Myth: Ketamine should not be used as an induction agent for intubation in patients with head injury

Medical Mythology

Yevgeny Filanovsky, MD;* Philip Miller, MD;† Jesse Kao, MD‡

From the *Emergency Department, Nanaimo Regional General Hospital, Nanaimo BC, the †Department of Emergency Medicine, University of Toronto, Toronto, Ont., and the ‡Department of Emergency Medicine, University of British Columbia, Vancouver, BC

CJEM 2010;12(2):154-157

This article has not been peer reviewed.

Background

Ketamine has many unique attributes making it well suited to certain applications in the emergency department (ED), including pediatric procedural sedation, and as an induction agent in patients with asthma and exacerbation of chronic obstructive pulmonary disease. However, ketamine has been historically contraindicated for induction use in patients with head injury because of a concern that it may increase intracranial pressure (ICP). The most recent edition of Tintinalli and colleague's Emergency Medicine1 states that ketamine " should be avoided in patients with closed head injuries." There have been 2 more recent review articles on this topic challenging this myth.2,3

Methodology

We used the following indexed search terms in EMBASE and MEDLINE: "ketamine," "brain injuries" or "craniocerebral trauma," "intracranial pressure" or "intracranial hypertension" or "cerebrovascular circulation" or "brain circulation," and "sedation." We used the keywords/phrases "rapid sequence intubation," "rapid sequence induction," "inductive agent" and "neuroprotection." We then reviewed the abstracts and references from all initially identified papers for further relevant studies.

Pharmacology

Ketamine is a dissociative anesthetic, analgesic, amnestic and anxiolytic.4 It can be given intravenously (IV), intramuscularly or by mouth. The typical dose of ketamine given for general anesthesia is 2-2.5 mg/kg IV, whereas the commonly used dose for rapid sequence induction (RSI) in the ED is 1-2 mg/kg IV.5 Ketamine is known to have a stimulatory effect on the sympathetic nervous system with corresponding increases in heart rate, blood pressure and cardiac output, although the exact mechanism has not been fully determined.4 In addition, ketamine has minimal effects on central respiratory drive, and also acts as a bronchial smooth muscle relaxant.

Origins of the Myth

Six studies from the 1970s are listed in Table 1.6-11 The data on ketamine from early studies are quite variable in their methods and quality. They are a combination of case reports and small case-control studies. They identified an association between ketamine and increased ICP in patients with abnormal cerebrospinal fluid path ways (such as those caused by aqueductal stenosis, obstructive hydrocephalus and other mass effects). However, in healthy volunteers, ICP stayed within normal range (i.e., < 10 mm Hg) with a corresponding increase in mean arterial pressure (MAP) and calculated cerebral perfusion pressure (CPP).

Table 1. Summary of 1970s studies on ketamine and intracranial pressure
Study Study type Ketamine dosage Study population ICP MAP Calculated CPP
Garner et al.6 Case-control 2 mg/kg IV 11 healthy males for simple surgery CSFP ↑ by mean 18 mm Hg ↑ by mean
28 mm Hg
Wyte et al.7 Case report 2 mg/kg
(route unknown)
2 patients (aged 8 and 17 yr)
with VP shunts, obstructive hydrocephalus (secondary to aqueductal stenosis and astrocytoma)
ICP ↑ to 75 mm Hg in only
1 patient; no change in other patient
Gibbs8 Case-control 1-1.3 mg/kg IV 11 healthy patients for lumbar discectomy; second group of
9 patients with intracranial space occupying lesions
No change in CSFP in healthy patients; in group 2, CSFP ↑ by
~ 12 mm Hg in 6/9
↑ by
24 mm Hg
Gardner et al.9 Case report 2 mg/kg IV 13-year-old boy with glioma, midline shift CSFP ↑ by ~ 8 mm Hg ↑ by
~ 16 mm Hg
Shapiro et al.10 Case-control 2 mg/kg IV or
4 mg/kg IM
7 patients (5 with external
shunts and ↑ ICP)
No change in patients without shunts; ICP ↑ up to 60 mm Hg in certain patients ↑ up to
22 mm Hg
Variable
List et al.11 Case-control 2 mg/kg IV 7 patients with hydrocephalus 1 patient had ↑ CSFP to
~ 25 mm Hg; others had mild ↑ CSFP within normal range
CPP = cerebral perfusion pressure; CSFP = cerebrospinal fluid pathways; ICP = intracranial pressure; IM = intramuscularly; IV = intravenously; MAP = mean arterial pressure;
VP = ventriculoperitoneal.

