Continuous Infusion Ketamine for Adjunctive Analgosedation in Mechanically Ventilated, Critically Ill Patients

Abstract

Objective Ketamine is an N‐methyl‐D‐aspartate antagonist with emerging evidence assessing its use as a continuous infusion agent to provide concomitant analgesia and sedation. The role of ketamine as adjunctive therapy in mechanically ventilated patients is unclear. This study sought to investigate the impact of adjunctive continuous infusion ketamine on concomitant analgesic and sedative dosing while providing goal comfort in mechanically ventilated patients. Methods This retrospective two‐center intrapatient comparison study included mechanically ventilated adult ICU patients who received continuous infusion ketamine with at least one other analgesic or sedative infusion. The primary outcome assessed percent relative change in concomitant analgesic‐sedative doses 24 hours after ketamine initiation. Secondary outcomes included percent of Richmond Agitation and Sedation Score (RASS) assessments at goal, adverse effects, and delirium incidence. Exploratory evaluation of independent factors associated with ketamine responders (50% or more relative reduction in analgesic‐sedative dosing requirements at 24 hrs) and nonresponders (less than 50% relative reduction) was performed using multivariate logistic regression. Results Overall, 104 patients were included. A total of 160 concomitant analgesic‐sedative infusions were used in combination with ketamine, most commonly fentanyl (98 [61.3%]) and propofol (46 [28.8%]). A 20% (interquartile range [IQR] −63.6 to 0.0, p<0.001) relative reduction in total analgesic‐sedative infusion pharmacotherapy was achieved at 24 hours after ketamine initiation. Analgesic and sedative infusion doses decreased at 24 hours (fentanyl: pre, 175 μg/hr [IQR 100–200 μg/hr] vs post, 125 μg/hr [IQR 50–200 μg/hr], p<0.001; propofol: pre, 42.5 μg/kg/min [IQR 20.0–60.0 μg/kg/min] vs post, 20.0 μg/kg/min [IQR 3.8–31.3 μg/kg/min], p<0.001). Median percent time within goal RASS improved after ketamine initiation (pre, 7.1% [0–40%] vs post, 25% [0–66.7%], p=0.005). No differences were observed in secondary outcomes between responders and nonresponders, except a longer non‐ICU hospital length of stay in responders. Independent factors associated with ketamine response included a lower body mass index, higher starting dose of ketamine, lower severity of illness, and need for multiple concomitant analgesic‐sedative infusions before initiation of ketamine. Conclusions Adjunctive continuous infusion ketamine promotes analgesic and sedative dose‐sparing effects in mechanically ventilated patients while improving time spent within goal sedation range. Further prospective research is warranted.

Adjunct low-dose ketamine infusion vs standard of care in mechanically ventilated critically ill patients at a Tertiary Saudi Hospital (ATTAINMENT Trial): study protocol for a randomized, prospective, pilot, feasibility trial

“…The incidence of side effects (i.e., nausea, delirium, hallucination, hypoventilation, pruritus, and sedation) did not differ between the ketamine and opioidalone groups. Based on this generally positive ICU RCT, the 2018 PADIS panel made a conditional recommendation for the use of low-dose ketamine as an adjunct to opioids to optimize acute post-operative pain management in critically ill adults (refer to Supplementary Table 1: Previous ketamine trials in the ICU setting) [2][3][4][5][6][7][8][9][10][11].…”

“…However, most patients in the ICU are sedated with a combination of drugs. Moreover, most trials had a limited focus on patientcentered outcomes, such as duration of MV or ICU LOS, as the primary outcome favoring surrogate outcomes, such as sedation scores and changes in analgesics and sedatives [2][3][4][5][6][7][8][9][10][11]. To help further delineate ketamine's role as a maintenance analgo-sedation agent in the ICU, further RCTs need to be conducted to compare the effects of ketamine to those of other analgesics and sedatives on reducing the duration of MV, ICU LOS, and delirium occurrence.…”

Pain and Delirium in Critical Illness: An Exploration of Key 2018 SCCM PADIS Guideline Evidence Gaps

“…In one cohort study of 104 medical critically-ill adults, the addition of a ketamine infusion (2-8 mcg/kg/min) did not affect fentanyl doing requirements. 30 When low-dose ketamine was added to a sedation protocol for patients with acute lung injury requiring venovenous extracorporeal membrane oxygenation (ECMO) support, opioid requirements remained unchanged. 31 All adjunctive nonopioid analgesics, when used in the context of multimodal analgesia, require larger-sized studies in critically-ill adults, particularly those admitted with a medical condition to evaluate their opioid-sparing properties and their ability to reduce opioid-related side effects.…”

Prevention Strategies to Improve Outcomes in Critically Ill Adults

“…A study used a so-called old drug, Nmethyl-D-aspartate antagonist ketamine, and showed reduced exposure to GABAergic-modulating sedatives. 13 A study 14 challenged the doctrine of using neuromuscular blockers in patients with an open abdomen by showing reduced use of sedatives in patients not receiving pharmacologic paralytics. Future studies will be needed to investigate whether these strategies improve outcomes by preventing harm associated with traditional sedatives.…”

“…Therapeutic strategies leading to less use of GABAergic‐modulating sedatives may also produce positive outcomes. A study used a so‐called old drug, N‐methyl‐ d ‐aspartate antagonist ketamine, and showed reduced exposure to GABAergic‐modulating sedatives . A study challenged the doctrine of using neuromuscular blockers in patients with an open abdomen by showing reduced use of sedatives in patients not receiving pharmacologic paralytics.…”