Pediatric Anesthesia ISSN 1155-5645
ORIGINAL ARTICLE
Prolonged perioperative infusion of low-dose ketamine does not alter opioid use after pediatric scoliosis surgery Sophie R. Pestieau1,2, Julia C. Finkel1,2,3, Mariana M. Junqueira3, Yao Cheng4, John F. Lovejoy5, Jichuan Wang4 & Zenaide Quezado1,2,3 1 2 3 4 5
Division of Anesthesiology, Sedation and Perioperative Medicine, Children’s National Health Systems, Washington, DC, USA Division of Pain Medicine, Children’s National Health Systems, Washington, DC, USA The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Health Systems, Washington, DC, USA Division of Biostatistics and Study Methodology, Center for Translational Science, Children’s National Health Systems, Washington, DC, USA Division of Orthopaedic Surgery and Sports Medicine, Children’s National Health Systems, Washington, DC, USA
Keywords opioid; tolerance; ketamine; hyperalgesia; children; scoliosis Correspondence Dr S. R. Pestieau, Division of Anesthesiology, Sedation and Perioperative Medicine Children’s National Health Systems, 111 Michigan Avenue, NW Washington, DC 20010, USA Email: [email protected] Section Editor: Neil Morton Accepted 28 March 2014 doi:10.1111/pan.12417
Summary Background: Opioid consumption after posterior spinal fusion is known to be high and often exceeds those reported in other major surgical procedures. A number of clinical trials provide evidence that the perioperative use of subanesthetic doses of ketamine reduces pain and opioid requirements in some surgical procedures, but the effect of prolonged perioperative low-dose ketamine infusion in patients undergoing posterior spinal fusion for pediatric scoliosis surgery is unknown. Objective: To test the hypothesis that a 72-h perioperative low-dose ketamine infusion would decrease opioid use in pediatric patients undergoing posterior spinal fusion. Methods: In a double-blind prospective controlled trial, patients undergoing posterior spinal fusion for scoliosis were randomized to receive perioperative low-dose ketamine or placebo control. Patients received general anesthesia, intraoperative remifentanil, and morphine patient-controlled analgesia postoperatively. Daily opioid consumption, self-reported pain scores, and sedation scores were measured. Results: Fifty-four patients were enrolled and 50 completed the study. Contrary to our hypothesis, ketamine– and control-treated patients had similar postoperative opioid use, pain scores, and sedation scores measurements. In contrast, ketamine-treated patients required less intraoperative remifentanil compared with control (mean 2.9 mg vs. 4 mg, P = 0.0415). Number of vertebrae instrumented, time between end-of-surgery and 24 h assessment, or remifentanil doses did not impact on postoperative opioid use. Over 96-h postoperatively, morphine-equivalent consumption was lower ( 0.40, P = 0.006) and sedation score was higher (0.47, P = 0.0211) in male patients, compared with female patients. Conclusions: These findings do not support the use of perioperative low-dose ketamine to decrease opioid use in children with scoliosis undergoing posterior spinal fusion.
Introduction Anesthesiologists caring for patients with scoliosis undergoing posterior spinal fusion have reported that opioid use after these procedures are high and often 582
exceed those for other major surgical procedures (1). In addition, the anesthetic techniques used for posterior spinal fusion often involve prolonged use of high doses of short acting opioids such as remifentanil to facilitate neurologic monitoring. In turn, patients who receive © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 582–590
S.R. Pestieau et al.