Recent Studies of Ketamine's Effect on ICP

Several recent studies have examined the use of ketamine as a sedative in the setting of the neurosurgical intensive care unit. Pertinent randomized prospective studies are outlined in Table 2.12-16 These studies have some methodological limitations including small sample sizes and the presence of other sedative agents as potential confounders. Each of these studies examined continuous infusions of ketamine in patients treated with mechanical ventilation, so the generalizability of data from continuous infusion to induction use for RSI has not been determined. No statistically significant increase in ICP was observed following the administration of ketamine in patients with head injury. Some of the studies showed a net increase in CPP following ketamine administration.

Table 2. Key studies of prospective trials of ketamine and intracranial pressure
Study Study type Study population ICP CPP
Mayberg et al.12 Prospective trial • 20 neurosurgical patients (10 with supratentorial tumours, the rest with intracranial aneurysms)
• ICP measured before and after administration of ketamine 1 mg/kg IV
Small but statistically significant decrease in ICP after ketamine administration No significant change over 10 min
Kolenda et al.13 Prospective RCT • 35 patients with moderate or severe head injury
• Ketamine + midazolam sedation v. fentanyl + midazolam sedation
Slightly higher ICP values in the ketamine group
(~ 2 mm Hg difference)
Higher in the ketamine group than the control group by average of
8 mm Hg
Bourgoin et al.14 Prospective double-blind RCT • 25 patients with severe
head injury
• Continuous infusion ketamine-midazolam v. sufentanil-midazolam infusion
No significant difference between groups No significant difference between groups
Bourgoin et al.15 Prospective double-blind RCT • 30 patients with TBI receiving sufentanil-midazolam or ketamine-midazolam using target controlled infusion No significant difference between groups No significant difference between groups
Schmittner et al.16 Randomized prospective trial • 24 patients with TBI
• Group 1: methohexitone + ketamine sedation
• Group 2: methohexitone + fentanyl sedation
No significant difference between groups No significant difference between groups
CPP = cerebral perfusion pressure; ICP = intracranial pressure; IV = intravenously; RCT = randomized controlled trial; TBI = traumatic brain injury.

Ketamine and Cerebral Physiology in Traumatic Brain Injury

In cerebral contusions, a central core of contused tissue is surrounded by a penumbra at risk for further ischemic injury.17-22 Some studies have looked at whether increasing CPP increases the cerebral blood flow and cerebral blood volume in ischemic brain tissue (by a norepinephrine infusion), with conflicting results.23-25 Although the historical contraindication for ketamine in head injury was based on elevation of ICP, few studies have focused on its effect on regional blood flow and perfusion pressures. Ketamine, with its effect on increasing MAP (and thus CPP), may increase the blood flow to ischemic areas where autoregulation is absent, but the effect of increasing CPP in ischemic brain penumbra remains controversial.

Postulated Neuroprotective Characteristics of Ketamine

Some studies have supported the idea that ketamine is "neuroprotective."3 Ketamine, an N-methyl-D-aspartate antagonist, decreases the release of glutamate, which is neurotoxic. This evidence is based on in vitro and animal studies.26-28 However, very few studies have examined long term outcomes in humans.

