Sex-related Differences in the Influence of Morphine on Ventilatory Control in Humans

Background: Opiate agonists have different analgesic effects in male and female patients. The authors describe the influence of sex on the respiratory pharmacology of the micro-receptor agonist morphine.

Methods: The study was placebo-controlled, double-blind, and randomized. Steady-state ventilatory responses to carbon dioxide and responses to a step into hypoxia (duration, 3 min; oxygen saturation, [approximately] 82%; end-tidal carbon dioxide tension, 45 mmHg) were obtained before and during intravenous morphine or placebo administration (bolus dose of 100 micro gram/kg, followed by a continuous infusion of 30 micro gram [center dot] kg sup -1 [center dot] h sup -1) in 12 men and 12 women.

Results: In women, morphine reduced the slope of the ventilatory response to carbon dioxide from 1.8 +/- 0.9 to 1.3 +/- 0.7 l [center dot] min sup -1 [center dot] mmHg sup -1 (mean +/- SD; P < 0.05), whereas in men there was no significant effect (control = 2.0 +/- 0.4 vs. morphine = 1.8 +/- 0.4 l [center dot] min sup -1 [center dot] mmHg sup -1). Morphine had no effect on the apneic threshold in women (control = 33.8 +/- 3.8 vs. morphine = 35.3 +/- 5.3 mmHg), but caused an increase in men from 34.5 +/- 2.3 to 38.3 +/- 3 mmHg, P < 0.05). Morphine decreased hypoxic sensitivity in women from 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 to 0.5 +/- 0.4 l [center dot] min sup -1 [center dot] % sup -1 (P < 0.05) but did not cause a decrease in men (control = 1.0 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1 vs. morphine = 0.9 +/- 0.5 l [center dot] min sup -1 [center dot] % sup -1). Weight, lean body mass, body surface area, and calculated fat mass differed between the sexes, but their inclusion in the analysis as a covariate revealed no influence on the differences between men and women in morphine-induced changes.     

Comparison of Remifentanil and Fentanyl in Patients Undergoing Craniotomy for Supratentorial Space-occupying Lesions

Background: Remifentanil hydrochloride is an ultra-short-acting, esterase-metabolized micro-opioid receptor agonist. This study compared the use of remifentanil or fentanyl during elective supratentorial craniotomy for space-occupying lesions.

Methods: Sixty-three adults gave written informed consent for this prospective, randomized, double-blind, multiple-center trial. Anesthesia was induced with thiopental, pancuronium, nitrous oxide/oxygen, and fentanyl (n = 32; 2 micro gram [center dot] kg [center dot] sup -1 min sup -1) or remifentanil (n = 31; 1 micro [center dot] kg sup -1 [center dot] min sup -1). After tracheal intubation, infusion rates were reduced to 0.03 micro gram [center dot] kg sup -1 [center dot] min sup -1 (fentanyl) or 0.2 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil) and then adjusted to maintain anesthesia and stable hemodynamics. Isoflurane was given only after specified infusion rate increases had occurred. At the time of the first burr hole, intracranial pressure was measured in a subset of patients. At bone flap replacement either saline (fentanyl group) or remifentanil ([nearly equal] 0.2 micro gram [center dot] kg sup -1 [center dot] min sup -1) were infused until dressing completion. Hemodynamics and time to recovery were monitored for 60 min. Analgesic requirements and nausea and vomiting were observed for 24 h. Neurological examinations were performed before operation and on postoperative days 1 and 7.

Results: Induction hemodynamics were similar. Systolic blood pressure was greater in the patients receiving fentanyl after tracheal intubation (fentanyl = 127 +/- 18 mmHg; remifentanil = 113 +/- 18 mmHg; P = 0.004). Intracranial pressure (fentanyl = 14 +/- 13 mmHg; remifentanil = 13 +/- 10 mmHg) and cerebral perfusion pressure (fentanyl = 76 +/- 19 mmHg; remifentanil = 78 +/- 14 mmHg) were similar. Isoflurane use was greater in the patients who received fentanyl. Median time to tracheal extubation was similar (fentanyl = 4 min: range = -1 to 40 min; remifentanil = 5 min: range = 1 to 15 min). Seven patients receiving fentanyl and none receiving remifentanil required naloxone. Postoperative systolic blood pressure was greater (fentanyl = 134 +/- 16 mmHg; remifentanil = 147 +/- 15 mmHg; P = 0.001) and analgesics were required earlier in patients receiving remifentanil. Incidences of nausea and vomiting were similar.     

A Comparison of Remifentanil and Morphine Sulfate for Acute Postoperative Analgesia after Total Intravenous Anesthesia with Remifentanil and Propofol

Background: The transition from remifentanil intraoperative anesthesia to postoperative analgesia must be planned carefully due to the short duration of action (3-10 min) of remifentanil hydrochloride, a potent, esterase-metabolized micro-opioid agonist. This study compared the efficacy and safety of transition regimens using remifentanil or morphine sulfate for immediate postoperative pain relief in patients who had surgery under general anesthesia with remifentanil/propofol.

