(November 2022)

Emergency Medicine Executive Summary

Lorazepam is an intermediate acting benzodiazepine (BDZ) –a GABA receptor enhancer– with CNS depressant effects including sedative, hypnotic, skeletal muscle relaxing and anticonvulsant activity. It can be administered either by intravenous, intramuscular, sublingual or oral routes. Along with midazolam and clonazepam, lorazepam is one of the most frequently indicated BDZ  in the ED. 

Sedation timing with single 2-4mg dose:

• Intravenous

Onset (IV): 5-10 minutes*

Peak Effect (IV): 30 minutes

Duration (IV): 2-6 hours
(*shorter to terminate seizures)

• Intramuscular

Onset (IM) 15 minutes

Peak Effect (IM) 60 minutes

Duration (IM) 6-8 hours

Dosing

• Adult dose for status epilepticus:
  0.1mg/kg IV (max 4mg/dose).
  Repeat every 5-10 min until the crisis has ceased.
  Consider initiating an antiepileptic if a second lorazepam dose is required. 

• Adult dose for undifferentiated agitation:
  2-4mg sublingual, IV or IM as needed (if severely agitated, IM route is preferred).
  Repeat every 20-30 min if necessary.
  The BDZ of choice to treat severe undifferentiated agitation is considered to be midazolam IM for its faster onset of action (22).

• Acute anxiety disorder:
  0.5-2mg sublingual, PO or IV as needed.
  Repeat every 20-30 minutes if necessary.

FDA approved, frequently elected as the first-line BDZ (6): 

• Status epilepticus (IV)

• Anxiety disorders (sublingual, IV)
  
  

FDA not approved, frequently elected BDZ (16, 17, 20): 

• Undifferentiated agitation (sublingual, IM, IV)
  
  

FDA not approved, sometimes elected amongst other BDZ (3, 8, 17, 24): 

• Sympathomimetic toxicity (cocaine, methamphetamines)

• Alcohol withdrawal

• Vertigo

Introduction

Benzodiazepines (BDZs) are used for a significant variety of conditions in the ED; their different pharmacological properties allow emergency clinicians to have a wide arsenal to treat each particular patient. 

• The most frequently used BZDs in the ED are lorazepam, diazepam, midazolam and clonazepam;  and there is an overall deficit of comparative studies between BDZs to support one preference over another for most disorders. 

• In the case of lorazepam, it is the BDZ of choice (for IV use) to treat status epilepticus and seizures.  For every other condition, the decision-making process of  which BDZ to use mostly depends on individual pharmacokinetic profile and its appropriateness on the desired effect. 

Seizures and Status Epilepticus (SE):

IV lorazepam is superior to other IV BDZs to treat SE. 

• There is an established consensus of using lorazepam as the first-line IV BDZ, with a high level of evidence and recommendation for both children and adults (1, 2, 3, 5, 7, 8, 10, 11, 12, 14). 

• In case of unavailable IV access, midazolam 10mg IM is preferred because it is at least comparable in efficacy to IV lorazepam and is easier to administer (1, 9, 11, 13). In the case of unavailable midazolam, lorazepam is a good alternative for IM route as it has good bioavailability as well. Do not administer diazepam by IM route because of its erratic response (13). 

Anxiety disorders, acute anxiety states: 

Benzodiazepines have a dominant role for short-term, acute management of anxiety disorders in the ED (3). Amongst them, lorazepam is a good alternative between other BDZ for the management of anxiety disorders in the ED, considering its rapid onset of action and long lasting effect. 

Agitation:

Lorazepam is indicated as an adjunctive or single medication to treat undifferentiated agitation in the ED, but midazolam (IM) is considered to be the BDZ of choice to treat severe undifferentiated agitation for its faster onset of action compared with lorazepam (22).

• Historically some clinicians have considered lorazepam as a first-line medication, usually in combination with a first generation (typical) antipsychotic such as haloperidol (3), but the latest evidence shows preference for olanzapine and droperidol over haloperidol (22). 

• Studies have shown lorazepam to have a similar efficacy compared with haloperidol but inferior to the combination of both (15, 21).

• It can be administered with haloperidol in the same syringe, a feature that could be useful in the ED compared with other BDZ (20). 

Hyperadrenergic states:

This wide spectrum of conditions can be divided into (i) pathological sympathetic stimulation (eg. thyroid storm, tetanus disease, pain, etc), (ii) exogenous sympathomimetic toxicity and (iii) substance withdrawal response. Caution should be taken as these condition’s syndromic presentations can frequently overlap with undifferentiated agitation, and many of them have serious short-term morbidity and mortality. 

• Benzodiazepines are part of the standard therapy for acute cocaine intoxication (23, 24, 26). Diazepam and lorazepam are the most studied BDZ for cocaine-associated chest pain, and both are considered as first-line alternatives (3, 4, 26). 