intraoperative remifentanil have been shown to have significantly high postoperative opioid use (2). Those findings thus suggest that the intraoperative anesthetic management of spinal fusion procedures might be associated with the development of clinically relevant opioid tolerance, which might contribute to increased opioid consumption (2). A number of clinical trials show that patients treated with subanesthetic doses of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine have lower opioid use after some surgical procedures (3–5). Investigators propose that by blocking the NMDA receptor, ketamine reduces the sensitization of nociceptive pathways associated with tissue injury and may thus prevent the development of opioid-induced tolerance and hyperalgesia. However, some studies have yielded discrepant results as the perioperative use of subanesthetic doses of ketamine yielded no difference in postoperative opioid use in some renal, thoracic, urologic, and gynecologic surgeries (6–9). In patients undergoing posterior spinal fusion, researchers showed that when used intraoperatively only, low-dose ketamine does not prevent remifentanil-induced increases in postoperative opioid use (10). Some investigators propose that these conflicting results could be explained by variations in doses, timing, and duration of ketamine administration (4). Here the authors hypothesize that intraoperative administration followed by a 72-h infusion of subanesthetic doses of ketamine would decrease daily opioid consumption by preventing the development of acute opioid tolerance and hyperalgesia in children undergoing posterior spinal fusion. Methods Study design We conducted a single-center, double-blind, randomized clinical trial between April 2010 and April 2012 (ClinicalTrials.gov identifier NCT01325493). Institutional review board approval, written parental consent, and patient assent were obtained. Patients were screened and enrolled by the investigators. Patients Male and female patients (ages 10 to 18 years, ASA I, II, or III) scheduled for posterior spinal fusion for scoliosis were eligible for the study. Children with personal or family history of malignant hyperthermia, significant renal or hepatic disorders, history of dysrhythmias or congenital heart disease, a scheduled surgical subprocedure (i.e. anterior spinal fusion), planned postoperative mechanical ventilation, allergy to morphine, remifenta© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 582–590
Low-dose ketamine does not alter opioid use after scoliosis surgery
nil, or ketamine, inability to self-administer morphine using a patient-controlled analgesia (PCA) pump, and recent opioid exposure (within 1 month of surgery) were excluded. After enrollment, patients were instructed how to use the PCA pump and the numeric pain scale for assessment of pain intensity. Interventions Study subjects were randomly assigned to ketamine or placebo control groups. Treatment assignments were based on a computerized randomization schedule created via a uniform random number generator for 90 patients. Ketamine was diluted in 50 ml of normal saline to a concentration of 10 mgml 1 and the placebo control consisted of 50 ml of normal saline. The study solutions were labeled as ‘study drug 10 mgml 1, and were administered by the patient’s primary anesthesiologist who was unaware of its content. Ketamine was administered intravenously (IV) as follows: a loading dose of 0.5 mgkg 1 prior to surgical incision, an intraoperative infusion at 0.25 mgkgh 1 and a postoperative infusion at 0.1 mgkgh 1. Patients in the control group received a volume equivalent dose and infusion of normal saline. All patients, caregivers, and research assistants were blinded to the study drug which continued for a total of 72 h. Anesthetic technique Patients received midazolam orally (0.5 mgkg 1 up to 20 mg) or IV (0.05–0.1 mgkg 1) as premedication. Anesthesia was induced either by inhalation of sevoflurane in a nitrous oxide in oxygen (2 : 1) gas mixture or by IV administration of propofol (2 mgkg 1). Fentanyl was administered at time of induction at the discretion of the anesthesiologist and rocuronium 0.6 mgkg 1 was given to facilitate tracheal intubation. Anesthesia was maintained with 0.5 MAC equivalent of desflurane in oxygen (0.5 FiO2). Immediately after the patient was positioned prone, the study drug loading dose infusion were started. Remifentanil infusion was started at 0.25 µgkg 1min 1 and titrated according to hemodynamic response (mean arterial blood pressure was kept within 20% of baseline). In order to not restrict intraoperative anesthetic management, if necessary to increase anesthetic depth, additional propofol boluses could be administered at the discretion of the blinded anesthesiologist. Methods of blood conservation included one or more of the following: donation of autologous blood, use of cell saver, skin infiltration with epinephrine and bone wax at the subperiosteal space along spinal laminae. Remifentanil and desflu583
S.R. Pestieau et al.
