Alan N. Sandler

Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes.

Ketamine hydrochloride is a well known general anesthetic and short acting analgesic in use for almost 3 decades. The role of the NMDA receptor in the processing of nociceptive input has led naturally to renewed clinical interest in N-methyl-D-aspartate (NMDA) receptor antagonists such as ketamine. This paper reviews the use and efficacy of low-dose ketamine in the management of acute postoperative pain. The literature was obtained from a computer search of the MEDLINE database from 1966 through December 1998. Studies were included for review if they were randomized, prospective, controlled, double-blind and reported pain scores. We evaluate the clinical literature and discuss the efficacy of low-dose ketamine in the management of acute postoperative pain when administered alone or in conjunction with other agents via the oral, intramuscular, subcutaneous, intravenous and intraspinal routes. Low-dose ketamine is defined as a bolus dose of less than 2 mg/g when given intramuscularly or less than 1 mg/kg when administered via the intravenous or epidural route. For continuous i.v. administration low-dose ketamine is defined as a rate of < or =20 microg/kg per min. We conclude that ketamine may provide clinicians with a tool to improve postoperative pain management and to reduce opioid related adverse effects. The evidence suggests that low-dose ketamine may play an important role in postoperative pain management when used as an adjunct to local anesthetics, opioids, or other analgesic agents. Further research is required in the following areas: (a) dose-finding studies for ketamine as an adjunct to opioids and local anesthetics (b) efficacy and optimal route of administration (c) the role of S(+)-ketamine; (d) the influence of ketamine on long-term outcome such as chronic pain (e) long-term physical and chemical stability of mixtures containing ketamine (f) spinal toxicity of ketamine and (g) effects of low-dose ketamine on cognitive and memory functioning after surgery.

Preemptive analgesia. Clinical evidence of neuroplasticity contributing to postoperative pain.

Recent evidence suggests that surgical incision and other noxious perioperative events may induce prolonged changes in central neural function that later contribute to postoperative pain. The present study tested the hypothesis that patients receiving epidural fentanyl before incision would have less pain and need fewer analgesics post-operatively than patients receiving the same dose of epidural fentanyl after incision. Thirty patients (ASA physical status 2) scheduled for elective thoracic surgery through a posterolateral thoracotomy incision were randomized to one of two groups of equal size and prospectively studied in a double-blind manner. Epidural catheters were placed via the L2-L3 or L3-L4 interspaces preoperatively, and the position was confirmed with lidocaine. Group 1 received epidural fentanyl (4 micrograms/kg, in 20 ml normal saline) before surgical incision, followed by epidural normal saline (20 ml) infused 15 min after incision. Group 2 received epidural normal saline (20 ml) before surgical incision, followed by epidural fentanyl (4 micrograms/kg, in 20 ml normal saline) infused 15 min after incision. No additional analgesics were used before or during the operation. Anesthesia was induced with thiopental (3-5 mg/kg) and maintained with N2O/O2 and isoflurane. Paralysis was achieved with pancuronium (0.1 mg/kg). Postoperative analgesia consisted of patient-controlled intravenous morphine. Visual analogue scale pain scores were significantly less in group 1 (2.6 +/- 0.44) than in group 2 (4.7 +/- 0.58) 6 h after surgery (P less than 0.05), by which time plasma fentanyl concentrations had decreased to subtherapeutic levels (less than 0.15 ng/ml) in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Early tracheal extubation after coronary artery bypass graft surgery reduces costs and improves resource use. A prospective, randomized, controlled trial.