Methods: One hundred fifty patients who had received open-label remifentanil and propofol for intraoperative anesthesia participated in this multicenter, double-blind, double-dummy study and were randomly assigned to either the remifentanil (R) group or the morphine sulfate (M) group. Twenty minutes before the anticipated end of surgery, the propofol infusion was decreased by 50%, and patients received either a placebo bolus (R group) or a bolus of 0.15 mg/kg morphine (M group). At the end of surgery, the propofol and remifentanil maintenance infusions were discontinued and the analgesic infusion was started: either 0.1 micro gram [center dot] kg sup -1 [center dot] min sup -1 remifentanil (R group) or placebo analgesic infusion (M group). During the 25 min after tracheal extubation, remifentanil titrations in increments of 0.025 micro gram [center dot] kg sup -1 [center dot] min sup -1 and placebo boluses (R group), or 2 mg intravenous morphine boluses and placebo rate increases (M group) were administered as necessary at 5-min intervals to control pain. Patients received the 0.075 mg/kg intravenous morphine bolus (R group) or placebo (M group) at 25 and 30 min after extubation, and the analgesic infusion was discontinued at 35 min. From 35 to 65 minutes after extubation, both groups received 2-6 mg open-label morphine analgesia every 5 min as needed.

Results: Successful analgesia, defined as no or mild pain with adequate respiration (respiratory rate [RR] >or= to 8 breaths/min and pulse oximetry >or= to 90%), was achieved in more patients in the R group than in the M group (58% vs. 33%, respectively) at 25 min after extubation (P < 0.05). The median remifentanil rate for successful analgesia was 0.125 micro gram [center dot] kg sup -1 [center dot] min sup -1 (range, 0.05-0.23 micro gram [center dot] kg sup -1 [center dot] min sup -1), and the median number of 2-mg morphine boluses used was 2 (range, 0-5 boluses). At 35 min after extubation, >or= to 74% of patients in both groups experienced moderate to severe pain. Median recovery times from the end of surgery were similar between groups. Transient respiratory depression, apnea, or both were the most frequent adverse events (14% for the R group vs. 6% for the M group; P > 0.05).     

Effect of Combining Naloxone and Morphine for Intravenous Patient-controlled Analgesia

Background: An early study showed that a naloxone infusion decreased the incidence of morphine-related side effects from intravenous patient-controlled analgesia. The authors tested the hypothesis that a more convenient combination of morphine and naloxone via patient-controlled analgesia would decrease the incidence of side effects compared to morphine alone.

Methods: Patients scheduled for hysterectomy under general anaesthesia were enrolled in a double-blind, randomized, placebo-controlled trial. Patients received a standardized general anesthetic and postoperative patient-controlled analgesia. They were randomized to receive 60 mg patient-controlled analgesia morphine in 30 ml saline or 60 mg morphine in 30 ml saline with naloxone 0.8 mg. Parameters for patient-controlled analgesia were a 1-mg bolus of morphine with a 5-min lockout and no background infusion. Patient recall of nausea, vomiting, itching, and pain (at rest and with movement) were assessed at 6 and 24 h postoperatively by verbal rating score. Pain was also assessed by a 0- to 100-mm visual analog score, and sedation was assessed by an observer. The amount of morphine used and the requirements for symptomatic treatment were also recorded.

Results: Ninety-two patients completed the study, with no significant differences in outcomes between groups. At 24 h, the incidence of nausea was 84.8% in each group; the incidence of pruritus was 56.5% in the naloxone group and 58.7% in the placebo group. There were also no differences in symptomatic treatment requirements, pain scores, morphine use, or sedation between groups. The median dose of naloxone received equated to 0.38 [mu]g [middle dot] kg-1 [middle dot] h-1 over 24 h.     

Lack of Analgesic Activity of Morphine-6-glucuronide after Short-term Intravenous Administration in Healthy Volunteers

Background: The analgesic activity of morphine-6-glucuronide (M-6-G) is well recognized for its contribution to the effects of morphine and its possible use as an opioid analgesic with a wider therapeutic range than morphine. The present study attempted to quantify the relative contribution of M-6-G to analgesia observed after systemic administration of morphine.

Methods: In a placebo-controlled, sixfold crossover study in 20 healthy men, the effects of M-6-G were assessed at steady-state plasma concentrations of M-6-G identical to and two and three times higher than those measured after administration of morphine. Morphine and M-6-G were administered as an intravenous bolus followed by infusion over 4 h. Dosage A was M-6-G-bolus of 0.015 mg/kg plus infusion of 0.0072 mg [center dot] kg sup -1 [center dot] h sup -1. Dosage B was M-6-G-bolus of 0.029 mg/kg plus infusion of 0.014 mg [center dot] kg sup -1 [center dot] h sup -1. Dosage C was M-6-G-bolus of 0.044 mg/kg plus infusion of 0.022 mg [center dot] kg sup -1 [center dot] h sup -1. Dosage D was a morphine bolus of 0.14 mg/kg plus infusion of 0.05 mg [center dot] kg sup -1 [center dot] h sup -1 for 4 h. Dosage E was M-6-G combined with morphine (doses A + D). Dosage F was a placebo. The analgesic effects of M-6-G and morphine were measured before administration of the bolus and after 3.5 h using an experimental pain model based on pain-related cortical potentials and pain ratings after specific stimulation of the nasal nociceptor with short pulses of gaseous carbon dioxide.

