Michael B. Howie

A randomized, double-blind comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting

BACKGROUND: Antiemetics currently in use are not totally effective. Neurokinin-1 receptor antagonists are a new class of antiemetic that have shown promise for chemotherapy-induced nausea and vomiting. This is the first study evaluating the efficacy and tolerability of the neurokinin-1 receptor antagonist, aprepitant, for the prevention of postoperative nausea and vomiting. METHODS: In this multicenter, double-blind trial, we randomly assigned 805 patients receiving general anesthesia for open abdominal surgery to a preoperative dose of aprepitant 40 mg orally, aprepitant 125 mg orally, or ondansetron 4 mg IV. Vomiting, nausea, and use of rescue therapy were assessed over 48 h after surgery. Treatments were compared using logistic regression. RESULTS: Incidence rates for the primary end point (complete response [no vomiting and no use of rescue] over 0–24 h after surgery, tested for superiority of aprepitant) were not different across groups (45% with aprepitant 40 mg, 43% with aprepitant 125 mg, and 42% with ondansetron). The incidence of no vomiting (0–24 h) was higher with aprepitant 40 mg (90%) and aprepitant 125 mg (95%) versus ondansetron (74%) (P < 0.001 for both comparisons), although between-treatment use of rescue and nausea control was not different. Both aprepitant doses also had higher incidences of no vomiting over 0–48 h (P < 0.001). No statistically significant differences were seen among the side effect profiles of the treatments. CONCLUSIONS: Aprepitant was superior to ondansetron for prevention of vomiting in the first 24 and 48 h, but no significant differences were observed between aprepitant and ondansetron for nausea control, use of rescue, or complete response.

A Phase III, Double-blind, Placebo-controlled, Multicenter Study on the Efficacy of Recombinant Human Antithrombin in Heparin-resistant Patients Scheduled to Undergo Cardiac Surgery Necessitating Cardiopulmonary Bypass

Background:The study evaluated the efficacy of recombinant human antithrombin (rhAT) for restoring heparin responsiveness in heparin resistant patients undergoing cardiac surgery. Methods:This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing cardiac surgery with cardiopulmonary bypass. Heparin resistance was diagnosed when the activated clotting time was less than 480 s after 400 U/kg heparin. Fifty-four heparin-resistant patients were randomized. One cohort received 75 U/kg rhAT, and the other received normal saline. If the activated clotting time remained less than 480 s, this was considered treatment failure, and 2 units fresh frozen plasma was transfused. Patients were monitored for adverse events. Results:Only 19% of patients in the rhAT group received fresh frozen plasma, compared with 81% of patients in the placebo group (P < 0.001). During their hospitalization, 48% of patients in the rhAT group received fresh frozen plasma, compared with 85% of patients in the placebo group (P = 0.009). Patients in the placebo group required higher heparin doses (P < 0.005) for anticoagulation. There was no increase in serious adverse events associated with rhAT. There was increased blood loss 12 h postoperatively (P = 0.05) with a trend toward increased 24-h bleeding in the rhAT group (P = 0.06). There was no difference between the groups in blood and platelet transfusions. Conclusion:Treatment with 75 U/kg rhAT is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation in the majority of heparin-resistant patients. Treating heparin-resistant patients with rhAT may decrease the requirement for heparin and fresh frozen plasma.

A randomized double-blinded multicenter comparison of remifentanil versus fentanyl when combined with isoflurane/propofol for early extubation in coronary artery bypass graft surgery

We compared a fentanyl/isoflurane/propofol regimen with a remifentanil/isoflurane/propofol regimen for fast-track cardiac anesthesia in a prospective, randomized, double-blinded study on patients undergoing elective coronary artery bypass graft surgery. Anesthesia was induced with a 1-min infusion of 0.5 mg/kg propofol followed by 10-mg boluses of propofol every 30 s until loss of consciousness. After 0.2 mg/kg cisatracurium, a blinded continuous infusion of remifentanil at 1 &mgr;g · kg−1 · min−1 or the equivalent volume rate of normal saline was then started. In addition, a blinded bolus syringe of 1 &mgr;g/kg remifentanil or 10 &mgr;g/kg fentanyl, respectively, was given over 3 min. Blinded remifentanil, 1 &mgr;g · kg−1 · min−1 (or the equivalent volume rate of normal saline), together with 0.5% isoflurane, were used to maintain anesthesia. Significantly more patients (P < 0.01) in the fentanyl regimen experienced hypertension during skin incision and maximum sternal spread compared with patients in the remifentanil regimen. There were no differences between the groups in time until extubation, discharge from the surgical intensive care unit, ST segment and other electrocardiogram changes, catecholamine levels, or cardiac enzymes. The remifentanil-based anesthetic (consisting of a bolus followed by a continuous infusion) resulted in significantly less response to surgical stimulation and less need for anesthetic interventions compared with the fentanyl regimen (consisting of an initial bolus, and followed by subsequent boluses only to treat hemodynamic responses) with both drug regimens allowing early extubation.

