Does Co-Administration of Haldol or Versed Diminish Recovery Agitation with Ketamine in Adults Undergoing Procedural Sedation?

Background: Working in the emergency department means frequently performing painful procedures on patients, often we turn to procedural sedation to make these procedures more tolerable for patients, families and clinicians alike.  Ketamine is often used for this purpose, particularly in pediatrics, however, many clinicians are reluctant to use this agent due to concerns for recovery agitation or the dreaded “emergence phenomenon.” Clinicians often turn to the co-administration of various agents, including benzodiazepines and antipsychotics, to blunt this effect.  The definition of recovery agitation and the means by which it is measured are inconsistent in the previous literature, leading to a dearth of evidence as to whether the practice of co-administration of medications is effective in reducing recovery agitation.

Article:

Akhlaghi N et al. Premedication with Midazolam or Haloperidol to Prevent Recovery Agitation in Adults Undergoing Procedural Sedation with Ketamine: A Randomized Double-Blind Clinical Trial. Ann Emerg Med 2018. PMID: 30611640

Clinical Question:

Does premedication with haloperidol or midazolam effect ketamine-induced recovery agitation?

Population:

Patients >18 years of age who needed procedural sedation during shifts when one of the researchers was present.

Primary Outcomes:

• Recovery agitation as assessed by the Richmond Agitation-Sedation Scale score at 5, 15, and 30 minutes after ketamine administration.
• Maximum observed Pittsburgh Agitation Scale score.

Secondary Outcomes:

• Clinician satisfaction using the Clinician Satisfaction with Sedation Instrument.
• Recovery duration measured as the time from administration of the first syringe of ketamine to the time at which the patient was alert and awake or easily arousable to minimal stimulation.

Design:

• A randomized, double-blind, placebo-controlled, multi-arm trial.
• 185 patients were randomized to one of three groups: ketamine (1 mg/kg) plus placebo (distilled water), ketamine plus midazolam (0.05 mg/kg) or ketamine plus haloperidol (5 mg).
• Five minutes after premedication, patients received IV ketamine administered over 60 seconds.
• During sedation, all patients received supplemental oxygen by nasal cannula (5L/min) continuously monitored by 3-lead ECG, pulse rate, respiratory rate, and oxygen saturation. Blood pressure was recorded every 5 minutes by an automatic BP cuff.  End tidal CO2 was not used during procedural sedation in this study.
• Recovery time defined time from administration of 1^st syringe to the time at which the patient was alert and awake or easily aroused by minimal stimulation.

Exclusion:

• Age <18 years
• History of significant cardiovascular disease, CHF class 3, 4
• History of central nervous system lesions or injuries, increased ICP
• History of ocular pathology, increased IOP
• History of thyroid disease
• Acute pulmonary infections according to patient’s history and physical examination results
• Conditions requiring stimulation of the posterior pharynx
• Ingested solid food in the previous 4 hours or clear liquids in the previous 2 hours
• History of acute intermittent porphyria
• History of alcoholism
• History of hepatic impairment
• History of myasthenia gravis
• Respiratory depression (RR<10, cyanosis, or pulse oximeter oxygen saturation <90%)
• Moderate to severe dementia, as documented by medical history
• History of Parkinson’s disease
• History of structural brain damage
• Corrected QTc interval >500 ms in previous records or on current ECG
• History of drug use with prolonged QT interval
• History of torsades de pointes
• History of neuroleptic malignant syndrome
• Family history of dystonic reactions to drugs
• Epilepsy or history of seizures
• Chronic psychiatric disease
• Intoxication based on patient’s symptoms and physical examination results
• History of bone marrow suppression
• Allergy to haloperidol, ketamine or midazolam as established by direct questioning and available medical history 

Enrollment:

• Mean Age: 37.5
• 7% male
• Patients assess for eligibility: 207
• Patients randomized: 185

Critical Results:

• Incidence ketamine-induced agitation
  • No premedication: 63.9%
  • Midazolam: 25% (Relative Risk Reduction 60.9%; Absolute Risk Reduction 38.9%)
  • Haloperidol: 19.7% (Relative Risk Reduction 69.2%; Absolute Risk Reduction 44.2%)

Secondary Results:

• Recovery time
  • No premedication: 15-25 minutes
  • Midazolam: 30-42.5 minutes
  • Haloperidol: 40-60 minutes
• Overall clinical satisfaction with sedation was not significantly different between the three groups

Strengths:

• Well-designed blinding
• Answers clinically significant question
• Used validated objective measures of agitation
• Baseline clinical and demographic features were well balanced between groups

Limitations:

• Small sample
• Convenience sample rather than consecutive sampling of patients
  • Convenience sampling entails selecting patients on the basis of the researcher’s availability. Patients with certain characteristics are more likely to be chosen via convenience sampling. This could lead to over- or under-representation of certain population attributes and therefore decrease the generalizability of the study results.
• Differing definitions and various standardized rating scales used in this study prevented authors from directly comparing the results of this study with previous studies
• 90% of patient population was male, not allowing for differences between sexes
• Majority of patients required sedation for orthopedic procedures due to injuries sustained from fights or accidents, which may predispose the patient population to agitation.
• Large excluded population
• While adverse events were recorded in Table 3 of the publication, it is not clear the study was designed to evaluate these events.
• Majority of procedures were due to orthopedic injuries (upper and lower extremity fractures, and shoulder dislocations) 24.7%, 37.9% and 24.7% respectively
• Although the incidence of ketamine-induced agitation was 63.9% in this study, the incidence of disruptive behaviors that are clinically important was 26.2%
• The incidence of ketamine-induced agitation is difficult to ascertain, in part due to different in-patient populations, but also due to inconsistencies in the classification, measurement and definition of agitation. This study attempted to structure the discussion of this type of agitation using established scales, allowing for future studies to be compared more directly to this one.
• Despite these inconsistencies in agitation measurement, this study is in line with prior studies demonstrating that benzodiazepines are effective in reducing ketamine-induced agitation.

Author Conclusion:

“For adult procedural sedation, premedication with either midazolam 0.05mg/kg or haloperidol 5mg intravenously significantly reduces ketamine-induced recovery agitation while delaying recovery.”

Our Conclusion:

While this is a small study of primarily young, male patients, it does suggest that premedication with haloperidol or midazolam may reduce the incidence of recovery agitation in patients receiving ketamine for procedural sedation.  Premedication did lengthen the patients’ recovery times but did not have an overall detrimental effect on the clinician’s satisfaction with the procedural sedation.

Clinical Bottom Line:

Premedication with midazolam or haloperidol prior to procedural sedation with ketamine likely reduces the incidence of recovery agitation but increases the duration until recovery. Further studies need to be performed to confirm this finding and to assess the differences in adverse events.

References:

1. Rosen J et al. The Pittsburgh Agitation Scale: A User-Friendly Instrument for Rating Agitation in Dementia Patients. Am J Geriatr Psychiatry.1994 Winter;2(1):52-59. doi: 10.1097/00019442-199400210-00008. Epub 2013 Jan 28. PMID 28531073
2. Sessler CN et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med.2002 Nov 15;166(10):1338-44. PMID 12421743
3. Vargo J et al. Development and validation of the patient and clinician sedation satisfaction index for colonoscopy and upper endoscopy. Clin Gastroenterol Hepatol.2009 Feb;7(2):156-62. doi: 10.1016/j.cgh.2008.09.004. Epub 2008 Sep 20. PMID 18930167

For More Thoughts on This Topic Checkout:

• REBEL EM: Complications of Procedural Sedation
• St. Emlyn’s Blog: JC – Should we Premedicate for Ketamine Sedation?

Post Peer Reviewed By: Salim R. Rezaie, MD (Twitter: @srrezaie)