Background Economics has caused the trend of early tracheal extubation after cardiac surgery, yet no prospective randomized study has directly validated that early tracheal extubation anesthetic management decreases costs when compared with late extubation after cardiac surgery. Methods This prospective, randomized, controlled clinical trial was designed to evaluate the cost savings of early (1-6 h) versus late tracheal extubation (12-22 h) in patients after coronary artery bypass graft (CABG) surgery. The total cost for the services provided for each patient was determined for both the early and late groups from hospital admission to discharge home. All costs applicable to each of the services were classified into direct variables, direct fixed costs, and overhead (an indirect cost). Physician fees and heart catheterization costs were included. The total service cost was the sum of unit workload and overhead costs. Results One hundred patients having elective CABG who were younger than 75 yr were studied. Including all complications, early extubation (n = 50) significantly reduced cardiovascular intensive care unit (CVICU) costs by 53% (P < 0.026) and the total CABG surgery cost by 25% (P <0.019) when compared with late extubation (n = 50). Forty-one patients (82%) in each group were tracheally extubated within the defined period. In the early extubation group, the actual departmental cost savings in CVICU nursing and supplies was 23% (P < 0.005), in ward nursing and supplies was 11% (P < 0.05), and in respiratory therapy was 12% (P <0.05). The total cost savings per patient having CABG was 9% (P < 0.001). Further cost savings using discharge criteria were 51% for CVICU nursing and supplies (Pt < 0.001), 9% for ward nursing and supplies (P <0.05), and 29% for respiratory therapy (P < 0.001), for a total cost savings per patient of 13% (P < 0.001). Early extubation also reduced elective case cancellations (P < 0.002) without any increase in the number of postoperative complications and readmissions. Conclusions Early tracheal extubation anesthetic management reduces total costs per CABG surgery by 25%, predominantly in nursing and in CVICU costs. Early extubation reduces CVICU and hospital length of stay but does not increase the rate or costs of complications when compared with patients in the late extubation group. It shifts the high CVICU costs to the lower ward costs. Early extubation also improves resource use after cardiac surgery when compared with late extubation.

Morbidity outcome in early versus conventional tracheal extubation after coronary artery bypass grafting : A prospective randomized controlled trial

INTRODUCTION We undertook a prospective, randomized, controlled clinical trial to evaluate morbidity outcomes and safety of a modified anesthetic technique to provide shorter sedation and early extubation (1 to 6 hours) than those of the conventional anesthetic protocol used for prolonged sedation and extubation (12 to 22 hours) in patients after coronary artery bypass grafting. METHODS One hundred twenty patients undergoing elective coronary artery bypass grafting were prospectively assigned randomly to either an early extubation group (n = 60; 15 micrograms.kg-1 fentanyl and 2 to 6 mg.kg-1.hour-1 propofol and isoflurane) or to a conventional extubation group (n = 60; 50 micrograms.kg-1 fentanyl and 0.1 mg.kg-1 midazolam and isoflurane). Cardiac morbidity (postoperative myocardial ischemia, postoperative myocardial infarction, and perioperative sympathoadrenal stress response), respiratory morbidity (postextubation apnea, alveolar-arterial oxygen gradient, pulmonary shunting, oxygen consumption, atelectasis, and reintubation), hemodynamic values and vasoactive medication requirements, intraoperative awareness, postoperative cognitive function, 30 day mortality, and intensive care unit and hospital lengths of stay were compared between the two groups. RESULTS Fifty-one of the 60 patients in each group (85%) were extubated within the defined time period. Postoperative extubation time and intensive care unit and hospital lengths of stay were significantly shorter in the early group. At 48 hours after operation, there were no significant differences between the two groups in myocardial ischemia incidences, ischemia burdens, or creatine kinase isoenzyme MB levels. Four patients in the conventional group, but not in the early group, had postoperative myocardial infaction. The extubation anesthetics used were effective in suppressing the perioperative plasma catecholamine stress response in both groups. Postextubation apnea characteristics were similar between the groups. Intrapulmonary shunt fraction improved significantly in the early group at 4 hours after extubation. The incidences and degree of atelectasis did not differ significantly between the two groups. The incidences of treated postoperative complications were comparable between the two groups, but three patients in the conventional group died as a result of stroke or postoperative myocardial infarction. CONCLUSION Early extubation after coronary artery bypass grafting is safe and does not increase perioperative morbidity. There is an improvement in postextubation intrapulmonary shunt fraction and a reduction in intensive care unit and hospital lengths of stay.