For Alcohol Withdrawal Syndrome lorazepam and diazepam are considered the best alternatives (3), but most authors recommend escalating doses of diazepam as the BDZ of choice (4, 25). 

Caution should be taken with profound sedation, coma and respiratory depression; particularly when repeated doses are administered, or combined with other CNS depressants and/or opioids. 

Benzodiazepines are prone to develop dependence, they should be administered for immediate or short-term therapy in the ED; it is recommended not to prescribe more than a 7-days course of BDZ in this setting (1, 3). Adequate outpatient follow-up should be planned to establish a long-term therapeutic approach to patients who have required BDZs in the ED.

• Status epilepticus and seizures:
  0.1mg/kg IV (max 4mg/dose).
  Repeat every 5-10 min until crisis cessation.
  Initiate load with antiepileptic agent if a second lorazepam dose is required.
  
  

• Acute anxiety disorder:
  0.5-2mg sublingual, PO or IV as needed.
  Repeat every 20-30 minutes if necessary.
  
  

• Agitation:
  2-4mg sublingual or IM as needed.
  Consider as an adjunct with 1st generation antipsychotic (droperidol).
  Repeat every 20-30 min if necessary.
  
  

• Hyperadrenergic states (cocaine and other sympathomimetic toxicity, substance withdrawal, neuroleptic malignant syndrome, serotonin syndrome, tetanus, etc):
  2-4mg IV.
  Repeat every 10-20 min as needed.
  
  

• Vertigo:
  1-2mg sublingual or IV.
  BDZ are given as an adjunctive therapy along with other vestibular- inhibiting medications and non-pharmacological interventions depending on the cause of vertigo.
  
  

• Procedural sedation:
  EMDrugs do not recommend lorazepam for procedural sedation.
  Short acting BDZ (eg. midazolam) or ketamine are the most often appropriate alternatives.

• Status epilepticus and seizures (1, 2, 7, 12):
  0.1mg/kg IV (max 4mg per dose)*.
  Repeat every 5 minutes if necessary.
  *If unavailable IV access, consider diazepam 0.5mg/kg rectal (max 20mg per dose).
  
  

• Acute anxiety disorder (3):
  A comprehensive approach is essential to treat anxiety in children (non-pharmacological interventions).
  0.05mg/kg sublingual, IV depending on severity.
  Repeat every 30 minutes if necessary.
  
  

• Undifferentiated Agitation (18, 19):
  0.05-0.1mg/kg, usual dose  0.5-2mg sublingual, IV, IM depending on severity.
  Combined therapy with first generation antipsychotics (eg. haloperidol) is more effective. Consider monotherapy with second generation antipsychotic (eg. olanzapine).
  
  

• Agitation due to substance intoxication or withdrawal (19):
  0.05-0.1mg/kg  (max 4mg/dose) sublingual, PO, IV, IM depending on severity.
  
  

• Procedural sedation:
  EMDrugs do not recommend lorazepam for procedural sedation.
  Short acting benzodiazepines are the most appropriate alternatives (eg. midazolam).

Overview: 

1. Walls RM, Hockberger RS, Gausche-Hill M. Rosen’s Emergency Medicine : Concepts and Clinical Practice. 9th edition. Philadelphia, PA: Elsevier; 2018
   Elsevier

2. Marcdante KJ, Kliegman RM. Nelson Essentials of Pediatrics. 8th edition. Philadelphia, PA: Elsevier 2019
   Elsevier

3. Tintinalli JE, Ma O, Yealy DM, Meckler GD, Stapczynski J, Cline DM, Thomas SH. Tintinalli J.E.). Tintinalli's Emergency Medicine: A Comprehensive Study Guide. 9th edition. McGraw Hill; 2019
   McGraw-Hill

4. Nelson LS, Howland MA, Lewin NA, et al. Goldfrank’s Toxicologic Emergencies. 11th edition. New York, NY: McGraw-Hill Education; 2019
   McGraw-Hill

5. DeWitt KM, Porter BA. Emergency Neuropharmacology. Emerg Med Clin North Am. 2021;39(1):133-154. doi:10.1016/j.emc.2020.09.008
   Pubmed

6. NIH-NLM (National Institutes of Health National Library of Medicine). DailyMed. Label: Ativan - lorazepam injection. Updated in March 2021
   DailyMed

Seizures and Status Epilepticus

7. Appleton R, Sweeney A, Choonara I, Robson J, Molyneux E. Lorazepam versus diazepam in the acute treatment of epileptic seizures and status epilepticus. Dev Med Child Neurol. 1995;37(8):682-688. doi:10.1111/j.1469-8749.1995.tb15014.x
   Pubmed

8. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med. 1998;339(12):792-798. doi:10.1056/NEJM199809173391202
   Pubmed