The efficacy and resource utilization of remifentanil and fentanyl in fast-track coronary artery bypass graft surgery : A prospective randomized, double-blinded controlled, multi-center trial

We compared (a) the perioperative complications; (b) times to eligibility for, and actual time of the following: extubation, less intense monitoring, intensive care unit (ICU), and hospital discharge; and (c) resource utilization of nursing ratio for patients receiving either a typical fentanyl/isoflurane/propofol regimen or a remifentanil/isoflurane/propofol regimen for fast-track cardiac anesthesia in 304 adults by using a prospective randomized, double-blinded, double-dummy trial. There were no differences in demographic data, or perioperative mortality and morbidity between the two study groups. The mini-mental status examination at postoperative Days 1 to 3 were similar between the two groups. The eligible and actual times for extubation, less intense monitoring, ICU discharge, and hospital discharge were not significantly different. Further analyses revealed no differences in times for extubation and resource utilization after stratification by preoperative risk scores, age, and country. The nurse/patient ratio was similar between the remifentanil/isoflurane/propofol and fentanyl/isoflu-rane/propofol groups during the initial ICU phase and less intense monitoring phase. Increasing preoperative risk scores and older age (>70 yr) were associated with longer times until extubation (eligible), ICU discharge (eligible and actual), and hospital discharge (eligible and actual). Times until extubation (eligible and actual) and less intense monitoring (eligible) were significantly shorter in Canadian patients than United States’ patients. However, there was no difference in hospital length of stay in Canadian and United States’ patients. We conclude that both anesthesia techniques permit early and similar times until tracheal extubation, less intense monitoring, ICU and hospital discharge, and reduced resource utilization after coronary artery bypass graft surgery.

Desflurane and isoflurane produce similar alterations in systemic and pulmonary hemodynamics and arterial oxygenation in patients undergoing one-lung ventilation during thoracotomy.

We tested the hypothesis that desflurane (DES) and isoflurane (ISO) produce similar effects on systemic and pulmonary hemodynamics and arterial oxygenation before, during, and after one-lung ventilation (OLV) in patients undergoing thoracotomy. After obtaining informed consent, anesthesia was induced with sodium thiopental or thiamylal, fentanyl, and vecuronium in 61 ASA physical status II-IV patients. Patients were randomly assigned to receive either DES (n = 30) or ISO (n = 31) in 100% O2 in separate groups. Hemodynamic data (radial and pulmonary artery [PA] catheters) were recorded, and blood gas values were obtained before and after induction; at selected intervals before, during, and after OLV; and before emergence. DES significantly (P < 0.05) increased heart rate (HR) and decreased mean arterial pressure (MAP) and cardiac output (CO). PA pressures and pulmonary vascular resistance (PVR) increased; systemic vascular resistance (SVR) was unchanged. Increases in HR and CO and decreases in MAP and SVR occurred during OLV and DES. Reductions in PaO2 (411 +/- 88 to 271 +/- 131 mm Hg 5 min after beginning OLV; mean +/- SD) and content (CaO2) and increases in shunt fraction (Qs/Qt; 0.25 +/- 0.12 to 0.40 +/- 0.19 at 5 min after beginning OLV) were also observed. ISO increased HR and PA pressures but did not alter MAP, CO, and PVR, in contrast to the findings with DES. Reductions in MAP and SVR and increases in CO and PA pressures were observed during OLV in the presence of ISO. Similar to the findings during DES, decreases in PaO2 and CaO2 and increases in Qs/Qt occurred during OLV and ISO. We conclude that DES and ISO produce very similar alterations in systemic and pulmonary hemodynamics and arterial oxygenation in patients undergoing OLV during thoracotomy. Implications: Desflurane and isoflurane produce similar cardiovascular and pulmonary effects before, during, and after one-lung ventilation in patients undergoing lung surgery. (Anesth Analg 1998;87:800-7)

