Sex differences in morphine-induced ventilatory depression reside within the peripheral chemoreflex loop.

BACKGROUND: This study gathers information in humans on the sites of sex-related differences in ventilatory depression caused by the mu-opioid receptor agonist morphine. METHODS: Experiments were performed in healthy young men (n = 9) and women (n = 7). Dynamic ventilatory responses to square-wave changes in end-tidal carbon dioxide tension (7.5-15 mmHg) and step decreases in end-tidal oxygen tension (step from 110 to 50 mmHg, duration of hypoxia 15 min) were obtained before and during morphine infusion (intravenous bolus dose 100 microg/kg, followed by 30 microg x kg(-1) x h(-1)). Each hypercapnic response was separated into a fast peripheral and slow central component, which yield central (Gc) and peripheral (Gp) carbon dioxide sensitivities. Values are mean +/- SD. RESULTS: In carbon dioxide studies in men, morphine reduced Gc from 1.61 +/- 0.33 to 1.23 +/- 0.12 l x min(-1) x mmHg(-1) (P < 0.05) without affecting Gp (control, 0.41 +/- 0.16 and morphine, 0.49 +/- 0.12 l x min(-1) x mmHg(-1), not significant). In carbon dioxide studies in women, morphine reduced Gc, from 1.51 +/- 0.74 to 1.17 +/- 0.52 l x min(-1) x mmHg(-1) (P < 0.05), and Gp, from 0.54 +/- 0.19 to 0.39 +/- 0.22 l x min(-1) x mmHg(-1) (P < 0.05). Morphine-induced changes in Gc were equal in men and women; changes in Gp were greater in women. In hypoxic studies, morphine depressed the hyperventilatory response at the initiation of hypoxia more in women than in men (0.54 +/- 0.23 vs. 0.26 +/- 0.34 l x min(-1) x %(-1), respectively; P < 0.05). The ventilatory response to sustained hypoxia (i/e., 15 min) did not differ between men and women. CONCLUSIONS: The data indicate the existence of sex differences in morphine-induced depression of responses mediated via the peripheral chemoreflex pathway, with more depression in women, but not of responses mediated via the central chemoreflex pathway. In men and women, morphine did not change the translation of the initial hyperventilatory response to short-term hypoxia into the secondary decrease in inspired minute ventilation (Vi) caused by sustained hypoxia.     

Respiratory depression after low-dose caudal morphine

Purpose

To report a case of respiratory depression after a small dose of caudal morphine administered to a 15-mo-old child.

Clinical features

A 15 mo, 9.8 kg boy underwent ureteral reimplantation with general endotracheal anaesthesia and 10 ml bupivacaine 0.25% (2.5 mg · kg^?1). Ninety minutes after the bupivacaine, 0.4 mg (1 mg · ml^?1, 0.4 ml, 0.04 mg · kg^?1) preservative-free morphine was injected after negative aspiration. Slighly more than two hours after caudal morphine, the patient became lethargic and developed decreases in oxygen saturation (to 62%) without change in heart rate or respiratory rate. Intravenous naloxone 0.1 mg (0.01 mg · kg^?1) markedly improved his level of consciousness. Racemic epinephrine was administered for treatment of coincident stridor. The patient required 11 hr continuous naloxone infusion (0.001–0.002 mg · kg^?1 · hr^?1) in the intensive care unit. He was discharged on the second postopertive day without further complication.

Conclusion

Respiratory depression can occur in children greater than one year of age, even when small doses of caudal morphine are used. Decreased arterial oxygen saturation and lethargy are important heralds. A normal respiratory rate despite substantial hypoxaemia argues that pulse oximetry (without supplemental oxygen where possible) has a clear advantage over impedance pneumography for electronic monitoring.     

Alfentanil-mediated analgesia during propofol injection: no evidence for a peripheral action

We have investigated if alfentanil acts via peripheral opioid receptors to relieve the pain which occurs on injection of propofol. Thirty seconds before induction of anaesthesia and immediately after a tourniquet at 50 mm Hg greater than systolic pressure was inflated on the upper arm, patients were given either placebo (n = 22), alfentanil 1 mg (n = 22) or lignocaine 40 mg (n = 22) via an i.v. cannula in the dorsum of the hand. Pain during injection of propofol was assessed using a three-point verbal rating scale, recorded at 8-s intervals. We found a significant reduction in pain after lignocaine compared with the two other groups (P < 0.001), but there was no difference between the placebo and alfentanil groups. We conclude that alfentanil does not relieve pain on injection with propofol via an action on peripheral opioid receptors when alfentanil is limited to the forearm for 30 s before induction of anaesthesia.      

Respiratory effects of propofol

Like other general anaesthetics, propofol exerts a respiratory depressant effect. Apnoea is especially frequent during induction of anaesthesia by propofol; it differs from that caused by barbiturates by its longer duration. During continuous administration, propofol exerts the same effect on respiratory function as other general anaesthetics, with an increased respiratory rate, diminished tidal volume and hypercapnia.     

The antiemetic action of propofol

Eighty patients who underwent minor gynaecological surgery were anaesthetised with either incremental propofol or incremental methohexitone after an opioid premedication. The group anaesthetised with propofol had significantly fewer emetic sequelae and the results suggest that propofol has a definite antiemetic action.     

