Effect of perioperative ketamine on postoperative cognition – a randomized placebo-controlled trial

S(+)-ketamine (ketanestTM) is an N-methyl-D-aspartate receptor (NMDAR) antagonist available for various indications including the induction and maintenance of anesthesia (in high dose), perioperative pain relief (in moderate dose) and chronic pain relief (in low dose). At LUMC perioperative ketanest is used as adjuvant during large surgical procedures for treatment of pain and stress (consequently the opioid dose may be reduced) and for reduction of perioperative inflammation. Worldwide the use of ketamine is rapidly increasing taking its beneficial effect on chronic pain and ability to produce a rapid (within hours) onset relief of depression-related symptoms in therapy-resistant depression.

Both surgery and anesthesia have long-term postoperative effects on cognition. Especially in the elderly there are indications that stress from surgery (and hospital admittance) and anesthesia have deleterious effects on postoperative cognitive dysfunction. Moreover, pain and inflammation may contribute to postoperative cognitive deterioration. There are indications that ketamine could improve cognition 1 week following cardiac surgery (Hudetz et al. Ketamine attenuates post-operative cognitive dysfunction after cardiac surgery. Acta Anaesthesiol Scand 2009; 53: 864-72). This was related to the anti-inflammatory effects of ketamine. The current study is aimed at assessing the effect of ketamine exposure during and following anesthesia on cognition in patients undergoing elective non-cardiac surgical procedures. To that end patients will be randomized to receive ketanest or placebo in the peri- and postoperative phase and cognitive tests will be performed at day 1 and ~30 following surgery.

We hypothesize that perioperative ketamine will reduce cognitive decline in postoperative patients, in line with its analgesic and anti-inflammatory properties.

- Pre-operative: blood sample, cognition testing

- Peroperative: blood pressure, heart rate, bispectral index, NoL, sufentanil dose, propofol inhalational anesthesia dose

- Acute postoperative: pain scores, occurrence of nausea/vomiting, lightheadedness/dizziness, drug high, psychomimetic side effects

- 1 day postoperative: blood sample, cognition test, pain scores, occurrence of nausea/vomiting, lightheadedness/dizziness, drug high and other psychomimetic side effects, respir8 monitor assessment in the PACU

- 2 days postoperative: blood sample, occurrence of nausea/vomiting, lightheadedness/dizziness, drug high, psychomimetic side effects

- 30 days postoperative: cognition test, pain scores

The pharmacy will randomize patients to receive placebo (normal saline; placebo group) or ketanest (S(+)-ketamine; Eurocept BV, Ankeveen, NL) according to the LUMC protocol. This protocol states:

1. Initiate administration prior to surgical incision

2. Start with an intravenous bolus administration of 0.35 mg/kg of ketanest followed by 0.4 mg/kg per h.

3. Surgeries > 2 h: Stop infusion 30-min prior to the end of surgery.

4. Continue or restart infusion in the postoperative phase at 0.1 mg/kg per h and continue for 48 h.