Introduction
More than 40 years ago during the Vietnam War, ketamine, a nonbarbiturate phencyclidine derivative, was considered an ideal “battlefield anesthetic” because it does not alter hemodynamics and has sedative, hypnotic, analgesic, and amnestic properties. Its popularity waned, however, because of an undesirable side effect profile: hallucinations, delirium, lacrimation, tachycardia, and the potential for an increase in intracranial pressure (ICP) and coronary ischemia. Recent reports suggest that with lower doses, ketamine may not be associated with untoward effects and may reduce perioperative pain, prevent opioid-induced hyperalgesia, decrease inflammation, reduce bronchoconstriction, and improve the quality of life in a palliative care setting.
Ketamine binds with the N-methyl-D-aspartate (NMDA) and sigma opioid receptors to produce intense analgesia and a state of “dissociated anesthesia” in which the patient appears calm, does not react to pain, and maintains airway reflexes. Ketamine also interacts with nicotinic and muscarinic acetylcholine receptors, reduces neuronal sodium permeability, and blocks L-type Ca 2+ channels in the muscle and myocardium. Ketamine possesses a chiral center and exists commonly as a mixture of S(+) and R(−) stereoisomers. S(+) ketamine has greater analgesic potency and a shorter duration of action compared with R(−) ketamine because it has a fourfold greater affinity for the NMDA receptor. The liver metabolizes ketamine (via the cytochrome CYP3A4 and CYP2B6 pathways) into norketamine, a weaker active metabolite that is excreted in the urine.
Options/Therapies
Intravenous (IV) (patient-controlled analgesia [PCA]), intramuscular, sublingual, rectal, and epidural administration of ketamine achieves effective plasma levels. Ketamine is not currently approved for intrathecal administration because of the potential neural toxicity.
General Anesthesia
Ketamine crosses the blood–brain barrier rapidly and reaches maximal effect in 1 minute. A single dose of ketamine (2 mg/kg IV) lasts 10 to 15 minutes and the half-life elimination is 2.5 to 3 hours. Ketamine is used in clinical anesthesia as an induction agent to preserve hemodynamic stability, as an adjunctive anesthetic to spare opioid use, and as a sole anesthetic for painful procedures such as dressing changes.
Intensive Care
Concerns about ketamine’s psychotropic effects have limited its use as a sedative-analgesic in the intensive care unit (ICU). Ketamine’s potential advantages include preserved heart rate and blood pressure for patients with poor cardiopulmonary reserve, antagonism of the NMDA receptor in patients experiencing short-term and repetitive pain (e.g., suctioning and turning), decreased opioid consumption, and bronchodilation for patients with status asthmaticus.
Palliative Care
Ketamine has been used as an analgesic and as an antidepressant in the palliative care setting. Reports of “burst doses” of ketamine to relieve symptoms have been published. Despite ketamine’s potential to relieve refractory cancer and neuropathic pain, a systematic review found insufficient evidence to evaluate ketamine’s effectiveness as an adjuvant to opioid treatment in cancer pain.
Organ and Physiologic Responses to Ketamine
Cardiovascular Response
Ketamine acts on the heart via sympathetic-mediated stimulation and inhibition of catecholamine uptake. At clinical concentrations, ketamine has a positive inotropic action and induces vasoconstriction, probably by inhibiting endothelial nitric oxide production, which preserves hemodynamic stability even in septic shock. Ketamine may act as a myocardial depressant in patients who are catecholamine depleted. Its sympathetic activity can be attenuated by concomitant administration of benzodiazepines or alpha-2 agonists. Ketamine has been proposed as an antiarrhythmic agent and an antiinflammatory agent because it inactivates neutrophils and suppresses cytokines.
Respiratory Response
Ketamine causes clinically significant bronchodilation. Potential mechanisms include preventing reuptake of circulating catecholamines to stimulate the beta-2-adrenergic receptor, relaxation of bronchial smooth muscle via vagolysis and reduction of calcium influx, and direct antagonism of histamine. In contrast to other general anesthetics, ketamine preserves functional residual capacity, minute ventilation, and tidal volume and enhances thoracic compliance.
Neurologic Response
Ketamine increases cerebral metabolism and blood flow in patients breathing spontaneously. In patients whose lungs are mechanically ventilated, it preserves cerebral perfusion pressure without increasing intracranial pressure. Ketamine enhances cortical somatosensory evoked potentials and maintains or increases bispectral index values. The potential for neuroprotection against ischemic damage with ketamine is intriguing. During neuronal injury, the NMDA receptor is activated to release Ca 2+ and glutamate by ischemic neurons, which initiate cell necrosis and apoptosis. Blockade of NMDA receptors may be therapeutic. Abolition of dysarthria and tremor in patients with Parkinson disease has been observed. Animal studies suggest that ketamine may cause neuronal cell death in newborns.
