Ketamine

Observational studies

The addition of ketamine to propofol is thought to counteract the cardiorespiratory depression that occurs when propofol is used alone, whereas propofol is thought to reduce the psychometric and emetic effects of ketamine. In a prospective case series of 114 patients of all ages, a mixture of propofol 10 mg/ml + ketamine 10 mg/ml (“ketofol”) was used for procedural sedation in an emergency department [ ]. There was no standardization of the preprocedural analgesia used, and a large proportion (42/114) received intravenous or oral opioids. Only three patients required additional propofol to complete the procedure. Eight had minor adverse events, including three airway malalignments requiring manipulation, two emergence reactions, and one case of self-limiting atrial fibrillation. Four had major adverse events, including three patients with apnea and/or hypoxia requiring airway adjuncts and 100% oxygen, one of whom was acutely intoxicated and one had received narcotics.

Comparative studies

The addition of ketamine to bupivacaine for spinal anesthesia has been studied in 60 patients undergoing spinal anesthesia for insertion of intracavitary brachytherapy implants for cervical carcinoma [ ]. They were randomly assigned to receive either bupivacaine 10 mg or bupivacaine 7.5 mg plus ketamine 25 mg. Motor recovery was significantly quicker in the ketamine group. Blood pressure was significantly lower in the bupivacaine group 5 minutes after administration, and perioperative intravenous fluid requirements were significantly higher. Patients given ketamine reported more sedation and dizziness, both intraoperatively and postoperatively. There were no nightmares or dissociative features. Overall satisfaction was better with bupivacaine. The study was abandoned after 30 patients, because of the high rate of adverse with ketamine. Although ketamine had local anesthetic-sparing properties, adverse reactions made it unsuitable for intrathecal administration.

When added to standard doses of morphine and a non-steroidal analgesic, S-ketamine 0.5 mg/kg had no additional benefit in a randomized, double-blind study in 30 patients undergoing anterior cruciate ligament repair [ ].

The effects of midazolam on ketamine-induced emergence reactions have been investigated in 100 children undergoing adenotonsillectomy [ ]. All were given intramuscular ketamine 7 mg/kg and atropine 0.015 mg/kg and half were given midazolam 0.1 mg/kg. There were no severe adverse events in either group. In the immediate postoperative period, mild reactions were similar, but moderate reactions were less common in those who received midazolam (3.6% versus 25%). On day 1, mild reactions were frequent in both groups. On day 2, 71% of the children who received ketamine without midazolam had mild reactions, whereas 75% of those who received midazolam group had no emergence reactions. The incidence of immediate postoperative nausea and vomiting (at 0–4 hours) was significantly reduced by midazolam, but this was reversed in the period up to 24 hours, when those who received midazolam had a higher incidence of vomiting. This may have been attributable to the relative half-lives of the drugs.

Placebo-controlled studies

The effect of low-dose intravenous ketamine in combination with continuous femoral nerve block on postoperative pain and rehabilitation after total knee arthroplasty has been evaluated in a randomized placebo-controlled study [ ]. Those who received ketamine required significantly less morphine. No patients reported sedation, hallucinations, nightmares, or diplopia, and there were no differences in the incidence of nausea and vomiting between the two groups.

Systematic reviews

In a systematic review perioperative subanesthetic doses of ketamine reduced rescue analgesic requirements, pain intensity, or both in 27 of 37 clinical trials (2240 participants) [ , ]. Ketamine reduced both 24-hour PCA morphine consumption and postoperative nausea and vomiting. Adverse reactions were mild or absent.

Cardiovascular

Tachycardia and hypertension are common after anesthetic induction with ketamine, although the hypertension can be limited by the addition of diazepam [ ]. Nodal dysrhythmias can also occur [ ]. Because of possible reduced cardiac and pulmonary performance, ketamine should be avoided in critically ill patients [ ]. Pulmonary vasoconstriction and increased ventricular preload secondary to ketamine can be deleterious [ ].

The effects of intramuscular premedication with either clonidine 2 micrograms/kg or midazolam 70 micrograms/kg on perioperative responses to ketamine anesthesia have been assessed in a placebo-controlled study in 30 patients [ ]. Clonidine significantly reduced intraoperative oxygen consumption, mean arterial pressure, and heart rate compared with midazolam and placebo. Thus, clonidine was as effective as midazolam, the standard drug used for this purpose, in reducing the undesirable sympathetic stimulation of ketamine.

Oral clonidine, 2.5 or 5.0 micrograms/kg, 90 minutes before ketamine 2 mg/kg has been compared with placebo in 39 patients [ ]. In those given clonidine 2.5 micrograms/kg, heart rate responses were reduced compared with placebo (maximum heart rate 97 versus 76 beats/minute). In those given clonidine 5 micrograms/kg, heart rate responses were less (maximum heart rate 97 versus 77 beats/minute) and mean arterial pressure was lower (121 versus 141 mmHg), and there were fewer nightmares and less drooling.

Angina pectoris has been reported with subanesthetic low-dose ketamine.

• Subcutaneous low-dose ketamine precipitated angina in an elderly man with metastatic bladder cancer and venous gangrene of a leg, in whom antianginal medication had been withdrawn [ ].

Respiratory

Apnea occurred after the intramuscular injection of ketamine 4 mg/kg to sedate a healthy 4-year-old boy [ ]. This case illustrates the need for adequate monitoring and preparation for emergency airway management when using ketamine for sedation.

Prolonged apnea has been reported after the use of ketamine [ ].

• An 11-month-old, 7 kg full-term girl was given intramuscular ketamine 35 mg and glycopyrrolate 0.05 mg before elective plastic surgery. She started to have ineffective respirations, followed by apnea requiring intubation. There was no laryngospasm or excessive secretions. Spontaneous respiration resumed after 90 minutes. There were no complications.

Respiratory depression has been noted before with high doses of intramuscular ketamine (10 mg/kg), or when it is co-administered with other sedatives, or in neonates with electrolyte abnormalities. However, it is unusual with a low dose in an otherwise healthy subject.