Results: Morphine significantly reduced subjective and objective pain correlates compared with placebo. In contrast, M-6-G produced no statistically significant effects. The addition of M-6-G to morphine did not increase the effects of morphine. Morphine produced significantly more side effects than M-6-G.     

Remifentanil versus Remifentanil/midazolam for Ambulatory Surgery during Monitored Anesthesia Care

Background: This study was designed to define the appropriate dose of remifentanil hydrochloride alone or combined with midazolam to provide satisfactory comfort and maintain adequate respiration for a monitored anesthesia care setting.

Methods: One hundred fifty-nine patients scheduled for outpatient surgery participated in this multicenter, double-blind study. Patients were randomly assigned to one of two groups: remifentanil, 1 micro gram/kg, given over 30 s followed by a continuous infusion of 0.1 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil); remifentanil, 0.5 micro gram/kg, given over 30 s followed by a continuous infusion of 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil + midazolam). Five minutes after the start of the infusion, patients received a loading dose of saline placebo (remifentanil) or midazolam, 1 mg, (remifentanil + midazolam). If patients were not oversedated, a second dose of placebo or midazolam, 1 mg, was given. Remifentanil was titrated (in increments of 50% from the initial rate) to limit patient discomfort or pain intraoperatively, and the infusion was terminated at the completion of skin closure.

Results: At the time of the local anesthetic, most patients in the remifentanil and remifentanil + midazolam groups experienced no pain (66% and 60%, respectively) and no discomfort (66% and 65%, respectively). The final mean (+/- SD) remifentanil infusion rates were 0.12 +/- 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil) and 0.07 +/- 0.03 micro gram [center dot] kg sup -1 [center dot] min sup -1 (remifentanil + midazolam). Fewer patients in the remifentanil + midazolam group experienced nausea compared with the remifentanil group (16% vs. 36%, respectively; P < 0.05). Four patients (5%) in the remifentanil group and two patients (2%) in the remifentanil + midazolam group experienced brief periods of oxygen desaturation (SpO2 < 90%) and hypoventilation (< 8 breaths/min).     

Remifentanil versus Morphine Analgesia and Sedation for Mechanically Ventilated Critically Ill Patients: A Randomized Double Blind Study

Background: The rapid onset and offset of action of remifentanil could make it quickly adjustable to the required level of sedation in critically ill patients. The authors hypothesized that the efficacy of a remifentanil-based regimen was greater than that of a morphine-based regimen.

Methods: Forty intent-to-treat patients were randomly allocated to receive a blinded infusion of either remifentanil 0.15 [mu]g[middle dot]kg-1[middle dot]min-1 or morphine 0.75 [mu]g[middle dot]kg-1[middle dot]min-1. The opioid infusion was titrated, in the first intent, to achieve optimal sedation defined as Sedation Agitation scale of 4. A midazolam open-label infusion was started if additional sedation was required.

Results: The mean percentage hours of optimal sedation was significantly longer in the remifentanil group (78.3 +/- 6.2) than in the morphine group (66.5 +/- 8.5). This was achieved with less frequent infusion rate adjustments (0.34 +/- 0.25 changes/h) than in the morphine group (0.42 +/- 0.22 changes/h). The mean duration of mechanical ventilation and extubation time were significantly longer in the morphine group (18.1 +/- 3.4 h, 73 +/- 7 min) than in the remifentanil group (14.1 +/- 2.8 h, 17 +/- 6 min), respectively. Remifentanil mean infusion rate was 0.13 +/- 0.03 [mu]g[middle dot]kg-1[middle dot]min-1, whereas morphine mean infusion rate was 0.68 +/- 0.28 [mu]g[middle dot]kg-1[middle dot]min-1. More subjects in the morphine group (9 of 20) than in the remifentanil group (6 of 20) required midazolam. The incidence of adverse events was low and comparable across the two treatment groups.     

Double-blind, Randomized Comparison of Ondansetron and Intraoperative Propofol to Prevent Postoperative Nausea And Vomiting

Background: Breast surgery is associated with a high incidence of postoperative nausea and vomiting. Propofol and prophylactic administration of ondansetron are associated with a lower incidence of postoperative nausea and vomiting. To date no comparison of these two drugs has been reported. A randomized study was done to compare the efficacy of ondansetron and intraoperative propofol given in various regimens.

Methods: Study participants included 89 women classified as American Society of Anesthesiologists physical status 1 or 2 who were scheduled for major breast surgery. Patients were randomly assigned to one of four groups. Group O received 4 mg ondansetron in 10 ml 0.9% saline and groups PI, PIP, and PP received 10 ml 0.9% saline before anesthesia induction. Group O received thiopental, isoflurane, nitrous oxide-oxygen, and fentanyl for anesthesia. Group PI received propofol, isoflurane, nitrous oxide-oxygen, and fentanyl. Group PIP received propofol, isoflurane, nitrous oxide-oxygen, and fentanyl. Thirty minutes before expected skin closure, isoflurane was discontinued and 50 to 150 micro gram [centered dot] kg sup -1 [centered dot] min sup -1 propofol was given intravenously to maintain anesthesia. Group PP received propofol for induction and maintenance of anesthesia, nitrous oxide-oxygen, and fentanyl. Postoperative pain relief was provided with morphine administered by a patient-controlled analgesia pump. The incidence of nausea and vomiting, requests for rescue antiemetic and sedation, pain scores, and hemodynamic data were recorded for 24 h.