Postthoracotomy Pain and Pulmonary Function Following Epidural and Systemic Morphine

Thirty patients undergoing thoracotomy for lung resection were entered in a randomized, double-blind trial comparing the effects of epidural (E) versus intravenous (iv) morphine on postoperative pain and pulmonary function. Postoperatively the patients were given repeated doses of either 5.0 mg of morphine epidurally or 0.05–0.07 mg/kg morphine intravenously until there were no further spontaneous complaints of pain. Two, 8, and 24 h post-operatively, the following indices were measured: linear analogue pain score, somnolence score, vital signs, arterial PaO2, PaCO2 and pH, forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and peak expiratory flow rate (PEFR). Patients receiving epidural morphine had significantly less pain at 2 h (P < 0.01) and 8 h (P < 0.004) postoperatively. There was no difference in vital signs except for significantly slower respiratory rates at 2 h (P < 0.04), 8 h (P < 0.02) and 24 h (P < 0.01) in the epidural group. No significant differences occurred in the somnolence scores or blood–gas measurements, which were within normal limits. The epidural morphine group has significantly less decrease in both FVC at 2 h (E –1.8 ± 2 l, iv –2.5 ± 0.2 l, P < 0.03), 8 h (E –1.4 ± 0.2 l, iv –2.1 ± 0.2 l, P < 0.01), and 24 h (E –1.2 ± 0.2 l, iv –2.0 ± 0.2 l, P < 0.02), and FEV1 at 2 h (E –1.3 ± 0.2 l, iv –1.9 ± 0.2 l, P < 0.04), 8 h (E –1.0 ± 0.2 l, iv –1.7 ± 0.2 l, P < 0.01), and 24 h (E –0.8 ± 0.1 l, iv –1.5 ± 0.2 l, P < 0.01). In addition, the epidural morphine group had significantly less decrease in PEFR at 24 h (E –134 ± 29 l · min ·-1, iv –238 ± 30 l · min-1, P < 0.03). The authors conclude that lumbar epidural morphine is highly effective in alleviating pain and improving respiratory function in postthoracotomy patients.

Tranexamic Acid Reduces Blood Loss, Transfusion Requirements, and Coagulation Factor Use in Primary Orthotopic Liver Transplantation

Background Patients with end-stage liver disease frequently incur large-volume blood loss during liver transplantation associated with mechanical factors, preexisting coagulopathy, and intraoperative fibrinolysis. Methods Between April 1992 and May 1994, the authors of this double-blind, randomized, placebo-controlled study examined the effect of high-dose tranexamic acid (maximum of 20 g) on blood loss and blood product requirements in patients undergoing primary isolated orthotopic liver transplantation. Primary outcome measures were volume of blood loss (intraoperative blood loss and postoperative drainage) and erythrocyte, plasma, platelet, and cryoprecipitate use during surgery and the first 24 h of intensive care unit stay. Results Patients receiving transexamic acid (n = 25) had less intraoperative blood loss (median, 4.3 l; interquartile range, 2.5 to 7.9; P = 0.006) compared with the placebo group (n = 20; median, 8 l; interquartile range, 5 to 15.8), and reduced intraoperative plasma, platelet, and cryoprecipitate requirements. Median perioperative erythrocyte use was 9 units (interquantile range, 4 to 14 units) in patients receiving transexamic acid and 13 units (interquantile range, 7.5 to 31 units) in controls (P = 0.03). Total perioperative donor exposure was 20.5 units (interquantile range, 16 to 41 units) in patients receiving transexamic acid and 43.5 units (interquantile range, 29.5 to 79 units) in controls (P = 0.003). Results for postoperative wound drainage were similar. Hospital stay and need for retransplantation were comparable in both groups. No patient in either group showed clinical evidence of hepatic artery or portal venous thrombosis within 1 month of transplantation. Conclusions High-dose tranexamic acid significantly reduces intraoperative blood loss and perioperative donor exposure in patients with end-stage parenchymal liver disease who are undergoing orthotopic liver transplantation, with marked reductions in platelet and cryoprecipitate requirements.

