Critical Care, Critical Care Alert

Critical Care Alert: The Benefit of Adding Lidocaine to Ketamine During Rapid Sequence Endotracheal Intubation in Patients with Septic Shock

Critical Care Alert

Fathy S, Hasanin A, Mostafa M, et al. The benefit of adding lidocaine to ketamine during rapid sequence endotracheal intubation in patients with septic shockAnaesth Crit Care Pain Med. 2021;40(1):100731.

To determine if a lidocaine-ketamine combination for RSI maintains hemodynamics better than full-dose ketamine in patients with septic shock

The intubation rate during ICU stays for septic shock patients ranges from 30-83%.1-3 These patients already have unstable hemodynamics, and the process of intubation can further destabilize them. Peri-intubation hypotension is due, in part, to decreased venous return from the positive pressure of ventilation.4 Induction agents can worsen peri-intubation hypotension through direct inhibition of myocardial contractility, effects on pre- and afterload, and alterations in sympathetic or baroreflex activity.5

Ketamine has been a popular choice for RSI in sepsis due to its sympathomimetic effects via inhibition of catecholamine reuptake.6 In vitro and animal studies have suggested, however, that ketamine can also act as a negative inotrope, especially in failing hearts7,8 by decreasing intracellular calcium availability.5,9,10  Theoretically, negative inotropy could outweigh Ketamine's sympathomimetic effect in sepsis, where catecholamine stores are depleted. Another popular RSI choice, etomidate, is thought to induce adrenal insufficiency, which may negatively impact severely ill septic patients.11 Ketamine has been historically favored in septic patients,12 though recent registry data suggests this choice may warrant further, thorough investigation.13,14

Some suggest that lower doses of ketamine could be used in septic shock to avoid theoretic negative inotropy.14 Lidocaine induces anesthesia15 and has a known sparing effect when combined with other induction agents.16,17 Considering the complicated pathophysiology of sepsis, the answer to maintaining hemodynamics during induction may not be as simple as a single agent.

Randomized, double-blinded, controlled study conducted in Cairo University Hospital between February and September 2019 with 2 RSI groups:

  • 0 mg/kg ketamine + 0.05 mg/kg midazolam    + 0.1 mg/kg saline (n=22)
  • 5 mg/kg ketamine + 0.05 mg/kg midazolam    + 1 mg/kg lidocaine (n=21)

Both groups were paralyzed with 1 mg/kg succinylcholine and received anesthesia maintenance with isoflurane 1% and 0.5 mg/kg atracurium.

Inclusion criteria

  • 18-65 years of age
  • Received treatment per surviving sepsis guidelines
  • Initial 30 mL/kg crystalloid therapy
  • IV antibiotics within first hour of hospital admission
  • All patients received hydrocortisone 100 mg
  • Septic shock according to sepsis 3 recommendations
  • Elevated serum lactate level (above 2 mmol/L)
  • Norepinephrine titrated to maintain MAP > 65 mmHg
  • Requiring emergency surgical intervention for source control

Exclusion criteria

  • Cardiac arrhythmias
  • Head trauma
  • Burns or skin lesions that impaired application of EKG electrodes

Primary outcome

  • Average MAP by invasive blood pressure monitoring during the first 5 min after induction of anesthesia, with readings obtained at baseline and 1-minute intervals.

Secondary outcomes

  • Frequency of post-induction hypotension
  • Hypotension: a reduction of MAP > 20% or requirement of increasing vasopressors by 20% from baseline
  • Heart rate and cardiac output
  • Central venous blood gas values
  • Serum lactate

Primary outcome

  • The average MAP reading in the first 5 min post-induction was higher in the ketamine-lidocaine group, 82.8 (±6) mmHg vs 73 (±10.2) mmHg, respectively (p < 0.001).

Selected secondary outcomes

  • Post induction hypotension was significantly lower in the ketamine-lidocaine group (5%) compared to the ketamine group (77%), (p < 0.001)
  • Total norEpi requirements per kg were not significantly different (all patients were on norepinephrinefor sepsis and all were on hydrocortisone already)
  • Central venous oxygen saturation (ScvO2), HCO3, lactate, and pH at baseline and at 20 min were not significantly different


  • Randomized, double-blinded control study


  • Small sample size of 44 patients
  • Generalizability of these results is limited:
    • Patients older than 65 excluded – the mean age of sepsis is 64 years18
    • Took place at a single center
    • Only patients in need of emergent surgery for source control were included
  • Depth of anesthesia was not monitored (inability to respond to a simple verbal order was the endpoint of hypnosis)
    • In the ketamine-lidocaine group, 19% of patients required an additional bolus (0.25 mg/kg) of Ketamine
  • Potential pharmacokinetic interactions between Ketamine, Lidocaine, and Versed (given to both groups) cannot be excluded
  • Confounding factors:
    • Maintenance of anesthesia was achieved with isoflurane 1%. Authors did not report when maintenance was initiated; given that ketamine’s effects last 5-15 minutes, presumably it was initiated sometime while outcomes were still being recorded. Isoflurane also induces hypotension.19

