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Patient Care

Ketamine and Drug-Assisted Intubation

This article is available on our LMS for CE credit.

Objectives

  • Outline the mechanism of action and effects of ketamine
  • Critically examine earlier studies linking ketamine to increased ICP in TBI patients
  • Identify therapeutic applications of ketamine for procedural sedation 

You’re responding to a call for a pedestrian struck. Upon arrival you see a young male lying on the street several feet from the car that hit him. The patient is conscious but cannot answer questions or follow commands.

You calculate his GCS score to be 8 (eye response 2, verbal response 2, motor response 4) and note him to be hypotensive, with an initial blood pressure of 86/58, and tachycardic, with a heart rate in the 120s. 

Further examination of the patient reveals multiple facial abrasions and lacerations, a palpable skull fracture, and an obvious left lower extremity deformity. You know the patient will require airway stabilization, given his GCS and the copious amount of bloody oral secretions. You consider your options for induction agents and request that ketamine be drawn up, as its hemodynamic stability will be helpful for this patient in shock. 

Upon hearing this your partner questions whether ketamine is really the best option, given the patient’s likely traumatic brain injury and risk of elevated intracranial pressure (ICP). Should drug-assisted intubation (DAI) with ketamine be avoided in head-injured patients for concern it raises ICP? 

Background

Ketamine was developed in 1962 as a veterinary anesthetic for research.1 After showing promise as a favorable dissociative anesthetic alternative to phencyclidine (PCP), it was approved for use in humans in 1970.2,3 Initially utilized mostly by anesthesiologists, this multifaceted drug has now found its role in the prehospital and emergency settings as well. 

Ketamine, which is structurally similar to phencyclidine, has dissociative, analgesic, and amnestic effects, making it a useful agent for acute pain control, procedural sedation, and RSI. Its mechanism of anesthesia and analgesia is complex and not completely understood; however, it is well established that ketamine binds to multiple receptors, including NMDA, opioid, monoaminergic, muscarinic, and neuronal nicotinic acetylcholine receptors.4

Subanesthetic dosing of ketamine is 0.2–0.5 mg/kg IV, while dosing for DAI or induction of anesthesia is 1–2 mg/kg IV. When administered intravenously, ketamine will exert its effects in 45–60 seconds and typically has a duration of action of 10–20 minutes.4

From a hemodynamic and cardiovascular standpoint, ketamine exerts interesting effects. In vitro ketamine causes direct myocardial suppression. However, its indirect stimulation of the central nervous system causes sympathetic activation, leading to an overall increase in systemic blood pressure, heart rate, cardiac output, cardiac work, and myocardial oxygen requirements. Therefore, in patients with intact catecholamine stores and the ability to mount a sympathetic response, ketamine is a positive inotrope and vasopressor.4 

In addition to its cardiovascular impact, and paramount to the question at hand, are ketamine’s often-cited cerebral effects. Traditionally ketamine has been thought to increase cerebral blood flow and cerebral oxygen metabolism. Prior studies showed that in the setting of normocapnia, the cerebral vasodilatory effects could increase cerebral blood flow by up to 60%. Such studies, mainly performed in the 1970s, were the impetus for avoiding ketamine in patients with elevated ICP. 

However, the applicability of these studies to patients with TBI has come into question. The study subjects were individuals with space-occupying lesions or obstructive hydrocephalus, which is not the etiology for most trauma patients presenting with low GCS.

Additionally, cerebral blood flow was not directly measured, but rather changes in CSF pressures were used as surrogate markers.5 Furthermore, ketamine’s antagonism of NMDA receptors has been thought to serve a neuroprotective role.4

So what is the current evidence regarding the use of ketamine in patients with TBI?

Ketamine RSI In Trauma Patients

Given its hemodynamic stability, ketamine is an attractive option for DAI in the critically ill. There have been many studies comparing it to other induction agents. Most of these have either favored ketamine or shown no statistically significant difference between the drugs. 