9. RAMPART - Silbergleit R, Lowenstein D, Durkalski V, Conwit R; Neurological Emergency Treatment Trials (NETT) Investigators. RAMPART (Rapid Anticonvulsant Medication Prior to Arrival Trial): a double-blind randomized clinical trial of the efficacy of intramuscular midazolam versus intravenous lorazepam in the prehospital treatment of status epilepticus by paramedics. Epilepsia. 2011;52 Suppl 8(Suppl 8):45-47. doi:10.1111/j.1528-1167.2011.03235.x
   Pubmed

10. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care. 2012;17(1):3-23. doi:10.1007/s12028-012-9695-z
    Pubmed

11. Prasad M, Krishnan PR, Sequeira R, Al-Roomi K. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev. 2014;2014(9):CD003723. Published 2014 Sep 10. doi:10.1002/14651858.CD003723.pub3
    Pubmed

12. Santillanes G, Luc Q. Emergency department management of seizures in pediatric patients. Pediatr Emerg Med Pract. 2015;12(3):1-27
    Pubmed

13. Khoujah D, Abraham MK. Status Epilepticus: What's New?. Emerg Med Clin North Am. 2016;34(4):759-776. doi:10.1016/j.emc.2016.06.012
    Pubmed

14. VanHaerents S, Gerard EE. Epilepsy Emergencies: Status Epilepticus, Acute Repetitive Seizures, and Autoimmune Encephalitis. Continuum (Minneap Minn). 2019;25(2):454-476. doi:10.1212/CON.0000000000000716
    Pubmed

Agitation

15. Battaglia J, Moss S, Rush J, et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study. Am J Emerg Med. 1997;15(4):335-340. doi:10.1016/s0735-6757(97)90119-4
    Pubmed

16. Yildiz A, Sachs GS, Turgay A. Pharmacological management of agitation in emergency settings. Emerg Med J. 2003;20(4):339-346. doi:10.1136/emj.20.4.339
    Pubmed

17. Wilson MP, Pepper D, Currier GW, Holloman GH Jr, Feifel D. The psychopharmacology of agitation: consensus statement of the american association for emergency psychiatry project Beta psychopharmacology workgroup. West J Emerg Med. 2012;13(1):26-34. doi:10.5811/westjem.2011.9.6866
    Pubmed

18. Chun Th, Mace Se, Katz Er; American Academy of Pediatrics; Committee On Pediatric Emergency Medicine, and American College of Emergency Physicians; Pediatric Emergency Medicine Committee. Evaluation and Management of Children and Adolescents with Acute Mental Health or Behavioral Problems. Part I: Common Clinical Challenges of Patients With Mental Health and/or Behavioral Emergencies. Pediatrics. 2016;138(3):E20161570. Doi:10.1542/Peds.2016-1570
    Pubmed

19. Gerson R, Malas N, Feuer V, Silver GH, Prasad R, Mroczkowski MM. Best Practices for Evaluation and Treatment of Agitated Children and Adolescents (BETA) in the Emergency Department: Consensus Statement of the American Association for Emergency Psychiatry [published correction appears in West J Emerg Med. 2019 May;20(3):537] [published correction appears in West J Emerg Med. 2019 Jul;20(4):688-689]. West J Emerg Med. 2019;20(2):409-418. doi:10.5811/westjem.2019.1.41344
    Pubmed

20. Guerrero P, Mycyk MB. Physical and Chemical Restraints (an Update). Emerg Med Clin North Am. 2020;38(2):437-451. doi:10.1016/j.emc.2020.02.002
    Pubmed

21. Amore M, D'Andrea M, Fagiolini A. Treatment of Agitation With Lorazepam in Clinical Practice: A Systematic Review. Front Psychiatry. 2021;12:628965. Published 2021 Feb 22. doi:10.3389/fpsyt.2021.628965
    Pubmed

22. ACEP Task Force Report on Hyperactive Delirium with Severe Agitation in Emergency Settings. Approved by the ACEP Board of Directors, June 23, 2021.
    ACEP

Sympathomimetic toxicity, alcohol withdrawal

23. Honderick T, Williams D, Seaberg D, Wears R. A prospective, randomized, controlled trial of benzodiazepines and nitroglycerine or nitroglycerine alone in the treatment of cocaine-associated acute coronary syndromes. Am J Emerg Med. 2003;21(1):39-42. doi:10.1053/ajem.2003.50010
    Pubmed

24. McCord J, Jneid H, Hollander JE, et al. Management of cocaine-associated chest pain and myocardial infarction: a scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Circulation. 2008;117(14):1897-1907. doi:10.1161/CIRCULATIONAHA.107.188950
    Pubmed

25. Yanta JH, Swartzentruber GS, Pizon AF. Alcohol Withdrawal Syndrome: Improving Outcomes Through Early Identification And Aggressive Treatment Strategies. Emerg Med Pract. 2015;17(6):1-19
    Pubmed

26. Richards JR, Garber D, Laurin EG, et al. Treatment of cocaine cardiovascular toxicity: a systematic review. Clin Toxicol (Phila). 2016;54(5):345-364. doi:10.3109/15563650.2016.1142090
    Pubmed