Deep sedation with ketamine benefits COVID-19 ARDS patients requiring intubation

In patients with the coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome (ARDS) who require mechanical ventilation and deep sedation, the use of ketamine has a propofol- and vasopressor-sparing effect, as shown in a study.

Among 59 intensive care unit (ICU) patients on mechanical ventilation needing sedation, the introduction of a ketamine infusion led to a significant reduction in median propofol dose, from 54.7 mg/kg in the initial 24 hours after infusion to 34.2 mg/kg at 72 hours (p=0.003). [Respir Med 2021;doi:10.1016/j.rmed.2021.106667]

There was also a marked decline in the dose of norepinephrine equivalents, from a median of 62.8 mcg/kg at 24 hours to 38 mcg/kg at 48 hours (p=0.028), with a nonsignificant reduction at 72 hours.

The propofol-sparing effects of ketamine in deep sedation in the present study are consistent with those described in other studies targeting light sedation. This may have important clinical implications, according to the investigators, because infusions of propofol at high doses and for a prolonged duration can lead to a host of complications, such as treatment-related infusion syndrome, hypertriglyceridaemia, and pancreatitis. [Pharmacotherapy 2019;39:288-296; Minerva Anestesiol 2009;75:339-344; Curr Pharm Des 2004;10:3639-3649]

With regards to opioids, the current study showed no changes in median fentanyl requirements, although there was an increase in median hydromorphone doses.

“We had a high obesity population in our cohort, which may have contributed to higher requirements of opioids and attenuated the impact of ketamine. Of note, our institution favoured hydromorphone infusions over fentanyl due in part to drug supply shortages during the time period this cohort of patients was studied,” the investigators explained.

Sedation and analgesia in ICU

Both sedation and analgesia drive multiple clinical outcomes in the ICU, especially when it involves the care of patients requiring mechanical ventilation. Patients achieving adequate analgesia prior to sedation are more likely to spend reduced time on mechanical ventilation, and this is typically facilitated by opioids. [Crit Care Med 2013;41:263-306; Ann Pharmacother 2012;46:530-540; Crit Care 2005;9:R200-R210; Anesth Analg 2016;123:903-909]

“Although opioids are effective analgesics, their use has been associated with respiratory depression and constipation which can have detrimental effects on ventilator liberation,” the investigators noted.

On the other hand, nonbenzodiazepine drugs, such as propofol and dexmedetomidine, as well as adjunctive benzodiazepines are commonly used for sedation. However, nonbenzodiazepine drugs may exert less-than-favourable effects on haemodynamic parameters, such as hypotension and bradycardia. Furthermore, benzodiazepines have the potential to up the risk of delirium, which in turn can lead to prolonged mechanical ventilation, ICU length of stay, and increased mortality. [Crit Care Med 2009;37:177-183; Chest 2017;152:867-879; Crit Care Clin 2017;33:225-243]

Ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist, is often utilized as a sedative and nonopioid analgesic outside the ICU because its use is not associated with respiratory depression and maintains upper airway reflexes. [J Intensive Care Med 2017;32:387-395]

Compared with other commonly utilized sedatives in the ICU, ketamine does not cause hypotension or bradycardia and can be used as an adjunct agent in patients with severe bronchospasm since it induces smooth muscle relaxation of the lower airways, the investigators said. “These effects, coupled with its abilities to provide sedation, analgesia, and amnesia, support ketamine’s use as an adjunctive sedative for mechanically ventilated ICU patients. [Pharmacotherapy 2017;37:1537-1544; Indian J Crit Care Med 2013;17:154-161]

“To our knowledge this is the only published study looking at the impact of ketamine on other sedative, analgesic, paralytic and vasopressor infusions in patients requiring sedation for ARDS… Further prospective studies are needed to assess the efficacy and clinical benefits of ketamine as a sedative in mechanically ventilated ARDS patients,” they said.