Intubating patients with septic shock in the ED should be done with the utmost care and with a clear plan. Peri-intubation hypotension is associated with adverse events, including death.13 The choice of agents for RSI in shock may be limited by potential adrenal-suppressant effects of etomidate and potential negative-inotropic effects of ketamine. Animal and in vitro studies suggest ketamine-induced myocardial depression may be dose-dependent.5 Lower doses (0.5-1 mg/kg) of ketamine for RSI in shock patients should be used to minimize hemodynamic compromise.12

In this early study, which again has a small sample size with limited generalizability, authors demonstrate that Lidocaine may have a ketamine-sparing effect in patients with septic shock. They show that under certain conditions, using lower-dose ketamine with lidocaine induces less hypotension after RSI than using higher-dose ketamine alone.

These findings should not be misinterpreted as representing the standard of care, but they do add to a growing body of literature regarding the ideal induction agent.

Discussion regarding the best choice of sedative agent to avoid hypotension is ongoing. In 2020, two studies that analyzed the National Emergency Airway Registry (NEAR) suggested that peri-intubation hypotension in patients receiving ketamine may be higher than in those receiving etomidate. You can find the original articles here and here, and you can find a frank discussion of study limitations on Critical Care Now. This review from Life in the Fast Lane  includes some valuable resources as well.


  1. Investigators P. Early, goal-directed therapy for septic shock—a patient-level meta-analysis. N Engl J Med. 2017;376(23):2223-34.
  2. Quenot J-P, Binquet C, Kara F, et al. The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study. Crit Care. 2013;17(2):R65.
  3. Darreau C, Martino F, Saint-Martin M, et al. Use, timing and factors associated with tracheal intubation in septic shock: a prospective multicentric observational study. Ann Intensive Care. 2020;10(1):62.
  4. Smischney NJ, Demirci O, Diedrich DA, et al. Incidence of and risk factors for post-intubation hypotension in the critically ill. Med Sci Monit. 2016;22:346-355.
  5. Gelissen HP, Epema AH, Henning RH, Krijnen HJ, Hennis PJ, Den Hertog A. Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle. Anesthesiology. 1996;84(2):397-403.
  6. Johnstone M. The cardiovascular effects of ketamine in man. Anaesthesia. 1976;31(7):873-882.
  7. Pagel PS, Kampine JP, Schmeling WT, Warltier DC. Ketamine depresses myocardial contractility as evaluated by the preload recruitable stroke work relationship in chronically instrumented dogs with autonomic nervous system blockade. Anesthesiology. 1992;76(4):564-572.
  8. Sprung J, Schuetz SM, Stewart RW, Moravec CS. Effects of ketamine on the contractility of failing and nonfailing human heart muscles in vitro. Anesthesiology. 1998;88(5):1202-1210.
  9. Weiskopf RB, Bogetz MS, Roizen MF, Reid IA. Cardiovascular and metabolic sequelae of inducing anesthesia with ketamine or thiopental in hypovolemic swine. Anesthesiology. 1984;60(3):214-219.
  10. Kongsayreepong S, Cook DJ, Housmans PR. Mechanism of the direct, negative inotropic effect of ketamine in isolated ferret and frog ventricular myocardium. Anesthesiology. 1993;79(2):313-322.
  11. Albert SG, Sitaula S. Etomidate, Adrenal Insufficiency and Mortality Associated With Severity of Illness: A Meta-Analysis. J Intensive Care Med. 2020:0885066620957596.
  12. 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;38:209-214.
  13. Miller M, Kruit N, Heldreich C, et al. Hemodynamic response after rapid sequence induction with ketamine in out-of-hospital patients at risk of shock as defined by the shock index. Ann Emerg Med. 2016;68(2):181-188. e2.
  14. Kim JM, Shin TG, Hwang SY, et al. Sedative dose and patient variable impacts on postintubation hypotension in emergency airway management. Am J Emerg Med. 2019;37(7):1248-1253.
  15. Gaughen CM, Durieux M. The effect of too much intravenous lidocaine on bispectral index. Anesth Analg. 2006;103(6):1464-1465.
  16. Ben-Shlomo I, Tverskoy M, Fleyshman G, Cherniavsky G. Hypnotic effect of iv propofol is enhanced by im administration of either lignocaine or bupivacaine. Br J Anaesth. 1997;78(4):375-377.
  17. Tverskoy M, Ben-Shlomo I, Vainshtein M, Zohar S, Fleyshman G. Hypnotic effect of iv thiopentone is enhanced by im administration of either lignocaine or bupivacaine. Br J Anaesth. 1997;79(6):798-800.
  18. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med. 2001;29(7):1303-1310.
  19. Torri G. Inhalation anesthetics: a review. Minerva Anestesiol. 2010;76(3):215-228.

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