Results: Within 6 h of surgery, groups O and PP had a lower incidence of nausea compared with groups PI and PIP (P < 0.05). Fewer patients in group PP (19%) vomited during the 24-h period compared with groups O (48%), PI (64%), and PIP (52%) (P < 0.05). The incidence of antiemetic use was also less in group PP (P < 0.05). Patients in group PP had lower sedation scores at 30 min and at 1 h (P < 0.05). There were no differences among the groups in pain scores, blood pressure, heart rate, respiratory rate, and incidence of pruritus.     

Influence of Acidosis on Cardiotonic Effects of Milrinone

Background: The present study was designed to determine whether augmentation of cardiac performance by milrinone is affected by acidosis in in vivo canine and in vitro guinea pig preparations, and to elucidate a mechanism in relation to the cyclic adenosine monophosphate (cAMP) formation.

Methods: Halothane-anesthetized, ventilated dogs were randomly assigned to a control group (arterial pH [pHa] [nearly =] 7.4, base excess [BE] > -2 mM; n = 7), mild acidosis group (pHa [nearly =] 7.2, BE < -9 mM; n = 7), or severe acidosis group (pHa < 7, BE < -20 mM; n = 6). Arterial blood pressure, left ventricular pressure (including maximum rate of increase, LV dP/dtmax), and pulmonary blood flow (PBF) were measured. Acidosis was induced by transient hypoxia and maintained with hydrogen chloride infusion. Hemodynamic responses to milrinone infusions at 2 and 5 micro gram [center dot] kg sup -1 [center dot] min were then studied. In addition, left atria and right ventricular strips were dissected from guinea pig hearts and suspended in HEPES-Tyrode solution, with pH values adjusted to 7.4, 7, or 6.6. The concentration-response relation of isometric contractions for milrinone (10 sup -7 to 10 sup -4 M) and 8-bromo-cAP (10 sup -4 to 10 sup -3 M) were determined.

Results: In the control group of dogs, significant increases in LN dP/dtmax (2,674 +/- 822 to 3,999 +/- 1,016 mmHg/s [means +/- SD]) and PBF (2.04 +/- 0.98 to 2.44 +/- 0.96 l/min [means +/- SD]) were seen with a milrinone infusion of 5 micro gram [center dot] kg sup -1 [center dot] min sup -1. In the mild acidosis group, 5 micro gram [center dot] kg sup -1 min sup -1 milrinone also increased LV dP/dtmax and PBF. However, neither LV dP/dtmax nor PBF changed in the severe acidosis group. In in vitro experiments, milrinone exerted a positive inotropic effect in a concentration-dependent manner on the right ventricular preparations at pH 7.4, but not at pH 7 and 6.6, whereas no significant difference was observed in inotropic responses to 8-bromo-cAMP at pH values of 6.6, 7, and 7.4 on the right ventricular strips. In the right ventricular in vitro preparation, 10 sup -4 M milrinone was accompanied by a significant increase in intracellular cAMP content at a pH of 7.4 but not 7.     

Meperidine Decreases the Shivering Threshold Twice as Much as the Vasoconstriction Threshold

Background: Meperidine administration is a more effective treatment for shivering than equianalgesic doses of other opioids. However, it remains unknown whether meperidine also profoundly impairs other thermoregulatory responses, such as sweating or vasoconstriction. Proportional inhibition of vasoconstriction and shivering suggests that the drug acts much like alfentanil and anesthetics but possesses greater thermoregulatory than analgesic potency. In contrast, disproportionate inhibition would imply a special antishivering mechanism. Accordingly, the authors tested the hypothesis that meperidine administration produces a far greater concentration-dependent reduction in the shivering than vasoconstriction threshold.

Methods: Nine volunteers were each studied on three days: 1) control (no opioid); 2) a target total plasma meperidine concentration of 0.6 micro gram/ml (40 mg/h); and 3) a target concentration of 1.8 micro gram/ml (120 mg/h). Each day, skin and core temperatures were increased to provoke sweating and then subsequently reduced to elicit vasoconstriction and shivering. Core-temperature thresholds (at a designated skin temperature of 34 degrees Celsius) were computed using established linear cutaneous contributions to control sweating (10%) and vasoconstriction and shivering (20%). The dose-dependent effects of unbound meperidine on thermoregulatory response thresholds was then determined using linear regression. Results are presented as means +/- SDs.

Results: The unbound meperidine fraction was [nearly equal] 35%. Meperidine administration slightly increased the sweating threshold (0.5 +/- 0.8 degrees Celsius [center dot] micro gram sup -1 [center dot] ml; r2 = 0.51 +/- 0.37) and markedly decreased the vasoconstriction threshold (-3.3 +/- 1.5 degrees Celsius [center dot] micro gram sup -1 [center dot] ml; r sup 2 = 0.92 +/- 0.08). However, meperidine reduced the shivering threshold nearly twice as much as the vasoconstriction threshold (-6.1 +/- 3.0 degrees Celsius [center dot] micro gram sup -1 [center dot] ml; r2 = 0.97 +/- 0.05; P = 0.001).     

