Resident and Fellow Corner
Ketamine and Intracranial Pressure
By Shobhit Jain, MD
Ketamine is an optimal drug for rapid sequence intubation (RSI) as it provides analgesia, sedation and amnesia with stable hemodynamic properties and a limited suppression of respiratory drive. However, the use of ketamine for RSI in patients with known or suspected traumatic brain injury (TBI) is limited, based on concerns surrounding effects on intracranial pressure (ICP) and cerebral perfusion pressure (CPP). This concern has perpetuated from small reports originating in the 1970s, but there is a fresh debate on this topic in light of new evidence. In this article, we will review the literature and aim to provide the latest evidence on this issue with a focus on the emergency usage of ketamine.
ICP and CPP
In initial studies with ketamine, authors described abrupt increases in intracranial pressure levels with intravenous ketamine dosing in patients with abnormal cerebrospinal fluid flow dynamics or other intracranial pathology.1,2 A study involving critically ill children requiring sedation noted that pretreatment with midazolam is associated with reduction in ICP compared to sedation with ketamine alone.3 Recent RCTs compared ICP and CPP in patients receiving ketamine and sufentanil infusion in the ICU with severe TBI and found no difference in ICP or CPP.4 Another study compared the effect of ketamine and fentanyl and found no significant differences.5 Mayberg et al. studied the effect of a single bolus dose in neurosurgery patients and reported decreased ICP without changes to CPP.6 In their prospective controlled study, Albanese et al. reported no difference in the CPP from baseline in patients with TBI who received several bolus doses of ketamine. However, they noticed a decreased ICP at two minutes, and increase at 30 minutes after ketamine administration.7
Morbidity and Mortality
Jabre et al. conducted a large RCT comparing ketamine to etomidate for RSI in undifferentiated critically ill patients.8 In this study involving 655 undifferentiated critically ill adult patients, the authors found significantly higher incidence of adrenal insufficiency in the etomidate group. However, they did not find any significant difference in 28-day organ dysfunction, mortality, ICU length of stay, or difficulty with intubation between the etomidate and ketamine groups. Bourgoin et al. found no difference in mortality with patients with severe TBI sedated with ketamine versus sufentanil infusions.9
There is a growing body of literature suggesting that ketamine may have an important neuro-protective effect in critically ill patients. This is primarily based on the understanding that ketamine non-competitively antagonizes the NMDA receptor which is otherwise activated and leads to an injury cascade.10 In a systematic review, Roberts et al. compared several variables including ICP, CPP and mortality with use of different intravenous sedative agents in severe TBI and concluded that no one agent was superior to others.11 Filanovsky et al. suggested that mild increased ICP and CPP that may be associated with ketamine would increase cerebral blood flow and prevent secondary ischemic injury to the brain tissue.12 Ketamine also offers benefit with its potential anti-inflammatory, antiepileptic and hemodynamic properties.5,13
Use in non-traumatic neurologic illness
Zeiler et al. published a systemic review on the use of ketamine for this group and noted that when co-administered with midazolam, ketamine does not lead to an increased ICP. They also noted that there was no relationship between specific neurologic illness and ICP change with ketamine use, and there were no significant non-ICP related adverse effects with ketamine.14
Etomidate had emerged as an alternative rapidly acting intravenous agent with stable hemodynamic profile. However, etomidate is known to cause transient adrenal suppression.15,16 Adequate adrenal function is associated with improved mortality in critically ill patients.17,18 In light of this new knowledge, there is an urgent need to clarify the speculation that ketamine increases ICP.
Cohen et al. authored a robust meta-analysis and concluded that there is not enough evidence to avoid the use of ketamine for RSI in head-injured critically ill patients.19 Also, numerous authors now note that the ICP elevation reported in initial reports were exclusively in patients with pre-existing hydrocephalus and CSF tract obstruction. Additionally, the potential increase in intracranial blood flow occurs through vasodilation and the cerebral perfusion is maintained or improved.7,19,20
There has been important debate about the use of ketamine as an induction agent for RSI in critically ill patients in whom TBI has not been ruled out. There is a strong association between the hypotension and neurologic outcome in patients with TBI, suggesting against the use of opioids or benzodiazepines. Etomidate has been associated with adrenal suppression, and that raises a concern for its use since sepsis is a frequent complication with trauma. The available evidence suggests that ketamine does not adversely affect ICP or CPP, neurologic outcomes or mortality compared with other induction agents. However, based on prior studies, more caution is advised with the use of ketamine in patients with known CSF tract pathology. High-quality randomized control trials are urgently needed to compare the agents and determine optimal management strategy.