Two small randomized controlled trials looked at 6 month outcomes after ketamine, fentanyl or sufentanil for sedation in neurosurgical intensive care units.13,29 They both report no differences in neurologic outcomes (Glasgow Outcome Scale in one study, and death, vegetative survival, or severe or moderate disability in the other) at 6 months. However, both studies were underpowered to detect such differences for or against ketamine.

Another randomized controlled trial (120 patients) looked at ketamine for bypass surgery and possible neuroprotective effects. There was no difference in neuropsychological testing between groups at 10 weeks, except in 1 test, which was ascribed to chance.30

Comparison to Other Inductive Agents

Ketamine may be of value as an inductive and sedative agent in patients with hemodynamic instability, since other inductive agents such as propofol can cause hypotension.31 Hypotension has been shown to predict increased mortality and worsen secondary brain injury.32 Etomidate is a common induction agent in patients with hemodynamic instability. However, etomidate is often not available in smaller EDs across the country. In addition, recent concerns have been expressed about etomidate and adrenal suppression, particularly in septic patients.33-36

Conclusion

Based on its pharmacological properties, ketamine appears to be the perfect agent for the induction of head injured patients for intubation. The evidence for neuroprotection in humans remains inconclusive at this time. However, more recent prospective data examining ketamine usage as a sedative agent in patients treated with mechanical ventilation suggests that there is no association with increased ICP in head injury.

Despite limited evidence specific to its use as an induction agent, we feel that additional consideration must be paid to the possible usage of ketamine for RSI in patients with head injury, especially when alternative agents that do not cause hypotension are unavailable.

References

  1. Tintinalli J, Kelen G, Stapczynski J. Emergency medicine. New York (NY): McGraw Hill; 2004. p. 113 4; 260.

  2. Sehdev RS, Symmons DA, Kindl K. Ketamine for rapid sequence induction in patients with head injury in the emergency department. Emerg Med Australad 2006;18:37-44.

  3. Himmelseher S, Durieux ME. Revising a dogma: Ketamine for patients with neurological injury? Anesth Analg 2005;101:524-34.

  4. Miller RD, editor. Miller's anesthesia. New York (NY): Elsevier/Churchill Livingstone; 2005. p. 346-8.

  5. Tintinalli J, Kelen G, Stapczynski J. Emergency medicine. New York (NY): McGraw Hill; 2004. p. 279.

  6. Gardner AE, Olson BE, Lichtiger M. Cerebrospinal fluid pressure during dissociative anesthesia with ketamine. Anesthesiology 1971;35:226-8.

  7. Wyte SR, Shapiro HM, Turner P, et al. Ketamine induced intracranial hypertension. Anesthesiology 1972;36:174-6.

  8. Gibbs JM. The effect of intravenous ketamine on cere brospinal fluid pressure. Br J Anaesth 1972;44:1298-302.

  9. Gardner AE, Dannemiller FJ, Dean D. Intracranial cere brospinal fluid pressure in man during ketamine anesthesia. Anesth Analg 1972;51:741-5.

  10. Shaprio HM, Wyte SR, Harris AB. Ketamine anesthesia in patients with intracranial pathology. Br J Anaesth 1972;44:1200-4.

  11. List WF, Crumrine RS, Cascorbi HF, et al. Increased cere brospinal fluid pressure after ketamine. Anesthesiology 1972; 36:98-9.

  12. Mayberg TS, Lam AM, Matta BF, et al. Ketamine does not increase cerebral blood flow velocity or intracranial pressure during isoflurane/nitrous oxide anesthesia in patients under going craniotomy. Anesth Analg 1995;81:84-9.

  13. Kolenda H, Gremmelt A, Rading S, et al. Ketamine for analgosedative therapy in intensive care treatment of head injured patients. Acta Neurochir (Wien) 1996;138:1193-9.

  14. Bourgoin A, Albanèse J, Wereszczynski N, et al. Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil. Crit Care Med 2003;31:711-7.

  15. Bourgoin A, Albanese J, Leone M, et al. Effects of sufentanil or ketamine administered in target controlled infusion on the cerebral hemodynamics of severely brain injured patients. Crit Care Med 2005;33:1109-13.

