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Three Part Question

In [adults with head injury necessitating emergency intubation] does [the use of ketamine as an induction agent, compared to any other standard agent] lead to [increased morbidity/mortality]?

Clinical Scenario

A 26 year-old male is brought to the Emergency Department after being struck by a car. His Glasgow coma scale on arrival is 8/15 with obvious evidence of head injury and thoracoabdominal trauma. He has a profusely bleeding scalp wound and is tachycardic. You decide to undertake a rapid sequence intubation (RSI) and begin drawing up ketamine as an induction agent. Your colleagues raise a collective eyebrow and ask you to defend your choice of agent. You offer cardiovascular stability and familiarity as two main indications. They remain concerned about the risk of raising intracranial pressure (ICP) and insist that Ketamine is contraindicated in head injured patients. They are unable to cite any evidence to support this view.

You propose a BET to methodically examine the literature.

Search Strategy

Medline and Embase using the OVID interface

Medline (1948 to week 4 September 2011):
[(ketamine.mp) or (exp ketamine/)] AND [(exp intubation, intratracheal/) or (rapid sequence induction.mp) or exp (anesthesia, general/) or (rapid sequence intubation.mp)] AND [(intracranial pressure.mp) or (exp intracranial pressure/) or ICP.mp] AND [(head injury.mp) or (exp craniocerebral trauma/) or (head injur$.mp)]

EMBASE (1980 to week 4 September 2011):
{[(exp ketamine/)]} AND {[(exp intracranial hypertension/) OR (exp head injury/)] AND [exp anesthesia, induction] OR (exp endotracheal intubation/)]}
Both search strategies were limited to English language, humans and adults

The Cochrane database of systematic reviews was also searched for any articles including the term ketamine.

Search Outcome

276 articles were identified. Of these, 18 were deemed directly relevant and assessed by abstract. Following further review, 5 papers were retained for critical appraisal. Of these articles, two narrative literature reviews and a predefined subgroup analysis within a prospective single blind randomised controlled trial (RCT) formed the highest level of evidence. All five articles are reviewed below:

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Filanovsky et al 2010 Canada	Narrative review article.	Qualitative Literature review and expert opinion based on physiological data (level 5 evidence).	Opinion based conclusion	'ketamine appears to be the perfect agent for the induction of head injured patients for intubation.'	No attempt made at meta-analysis. Poor explanation of search strategy. Conclusions based on interpretation of individual case control/case studies.
Sehdev et al 2006 Australia	Narrative review article.	Qualitative Literature review and expert opinion based on physiological data (level 5 evidence).	Opinion based conclusion	'ketamine might be a suitable agent for induction of anaesthesia, particularly in those patients with potential cardiovascular instability.'	No attempt made at meta-analysis. Poor explanation of search strategy. Conclusions based on interpretation of individual articles.
Grathwohl K et al 2009 USA	Patients with traumatic brain injury undergoing operative neurosurgical intervention	Retrospective cohort with subgroup analysis of total intravenous anaesthesia (TIVA) patients and comparison of ketamine including regimens to non ketamine including regimens. (Level of evidence 2b)	Good outcome (Glasgow Outcome Score 4-5)	79% patients in the ketamine group vs 72% patients in the non ketamine group (p=0.47)	Method of induction unregulated and unclear. Retrospective analysis renders the study open to multiple confounders. Ketmaine used in tandem with other anaesthetic agents as part of TIVA. No raw ICP data provided
			Mortality	8.5% in the ketamine group vs 2.2% in the non ketamine group (p=0.36)
Gofrit et al 1996 Israel	29 prehospital care patients with GCS<8, following a single failed attempt at intubation using standard techniques. Head was the primary site of injury in 25 of these patients.	Prospective cohort study (level of evidence 4).	Successful intubation following ketamine administration	19 patients (65.5%)	No comparator group. No standardised description of initial pharmacological/practical approach to intubation. No ICP data of any kind. No presentation of morbidity data. Large standardised ketamine dosage.
			Survival to hospital	100%
			Complications attributed to ketamine	0%
Jabre et al. 2009 France	104 trauma patients within 655 prospectively enrolled critically ill patients needing sedation for emergency intubation. No clarification of proportion with associated traumatic brain injury. Patients were randomly assigned to recieve intial sedation for RSI with either 0.3mg/kg Etomidate or 2mg/kg Ketamine.	Subgroup analysis within single blind prospective RCT (level of evidence 2b).	Maximum Sequential Organ Failure Assessment (SOFA) score during the first three days ICU admission	Mean SOFAmax for etomidate group 10.0(SD3.5) vs 9.9(SD2.8). Asolute difference 0.1 (95% CI -1.2 to 1.3)	Approximately 30% initially recruited patients withdrawn following early critical care discharge, death or missing data. Underpowered for analysis of trauma patients and therefore at significant risk of type 2 error. Patients dying before arrival to hospital also exlcuded, a potential cohort of interest regarding the BET subject matter.
			Mortality at 28 days	26.3% (Etomidate group) vs 29.8% (Ketamine group). Odds ratio 0.8 (95% CI 0.4 to 2.0)