Selective Pulmonary Vasodilation by Intravenous Infusion of an Ultrashort Half-life Nucleophile/Nitric Oxide Adduct

Background: PROLI/NO (C5 H7 N3 O4 Na2 [center dot] CH3 OH) is an ultrashort-acting nucleophile/NO adduct that generates NO (half-life 2 s at 37 [degree sign] Celsius and pH 7.4). Because of its short half-life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension.

Methods: In eight awake healthy sheep with pulmonary hypertension induced by 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F sub 2 alpha, the authors compared PROLI/NO with two reference drugs-inhaled NO, a well-studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 micro gram [center dot] kg sup -1 [center dot] min sup -1 of SNP or 0.75, 1.5, 3, 6, and 12 micro gram [center dot] kg sup -1 [center dot] min sup -1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized.

Results: Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 micro gram [center dot] kg sup -1 [center dot] min sup -1, which decreased pulmonary vascular resistance by 63% (P < 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 micro gram [center dot] kg sup -1 [center dot] min sup -1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P < 0.01 with all data pooled).     

Interactions between Midazolam and Remifentanil during Monitored Anesthesia Care

Background: Remifentanil, an ultra-short-acting opioid analgesic, may be useful as an intravenous adjuvant to local anesthesia for treating patient discomfort and pain during monitored anesthesia care (MAC). However, the remifentanil dose requirements, interactions with other commonly used sedative drugs (such as midazolam), and recovery characteristics after ambulatory procedures have not been determined. Therefore, this study was designed to evaluate the safety and efficacy of remifentanil alone and in combination with different doses of midazolam during MAC.

Methods: Eighty-one healthy consenting women scheduled for elective breast biopsy procedures were randomly assigned to one of four treatment groups according to an institutional review board-approved, double-blind, placebo-controlled protocol. The study medication (containing either saline or 2 mg, 4 mg, or 8 mg of midazolam) was administered intravenously 5 min before starting an infusion of remifentanil at 0.1 micro gram [centered dot] kg sup -1 [centered dot] min sup -1. The remifentanil infusion was subsequently adjusted in 0.025- and 0.05-micro gram [centered dot] kg sup -1 [centered dot] min sup -1 increments to maintain patient comfort and adequate ventilation during the operation. The level of sedation was assessed at 1- to 10-min intervals during the procedure using the inverted observer's assessment of alertness/sedation (OAA/S) scale, with a score of 1 = awake, alert to 5 = asleep, unarousable. Discomfort and pain were assessed using numerical rating scales. Hemoglobin oxygen saturation, respiratory rate, blood pressure (systolic, diastolic, mean), and heart rate were monitored at 1- to 5-min intervals. Intraoperative amnesia was assessed by asking patients to recall a picture shown 5 min after the study medication was administered. Recovery was evaluated using the Aldrete score and the times to "home readiness" and actual discharge. Side effects and patient satisfaction were assessed in a follow-up telephone interview on the first postoperative day.

Results: Midazolam produced dose-dependent increases in the median level of sedation. Remifentanil produced a greater reduction in respiratory rate in the 4-mg and 8-mg midazolam groups. However, there were no significant differences in the hemodynamic variables or discharge times. Patients with OAA/S scores of 1 to 3 ("light" sedation) 5 min after the study medication experienced a greater incidence of intraoperative pruritus and postoperative nausea and vomiting (PONV) compared with those with OAA/S scores of 4 to 5 ("deep" sedation). Discharge times were prolonged for patients in the light sedation group in whom PONV developed.     

Effect of Flumazenil on Ventilatory Drive during Sedation with Midazolam and Alfentanil

Background: Patients who receive a combination of a benzodiazepine and an opioid for conscious sedation are at risk for developing respiratory depression. While flumazenil effectively antagonizes the respiratory depression associated with a benzodiazepine alone, its efficacy in the presence of both a benzodiazepine and an opioid has not been established. This study was designed to determine whether flumazenil can reverse benzodiazepine-induced depression of ventilatory drive in the presence of an opioid.

Methods: Twelve healthy volunteers completed this randomized, double-blind, crossover study. Ventilatory responses to carbon dioxide and to isocapnic hypoxia were determined during four treatment phases: (1) baseline, (2) alfentanil infusion; (3) combined midazolam and alfentanil infusions, and (4) combined alfentanil, midazolam, and "study drug" (consisting of either flumazenil or flumazenil vehicle) infusions. Subjects returned 2-6 weeks later to receive the alternate study drug.

Results: Alfentanil decreased the slope of the carbon dioxide response curve from 2.14 +/- 0.40 to 1.43 +/- 0.19 l [dot] min sup -1 [dot] mmHg sup -1 (x +/- SE, P < 0.05), and decreased the minute ventilation at PET CO2 = 50 mmHg (V with dotE 50) from 19.7 +/- 1.2 to 14.8 +/- 0.9 l [dot] min sup -1 (P < 0.05). Midazolam further reduced these variables to 0.87 +/- 0.17 l [dot] min sup -1 [dot] mmHg sup -1 (P < 0.05) and 11.7 +/- 0.8 l [dot] min sup -1 (P <0.05), respectively. With addition of flumazenil, slope and V with dot sub E 50 increased to 1.47 +/- 0.37 l [dot] min sup -1 [dot] mmHg sup -1 (P < 0.05) and 16.4 +/- 2.0 l [dot] min sup -1 (P < 0.05); after placebo, the respective values of 1.02 +/- 0.19 l [dot] min sup -1 [dot] mmHg sup -1 and 12.5 +/- 1.2 l [dot] min sup -1 did not differ significantly from their values during combined alfentanil and midazolam administration. The effect of flumazenil differed significantly from that of placebo (P < 0.05). Both the slope and the displacement of the hypoxic ventilatory response, measured at PET CO2 = 46 +/- 1 mmHg, were affected similarly, with flumazenil showing a significant improvement compared to placebo.     

