Ketamine is a pretty impressive medication; it is a hypnotic, amnestic, bronchodilator, antidepressant and analgesic that preserves airway reflexes and respiratory drive. Its use spans the fields of emergency medical services, critical care, emergency medicine and anesthesia due to its broad applications in sedation and airway management.
One of the highly touted aspects of ketamine is its preservation of hemodynamics and increased sympathetic activity during intubation, making it ideal for management of critically ill patients. However, two studies have recently challenged this assumption. Here, well deep dive the literature as well as cover some of the basics.
Mechanism of Ketamine:
Importantly, ketamine is an antagonist of the NMDA receptor producing its hypnotic effects and secondly acts to prevent catecholamine re-uptake producing its hemodynamic effects. In addition, it has been found to have activity on calcium channel, sodium channel, opioid and muscarinic receptors. While ketamine actually demonstrates a direct negative inotropic effect, this effect is generally outweighed by increasing total circulating catecholamines.1
This mechanism has repeatedly been shown to increase systolic blood pressure, diastolic blood pressure, stroke volume, cardiac index, mean pulmonary artery pressures. These studies often demonstrate an increase in these values by 10-30%. 1, 2, 3
However it has been postulated that in the setting of a catecholamine depleted state – think a protracted course of shock – it could be reasonable that the direct negative inotropic effect outweighs the increased circulating catecholamines. Two studies were recently published from the NEAR registry, both retrospective cohort studies that challenge the hemodynamic profile commonly associated with ketamine.
Ketamine Versus Etomidate and Peri-intubation Hypotension: A National Emergency Airway Registry Study. Michael D. April, MD, DPhil, MSc. 4
What they did:
- Included all normotensive adults patients undergoing RSI in the ED.
- Excluded patients with pre-intubation hypotension defined as SBP < 100mmHh and patients with pre-intubation hypertension, defined as SBP >140mmHg.
- This led to evaluation of 738 patients intubated with ketamine, 6068 patients intubated with etomidate. The majority of patients were deemed ‘medical’ versus trauma and ~20% vs 11%, respectively, were suspected to have sepsis as a leading diagnosis.
What they found:
- Peri-intubation hypotension was observed in 18.3% of ketamine and 12.4% of etomidate intubations.
- The ketamine group also required more post-intubation intervention.
- However the groups did not differ in first pass success or mortality.
- Using logistic regression modeling, there was no association with higher or lower doses of either ketamine or etomidate relative to rates of hypotension.
Etomidate Use Is Associated With Less Hypotension Than Ketamine for Emergency Department Sepsis Intubations: A NEAR Cohort Study. Nicholas M. Mohr, MD, MS. 5
What they did:
- Multi-center observational cohort study of the prospectively collected NEAR data registry.
- The authors aimed to describe practice patterns when selecting induction agents for the intubation of septic patients. This was chosen with respect to the ongoing controversy of using etomidate in septic shock.
- 531 patients were identified who were intubated for sepsis; 71% intubated with etomidate and 27% intubated with ketamine.
What they found:
- Primary outcome was induction agent choice for septic vs non-septic patients. Overall, etomidate was the most frequently used induction agent for all intubated patients. Etomidate was preferred in non-septic patients vs septic patients (85% vs 71%).
- Septic patients were more likely than non-septic patients to experience hypotension (47% vs 18%).
- Intubations utilizing ketamine had a higher rate of hypotension vs etomidate (74% vs. 50%).
- Ketamine and etomidate had similar first-pass success, rates of hypoxia.
These two studies challenge the widely held belief that ketamine is a hemodynamically neutral induction agent, especially when compared to etomidate. These studies both identified a significant risk of hypotension in both a general population and specifically septic patients. This is in direct conflict with prior physiologic studies, which are fairly robust, as well as previous retrospective matched studies. One such study of 384 patients observed less hypotension in the ketamine group, (51.3% versus 73%, p=0.001). The ketamine group on average received 1.8mg/kg versus 0.3mg/kg etomidate – pretty standard doses – with no significant differences in peri-intubation pressors.6
Furthermore, how are we to interpret a lack of a dose-dependent response to ketamine in the first study? Given very different clinical effects at dissociative and sub-dissociative dosing of ketamine, wouldn’t we expect different hemodynamic profiles? It also seems that the subgroup of patients with pre-intubation hypotension would have been extremely important to report however this was neglected in the analysis.
Excluding patients with pre-intubation hypotension is a significant limitation to interpretation of this data. One might expect some practitioners would preferentially use ketamine in this instance! What is worth emphasizing, however, is that there is no magic induction agent that will avoid all hypotension. In most cases, careful anticipation and preparation for the hypotensive patient requiring intubation is most important.
– Matt Siuba
From these studies, we can appreciate that our medically ill patients and specifically septic patients are at high risk of peri-intubation hypotension and mitigating this response still remains a priority. However these two registry studies largely muddy the waters and a prospective randomized study is still necessary to answer the questions raised by these studies.
- Ketamine is widely believed to have a hemodynamically supportive profile which has been demonstrated in multiple studies.
- Two recent database studies challenge this assumption with higher rates of hypotension in the ketamine groups when compared to etomidate.
- Given the conflicting data, a well designed prospective study is needed to shed light on ketamine’s hemodynamic profile during intubation.
Garg K, Grewal G, Grewal A, et al. Hemodynamic responses with different dose of ketamine and propofol in day care gynecological surgeries. J Clin Diagn Res. 2013;7(11):2548-2550. doi:10.7860/JCDR/2013/6860.3607
Suleiman Z, Ik K, Bo B. Evaluation of the cardiovascular stimulation effects after induction of anaesthesia with ketamine. J West Afr Coll Surg. 2012 Jan;2(1):38-52. PMID: 25452977; PMCID: PMC4170283.
Tweed WA, Minuck M, Mymin D. Circulatory response to ketamine anaesthesia. Anesthesiology. 1972;37:612–19.
Mohr NM, Pape SG, Runde D, Kaji AH, Walls RM, Brown CA 3rd. Etomidate Use Is Associated With Less Hypotension Than Ketamine for Emergency Department Sepsis Intubations: A NEAR Cohort Study. Acad Emerg Med. 2020 Nov;27(11):1140-1149. doi: 10.1111/acem.14070. Epub 2020 Jul 20. PMID: 32602974.
April MD, Arana A, Schauer SG, Davis WT, Oliver JJ, Fantegrossi A, Summers SM, Maddry JK, Walls RM, Brown CA 3rd; NEAR Investigators. Ketamine Versus Etomidate and Peri-intubation Hypotension: A National Emergency Airway Registry Study. Acad Emerg Med. 2020 Nov;27(11):1106-1115. doi: 10.1111/acem.14063. Epub 2020 Jul 18. PMID: 32592205.
Van Berkel MA, Exline MC, Cape KM, Ryder LP, Phillips G, Ali NA, Doepker BA. Increased incidence of clinical hypotension with etomidate compared to ketamine for intubation in septic patients: A propensity matched analysis. J Crit Care. 2017 Apr;38:209-214. doi: 10.1016/j.jcrc.2016.11.009. Epub 2016 Nov 15. PMID: 27974285.