Plasma cyclic guanosine 3',5'-monophosphate levels: a marker of glutamate-nitric oxide-guanyl cyclase activity?
OBJECTIVE
Remifentanil-based anesthesia can lead to acute opioid tolerance and/or hyperalgesia. A low-dose intraoperative infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine did not result in reduced postoperative morphine consumption after remifentanil-based anesthesia in adolescents. This study investigates the potential role of the glutamate-nitric oxide-cyclic guanosine 3'5'-monophosphate (cyclic GMP) pathway in the failure of low-dose ketamine to prevent remifentanil-induced acute opioid tolerance and/or hyperalgesia.


METHODS
Prospective, double-blind, placebo-controlled randomized clinical trial at a university teaching hospital. PATIENTS, PARTICIPANTS, AND INTERVENTIONS: Thirty-four adolescents receiving remifentanil-based anesthesia for surgical correction of idiopathic scoliosis were randomly assigned to receive either intraoperative ketamine administered as a bolus dose of 0.5 mg/kg in 10 mL of normal saline and a continuous intravenous infusion of 4.0 microg/kg/min or an equal volume of saline.


METHODS
Blood samples were collected before and after the administration of ketamine for analyzing the concentrations of cyclic GMP, ketamine, and norketamine. Blood samples were analyzed using high-performance liquid chromatography and an enzyme immunoassay.


RESULTS
The median (interquartile range) value of the concentration of plasma cyclic GMP decreased from 23.7 (17.4-26.7) to 14.8 (14.0-17.3) nmol/L after ketamine infusion (p < 0.005) and from 23.9 (16.3-29.2) to 163 (14.5-18.6) nmol/L after saline infusion (p < 0.005). The median value of the concentration of plasma cyclic GMP at the end of ketamine infusion did not differ significantly when compared with that after saline infusion (p = 0.07). The concentration of plasma cyclic GMP was inversely correlated with the concentration of plasma ketamine (r = -0.61).


CONCLUSIONS
This study suggests that the low dose of intraoperative ketamine infused was insufficient to suppress the NMDA receptor pathway. The concentrations of plasma cyclic GMP may serve as an indirect biological marker of ketamine-induced NMDA receptor antagonism.
Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, University of Toronto, Ontario, Canada.
Thomas
T
Engelhardt
Christian
C
Zaarour
Mark W
MW
Crawford
D000293:Adolescent; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000009:adverse effects / Q000494:pharmacology; D002648:Child; D006152:Cyclic GMP / Q000097:blood*; D004311:Double-Blind Method; D004361:Drug Tolerance; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006785:Hospitals, University; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010149:Postoperative Pain / Q000517:prevention & control; D010880:Piperidines / Q000009:adverse effects* / Q000494:pharmacology; D011446:Prospective Studies; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D000077208:Remifentanil; D012600:Scoliosis / Q000601:surgery
D000701:Analgesics, Opioid; D000778:Anesthetics, Dissociative; D018686:Anesthetics, Intravenous; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D018698:Glutamic Acid; D007649:Ketamine; D006152:Cyclic GMP; D000077208:Remifentanil; C033419:norketamine