A double-blind study of the respiratory effects of nalbuphine hydrochloride in spontaneously breathing anesthetized patients

Nalbuphine hydrochloride 0.2 mg/kg was compared with meperidine 0.5 mg/kg in a double-blind study in 20 patients undergoing elective inguinal hernia repair while breathing spontaneously under general anesthesia. The respiratory effects of the two drugs studied were continuously and accurately recorded with a wet wedge spirometer throughout the procedure. The acute respiratory effects of these analgesic drugs could therefore be assessed. The measurements recorded before any surgical stimulation showed that both nalbuphine and meperidine produce a similar degree of respiratory depression. These results are at variance with earlier studies that drew conclusions from measurements that were neither continuous nor accurate. Nalbuphine was found to be a satisfactory analgesic adjuvant in this anesthetic technique.     

The effects of morphine, nalbuphine, and butorphanol on adrenergic function in canine saphenous veins

Saphenous vein rings mounted in organ chambers containing Krebs-Ringer solution were used to determine if the venodilator effects of morphine, nalbuphine, and butorphanol are the result of interference with adrenergic neurotransmission or are caused by direct depressant actions on venous smooth muscle cells. Morphine (5 X 10(-5) M and 2 X 10(-4) M) caused a dose-dependent depression of the contractile response to transmural electrical stimulation. H1- and H2- histamine antagonists did not attenuate the inhibitory effect of morphine. Concentrations of morphine and nalbuphine lower than 5 X 10(-5) M had no effect, whereas 5 X 10(-6) M butorphanol significantly depressed the evoked tension response to electrical stimulation. The contractile responses of the veins to exogenous norepinephrine (NE) were not altered by morphine, indicating a presynaptic site of action rather than a direct action on the venous smooth muscle. Transmural electrical stimulation was used to evoke release of endogenous NE. Morphine (5 X 10(-5) M and 2 X 10(-4) M), nalbuphine (2 X 10(-4) M), and butorphanol (4 X 10(-6) M) significantly decreased release of NE. Naloxone did not alter NE release and did not attenuate the inhibition of NE release observed with the opiates, indicating that the effect of morphine on this neuroeffector junction is not mediated by a naloxone-sensitive opiate receptor. Blockade of presynaptic alpha receptors by phenoxybenzamine or phentolamine augments NE release caused by transmural electrical stimulation; morphine inhibited this augmentation. The results of these experiments indicate that high concentrations of morphine may decrease NE release, an effect that may contribute to the venodilation and hypotension observed following administration of high doses of morphine in humans. In the usual analgesic doses, the venodilatory effects of morphine cannot be explained by local action on either NE release or venous smooth muscle contractility.     

Behavioral and histopathologic effects following intrathecal administration of butorphanol, sufentanil, and nalbuphine in sheep.

A large number of opioids and nonopioids have been administered epidurally and intrathecally in the hope of providing segmental analgesia without serious adverse effects. However, neurotoxicity data are generally unavailable for many of these drugs. The present study evaluated the behavioral, motor, electroencephalographic, and histopathologic changes following intrathecal injection of large and small doses of butorphanol, sufentanil, and nalbuphine in sheep. Thirty-two sheep (20-32 kg) were anesthetized and catheters placed intrathecally after hemilaminectomy. The large doses of butorphanol, sufentanil and nalbuphine were 0.375 mg/kg (4.4-5.2 ml), 7.5 micrograms/kg (3.6-4.8 ml) and 0.75 mg/kg (1.5-2.4 ml), and the small doses were 0.075 mg/kg (0.9-1.1 ml), 1.5 micrograms/kg (0.7-0.9 ml) and 0.15 mg/kg (0.38-0.5 ml), respectively. The opioids were administered intrathecally every 6 h for 3 days and the above-mentioned parameters studied. Five sheep received intrathecal saline (1.1 or 5.2 ml) and served as controls. Histopathologic changes were evaluated by a neuropathologist blinded to the study protocol. Irrespective of dose, intrathecal injection of butorphanol was associated with severe behavioral responses such as agitation, rigidity, vocalization, and restlessness, as well as prolonged or irreversible hindlimb paralysis. Electroencephalography showed increased cortical activity or seizure activity. One sheep died because of severe respiratory depression that did not respond to naloxone. Spinal cord histologic changes consisted of suppurative meningitis and myelitis as well as neuronal changes such as spongiosis and chromatolysis. Large doses of intrathecal sufentanil were associated with similar though somewhat less severe responses. The behavioral and motor changes following the small dose of intrathecal sufentanil were of mild to moderate nature. Following intrathecal nalbuphine, the above-mentioned changes were similar to those seen in control animals. We conclude that butorphanol in doses of 0.075 and 0.375 mg/kg intrathecally and sufentanil 7.5 micrograms/kg intrathecally are neurotoxic in sheep.     