One such study was performed at an academic level 1 trauma center. All trauma patients requiring ED intubation underwent rapid sequence intubation (RSI) with ketamine and either rocuronium or succinylcholine. These patients were retrospectively compared to patients intubated the year prior with various combinations of midazolam, etomidate, fentanyl, succinylcholine, rocuronium, and vecuronium, chosen at the treating physician’s discretion. 

Despite similar baseline characteristics and injury severity, those intubated with ketamine required less redosing of meds to complete intubation and were intubated, on average, one minute faster. Although it could be argued that these findings are more likely a consequence of having an established RSI protocol as opposed to ketamine itself, it suggests that ketamine is a safe, if not superior, drug for RSI in the trauma patient.6

Another study compared the combination of ketamine/fentanyl/rocuronium to etomidate/succinylcholine for prehospital RSI in the trauma patient. Despite the cohort of patients receiving ketamine being older and more severely injured, this group tended to have better laryngeal views, higher first-attempt intubation success rates, and less of a hypertensive response to intubation. When overall mortality was compared among the groups, there was no statistical difference, even when subgroup analysis by head injury severity was taken into account.7

In addition to ketamine’s immediate benefits, its lack of long-term effects also makes it an attractive option. A randomized, controlled, single-blind trial sought to determine whether there was a difference in early and 28-day morbidity and mortality in patients receiving etomidate vs. ketamine for emergency intubation. When the groups were compared, there was no statistically significant difference in immediate morbidity or mortality; however, the etomidate group ultimately had a significantly higher rate of adrenal insufficiency.8

The aforementioned studies suggest that ketamine is a safe and likely favorable option for RSI in the trauma patient. Although these studies did not specifically look at patients with known TBI, this is the same diagnostic uncertainty prehospital providers face. In the setting of trauma, altered level of consciousness can be caused by multiple factors, including shock, intoxication, opiate analgesia, and TBI. While certain indicators can point toward head injury (palpable skull fractures, pupil irregularities, etc.), this is a diagnosis that can never be made with 100% certainty in the field. Let’s now examine studies that look specifically at the effects of ketamine on those with known TBI. 

Effect on ICP and CPP

Multiple studies have quantified the effects of ketamine on ICP since the initial studies were performed in the 1970s. In contrast to the initial data, newer studies have shown that ketamine has negligible, if not beneficial, effects on cerebral hemodynamics. One study consisted of 8 patients with TBI who were sedated and paralyzed with propofol and vecuronium while mechanically ventilated. These patients were given boluses of 1.5, 3, and 5 mg/kg of ketamine while ICP, CPP, and other parameters were observed. Overall CPP was not significantly changed after the boluses, while changes in ICP were variable (including a statistically significant decrease at 2 minutes with the 3- and 5-mg/kg boluses).9

Another study randomized 30 patients with severe TBI to receive sedation with either sufentanil/midazolam or ketamine/midazolam and followed their cerebral hemodynamics. There were no significant differences in the groups’ baseline ICP or CPP, nor was there a difference when the concentration of sedatives was doubled.10 Similarly, a study comparing ketamine to fentanyl for sedation in TBI patients showed no difference in ICP or CPP; however, the fentanyl group required more pressors to maintain an adequate MAP.11 

Systematic reviews on the topic have shown similar findings: One such review, encompassing 13 randomized controlled trials and 380 patients, showed there was no sedative agent that performed significantly better than others in terms of neurologic outcome or mortality for TBI patients. However, opioid bolusing frequently resulted in hypotension, causing compromised CPP.12

These findings have been duplicated in the pediatric population. In a prospective controlled clinical trial, pediatric patients with TBI and sustained elevated ICP (more than 18 mmHg) were given ketamine boluses as either a treatment for ICP or as a pretreatment prior to stimulating events (e.g., endotracheal tube suctioning). In the treatment group ICP decreased by 33% after the ketamine administration. In the pretreatment group ICP decreased by 30% initially and increased by more than 2 mmHg during the stimulating event in only one of 17 events.13

Bottom Line

As your partner continues to preoxygenate the patient, you calmly acknowledge his concerns and quickly bring him up to date on the evidence. “The recommendation to avoid ketamine in TBI patients was largely drawn from old studies in patients with nontraumatic intracranial lesions,” you tell him. “Newer data suggests ketamine doesn’t significantly increase ICP, and some studies assert it may actually lower ICP and improve CPP. Additionally, ketamine’s hemodynamic stability makes it a favorable induction agent for RSI in the trauma patient in shock. While studies looking specifically at ketamine RSI in the (known) TBI patient are lacking, the evidence supports that ketamine is likely safe, if not beneficial, for patients with TBI.” 