Myocardial electrical impedance responds to ischemia and reperfusion in humans

Myocardial electrical impedance (MEI) is correlated to ischemia and reperfusion of the heart muscle. The entire body of work with MEI to this point has been carried out in animal subjects in vivo and excised tissue samples. In this study, we measured MEI clinically for the first time in human patients who were undergoing off-pump coronary artery bypass (OPCAB) surgery. MEI was measured with a monitor designed in this laboratory and approved by the FDA for use on human subjects. Our patient population (n=18) had a 70%-100% stenosis of the diseased coronary artery targeted for bypass. We measured MEI continuously during surgery and at 3, 6, 24, and 72 h postoperatively from two temporary pacing electrodes attached to the heart muscle. Absolute baseline impedance ranged from 173 to 729 /spl Omega/. MEI increased with occlusion of the diseased artery prior to bypass. The percent increase from baseline was inversely correlated to the percent stenosis of the diseased artery. MEI decreased below baseline immediately on reperfusion following bypass in all patients and continued decreasing over the measurement period. MEI is a reliable clinical indicator of ischemia and reperfusion in humans and may indicate the effectiveness of coronary artery surgery. The parameter may have monitoring and diagnostic value in heart disease in humans.

A Comparison of Fentanyl-O2 and Sufentanil-O2 for Cardiac Anesthesia

In a prospective randomized study of 48 patients scheduled to undergo elective coronary artery surgery, sufentanil (20 μg/kg) was compared with fentanyl (100 μg/kg) anesthesia by assessing hemodynamic and plasma catecholamine level responses to surgery. At 15 points during the study, cardiovascular dynamics were recorded. At six points in the study, arterial blood was obtained for simultaneous assays of plasma concentrations of epinephrine, norepinephrine, and dopamine. Neither mean cardiovascular dynamics nor catecholamine concentrations were statistically significantly different between the groups preoperatively. Both agents provided generally stable hemodynamics during surgery. Sufentanil was associated with decreased systemic vascular resistance at several time points with concurrent increased cardiac index and heart rate. Although catecholamine levels increased somewhat during cardiopulmonary bypass in both groups, there were no significant differences between the groups at any point except that at chest closure patients given sufentanil had significantly lower dopatnine concentrations than those given fentanyl. Times for recovery from surgery failed to show any difference between the two groups of patients. Blood pressure increases with patients given sufentanil compared favorably with those given fentanyl. We conclude that at these doses, with this surgery, there were no major clinical differences, though sufentanil produced significantly lower systemic vascular resistance at several events and had a lower plasma dopamine concentration after cardiopulmonary bypass.

Esmolol reduces autonomic hypersensitivity and length of seizures induced by electroconvulsive therapy

We evaluated the clinical effectiveness of esmolol, an ultra-short-acting, β1-adrenergic receptor blocking drug, to control the sinus tachycardia and increase in arterial blood pressures induced by electroconvulsive therapy (ECT). Each of 20 patients, ASA physical status I-III, participated in a double-blind, randomized study involving four match-pair trials (placebo versus esmolol) during ECT. Each patient acted as his or her own control (total number of ECT procedures, 160). We administered a 4-min infusion of either placebo or esmolol at the rate of 500 μg · kg−1 · min−1. We then induced anesthesia with methohexital and succinylcholine. After administration of electrical stimulation for ECT, the rate of infusion decreased to 300 μg · kg−1 · min−1 for three additional minutes and was then discontinued. Statistically significant reductions in mean heart rate from minute 2 until minute 15 and in maximum heart rate (the mean of each patients maximum heart rate after seizure changed from 152 ± 23 to 115 ± 24 beats/min) occurred in patients given esmolol. During and immediately after infusion, arterial blood pressure also decreased. Finally, the length of seizures decreased, as manifested clinically from 48 ± 18 to 39 ± 14 s and on electroencephalogram from 86 ± 41 to 67 ± 28 s. We conclude that esmolol effectively controls the hyperdynamic response to ECT and reduces the length of seizures. The significance of the latter to the overall effectiveness of ECT is not known.