Low-dose ketamine does not alter opioid use after scoliosis surgery
rane were discontinued at skin closure. After removal of the endotracheal tube, morphine was titrated to patient comfort (absence of any verbal or behavioral expression of pain). Per our hospital’s policy, patients were transferred to the intensive care unit (ICU) for the first 24 h. Upon arrival to the ICU, morphine PCA was initiated at 0.02 mgkg 1h 1, 0.02 mgkg 1 per dose, and 8 min interval. The rate and dose of the PCA were adjusted at daily Pain Medicine rounds according to the patient’s pain to maintain pain scores
ORIGINAL ARTICLE
Prolonged perioperative infusion of low-dose ketamine does not alter opioid use after pediatric scoliosis surgery Sophie R. Pestieau1,2, Julia C. Finkel1,2,3, Mariana M. Junqueira3, Yao Cheng4, John F. Lovejoy5, Jichuan Wang4 & Zenaide Quezado1,2,3 1 2 3 4 5
Division of Anesthesiology, Sedation and Perioperative Medicine, Children’s National Health Systems, Washington, DC, USA Division of Pain Medicine, Children’s National Health Systems, Washington, DC, USA The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National Health Systems, Washington, DC, USA Division of Biostatistics and Study Methodology, Center for Translational Science, Children’s National Health Systems, Washington, DC, USA Division of Orthopaedic Surgery and Sports Medicine, Children’s National Health Systems, Washington, DC, USA
Keywords opioid; tolerance; ketamine; hyperalgesia; children; scoliosis Correspondence Dr S. R. Pestieau, Division of Anesthesiology, Sedation and Perioperative Medicine Children’s National Health Systems, 111 Michigan Avenue, NW Washington, DC 20010, USA Email: [email protected] Section Editor: Neil Morton Accepted 28 March 2014 doi:10.1111/pan.12417
Summary Background: Opioid consumption after posterior spinal fusion is known to be high and often exceeds those reported in other major surgical procedures. A number of clinical trials provide evidence that the perioperative use of subanesthetic doses of ketamine reduces pain and opioid requirements in some surgical procedures, but the effect of prolonged perioperative low-dose ketamine infusion in patients undergoing posterior spinal fusion for pediatric scoliosis surgery is unknown. Objective: To test the hypothesis that a 72-h perioperative low-dose ketamine infusion would decrease opioid use in pediatric patients undergoing posterior spinal fusion. Methods: In a double-blind prospective controlled trial, patients undergoing posterior spinal fusion for scoliosis were randomized to receive perioperative low-dose ketamine or placebo control. Patients received general anesthesia, intraoperative remifentanil, and morphine patient-controlled analgesia postoperatively. Daily opioid consumption, self-reported pain scores, and sedation scores were measured. Results: Fifty-four patients were enrolled and 50 completed the study. Contrary to our hypothesis, ketamine– and control-treated patients had similar postoperative opioid use, pain scores, and sedation scores measurements. In contrast, ketamine-treated patients required less intraoperative remifentanil compared with control (mean 2.9 mg vs. 4 mg, P = 0.0415). Number of vertebrae instrumented, time between end-of-surgery and 24 h assessment, or remifentanil doses did not impact on postoperative opioid use. Over 96-h postoperatively, morphine-equivalent consumption was lower ( 0.40, P = 0.006) and sedation score was higher (0.47, P = 0.0211) in male patients, compared with female patients. Conclusions: These findings do not support the use of perioperative low-dose ketamine to decrease opioid use in children with scoliosis undergoing posterior spinal fusion.
Introduction Anesthesiologists caring for patients with scoliosis undergoing posterior spinal fusion have reported that opioid use after these procedures are high and often 582
exceed those for other major surgical procedures (1). In addition, the anesthetic techniques used for posterior spinal fusion often involve prolonged use of high doses of short acting opioids such as remifentanil to facilitate neurologic monitoring. In turn, patients who receive © 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 582–590
S.R. Pestieau et al.