Your partner is impressed and proceeds with your plan of ketamine DAI. The intubation occurs without difficulty, and your team quickly transports to the hospital. As you sign out to the emergency department team, a young resident and nurse who hear about your ketamine DAI give you a doubtful look. Before you can say anything, the attending gives you a pat on the back and says, “Great job, man! Way to use cutting-edge medicine!” Before you can bask in the praise for too long, you get dispatched to another call. It looks like a busy night. Hopefully the next patient won’t need ketamine DAI, but if they do, you’re ready and armed with the most up-to-date evidence. 

References

1. Clark MR. Chronic Pain and Addiction. Basel, Switzerland: Karger AG, 2011.

2. Center for Substance Abuse Research. Ketamine. www.cesar.umd.edu/cesar/drugs/ketamine.asp.

3. Corssen G, Domino EF. Dissociative anesthesia: Further pharmacologic studies and first clinical experience with the phencyclidine derivative Cl-581. Anesth Analg, 1966 Jan–Feb; 45(1): 29-40.

4. Flood P, Rathmell JP, Shafer S. Stoelting’s Pharmacology & Physiology in Anesthetic Practice, 5th ed. Philadelphia: Wolters Kluwer Health, 2015.

5. Nickson C. Ketamine RSI for head injury. Life in the Fastlane, https://lifeinthefastlane.com/ccc/ketamine-rsi-for-head-injury/.

6. Ballow SW, Kaups KL, Anderson S, Chang M. A standardized rapid sequence intubation protocol facilitates airway management in critically injured patients. J Trauma Acute Care Surg, 2012 Dec; 73(6): 1,401–5.

7. Lyon RM, Perkins ZB, Chatterjee D, Lockey DJ, Russell MQ; Kent, Surrey & Sussex Air Ambulance Trust. Significant modification of traditional rapid sequence induction improves safety and effectiveness of pre-hospital trauma analgesia. Crit Care, 2015 Apr 1; 19: 134.

8. Jabre P, Combes X, Lapostolle F, et al.; KETASED Collaborative Study Group. Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: A multicenter randomised controlled trial. Lancet, 2009 Jul 25; 374(9,686): 293–300.

9. Albanese J, Arnaud S, Rey M, et al. Ketamine decreases intracranial pressure and electroencephalographic activity in traumatic brain injury patients during Propofol sedation. Anesthesiology, 1997 Dec; 87(6): 1,328–34.

10. Bourgoin A, Albanese J, Wereszczynski N, et al. Safety of sedation with ketamine in severe head injury patients: Comparison with sufentanil. Crit Care Med, 2003 Mar; 31(3): 711–7. 

11. Schmittner MD, Vajkoczy SL, Horn P, 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, 2007; 19: 257–62.

12. Roberts DJ, Hall RI, Kramer AH, et al. Sedation for critically ill adults with severe traumatic brain injury: A systematic review of randomized controlled trials. Crit Care Med, 2011; 39: 2,743–51.

13. Bar-Joseph G, Guilburd Y, Tamir A, Guilburd JN. Effectiveness of ketamine in decreasing intracranial pressure in children with intracranial hypertension. J Neurosurg Pediatr, 2009 Jul; 4(1): 40–6.

Caitlin Fuqua McDowell, MD, is a resident in the Division of Emergency Medicine at Washington University in St. Louis.

Hawnwan Philip Moy, MD, is medical director for ARCH Air Methods in Missouri, assistant medical director for Christian Northeast EMS, assistant medical director for the St. Louis Fire Department, and assistant professor of emergency medicine at Washington University in St. Louis.  

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