Pain Response
Ketamine decreases acute and chronic pain via the NMDA and opioid receptors. Major surgery, burns, trauma, and painful procedures in the ICU can induce prolonged noxious stimuli. Noxious stimuli cause central sensitization and lead to allodynia (a painful response to an innocuous stimulus), hyperalgesia (an exaggerated response to a painful stimulus), and eventually chronic pain syndromes. Administering short-acting opioids can result in early opioid tolerance and hyperalgesia. Ketamine antagonizes the NMDA receptor to block these responses, reducing windup pain and central hyperexcitability. In both animal and human models, subanesthetic ketamine doses prevented these effects from alfentanil, remifentanil, and fentanyl. Ketamine has the potential to decrease opioid requirements and tolerance and to prevent chronic pain.
Gastrointestinal Response
Ketamine inhibits reuptake of serotonin and may activate the chemoreceptor trigger zone to cause nausea and vomiting. Prolonged infusions of opioids such as fentanyl and morphine inhibit bowel function and promote constipation or even prolonged ileus. Ketamine does not inhibit bowel mobility and may reduce the feeding complications associated with opioids.
Evidence
Opioid Sparing
Table 33-1 summarizes randomized controlled trials of adults receiving IV perioperative ketamine. Table 33-2 summarizes meta-analyses of perioperative ketamine use. Recent reviews suggest that ketamine spares opioid use in the perioperative period at subanesthetic doses. In a meta-analysis of studies of more than 2000 patients randomly assigned to perioperative ketamine, subanesthetic ketamine administration reduced rescue analgesic requirements, pain intensity, and 24-hour PCA morphine consumption. Similar findings were reported in a review of randomized trials of ketamine in surgical patients. In a meta-analysis of studies of IV ketamine, opioid-sparing effects were greater in procedures associated with high postoperative pain scores (e.g., upper abdominal, orthopedic, and thoracic surgery). Ketamine’s opioid-sparing effect may not be uniform because different operations produce different stimuli for sensitization.
| Author | Procedure | Size | Design | Intervention | Outcome |
|---|---|---|---|---|---|
| Roytblat et al (1993) | Abdominal | N = 22 | RDBPCT | Preincision ketamine versus placebo | Reduction of opioid consumption and first 5-hr pain score |
| Stubhaug et al (1997) | Abdominal | N = 20 | RDBPCT | Preincision + intraoperative versus placebo | Increased global satisfaction; no difference in opioid consumption or pain scores except in first few postoperative hours |
| Mathisen et al (1999) | Abdominal (laparoscopic) | N = 60 | RDBPCT | Preincision versus postoperative versus placebo | Reduction of pain score in postoperative group only; no difference in opioid consumption |
| Suzuki et al (1999) | Ambulatory | N = 140 | RPCT | Intraoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Adriaenssens et al (1999) | Abdominal | N = 30 | RDBPCT | Postoperative ketamine versus placebo | Reduction of opioid consumption; no difference in pain score |
| Heinke and Grimm (1999) | Gynecologic | N = 39 | RPCT | Preincision + intraoperative + postoperative ketamine versus placebo | No difference in total opioid consumption or pain scores |
| Menigaux et al (2000) | Orthopedic | N = 45 | RDBPCT | Preincision versus postoperative ketamine versus placebo | Reduction of opioid consumption over control; no difference between preoperative or postoperative |
| Dahl et al (2000) | Gynecologic | N = 89 | RDBPCT | Preincision versus postincision ketamine versus placebo | Reduction of opioid consumption and pain score in postincision group only |
| Menigaux et al (2001) | Orthopedic (laparoscopic) | N = 50 | RDBPCT | Preincision ketamine versus placebo | Reduction of analgesic consumption and pain scores |
| Papaziogas et al (2001) | Abdominal (laparoscopic) | N = 55 | RDBPCT | Preincision ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Lehmann et al (2001) | Urologic (laparoscopic) | N = 80 | RDBPCT | Preincision ketamine versus placebo | No difference in total opioid consumption or pain scores |
| Guignard et al (2002) | Abdominal | N = 50 | RDBPCT | Preincision + intraoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Gilabert Morell and Sanchez Perez (2002) | Gynecologic | N = 69 | RDBPCT | Preincision versus postoperative ketamine versus placebo | No difference in total opioid consumption or pain scores |
| Jaksch et al (2002) | Orthopedic | N = 30 | RDBPCT | Preincision + intraoperative ketamine versus placebo | No difference in total opioid consumption or pains scores |
| Guillou et al (2003) | Abdominal | N = 101 | RDBPCT | Preincision + intraoperative + postoperative ketamine versus placebo | Reduction of opioid consumption; no difference in pain scores |
| Van Elstraete et al (2004) | Tonsillectomy | N = 40 | RDBPCT | Preincision + intraoperative ketamine versus placebo | No difference in total opioid consumption or pain scores |