intraoperative remifentanil have been shown to have significantly high postoperative opioid use (2). Those findings thus suggest that the intraoperative anesthetic management of spinal fusion procedures might be associated with the development of clinically relevant opioid tolerance, which might contribute to increased opioid consumption (2). A number of clinical trials show that patients treated with subanesthetic doses of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine have lower opioid use after some surgical procedures (3–5). Investigators propose that by blocking the NMDA receptor, ketamine reduces the sensitization of nociceptive pathways associated with tissue injury and may thus prevent the development of opioid-induced tolerance and hyperalgesia. However, some studies have yielded discrepant results as the perioperative use of subanesthetic doses of ketamine yielded no difference in postoperative opioid use in some renal, thoracic, urologic, and gynecologic surgeries (6–9). In patients undergoing posterior spinal fusion, researchers showed that when used intraoperatively only, low-dose ketamine does not prevent remifentanil-induced increases in postoperative opioid use (10). Some investigators propose that these conflicting results could be explained by variations in doses, timing, and duration of ketamine administration (4). Here the authors hypothesize that intraoperative administration followed by a 72-h infusion of subanesthetic doses of ketamine would decrease daily opioid consumption by preventing the development of acute opioid tolerance and hyperalgesia in children undergoing posterior spinal fusion. Methods Study design We conducted a single-center, double-blind, randomized clinical trial between April 2010 and April 2012 (ClinicalTrials.gov identifier NCT01325493). Institutional review board approval, written parental consent, and patient assent were obtained. Patients were screened and enrolled by the investigators. Patients Male and female patients (ages 10 to 18 years, ASA I, II, or III) scheduled for posterior spinal fusion for scoliosis were eligible for the study. Children with personal or family history of malignant hyperthermia, significant renal or hepatic disorders, history of dysrhythmias or congenital heart disease, a scheduled surgical subprocedure (i.e. anterior spinal fusion), planned postoperative mechanical ventilation, allergy to morphine, remifenta© 2014 John Wiley & Sons Ltd Pediatric Anesthesia 24 (2014) 582–590
Low-dose ketamine does not alter opioid use after scoliosis surgery
nil, or ketamine, inability to self-administer morphine using a patient-controlled analgesia (PCA) pump, and recent opioid exposure (within 1 month of surgery) were excluded. After enrollment, patients were instructed how to use the PCA pump and the numeric pain scale for assessment of pain intensity. Interventions Study subjects were randomly assigned to ketamine or placebo control groups. Treatment assignments were based on a computerized randomization schedule created via a uniform random number generator for 90 patients. Ketamine was diluted in 50 ml of normal saline to a concentration of 10 mgml 1 and the placebo control consisted of 50 ml of normal saline. The study solutions were labeled as ‘study drug 10 mgml 1, and were administered by the patient’s primary anesthesiologist who was unaware of its content. Ketamine was administered intravenously (IV) as follows: a loading dose of 0.5 mgkg 1 prior to surgical incision, an intraoperative infusion at 0.25 mgkgh 1 and a postoperative infusion at 0.1 mgkgh 1. Patients in the control group received a volume equivalent dose and infusion of normal saline. All patients, caregivers, and research assistants were blinded to the study drug which continued for a total of 72 h. Anesthetic technique Patients received midazolam orally (0.5 mgkg 1 up to 20 mg) or IV (0.05–0.1 mgkg 1) as premedication. Anesthesia was induced either by inhalation of sevoflurane in a nitrous oxide in oxygen (2 : 1) gas mixture or by IV administration of propofol (2 mgkg 1). Fentanyl was administered at time of induction at the discretion of the anesthesiologist and rocuronium 0.6 mgkg 1 was given to facilitate tracheal intubation. Anesthesia was maintained with 0.5 MAC equivalent of desflurane in oxygen (0.5 FiO2). Immediately after the patient was positioned prone, the study drug loading dose infusion were started. Remifentanil infusion was started at 0.25 µgkg 1min 1 and titrated according to hemodynamic response (mean arterial blood pressure was kept within 20% of baseline). In order to not restrict intraoperative anesthetic management, if necessary to increase anesthetic depth, additional propofol boluses could be administered at the discretion of the blinded anesthesiologist. Methods of blood conservation included one or more of the following: donation of autologous blood, use of cell saver, skin infiltration with epinephrine and bone wax at the subperiosteal space along spinal laminae. Remifentanil and desflu583
S.R. Pestieau et al.
Low-dose ketamine does not alter opioid use after scoliosis surgery
rane were discontinued at skin closure. After removal of the endotracheal tube, morphine was titrated to patient comfort (absence of any verbal or behavioral expression of pain). Per our hospital’s policy, patients were transferred to the intensive care unit (ICU) for the first 24 h. Upon arrival to the ICU, morphine PCA was initiated at 0.02 mgkg 1h 1, 0.02 mgkg 1 per dose, and 8 min interval. The rate and dose of the PCA were adjusted at daily Pain Medicine rounds according to the patient’s pain to maintain pain scores