Respiratory effects of expiratory flow-resistive loading in conscious and anesthetized humans

The response of breathing patterns to increased expiratory resistance is not only of physiologic interest, with respect to the control of breathing, but also of clinical interest because of its clinical relevance to obstructive diseases such as asthma and emphysema. To elucidate the response of breathing patterns to increased expiratory resistance during anesthesia, the respiratory effects of expiratory flow-resistive loading on breathing patterns were studied in 15 conscious and 10 lightly anesthetized subjects. Inspiratory time, expiratory time, respiratory frequency, inspiratory duty cycle, tidal volume, minute ventilation, and mean inspiratory flow rate were determined from a respiratory inductive plethysmograph. End-tidal CO2 was continuously recorded. In awake subjects, respiratory frequency was reduced without change in tidal volume or mean inspiratory flow rate, and minute ventilation was significantly decreased; the synchrony between rib cage and abdomen wall motion was well maintained during the loads. In contrast, in anesthetized subjects, respiratory frequency was reduced with remarkable increases in tidal volume, mean inspiratory flow rate, and minute ventilation, whereas coordination between rib cage and abdomen compartments was disturbed. End-tidal CO2 did not change in conscious subjects, but it increased in anesthetized subjects during the loads. These results indicate that there are differences between conscious and anesthetized subjects in breathing patterns during expiratory loading, and suggest that the ability to coordinate rib cage-abdomen wall motion is easily disturbed during anesthesia in patients with expiratory flow limitation.     

Hemodynamic effects of nalbuphine in patients with acute respiratory insufficiency

Examination of haemodynamic changes, after 20 mg nalbuphine had been administered IV to 11 ventilated patients with acute respiratory failure, showed that on average pulmonary arterial mean pressure increased by 8% of the initial value. This increase was reversed after the test dosage was doubled from 20 mg to 40 mg nalbuphine. Regression analysis of the correlation between changes in pulmonary arterial mean pressure and patient age resulted in an increase in mean pressure by 0.1 mmHg per year after 20 mg nalbuphine. These findings suggest that nalbuphine must be carefully monitored in elderly and pulmonary risk patients.     

A comparison of clinical and psychological effects of fentanyl and nalbuphine in ambulatory gynecologic patients

Drug dosages, length of stay (LOS), and incidence of psychological side effects of fentanyl and nalbuphine were compared in a randomized, double-blind study using unpremedicated female day-surgery patients undergoing diagnostic laparoscopy. Patients received either fentanyl 1.5 micrograms/kg (F group; n = 142), low-dose nalbuphine 300 micrograms/kg (LN group; N = 103), or high-dose nalbuphine 500 micrograms/kg (HN group; n = 41), intravenously (IV) before anesthesia consisting of thiopental, N2O, O2, and a succinylcholine infusion. Additional IV intraoperative and IM postoperative opioids were given if required for signs of inadequate anesthesia or postoperative pain. The patients' clinical and psychological status was evaluated at 20-min intervals postoperatively by a team of trained interviewers. The low- and high-dose nalbuphine groups clinically resembled the fentanyl group in terms of dosing frequency and patients' self-ratings of postoperative analgesia. Length of stay and postoperative sedation were significantly greater with nalbuphine. The incidence of psychological side effects, including dreaming and postoperative anxiety, was also greater with nalbuphine. However, patient acceptance of nalbuphine was high and was similar to that observed in patients given fentanyl.     