A randomized, double-blind comparison of lumbar epidural and intravenous fentanyl infusions for postthoracotomy pain relief. Analgesic, pharmacokinetic, and respiratory effects.

Although epidural opioids frequently are used to provide postoperative analgesia, several articles have suggested that the analgesia after epidural fentanyl is similar to that after an equal dose of fentanyl given intravenously. To address this issue further, 29 postthoracotomy patients were studied in a randomized, double-blinded trial comparing a lumbar epidural fentanyl infusion with an intravenous fentanyl infusion for analgesia, plasma fentanyl pharmacokinetics, and respiratory effects for 20 h postoperatively. In all patients in both groups, good analgesia was achieved (pain score less than 3, maximum 10) over a similar time course, although the patients receiving epidural infusion required a significantly larger fentanyl infusion dose than did the patients receiving intravenous infusion (group receiving epidural fentanyl infusion: 1.95 +/- 0.45 micrograms.kg-1.h-1; group receiving intravenous fentanyl infusion: 1.56 +/- 0.36 micrograms.kg-1.h-1; P = 0.0002). The time course for the plasma fentanyl concentrations was similar in the two groups, and plasma fentanyl concentrations were not significantly different at any sampling period (T7-T20; group receiving epidural fentanyl infusion: 1.8 +/- 0.5 ng/ml; group receiving intravenous fentanyl infusion: 1.6 +/- 0.6 ng/ml; P = 0.06). Similarly, calculated clearance values for the two groups were not significantly different (group receiving epidural fentanyl infusion: 0.95 +/- 0.26 l.kg-1.h-1; group receiving intravenous fentanyl infusion: 0.87 +/- 0.25 l.kg-1.h-1; P = 0.3). Both groups demonstrated a similar degree of mild to moderate respiratory depression postoperatively, which was assessed with continuous respiratory inductance plethysmography and sequential arterial blood gas analysis. Side effects (nausea, vomiting, pruritus) were mild and did not differ between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Pre-emptive lumbar epidural anaesthesia reduces postoperative pain and patient-controlled morphine consumption after lower abdominal surgery

&NA; The present study tested the hypothesis that patients receiving epidural bupivacaine before surgery would require less morphine postoperatively and/or report less intense pain than patients receiving epidural bupivacaine after incision but before the end of surgery. Forty‐two patients (ASA class I‐III) scheduled for lower abdominal surgery were randomly assigned to 1 of 2 groups of equal size and prospectively studied using a double‐blind, placebo‐controlled crossover design. Epidural catheters were placed in the T12‐L1 or L1‐L2 interspaces pre‐operatively, the position of the catheter was confirmed with 3% chloroprocaine with epinephrine 1:200,000, and sensory testing was carried out until levels had receded to below T12. Group 1 received 15 ml of 0.5% epidural bupivacaine injected 35 min before incision followed by 15 ml of epidural normal saline 30 min after incision. Group 2 received 15 ml of epidural normal saline injected 37 min before incision followed by 15 ml of 0.5% epidural bupivacaine 30 min after incision. General anaesthesia was induced with thiopental (4–6 mg/kg) and maintained with N2O/O2 and isoflurane. Paralysis was achieved with pancuronium (0.1 mg/kg). Opioids were not used as pre‐medication or during surgery. Postoperative analgesia consisted of patient‐controlled (PCA) intravenous morphine. Visual analogue pain scores (VAS) (at rest and after standardized mobilization) did not differ significantly between the 2 groups but McGill Pain Questionnaire (MPQ) pain ratings were significantly lower in group 1 at the 24 and 72 h assessments. Group 1 used significantly less morphine than did group 2 between 12 and 24 h after surgery. Cumulative PCA morphine consumption in group 1 (55.2 ± 4.7 mg) was significantly lower than in group 2 (71.7 ± 6.1 mg) 24 h and 48 h (group 1: 86.8 ± 6.3 mg vs. group 2: 108.9 ± 9.8 mg) after surgery, but not at the 72 h assessment. Reduction in morphine dose at 24, 48 and 72 h amounted to 30%, 25% and 22%, respectively. The results suggest that single‐shot pre‐emptive epidural local anaesthesia is associated with a short‐term morphine‐sparing effect which is most pronounced between 12 and 24 h after surgery. Extending the pre‐operative blockade into the postoperative period may prolong the initial advantage conferred by pre‐emptive epidural local anaesthesia.