- Shaprio, H. M., Wyte, S. R. & Harris, A. B. Ketamine anaesthesia in patients with intracranial pathology. Br. J. Anaesth. 44, 1200–4 (1972).
- List, W. F., Crumrine, R. S., Cascorbi, H. F. & Weiss, M. H. Increased cerebrospinal fluid pressure after ketamine. Anesthesiology 36, 98–9 (1972).
- Michalczyk, K., Sullivan, J. E. & Berkenbosch, J. W. Pretreatment with midazolam blunts the rise in intracranial pressure associated with ketamine sedation for lumbar puncture in children. Pediatr. Crit. Care Med. 14, e149–55 (2013).
- Bourgoin, A. et al. Effects of sufentanil or ketamine administered in target-controlled infusion on the cerebral hemodynamics of severely brain-injured patients. Crit. Care Med. 33, 1109–13 (2005).
- Schmittner, M. D. et al. Effects of fentanyl and S(+)-ketamine on cerebral hemodynamics, gastrointestinal motility, and need of vasopressors in patients with intracranial pathologies: a pilot study. J. Neurosurg. Anesthesiol. 19, 257–62 (2007).
- Mayberg, T. S., Lam, A. M., Matta, B. F., Domino, K. B. & Winn, H. R. Ketamine does not increase cerebral blood flow velocity or intracranial pressure during isoflurane/nitrous oxide anesthesia in patients undergoing craniotomy. Anesth. Analg. 81, 84–9 (1995).
- Albanèse, J. et al. Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during propofol sedation. Anesthesiology 87, 1328–34 (1997).
- Jabre, P. et al. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial. Lancet (London, England) 374, 293–300 (2009).
- Bourgoin, A. et al. Safety of sedation with ketamine in severe head injury patients: comparison with sufentanil. Crit. Care Med. 31, 711–7 (2003).
- Himmelseher, S. & Durieux, M. E. Revising a dogma: ketamine for patients with neurological injury? Anesth. Analg. 101, 524–34, table of contents (2005).
- Roberts, D. J. et al. Sedation for critically ill adults with severe traumatic brain injury: a systematic review of randomized controlled trials. Crit. Care Med. 39, 2743–51 (2011).
- Filanovsky, Y., Miller, P. & Kao, J. Myth: Ketamine should not be used as an induction agent for intubation in patients with head injury. CJEM 12, 154–7 (2010).
- Bhutta, A. T. et al. Ketamine as a neuroprotective and anti-inflammatory agent in children undergoing surgery on cardiopulmonary bypass: a pilot randomized, double-blind, placebo-controlled trial. Pediatr. Crit. Care Med. 13, 328–337 (2012).
- Zeiler, F. A., Teitelbaum, J., West, M. & Gillman, L. M. The ketamine effect on intracranial pressure in nontraumatic neurological illness. J. Crit. Care 29, 1096–106 (2014).
- Hohl, C. M. et al. The effect of a bolus dose of etomidate on cortisol levels, mortality, and health services utilization: a systematic review. Ann. Emerg. Med. 56, 105–13.e5 (2010).
- Cuthbertson, B. H. et al. The effects of etomidate on adrenal responsiveness and mortality in patients with septic shock. Intensive Care Med. 35, 1868–76 (2009).
- Annane, D. et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 288, 862–71 (2002).
- Annane, D. ICU physicians should abandon the use of etomidate! Intensive Care Med. 31, 325–6 (2005).
- Cohen, L. et al. The effect of ketamine on intracranial and cerebral perfusion pressure and health outcomes: a systematic review. Ann. Emerg. Med. 65, 43–51.e2 (2015).
- Bar-Joseph, G., Guilburd, Y., Tamir, A. & Guilburd, J. N. Effectiveness of ketamine in decreasing intracranial pressure in children with intracranial hypertension. J. Neurosurg. Pediatr. 4, 40–6 (2009).