A comparison of the analgesic and respiratory effects of epidural nalbuphine or morphine in postthoracotomy patients

This randomized, double-blind study compared the analgesic and respiratory effects of lumbar epidural morphine 5 mg, nalbuphine 10 mg, and nalbuphine 20 mg in repeated doses in patients after thoracotomy; the first dose was administered intraoperatively. Pre-and postoperative monitoring included continuous pulse oximetry, respiratory inductance plethysmography, and repeated arterial blood gas analysis. Postoperatively, visual analogue pain scores, somnolence scores, respiratory rate, and arterial blood gases were determined for 16 h. Preoperatively, episodes of apnea were common during sleep but were not associated with low hemoglobin oxygen saturation or increased arterial carbon dioxide tension (PaCO2). During sleep, some otherwise normal patients had increased PaCO2, and 2 of 15 patients had episodes of hemoglobin oxygen saturation of less than 90%. Postoperatively, 1 and 2 h after arrival in the recovery room, patients who received morphine had lower pain scores than did those who received nalbuphine 10 or 20 mg (P less than 0.05). All 6 patients who received morphine had satisfactory analgesia. Two of 4 patients who received nalbuphine 10 mg and all 5 who received nalbuphine 20 mg were withdrawn from the study because of inadequate analgesia (morphine vs. nalbuphine 10 mg, not significant; morphine vs. nalbuphine 20 mg, P less than 0.01). Two patients who received morphine had persistently increased PaCO2 postoperatively. Two patients who received morphine had episodes of apnea and slow respiratory rate, which were most frequent 6 h after arrival in the recovery room. We conclude that lumbar epidural nalbuphine does not provide adequate analgesia after thoracotomy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tolerance to the analgesic effect of buprenorphine, butorphanol, nalbuphine, and cyclorphan, and cross-tolerance to morphine

Purpose. The increased use of opioids in the chronic treatment of pain, especially with oncologic patients, encourages the search for drugs with potent analgesic activity, but with minimal induced tolerance and cross-tolerance to morphine. Methods. Four agonist-antagonist opioid derivatives (buprenorphine, butorphanol, nalbuphine, and cyclorphan) were examined. Tolerance to the analgesic effect of the four drugs and their cross-tolerance effects with morphine were evaluated in ICR albino mice by the "hot plate method". Measurements of the analgesic effect were taken before and after chronic treatment (of 14 days duration) with these drugs, as well as morphine. Results. All tested drugs produced tolerance after 14 days of treatment. Chronic treatment with morphine reduced the effects of nalbuphine and cyclorphan, but not those of buprenorphine and butorphanol. After 14 days treatment with buprenorphine and cyclorphan, the analgesic action of morphine was reduced, but this reduction did not occur after butorphanol and nalbuphine treatments. Conclusion. Of the four agonist-antagonists tested, butorphanol seems to be least liikely to produce cross-tolerance with morphine. Received: May 15, 2000 / Accepted: April 13, 2001     

Tolerance to the mydriatic effect of buprenorphine,butorphanol, nalbuphine,and cyclorphan,and cross-tolerance to morphine in mice

An increase in the use of opioid derivatives in the treatment of pain syndrome in clinical practice, and especially in the treatment of cancer, has added impetus to the search for an agent which does not induce tolerance and cross-tolerance to other opiodis. The mydriatic effect of opioids in mice, the correlation between analgesia and mydriasis, and tolerance to the analgesic effect of morphine in mice were evaluated previously. In the present work, tolerance to the mydriatic effect of four agonist-antagonists and cross-tolerance to morphine were examined. Measurement of the pupillary diameter was performed using a binocular operating microscope. Tolerance and cross-tolerance to morphine were developed following a chronic use of buprenorphine, nalbuphine, and cyclorphan. After chronic injection of butorphanol, no tolerance or cross-tolerance to morphine was observed.     

Comparison of the sedative effects of butorphanol and midazolam

Although kappa opioid agonists and certain agonist-antagonists are known to be sedating, this effect has not been well characterized in a drug-naive population. We compared the sedative properties of intravenous butorphanol with those of midazolam or the combination in 126 healthy preoperative patients. Subjects were randomly assigned to receive one of nine treatments in a double-blind fashion: 7.1, 22.5, or 71.4 micrograms/kg butorphanol; 4.3, 13.6, or 42.9 micrograms/kg midazolam; or 3.6 + 2.2, 11.3 + 6.8, or 35.7 + 21.5 micrograms/kg butorphanol and midazolam in combination. Eight visual analogue scales (VAS) were completed by the subject and an observer. The subject then performed two psychomotor tests (the Trieger dot test and the Halstead trail-making test) and was shown two playing cards in order to assess memory. The test drug was administered, and 5 min later the evaluations were repeated and two more cards were shown. On the following day the subjects were asked to recall the names of the playing cards. Butorphanol, midazolam, and their combination produced dose-related changes in VAS scores that were significant and qualitatively similar: subjects became sleepy, less nervous, weak, and less clear-thinking. There was no significant euphoria or dysphoria. The sedative and depressant effects on respiratory rate of the high-dose combination were significantly greater than those predicted by simple additivity: 14 of 14 subjects receiving the high dose of the butorphanol/midazolam combination had lid droop and marked sedation, and 2 of 14 subjects had respiratory rates of less than 4 breaths per min. All three drug treatments caused significant, dose-dependent impairment of psychomotor function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of endothelin in anesthetized dogs