Pharmacokinetics Anesthesiologists, and Pharmacodynamics of Remifentanil in Persons with Renal Failure Compared with Healthy Volunteers

Background: Remifentanil is an opioid analgesic for use in anesthesia. An ester linkage renders it susceptible to rapid metabolism by blood and tissue esterases. Thus it was hypothesized that remifentanil elimination would be independent of renal function. Because its principal metabolite (GR90291) is eliminated renally, it would depend on renal function. This study was designed to evaluate the pharmacokinetics and pharmacodynamics of remifentanil and its metabolite in persons with and without renal failure.

Methods: Two groups of volunteers received two-stage infusions of remifentanil: low dose with 0.0125 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 1 h followed by 0.025 micro gram kg sup -1 [center dot] min sup -1 for 3 h; and high dose with 0.025 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 1 h followed by 0.05 micro gram [center dot] kg sup -1 [center dot] min sup -1 for 3 h. Blood samples were collected for analysis of remifentanil and GR90291 concentrations. The pharmacokinetics of remifentanil were fit using a one-compartment pharmacokinetic model. Remifentanil's effect was determined intermittently using minute ventilation during a hypercapnic (7.5% CO2) challenge.

Results: Fifteen patients with renal failure and eight control participants were enrolled. The clearance and volume of distribution of remifentanil were not different between those with renal failure and the controls. Patients with renal failure showed a marked reduction in the elimination of GR90291; the half-life of the metabolite increased from 1.5 h in the controls to more than 26 h in patients with renal failure. The steady-state concentration of GR90291 is likely to be more than 25 times higher in persons with renal failure. There were no obvious differences in opioid effects on minute ventilation in the controls and in patients with renal failure.     

Epidural Clonidine Used as the Sole Analgesic Agent during and after Abdominal Surgery: A Dose-Response Study

Background: Many studies have shown the beneficial effect of epidural clonidine in postoperative pain management. In these studies, the patients received local anesthetics, opioids, or both in combination with clonidine. Due to the interactive potentiation of those drugs, the importance of the intrinsic analgesic properties of the alpha2 -adrenoceptor agonist is difficult to establish. The authors investigated the analgesic potency of epidural clonidine when used as the sole analgesic agent during and after major abdominal surgery.

Methods: Fifty young adult patients undergoing intestinal surgery under general anesthesia with propofol were studied. At induction, the patients received epidurally either an initial dose of 2 micro gram/kg clonidine followed by an infusion of 0.5 micro gram [center dot] kg-1 [center dot] h-1 (group 1, n = 10) or 4 micro gram/kg followed by 1 micro gram [center dot] kg-1 [center dot] h-1 (group 2, n = 20) or 8 micro gram [center dot] kg-1 [center dot] h-1 followed by an infusion of 2 micro gram [center dot] kg-1 [center dot] h-1 (group 3, n = 20). During the operation, increases in arterial blood pressure or heart rate that did not respond to a propofol bolus (0.5 mg/kg) were treated with a bolus of intravenous lidocaine (1 mg/kg). Three successive injections were allowed. When baseline values were not restored, opioids were added and the patient was removed from the study. After operation, the clonidine infusions were maintained for 12 h. During this period and at every 30 min, sedation scores and visual analog scale values at rest and at cough were noted. In case of subjective scores up to 5 cm at rest or up to 8 cm at cough, the patients were given access to a patient-controlled analgesia device that delivered epidural bupivacaine. The end point of the study was reached once the patient activated the analgesic delivery button.

Results: During surgery, 60% of patients in group 1 compared with 33% of patients in group 2 and only 5% of patients in group 3 were removed from the study protocol because of inadequate anesthesia (P < 0.05). After operation, epidural clonidine provided complete analgesia lasting 30 +/- 21 min in group 1 compared with 251 + 237 min in group 2 or 369 +/- 256 min in group 3 (P < 0.05 for group 1 vs. groups 2 and 3 and group 2 vs. group 3).     

Alterations in Canine Left Ventricular-arterial Coupling and Mechanical Efficiency Produced by Propofol

Background: Propofol reduces blood pressure by decreasing left ventricular (LV) afterload and myocardial contractility. This investigation tested the hypothesis that propofol preserves LV-arterial coupling and mechanical efficiency because of these simultaneous hemodynamic actions.

Methods: Experiments were conducted in open-chest dogs (n = 8) instrumented for measurement of aortic and LV pressure, dP/dtmax, and LV volume. Myocardial contractility was assessed with the slope (E sub es) of the LV end systolic pressure-volume relationship. Effective arterial elastance (Ea; the ratio of end systolic arterial pressure to stroke volume), stroke work (SW), and pressure-volume area (PVA) were determined from the LV pressure-volume relationships. Dogs were studied 30 min after instrumentation and after 15-min intravenous infusions of propofol at 5, 10, 20, and 40 mg [center dot] kg sup -1 [center dot] h sup -1.