An evaluation of a new two-electrode myocardial electrical impedance monitor for detecting myocardial ischemia.

The objective of this study was to determine the efficacy of a two-electrode myocardial electrical impedance (MEI) monitor in reproducibly detecting induced myocardial ischemia by comparing MEI changes with hemodynamic changes, including sonomicrometric changes. With institutional approval, 80 dogs were anesthetized with sodium thiamylal, intubated, ventilated, and had venous, arterial, and pulmonary artery catheters placed. Medial sternotomy was performed to facilitate myocardial exposure and allow the left anterior descending coronary artery (LAD) to be isolated. Two pacing electrodes were attached to the myocardium to measure MEI with a monitor. Seventy dogs were randomly assigned to the 15, 30, 45, 60, or 120 min LAD occlusion group. Sonomicrometric transducers were attached to the myocardium of the ten remaining dogs and their LAD was occluded for 36 min. MEI increased immediately after LAD occlusion to a level significantly more (P <0.05) than baseline and returned to the baseline level upon reperfusion. Twenty dogs developed ventricular fibrillation with no attempts at resuscitation. MEI changes paralleled the sonomicrometric changes expected with ischemia. No significant cardiovascular hemodynamic changes were found with less than 45 min of LAD occlusion. Sixty and 120 min LAD occlusion resulted in significant decreases in cardiac output. The results of these experiments demonstrate that the two-electrode MEI monitor reproducibly changes in response to myocardial ischemia. Implications We used dogs to determine if we could measure myocardial ischemia using a device that measures impedance and demonstrated that a two-electrode myocardial electrical impedance monitor reliably reflected changes induced by myocardial ischemia.

Effect of oral clonidine premedication on anesthetic requirement, hormonal response, hemodynamics, and recovery in coronary artery bypass graft surgery patients

STUDY OBJECTIVE To examine how premedication with clonidine affects opioid use, hemodynamic effects, hormonal responses, and recovery effects. DESIGN Double blind, placebo-controlled study. SETTING Operating room and surgical intensive care unit of a university medical center. PATIENTS 54 patients undergoing elective coronary artery bypass graft (CABG) surgery. INTERVENTIONS Patients received approximately 5 micrograms/kg of oral clonidine or a placebo together with 40 micrograms/kg lorazepam 90 minutes prior to titrated sufentanil induction of anesthesia. Thirty minutes prior to cardiopulmonary bypass, a second dose of either approximately 5 micrograms/kg clonidine or placebo was given as a slurry via a nasogastric tube. MEASUREMENTS AND MAIN RESULTS Opioid use, hemodynamic effects, hormonal responses, and recovery effects were recorded. Values for ten hemodynamic variables were compiled on the evening prior to surgery, prior to induction, and during seven additional events and compared. Catecholamines and beta-endorphins were measured prior to induction, after intubation, and after sternotomy. The amount of sufentanil used for induction, maintenance, and total opioid were compared. The times to awakening and response to verbal commands were compared. The two groups exhibited similar patient demographics, cardiopulmonary bypass time, and duration of surgery. Patients receiving clonidine required significantly (p < 0.04) less sufentanil for induction (clonidine: 2.19 +/- 0.95 micrograms/kg vs. placebo: 2.93 +/- 1.07 micrograms/kg) and total amount of sufentanil (clonidine: 9.1 +/- 3.9 micrograms/kg vs. placebo: 11.7 +/- 4.6 micrograms/kg). Patients receiving clonidine required significantly (p < 0.01) less isoflurane (9.7 +/- 6.8 MAC min vs. 19.7 +/- 9.9 MAC min) to maintain heart rate (HR) and mean arterial pressure (MAP) to within 15% of baseline without significant differences in other vasoactive drugs. Catecholamine concentrations were significantly (p < 0.02) lower in patients receiving clonidine without any difference in beta-endorphin concentrations. Patients receiving clonidine had significantly (p < 0.02) lower HR, systolic arterial pressure, MAP, and systemic vascular resistance prior to induction than patients receiving placebo without differences in other hemodynamic variables. CONCLUSION Clonidine decreases opioid use and lowers hormonal response while maintaining stable hemodynamics in patients undergoing CABG with sufentanil anesthesia.