  16. Schmittner MD, Vajkoczy SL, Horn P, et al. Effects of fen tanyl and S(+) ketamine on cerebral hemodynamics, gas trointestinal motility, and need of vasopressors in patients with intracranial pathologies: a pilot study. J Neurosurg Anesthesiol 2007;19:257-62.

  17. Schroder ML, Muizelaar JP, Fatouros P, et al. Early cerebral blood volume after severe traumatic brain injury in patients with early cerebral ischemia. Acta Neurochir Suppl 1998;71:127-30.

  18. Schroder ML, et al. Regional cerebral blood volume after severe head injury in patients with regional cerebral ischemia. Neurosurgery 1998;42:1276-80, discussion 1280-1.

  19. Hoelper BM, Reinert MM, Zauner A, et al. rCBF in hemor rhagic, non hemorrhagic and mixed contusions after severe head injury and its effect on perilesional cerebral blood flow. Acta Neurochir Suppl 2000;76:21-5.

  20. Bouma GJ, et al. Ultra early evaluation of regional cerebral blood flow in severely head injured patients using xenon enhanced computerized tomography. J Neurosurg 1992;77:360-8.

  21. McLaughlin MR, Marion DW. Cerebral blood flow and vasoresponsivity within and around cerebral contusions. J Neurosurg 1996;85:871-6.

  22. Bouma GJ, et al. Cerebral circulation and metabolism after severe traumatic brain injury: the elusive role of ischemia. J Neurosurg 1991;75:685-93.

  23. Steiner LA, et al. Responses of posttraumatic pericontusional cerebral blood flow and blood volume to an increase in cere bral perfusion pressure. J Cereb Blood Flow Metab 2003;23:1371-7.

  24. Chieregato A, Fainardi E, Tanfani A, et al. Induced acute arterial hypertension and regional cerebral flow in intracontu sional low density area. Acta Neurochir Suppl 2003;86:361-5.

  25. Chieregato A, Fainardi E, Compagnone C, et al. Cerebral blood flow in traumatic contusions is predominantly reduced after an induced acute elevation of cerebral perfusion pres sure. Neurosurgery 2007;60:115-23.

  26. Shapira Y, Artru AA, Lam AM. Ketamine decreases cerebral infarct volume and improves neurological outcome following experimental head trauma in rats. J Neurosurg Anesthesiol 1992;4:231-40.

  27. Shapira Y, et al. Therapeutic time window and dose response of the beneficial effects of ketamine in experimental head injury. Stroke 1994;25:1637-43.

  28. Hoffman WE, et al. Ketamine decreases plasma cate cholamines and improves outcome from incomplete cerebral ischemia in rats. Anesthesiology 1992;76:755-62.

  29. Bourgoin A, et al. Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil. Crit Care Med 2003;31:711-7.

  30. Nagels W, et al. Evaluation of the neuroprotective effects of S(+) ketamine during open heart surgery. Anesth Analg 2004;98:1595-603.

  31. Tintinalli J, Kelen G, Stapczynski J. Emergency medicine. New York (NY): McGraw Hill; 2004. p. 114.

  32. Chesnut RM, et al. The role of secondary brain injury in determining outcome from severe head injury. J Trauma 1993;34:216-22.

  33. Jackson WL Jr. Should we use etomidate as an induction agent for endotracheal intubation in patients with septic shock?: a critical appraisal. Chest 2005;127:1031-8.

  34. Sacchetti A. Etomidate: not worth the risk in septic patients. Ann Emerg Med 2008;52:14-6.

  35. Den Brinker M, et al. Adrenal insufficiency in meningococ cal sepsis: bioavailable cortisol levels and impact of inter leukin 6 levels and intubation with etomidate on adrenal function and mortality. J Clin Endocrinol Metab 2005;90:5110-7.

  36. Sivilotti ML. You need tube, me give one amp of etomidate and SUX. CJEM 2006;8:351-3.