According to the 2018 Society of Critical Care Medicine (SCCM) Clinical Practice Guidelines for the Management of Pain, Agitation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU, opioids remain a mainstay of pain management in critically ill adults; however, concerns regarding opioid-associated adverse effects, including sedation, delirium, respiratory depression, ileus, and immunosuppression, have led to evaluation of multimodal analgesic strategies incorporating nonopioid agents such as ketamine. The guideline panel generally supported multimodal pharmacotherapy as part of an analgesia-first approach to reduce opioid and sedative exposure. For ketamine specifically, the guideline issued a conditional recommendation based on very low-quality evidence suggesting the use of low-dose ketamine (0.5 mg/kg IV push followed by a continuous infusion of 1-2 mcg/kg/min) as an adjunct to opioid therapy when seeking to reduce opioid consumption in postsurgical adults admitted to the ICU. This recommendation was primarily based on a single-center randomized controlled trial of 93 postoperative abdominal surgery ICU patients in which adjunctive ketamine was associated with reduced morphine consumption compared with opioids alone, while patient-reported pain scores and the incidence of adverse effects, including delirium, hallucinations, hypoventilation, pruritus, nausea, and sedation, were similar between groups. [1]
According to a 2017 policy statement from the American College of Emergency Physicians (ACEP), sub-dissociative dose ketamine (SDK), also referred to as low-dose ketamine (LDK), is a safe and effective analgesic option for use in the emergency department and may be used alone or as part of a multimodal pain management strategy for both traumatic and non-traumatic pain. At analgesic doses, ketamine functions as an opioid-sparing agent and has demonstrated analgesic efficacy comparable to morphine, with evidence suggesting improved pain control in some settings, reduced opioid requirements, and less need for repeat opioid dosing. Additional advantages compared with opioids include minimal respiratory depression, preservation of hemodynamic stability and cardiac output, and utility in patients with opioid tolerance, contraindications to opioids, or hypotension related to trauma or sepsis. Recommended intravenous dosing is 0.1 to 0.3 mg/kg administered over approximately 15 minutes. ACEP notes that SDK has an excellent safety profile and generally does not require monitoring or administration procedures beyond those used for other standard parenteral analgesics. Patients should be counseled regarding the possibility of transient adverse effects, most commonly nausea, dizziness, and mild dysphoria, which are typically brief and may occur less frequently when ketamine is administered as a short infusion rather than a rapid bolus; emergence reactions are uncommon at analgesic dosing ranges, and available evidence does not support avoiding low-dose ketamine solely because of underlying psychiatric illness. Overall, ACEP considers SDK a safe, effective, and practical alternative to opioid therapy for acute pain management in the emergency department. [2], [3], [4]
According to the 2024 Veterans Health Administration (VHA) National Protocol Guidance for Ketamine for the Management of Acute Pain in Emergency Departments and Urgent Care Centers, ketamine may be used for acute pain or intractable pain when conventional treatments have failed or when ketamine is determined to be a more suitable agent. Sub-dissociative ketamine may be used as a safe and effective alternative or adjunct to opioids and does not produce many of the potentially adverse respiratory or hemodynamic effects associated with other analgesics. Ketamine has been studied in opioid-tolerant patients, as an adjunct to opioid therapy for acute pain, and may be advantageous in patients receiving partial opioid agonist or antagonist therapy who have acute tissue-trauma pain. The protocol allows repeat dosing or initiation of a continuous infusion of 0.15 to 0.2 mg/kg/hour for ongoing pain management. The guidance specifically addresses ketamine for acute pain management in the ED/UCC and excludes use for deep sedation, rapid sequence intubation, airway management, and mechanically ventilated patients. [5]
According to the 2018 consensus guidelines from the American Society of Regional Anesthesia and Pain Medicine (ASRA), American Academy of Pain Medicine (AAPM), and American Society of Anesthesiologists (ASA), ketamine infusions have become a mainstay of treatment in emergency departments, in the perioperative period in individuals with refractory pain, and in opioid-tolerant patients. Evidence supports the use of ketamine for acute pain as a stand-alone treatment or as an adjunct to opioids. The guidelines recommend that subanesthetic ketamine infusions should be considered for patients undergoing painful surgery (Grade B recommendation, moderate certainty) and may be considered for opioid-dependent or opioid-tolerant patients undergoing surgery (Grade B recommendation, low certainty), opioid-dependent or opioid-tolerant patients with sickle cell pain (Grade C recommendation, low certainty), and patients with obstructive sleep apnea as an adjunct to limit opioid use (Grade C recommendation, low certainty). Additionally, the guidelines note that ketamine has demonstrated opioid-sparing effects, including reduced opioid consumption in mechanically ventilated surgical ICU patients receiving opioid infusions; however, the supporting evidence is limited. [6]