Results: Propofol caused dose-dependent decreases in Ees (4.7 +/- 0.9 during control to 2.7 +/- 0.5 mmHg/ml during the high dosage) and dP/dtmax, indicating a direct negative inotropic effect. Ea increased at the 10 mg [center dot] kg sup -1 [center dot] h sup -1 dose of propofol but decreased at higher dosages. Propofol decreased the ratio of Ees to Ea (0.88 +/- 0.13 during control to 0.56 +/- 0.10 during the high dosage), consistent with impairment of LV-arterial coupling. Propofol also reduced the ratio SW to PVA (0.54 +/- 0.03 during control to 0.45 +/- 0.03 during the 20 mg [center dot] kg sup -1 [center dot] h sup -1), suggesting a decline in LV mechanical efficiency. SW and PVA recovered toward baseline values at the 40 mg [center dot] kg sup -1 [center dot] h sup -1 dose.     

Influence of Lidocaine on Endotoxin-induced Leukocyte-Endothelial Cell Adhesion and Macromolecular Leakage in Vivo

Background: Endotoxin activates leukocyte-endothelial cell adhesion, vascular leakage, and changes in vascular microhemodynamics. The aim of this study was to determine whether lidocaine, which inhibits the activation of leukocytes, could attenuate microcirculatory disturbances during endotoxemia.

Methods: Thirty anesthetized male rats were randomly assigned to receive one of three treatments (n = 10 for each group): infusion of saline (control group), infusion of Escherichia coli endotoxin (LPS group: 2 mg [center dot] kg sup -1 [center dot] h sup -1 lipopolysaccharides) without lidocaine treatment, or infusion of endotoxin with lidocaine pretreatment 30 min before baseline measurements (lidocaine group: intravenous bolus of 2 mg/kg and continuous infusion of 2 mg [center dot] kg sup -1 [center dot] h sup -1). Leukocyte adherence, erythrocyte velocity (VRBC), and vessel diameters (Dv) were determined at baseline and at 60 and 120 min in mesenteric post-capillary venules using in vivo videomicroscopy. Macromolecular leakage was determined by measuring the extravasation of fluorescence-labeled albumin. Venular wall shear rate (tau) was calculated according to the equation tau = 8 [center dot] VRBC [center dot] Dv sup -1.

Results: Lidocaine significantly attenuated the increase of leukocyte adherence during endotoxemia. There were no significant differences of tau within or between the groups. Macro-molecular leakage exhibited the greatest increase in the LPS group. In the lidocaine group, it was significantly decreased but still increased compared with the control group.     

Mechanisms whereby Propofol Mediates Peripheral Vasolidation in Humans: Sympathoinhibition or Direct Vascular Relaxation?

Background: Anesthetic induction and maintenance with propofol are associated with decreased blood pressure that is, in part, due to decreased peripheral resistance. Several possible mechanisms whereby propofol could reduce peripheral resistance include a direct action of propofol on vascular smooth muscle, an inhibition of sympathetic activity to the vasculature, or both. This study examined these two possibilities in humans by measuring the forearm vascular responses to infusions of propofol into the brachial artery (study 1) and by determining the forearm arterial and venous responses to systemic (intravenous) infusions of propofol after sympathetic denervation of the forearm by stellate blockade (study 2).

Methods: Bilateral forearm venous occlusion piethysmography was used to examine forearm vascular resistance (FVR) and forearm vein compliance (FVC). Study 1 used infusion of intralipid (time control) and propofol at rates between 83 and 664 micro gram/min into the brachial artery of 11 conscious persons and compared responses to arterial infusions of sodium nitroprusside (SNP) at 0.3, 3.0, and 10 micro gram/min. Venous blood from the infusion arm was assayed for plasma propofol concentrations. In study 2, after left stellate block (12 ml 0.25% bupivacaine + 1% lidocaine), six participants were anesthetized and maintained with propofol infusions of 125 and 200 micro gram [centered dot] kg sup -1 [centered dot] min sup -1. Simultaneous right forearm (unblocked) blood flow dynamics served as the time control. In three additional conscious participants, intrabrachial artery infusions of SNP and nitroglycerin, both at 10 micro gram/min, were performed before and after stellate blockade of the left forearm to determine whether the sympathetically denervated forearm vessels could dilate beyond the level produced by denervation alone.