The purpose of the present study was to investigate and compare the hemodynamic responses that can be elicited in anesthetized dogs by intravenous administration of endothelin at rates of 300 (group E-I, n = 9) and 600 pmol.kg-1 (group E-II, n = 9) for 15 minutes. In group E-I, no significant pressure response was observed after administration of endothelin and cardiac index remained unchanged throughout the experiment. However, right and left ventricular work indices increased significantly but left ventricular maximum dp/dt and pulmonary vascular resistance decreased significantly. In group E-II, mean arterial pressure increased significantly by elevating systemic vascular resistance with marked decrease in cardiac index. However, right and left ventricular work indices remained unchanged throughout the experiment. On the other hand, each dose of endothelin significantly increased pulmonary capillary wedge pressure and left ventricular end-diastolic pressure but decreased heart rate. The present data revealed that the hemodynamic effects were different according to the doses of endothelin infused. In conclusion, our results show that endothelin (600 pmol.kg-1 BW) produces a long lasting increase in arterial pressure and endothelin-induced pressure responses are caused by an elevation in systemic vascular resistance.     

Cardiovascular effects of esmolol in anesthetized humans

We studied the cardiovascular effects of esmolol, a newly synthesized beta-adrenocepter antagonist, in anesthetized humans. Forty patients (four groups of 10 each) with ischemic heart disease and normal ventricular function were anesthetized with diazepam, pancuronium, and N2O in O2. Esmolol was given by continuous infusion in cumulative doses of 1100 micrograms/kg (group 1), 2000 micrograms/kg (group 2), and 2700 micrograms/kg (group 3); a control group received no esmolol. Infusion of esmolol was begun 3 min prior to and ended 4 min after tracheal intubation. All three doses of esmolol significantly (P less than 0.001) attenuated the heart rate responses to intubation. Rate-pressure products were significantly (P less than 0.001) lower in esmolol-treated patients than in controls after intubation, but ST-segment changes compatible with ischemia occurred in one patient in each group. Increases in heart rate were associated with significant increases in plasma norepinephrine levels (r = 0.45, P = 0.02) in the control group, but not in esmolol-treated patients, a demonstration that esmolol antagonizes the beta-adrenergic effects of norepinephrine. The effect of esmolol on heart rate was absent 5 min after cessation of infusion, and plasma levels of esmolol were undetectable in 26 of 30 treated patients 15 min after the termination of esmolol infusion. Esmolol has a rapid onset and short duration of effect. It can be used safely during anesthesia in patients with normal ventricular function to attenuate cardiac response to sympathetic stimulation.     

Endocrine and hemodynamic effects of antagonism of fentanyl-induced respiratory depression by nalbuphine

Endocrine and hemodynamic changes associated with the antagonism of fentanyl by nalbuphine have not been reported. Therefore, the authors studied ten patients after anesthetic induction with thiopental, fentanyl, tracheal intubation aided by succinylcholine and maintenance with diazepam, pancuronium, N2O, and further doses of fentanyl. Eight of the patients underwent cholecystectomy, one had a hysterectomy, and another had an abdominoplasty. After reversal of neuromuscular block at the conclusion of surgery, normal ventilation was restored by 0.22 +/- 0.02 mg/kg intravenous nalbuphine (mean +/- SEM). Plasma levels of free norepinephrine, histamine, and cortisol did not increase after antagonism of the fentanyl-induced respiratory depression, but plasma concentration of epinephrine increased significantly but without significant hemodynamic changes. Minute ventilation was 1.5 +/- 0.4 L/min before and 11 +/- 1, 10 +/- 1, 11 +/- 1, and 10 +/- 1 L/min at 15, 30, 45, and 60 min after antagonism; corresponding PaCO2 levels were 56 +/- 2, 44 +/- 1, 49 +/- 7, 49 +/- 1, 42 +/- 1 mm Hg. The mean analogue pain score remained below 1.5. We conclude that nalbuphine effectively antagonizes fentanyl-induced respiratory depression without adverse endocrine and circulatory changes or loss of analgesia.     

