose, it’s colchicine.

5 things to know about colchicine toxicity

1. Colchicine inhibits microtubule formation and function, thereby inhibiting mitosis.

  • It also is a GABA-A antagonist.

2. Acute toxicity occurs in 3 phases.

  • 0-24 hours: Nausea, vomiting, diarrhea, salt and water depletion, and  leukocytosis
  • 1-7 days: Sudden cardiac death (24-48 hours), pancytopenia, acute kidney injury, sepsis, acute respiratory distress syndrome, rhabdomyolysis, and electrolyte imbalance
  • >7 days: Alopecia, myopathy, neuropathy, and myoneuropathy

3. Colchicine levels are not helpful.

  • They also aren’t readily available at most institutions.

4. Hemodialysis doesn’t remove the toxin.

  • Colchicine’s volume of distribution is large.
  • Extracorporeal treatment can be employed if kidney toxicity results from the poisoning.

5. There is no antidote.

  • Management is largely supportive with IV fluids, vasopressors, and colony-stimulating factors.
  • Experimental anti-colchicine Fab fragments are being studied [7].

This 2010 Clinical Toxicology review article provides further information and education on colchicine toxicity.

Want to learn more about EM Pharmacology?

Read other articles in the EM Pharm Pearls Series.

References:

  1. Montreal Heart Institute. Colchicine reduces the risk of COVID-19-related complications. GlobalNewswire website. January 22, 2021. Accessed January 26, 2021.
  2. Montretal Heart Institute. ColCorona. Accessed January 26, 2021.
  3. Tardif J-C, Bouabdallaoui N, L’Allier PL, et al. Efficacy of colchicine in non-hospitalized patients with covid-19. medRxiv. doi: Epub 2021 Jan 27.
  4. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of colchicine vs standard care on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019: the grecco-19 randomized clinical trial. JAMA Netw Open.  2020;3(6):e2013136. doi: 10.1001/jamanetworkopen.2020.13136. PMID: 32579195.
  5. Mahan KM, Hayes BD, North CM, et al. Utility of hypertonic saline and diazepam in covid-19–related hydroxychloroquine toxicity. The Journal of Emergency Medicine. doi: 10.1016/j.jemermed.2020.10.048. Epub 2020 Oct 2020. PMID: 33353811.
  6. Chai PR, Ferro EG, Kirshenbaum JM, et al. Intentional hydroxychloroquine overdose treated with high-dose diazepam: an increasing concern in the covid-19 pandemic. J Med Toxicol. 2020;16(3):314-320. doi: 10.1007/s13181-020-00790-8. PMID: 32514696.
  7. Eddleston M, Fabresse N, Thompson A, et al. Anti-colchicine Fab fragments prevent lethal colchicine toxicity in a porcine model: a pharmacokinetic and clinical study. Clinical Toxicology. 2018;56(8):773-781. doi: 10.1080/15563650.2017.1422510. PMID: 29334816.

 

2020 ACLS Guidelines on Medications for Toxicology-Related Conditions

ACLS 2020 toxicology

The 2020 ACLS guidelines provide recommendations on the medication-specific management recommendations for toxicology [1]. Although the name of the guidelines emphasize they are ‘Advanced,’ these are still relatively basic toxicology recommendations and largely apply to patients in cardiac arrest or refractory shock. There are also our 2020 ACLS guideline summaries on vasopressor and non-vasopressor medications used during cardiac arrest and arrhythmia management.

Benzodiazepines

  • Flumazenil if NOT recommended in undifferentiated coma (COR3, LOE B-R)

Cocaine

  • Benzodiazepines, alpha blockers, calcium channel blockers, nitroglycerin, and/or morphine can be beneficial for hypertension, tachycardia, agitation, or chest discomfort (COR 2a, LOE B-NR)
  • Pure beta-adrenergic blockers may be reasonable to avoid, although “contradictory evidence exists (COR 2b, LOE C-LD)

Local Anesthetics

  • IV lipid emulsion may be reasonable (COR 2b, LOE C-LD)

Sodium Channel Blockers (e.g. tricyclic antidepressants)

  • Sodium bicarbonate can be beneficial for cardiac arrest or life-threatening conduction delays, such as QRS >120 msec (COR 2a, LOE C-LD)
  • Extracorporeal membrane oxygenation (ECMO) may be considered for cardiac arrest or refractory shock (COR 2b, LOE C-LD)

Digoxin

  • Antidigoxin Fab should be administered in severe toxicity (COR 2b, LOE B-R)

Carbon Monoxide

  • Hyperbaric oxygen may be helpful in severe toxicity (COR 2b, LOE B-R)

Cyanide

  • Hydroxocobalamin can be beneficial, along with oxygen +/- sodium thiosulfate (COR 2a, LOE C-LD)

Atrioventricular Nodal Blockers

InterventionBeta-adrenergic blockerCalcium channel blockerEvidence (COR/LOE)
High-dose insulinReasonableReasonable2a/C-LD
Glucagon IVReasonableMay be considered2a/C-LD and 2b/C-LD
CalciumMay be consideredReasonable2b/C-LD and 2a/C-LD
ECMOMight be consideredMight be considered2b/C-LD

Table: Medications and interventions in the management of beta-adrenergic and calcium channel blocker toxicity (COR: class of recommendation, LOE: level of evidence, ECMO: extracorporeal membrane oxygenation)

Reference

Panchal AR, Bartos JA, Cabañas JG, et al; Adult Basic and Advanced Life Support Writing Group. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020 Oct 20;142(16_suppl_2):S366-S468. doi: 10.1161/CIR.0000000000000916. Epub 2020 Oct 21. PMID: 33081529.
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