Epidural Bupivacaine-Morphine Analgesia versus Patient-controlled Analgesia following Abdominal Aortic Surgery: Analgesic, Respiratory, and Myocardial Effects

Background The efficacy and effects of epidural analgesia compared with patient-controlled analgesia (PCA) have not been reported in patients undergoing major vascular surgery. We compared the effects of epidural bupivacaine-morphine with those of intravenous PCA morphine after elective infrarenal aortic surgery. Methods Forty patients classified as American Society of Anesthesiologists physical status 2 or 3 received general anesthesia plus postoperative PCA using morphine sulfate (group PCA; n = 21) or general anesthesia plus perioperative epidural morphine - bupivacaine (group EPI; n = 19) during a period of 48 h. During operation, EPI patients received 0.05 mg/kg epidural morphine and 5 ml 0.25% bupivacaine followed by an infusion of 0.125% bupivacaine with 0.1% morphine (0.1 mg/ml); group PCA received 0.1 mg/kg intravenous morphine sulfate. Continuous electrocardiographic monitoring (V4 and V5 leads) was performed from the night before surgery until 48 h afterward. Respiratory inductive plethysmographic data were recorded after tracheal extubation. Visual analog pain scores at rest and after movement were performed every 4 h after extubation. Results Nurse-administered intravenous morphine and time to tracheal extubation were less in group EPI, as were visual analog pain scores at rest and after movement from 20 to 48 h. Complications and the duration of intensive care unit and hospital stay were comparable. There was a similar, low incidence of postoperative apneas, slow respiratory rates, desaturation, and S-T segment depression. Conclusions Epidural morphine-bupivacaine is associated with reduced early postoperative intravenous opioid requirements, more rapid tracheal extubation, and superior analgesia after abdominal aortic surgery, with comparable respiratory effects.

Intraoperative Awareness in Fast-track Cardiac Anesthesia

Background Fast‐track cardiac anesthesia, using low‐dose narcotics combined with short‐acting anesthetic and sedative agents, facilitates early tracheal extubation after cardiac surgery. The incidence of awareness with this anesthetic technique has not been investigated previously. The purpose of this study was to prospectively investigate the incidence of intraoperative awareness with explicit memory of events during fast‐track cardiac anesthesia. Methods Data were collected prospectively over a 4‐month period from 617 consecutive adult patients undergoing cardiac surgery at a university hospital. All patients received a fast‐track cardiac anesthetic regimen. Patients underwent a structured interview by a research nurse 18 h after extubation. A standard set of questions was asked during this interview to determine if the patient had explicit memory of any event from induction of anesthesia to recovery of consciousness. Results Nine patients did not complete a postoperative interview because of death (n = 7) or postoperative confusion (n = 2). The last memory before surgery reported in 420 (69.1%) patients was waiting in the holding area at the operating suite, and in the remaining 188 (30.9%) patients it was lying on the operating Table beforeinduction of anesthesia. Two patients (0.3%) had explicit memory of intraoperative events. One of the two patients also had explicit memory of pain. Neither patient reported adverse psychological sequelae. Conclusions The authors report an incidence of awareness in fast‐track cardiac anesthesia of 0.3%. This is the lowest incidence of awareness currently reported during cardiac surgery. This low incidence of awareness may be related to the use of a balanced anesthetic technique involving the continuous administration of volatile (isoflurane) or intravenous (propofol) anesthetic agents before, during, and after cardiopulmonary bypass.