The effects of nicardipine on dynamic cerebral autoregulation in patients anesthetized with propofol and fentanyl

We investigated the effects of nicardipine on dynamic cerebral pressure autoregulation in 13 normal adult patients undergoing gynecologic or orthopedic surgery. Anesthesia was induced and maintained with propofol and fentanyl. Hypotension to a mean arterial pressure of 60-65 mm Hg was induced and maintained with a continuous infusion of nicardipine. Time-averaged mean blood flow velocity in the right middle cerebral artery was measured continuously by using transcranial Doppler ultrasonography. The cerebral autoregulatory responses were activated by releasing thigh cuffs. The actual blood flow velocity in the right middle cerebral artery response to acute change in mean arterial pressure was fitted to 1 of 10 computer-generated curves to determine the dynamic rate of cerebral autoregulation (dRoR), and the best fitting curve was used. The autoregulation test was repeated until two values of dRoR were obtained at baseline and during induced hypotension. Nicardipine significantly reduced dRoR values of 13.1% +/- 3.6%/s at baseline to 8.3% +/- 2.6%/s during hypotension (P: < 0.01). During deliberate hypotension induced by nicardipine, the cerebral dynamic autoregulatory response is impaired in normal adult patients. IMPLICATIONS: During deliberate hypotension induced by nicardipine, the cerebral dynamic autoregulatory response is impaired in normal adult patients.     

The respiratory depressant effects of nalbuphine and papaveretum as intramuscular premedication

Forty-four patients scheduled for routine gynaecological surgery through a Pfannenstiel incision were given either nalbuphine or papaveretum as premedication, with hyoscine. Respiratory depression was measured by carbon dioxide rebreathing before and one hour after premedication. Both combinations produced significant respiratory depression as measured by the rebreathing test but no significant difference could be shown between the drugs in this respect.     

Respiratory effects of almitrine on various levels of the fraction of inspired oxygen. A study in the anesthetized dog

The effects of intravenous almitrine under normoxic, hyperoxic, and hypoxic conditions were studied in 5 male beagle dogs (mean weight 15.2 +/- 5 kg) anaesthetized with thiopentone. Plasma concentrations of thiopentone were maintained constant at 27-29 mg.1(-1). Each animal underwent twice the three different experiments, with a lapse of a fortnight between each experiment: a) breathing room air, with intravenous administration of 1 mg.kg-1 almitrine over 30 s, b) breathing room air, then pure oxygen for 15 min, followed by an intravenous administration of 1 mg.kg-1 almitrine over 30 s with the dog still breathing pure oxygen, and c) breathing room air, then progressively less oxygen (FIO2 0.18, 0.16, 0.14, 0.12 for 5 min each), followed by an intravenous administration of 1 mg.kg-1 almitrine over 30 s with the dog still breathing a mixture with 12% oxygen. Tidal volume, respiratory rate, minute ventilation, inspiratory and expiratory duration, arterial pH, PaO2 and PaCO2 were measured respectively in room air, after 100% oxygen, in hypoxia (FIO2 = 0.12), before, 5 and 10 min after the injection of almitrine. Hyperoxia depressed ventilation (-21%), whilst hypoxia stimulated it (+126%), although significantly less than in the awake animal. Almitrine restored the respiratory response to hypoxia, but hyperoxia did not suppress respiratory stimulation due to the drug. It would therefore seem likely that almitrine acts on peripheral arterial chemoreceptors, but also on other structures. The results of this study suggest that almitrine may be useful in restoring the respiratory response to hypoxia during recovery from anaesthesia.     

比较布托啡诺、芬太尼及芬太尼联合曲马多用于老年患者术后镇痛的临床效果

目的研究布托啡诺用于老年患者术后静脉镇痛的疗效及不良反应。方法60例择期行上腹部手术的老年患者,随机均分为布托啡诺组(B组)、芬太尼组(F组)及芬太尼联合曲马多组(FT组),分别接受持续静脉镇痛。记录并比较术后48h内疼痛视觉模拟评分(VAS)、Ramsay镇静评分及不良反应。结果三组术后镇痛效果VAS组内比较差异无统计学意义。但术后6hF组和B组的VAS明显低于FT组(P<0.05);术后12h,B组的VAS仍低于FT组(P<0.05)。B组术后0.5、6、12h Ramsay镇静评分明显高于F组(P<0.05)。B组恶心呕吐发生率明显低于FT组(P<0.05)。结论布托啡诺可用于老年患者术后静脉镇痛。