Results: In study 1, infusion of intralipid or propofol into the brachial artery did not change FVR or FVC. Sodium nitroprusside significantly decreased FVR in a dose-dependent manner by 22 +/- 5%, 65 +/- 3%, and 78 +/- 2% (mean +/- SEM) but did not change FVC. During the incremental propofol infusions, plasma propofol concentrations increased from 0.2 to 10.1 micro gram/ml and averaged 7.4 +/- 1.1 micro gram/ml during the highest infusion rate. In study 2, stellate ganglion blockade decreased FVR by 50 +/- 6% and increased FVC by 58 +/- 10%. Propofol anesthesia at 125 and 200 micro gram [centered dot] kg sup -1 [centered dot] min sup -1 progressively reduced mean arterial pressure. In the arm with sympathetic denervation, FVR and FVC showed no further changes during propofol anesthesia, whereas in the control arm FVR significantly decreased by 41 +/- 9% and 42 +/- 7%, and FVC increased significantly by 89 +/- 27% and 85 +/- 32% during 125 and 200 micro gram [centered dot] kg sup -1 [centered dot] min sup -1 infusions of propofol, respectively. In the three additional conscious participants, intraarterial infusion of SNP and nitroglycerin (TNG) after the stellate blockade resulted in a further decrease of FVR and a further increase of FVC.     

The Dose-Response Relation and Cost-effectiveness of Granisetron for the Prophylaxis of Pediatric Postoperative Emesis

Background: Postoperative nausea and vomiting (PONV) may delay discharge from hospital after ambulatory surgery. The antiserotonin agents, ondansetron and granisetron, provide effective prophylaxis against chemotherapy-induced and postoperative nausea and vomiting in adults, but are expensive. We determined the dose-response relation of granisetron and the financial impact of using this drug in preventing PONV after pediatric outpatient surgery.

Methods: In a randomized, double-blind, placebo-controlled study, 97 pediatric outpatients received a placebo or 10 or 40 micro gram [centered dot] kg sup -1 granisetron intravenously during a standardized anesthetic. Episodes of postoperative retching, vomiting, and times to discharge readiness were recorded. A decision analysis tree was used to divide each study group into nine mutually exclusive subgroups, depending on the incidence of PONV, need for rescue therapy, and the side effects of antiemetics. Costs and probabilities were assigned to each subgroup, and the cost-effectiveness ratio was determined by dividing the sum of these weighted costs by the number of patients free from both PONV and antiemetic side effects.

Results: Granisetron (40 micro gram [centered dot] kg sup -1 intravenously) was more effective than a placebo or 10 micro gram [centered dot] kg sup -1 granisetron in decreasing the incidence and frequency of postoperative emesis, both in the ambulatory surgery center and during the first 24 h. Patients receiving 40 micro gram [centered dot] kg sup -1 granisetron also had shorter times to discharge readiness compared with those receiving a placebo. Administering this dose of granisetron to all high-risk patients would cost the ambulatory care center an additional $99 (95% CI, range $89-$112) per emesis-free patient if nursing labor costs are excluded and $101 (95% CI, range $91-$113) if nursing costs are included.     

Hypothermic Modulation of Cerebral Ischemic Injury during Cardiopulmonary Bypass in Pigs

Background: The aim of this study was to determine whether progressive levels of hypothermia (37, 34, 31, or 28 [degree sign] Celsius) during cardiopulmonary bypass (CPB) in pigs reduce the physiologic and metabolic consequences of global cerebral ischemia.

Methods: Sagittal sinus and cortical microdialysis catheters were inserted into anesthetized pigs. Animals were placed on CPB and randomly assigned to 37 [degree sign] Celsius (n = 10), 34 [degree sign] Celsius (n = 10), 31 [degree sign] Celsius (n = 11), or 28 [degree sign] Celsius (n = 10) management. Next 20 min of global cerebral ischemia was produced by temporarily ligating the innominate and left subclavian arteries, followed by reperfusion, rewarming, and termination of CPB. Cerebral oxygen metabolism (CMRO2) was calculated by cerebral blood flow (radioactive microspheres) and arteriovenous oxygen content gradient. Cortical excitatory amino acids (EAA) by microdialysis were measured using high-performance liquid chromatography. Electroencephalographic (EEG) signals were graded by observers blinded to the protocol. After CPB, cerebrospinal fluid was sampled to test for S-100 protein and the cerebral cortex was biopsied.

Results: Cerebral oxygen metabolism increased after rewarming from 28 [degree sign] Celsius, 31 [degree sign] Celsius, and 34 [degree sign] Celsius CPB but not in the 37 [degree sign] animals; CMRO2, remained lower with 37 [degree sign] Celsius (1.8 +/- 0.2 ml [center dot] min sup -1 [center dot] 100 g sup -1) than with 28 [degree sign] Celsius (3.1 +/- 0.1 ml [center dot] min sup -1 [center dot] 100 g sup -1; P < 0.05). The EEG scores after CPB were depressed in all groups and remained significantly lower in the 37 [degree sign] Celsius animals. With 28 [degree sign] Celsius and 31 [degree sign] Celsius CPB, EAA concentrations did not change. In contrast, glutamate increased by sixfold during ischemia at 37 [degree sign] Celsius and remained significantly greater during reperfusion in the 34 [degree sign] Celsius and 37 [degree sign] Celsius groups. Cortical biopsy specimens showed no intergroup differences in energy metabolites except two to three times greater brain lactate in the 37 [degree sign] Celsius animals. S-100 protein in cerebrospinal fluid was greater in the 37 [degree sign] Celsius (6 +/- 0.9 micro gram/l) and 34 [degree sign] Celsius (3.5 +/- 0.5 micro gram/l) groups than the 31 [degree sign] Celsius (1.9 +/- 0.1 micro gram/l) and 28 [degree sign] Celsius (1.7 +/- 0.2 micro gram/l) animals.