Comment(s)

The only controlled trial comparing ketamine as an induction agent to any other pharmacotherapy for RSI in patients with traumatic brain injury (TBI) is the paper by Jabre et al. Although predefined, the subgroup analysis of trauma patients within the overall cohort is underpowered and the authors are non specific about the prevalence of traumatic brain injury within this group. Thus the highest level of evidence to answer the predefined question is 2b only. Initial concerns with ketamine use in head injured patients originate from small case control studies in the early 1970's. Ketamine administration for diagnostic pneumoventriculography in spontaneously breathing patients and procedural sedation in those with abnormal CSF flow dynamics has previously demonstrated a potentially detrimental rise in ICP [1-5]. This rise was most pronounced in those with abnormal cerebrospinal fluid (CSF) pathways, with a consequent drop in cerebral perfusion pressure (CPP). However, the healthy patients involved in these studies actually demonstrated a rise in mean arterial pressure (MAP) and a concommitant increase in cerebral blood flow with intravenous ketamine usage, at doses compatible with induction. Calculations of CPP from this published data are suggestive that ketamine actually improves cerebral perfusion. Thus, in the absence of obstructed CSF flow pathways, this data goes some way to support the use of ketamine in head injured patients rather than refute it. Ketamine has been increasingly utilised in the prehospital environment in recent years [14], based on maintenance of airway reflexes, predictability and cardiovascular stability. Indeed, hypotension unarguably increases mortality and worsens secondary brain injury: ketamine has the potential to limit hypotensive sequelae in those necessitating emergency intubation. Prehospital practice has now encouraged adoption in secondary care, with increasing use of ketamine based agents for sedation in the emergency department [13]. Critical care physicians have also warmed to its use in limiting physiological disturbance during temporarily distressing procedures such as endotracheal suction and for prolonged sedation, even in known TBI [7,10]. In these patients, often with ICP monitors, a further evidence base is emerging to refute the previously proposed physiological disadvantages of the drug.

Clinical Bottom Line

There is no evidence to suggest harm with Ketamine use as induction agent for the patient with potential traumatic brain injury. The drug has major advantages in those patients with associated haemodynamic compromise and should potentially be regarded as the agent of choice.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Filanovsky Y, Miller P and Kao J. Myth: ketamine should not be used as an induction agent for intubation in patients with head injury. Canadian Journal of Emergency Medicine 2010;12(2):154-7
2. Sehdev RS, Symmons DA and Kindi K. Ketamine for rapid sequence induction in patients with head injury in the emergency department. Emergency Medicine Australasia 2006;18:37-44
3. Grathwohl KW, Black IH, Spinella PC, Sweeney J, Robalino J, Helminiak J, Grimes J, Gullick R and Wade CE Total Intravenous Anesthesia Including Ketamine versus Volatile Gas Anesthesia for Combat-related Operative Traumatic Brain Injury Anaesthesia 2008;109:44-53
4. Gofrit ON, Leibovici D, Shemer J, Henig A and Shapira SC. Ketamine in the field: the use of ketamine for induction of anaesthesia before intubation in injured patients in the field. Injury 1996;28(1):41-43
5. Jabre P, Cornbes X, Lapostolle F et al for the KETASED Collaborative Study Group. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. The Lancet 2009;374:293-300
6. Gibbs JM. The effect of intravenous ketamine on cerebrospinal fluid pressure British Journal of Anaesthesia 1972;44:1298-1301
7. Evans J, Rosen M, Weekes D et al. Ketamine in neurosurgical procedures The Lancet 1971;297:40-41
8. Gardner AE, Olson BE and Lichtiger M. Cerebrospinal fluid pressure during dissociative anesthesia with ketamine Anaesthesiology 1971;35(2):226-228
9. Shapiro HM, Wyte SR and Harris AB. Ketamine anaesthesia in patients with intracranial pathology British Journal of Anaesthesia 1972;44:1200-1204
10. List WF, Crumrine RS, Cascorbi HF and Weiss MH. Increased cerebrospinal fluid pressure after ketamine. Anaesthesiology 1972;36(1):98-99
11. Sener S, Eken C, Schultz C et al. Ketamine with and without midazolam for emergency department sedation in adults: a randomized controlled trial Annals of Emergency Medicine 2011;57:109-114
12. Bourgain A, Albanese J, Leone M et al. Effects of sufentanil or ketamine administered in target controlled infusion on the cerebral haemodynamics of severely brain injured patients Critical Care Medicine 2005;33(5):1109-1113
13. Bar-Joseph G, Guilburd Y and Guilburd J Ketamine effectively prevents intracranial pressure elevations during endotracheal suctioning and other distressing interventions in patients with severe traumatic brain injury Critical Care Medicine 2009:37(12 suppl. A402):0090-3493
14. Sibley A, Mackenzie M, Bawden J et al. A prospective review of the use of ketamine to facilitate endotracheal intubation in the helicopter emergency medical services (HEMS) setting Emergency Medicine Journal 2011;28:521-525