| Kwok et al (2004) | Gynecologic (laparoscopic) | N = 135 | RDBPCT | Preincision versus postoperative ketamine versus placebo | Reduction of opioid with preincision; no difference with postoperative |
| Lahtinen et al (2004) | Cardiac | N = 90 | RDBPCT | Preincision + intraoperative + postoperative ketamine versus placebo | Reduction of opioid consumption; no difference with pain scores |
| Katz et al (2004) | Urologic | N = 143 | RDBPCT | Preincision + intraoperative ketamine versus intraoperative versus placebo | No difference in total opioid consumption or pain scores |
| Kafali et al (2004) | Abdominal | N = 60 | RPCT | Preincision ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Kapfer et al (2005) | Abdominal | N = 77 | RDBPCT | Postoperative ketamine versus placebo | Reduction of opioid consumption |
| Ganne et al (2005) | ENT | N = 31 | RDBPCT | Preincision + intraoperative ketamine versus placebo | No difference in total opioid consumption or pain scores |
| Karaman et al (2006) | Gynecologic | N = 60 | RPCT | Preincision ketamine versus placebo | No difference in total opioid consumption or pain scores |
| Pirim et al (2006) | Gynecologic | N = 45 | RPCT | Postoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Lebrun et al (2006) | Oral | N = 84 | RPCT | Preincision versus postoperative ketamine versus placebo | No difference in total opioid consumption or pain scores |
| Gillies et al (2007) | Mixed | N = 41 | RDBPCT | Postoperative ketamine versus opioid | No difference in total opioid consumption or pain scores |
| McKay and Donais (2007) | Abdominal | N = 42 | RDBPCT | Postoperative ketamine versus placebo | No difference in total opioid consumption or pain scores; more hallucinations |
| Yamauchi et al (2008) | Spine | N = 202 | RPCT | Preincision + intraoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Engelhardt et al (2008) | Spine (pediatric) | N = 34 | RPCT | Preincision + intraoperative ketamine versus placebo | No difference in total opioid consumption or pain scores |
| Aveline et al (2009) | Orthopedic | N = 75 | RDBPCT | Preincision + intraoperative + postoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Remerand et al (2009) | Orthopedic | N = 150 | RDBPCT | Preincision + intraoperative + postoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Sen et al (2009) | Gynecologic | N = 60 | RDBPCT | Preincision + intraoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Deng et al (2009) | Orthopedic | N = 200 | RDBPCT | Intraoperative + postoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Dullenkopf et al (2009) | Mixed | N = 120 | RDBPCT | Preincision ketamine versus placebo | No difference in total opioid consumption or pain scores |
| Reza et al (2010) | Gynecologic | N = 60 | RDBPCT | Preincision ketamine versus placebo | Reduction of opioid consumption only 0-2 hr postoperatively; no differences thereafter |
| Lak et al (2010) | Abdominal | N = 50 | RDBPCT | Postoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Hadi et al (2010) | Spine | N = 30 | RDBCT | Intraoperative ketamine versus standard | Reduction of opioid consumption and time to first analgesic |
| Loftus et al (2010) | Spine | N = 102 | RDBPCT | Preincision + intraoperative ketamine versus placebo | Reduction of opioid consumption and pain scores |
| Author | Subjects | Intervention | Outcome |
|---|---|---|---|
| Elia and Tramer (2005) | Ketamine versus no ketamine (n = 2721) in adult and pediatric population | Perioperative ketamine (bolus/infusion/epidural/caudal/PCA) versus conventional analgesic | Reduction of total opioid consumption and decreased pain scores |
| Bell et al (2006) | Ketamine versus placebo (n = 2240) in adult population | Intraoperative ketamine (bolus or infusion or epidural) versus placebo or conventional analgesic | Reduction of total opioid consumption and decreased pain scores |
| Bell et al (2006) | Ketamine + opioid versus opioid only (n = 432) in adult population | Postoperative PCA with ketamine + opioid versus PCA with opioid | Reduction in opioid consumption in first 24 hr |
| Carstensen and Moller (2010) | Ketamine + opioid versus opioid only (n = 887) in adult population | Postoperative PCA with ketamine + opioid versus PCA with opioid | No clear advantage of ketamine over opioid PCA except in thoracic surgery |
| Laskowski et al (2011) | Ketamine versus placebo (n = 4701) in adult population | Intraoperative ketamine (bolus or infusion) versus placebo | Reduction in total opioid consumption and increased time to first opioid |
| Dahmani et al (2011) | Ketamine versus no ketamine (n = 985) in pediatric population | Ketamine (systemic, local, and caudal) versus conventional analgesic | Decreased PACU pain scores and nonopioid analgesic, no opioid-sparing effect |
| Schnabel et al (2011) | Ketamine + local versus local only (n = 584) in pediatric population | Intraoperative ketamine (caudal) + local versus local (caudal) | Reduction in rescue analgesic and increased time to first analgesic |
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