In a 2022 meta-analysis examining the impact of ketamine on analgosedative consumption in critically ill patients, investigators synthesized evidence comparing continuous infusion ketamine-based regimens with non-ketamine analgosedation strategies in ICU populations. The analysis included 19 studies in total (13 randomized controlled trials, 5 retrospective studies, and 1 prospective cohort study), encompassing 2,255 participants, with primary focus on daily opioid and sedative requirements. Across six randomized controlled trials included in the primary quantitative analysis (n= 494), ketamine-based regimens were associated with a significant reduction in opioid consumption, with a mean difference of -13.19 mcg/kg/hour morphine equivalents (95% confidence interval [CI] -22.10 to -4.28, p= 0.004). However, there was no significant difference observed in sedative requirements, duration of mechanical ventilation, ICU or hospital length of stay, intracranial pressure, or mortality between groups. Overall, the findings suggest that ketamine may serve as a useful adjunct in ICU analgosedation protocols primarily by reducing opioid exposure, particularly in postoperative and mechanically ventilated patients. However, the absence of consistent effects on broader clinical outcomes and the limited size of available trials highlight the need for further large, well-designed randomized controlled studies before routine adoption in select ICU populations. [7]
In the context of critically ill patients, several review articles discuss the use of ketamine across a broad range of intensive care unit (ICU) applications. The literature describes potential roles for ketamine as an opioid-sparing analgesic, an adjunctive sedative for mechanically ventilated patients, an induction agent for rapid sequence intubation, and a treatment option in patients with sepsis or septic shock. Additional areas of investigation include sedation following cardiac surgery, management of acute brain injury, super-refractory status epilepticus, acute severe asthma and severe asthma exacerbations, delirium prevention or management, and psychiatric conditions such as anxiety, depression, and post-traumatic stress disorder. These diverse applications stem from ketamine’s distinctive pharmacologic profile, which combines analgesic, sedative, dissociative, bronchodilatory, and sympathomimetic properties while generally preserving respiratory drive. Across these indications, ketamine has demonstrated potential benefits including reduced opioid and sedative requirements, maintenance of hemodynamic stability, facilitation of airway management, bronchodilation, anticonvulsant effects, and possible neuropsychiatric benefits. However, the overall quality of evidence remains limited by small sample sizes, heterogeneous patient populations, variable dosing strategies, and a predominance of observational data. Although current evidence suggests that ketamine may be particularly useful in selected critically ill patients, especially those with hemodynamic instability, experts consistently emphasize that its role in many ICU applications remains incompletely defined and that further large, high-quality randomized controlled trials are needed to clarify its efficacy, safety, and optimal use across these clinical settings. [8], [9], [10]
A 2016 review describes subdissociative-dose intravenous ketamine as effective and safe for the treatment of acute pain in the emergency department that may be used either as a single agent or as an adjunct to opioid analgesics. The review notes that ketamine may serve as a feasible alternative to traditional opioids, particularly given opioid-associated adverse effects such as respiratory depression, hypotension, sedation, and potential for abuse. Subdissociative-dose ketamine (0.1–0.4 mg/kg IV) preserves protective airway reflexes, spontaneous respiration, and cardiopulmonary stability and has been shown to provide analgesia while reducing opioid requirements in patients with acute traumatic and nontraumatic pain and in opioid-tolerant patients. The review concluded that ketamine is effective as both an adjunct to opioids (Class A recommendation) and as a single agent for acute pain management in the ED (Class A recommendation) and noted that its use is associated with relatively high rates of minor but short-lived adverse effects. [11]