Respiratory effects of low-dose bupivacaine interscalene block

In this double-blind study, interscalene brachial plexus (ISBP) block was performed in 11 volunteers using 10 ml of either 0.25% (n = 6) or 0.5% (n = 5) bupivacaine with epinephrine 1:200,000. Diaphragmatic excursion, respiratory function and neural function were assessed for 90 min. Our results showed that hemidiaphragmatic excursion declined significantly after block in the 0.5% group and paradoxical movement during inspiration was more common than in the 0.25% group. Forced vital capacity and forced expiratory volume in 1 s declined significantly in the 0.5% group (mean 74.6 (SD 13.0)% and 78.2 (19.9)% of baseline, respectively) but not in the 0.25% group. Sensory anaesthesia in the upper limb was found consistently in both groups, although biceps paralysis occurred earlier after 0.5% bupivacaine. We conclude that ISBP block using 10 ml of 0.25% bupivacaine provided upper limb anaesthesia to pinprick in C5-6 dermatomes with only occasional interference with respiratory function.      

Respiratory depression by tramadol in the cat: involvement of opioid receptors

BACKGROUND: Tramadol hydrochloride (tramadol) is a synthetic opioid analgesic with a relatively weak affinity at opioid receptors. At analgesic doses, tramadol seems to cause little or no respiratory depression in humans, although there are some conflicting data. The aim of this study was to examine whether tramadol causes dose-dependent inhibitory effects on the ventilatory carbon dioxide response curve and whether these are reversible or can be prevented by naloxone. METHODS: Experiments were performed in cats under alpha-chloralose-urethane anesthesia. The effects of tramadol and naloxone were studied by applying square-wave changes in end-tidal pressure of carbon dioxide (Petco2; 7.5-11 mmHg) and by analyzing the dynamic ventilatory responses using a two-compartment model with a fast peripheral and a slow central component, characterized by a time constant, carbon dioxide sensitivity, time delay, and a single offset (apneic threshold). RESULTS: In five animals 1, 2, and 4 mg/kg tramadol (intravenous) increased the apneic threshold (control: 28.3 +/- 4.8 mmHg [mean +/- SD]; after 4 mg/kg: 36.7 +/- 7.1 mmHg; P < 0.05) and decreased the total carbon dioxide sensitivity (control: 109.3 +/- 41.3 ml x min(-1) x mmHg(-1) ) by 31, 59, and 68%, respectively, caused by proportional equal reductions in sensitivities of the peripheral and central chemoreflex loops. Naloxone (0.1 mg/kg, intravenous) completely reversed these effects. In five other cats, 4 mg/kg tramadol caused an approximately 70% ventilatory depression at a fixed Pet co2 of 45 mmHg that was already achieved after 15 min. A third group of five animals received the same dose of tramadol after pretreatment with naloxone. At a fixed Petco of 45 mmHg, naloxone prevented more than 50% of the expected ventilatory depression in these animals. CONCLUSIONS: Because naloxone completely reversed the inhibiting effects of tramadol on ventilatory control and it prevented more than 50% of the respiratory depression after a single dose of tramadol, the authors conclude that this analgesic causes respiratory depression that is mainly mediated by opioid receptors.     

复合不同靶浓度异丙酚时瑞芬太尼引起神经外科手术病人呼吸抑制的效应室浓度

目的 确定复合不同靶浓度异丙酚时瑞芬太尼引起神经外科手术病人呼吸抑制的效应室浓度.方法 择期拟行神经外科手术的病人80例,年龄18～64岁,体重45～90 kg,随机分为4组(n=20):瑞芬太尼组(R组)、瑞芬太尼复合异丙酚1μg/ml(RP_1组)、瑞芬太尼复合异丙酚1.5 μg/ml(RP_(1.5)组)和瑞芬太尼复合异丙酚2 μg/ml(RP_2组)组.R组、RP_1组、RP_(1.5)组和RP_2组靶控输注异丙酚,血浆靶浓度分别为0、1、1.5、2μg/ml,达到预设的浓度后,靶控输注瑞芬太尼,初始血浆靶浓度为2 μg/ml,随后每3 min增加瑞芬太尼血浆靶浓度2 μg/ml,直至发生呼吸抑制.记录呼吸抑制时瑞芬太尼效应室浓度、瑞芬太尼用量和其他不良反应发生情况.结果 R组、RP1组、RP1.5组和RP_2组呼吸抑制时瑞芬太尼效应室浓度分别为(5.2±2.1)、(3.2±1.0)、(2.9±1.3)和(2.2±1.0)μg/ml.与R组比较,RP_1组、RP_(1.5)组和RP_2组呼吸抑制时瑞芬太尼效应室浓度降低(P<0.01);与RP1组和RP1.5组比较,RP2组呼吸抑制时瑞芬太尼效应室浓度降低(P<0.01);RP1组和RP1.5组呼吸抑制时瑞芬太尼效应室浓度比较差异无统计学意义(P>0.05).结论 神经外科手术病人清醒状态下瑞芬太尼效应室浓度为(5.2±2.1)ng/ml时可发生呼吸抑制;复合血浆靶浓度1、1.5、2 μg/ml异丙酚镇静时,瑞芬太尼引起呼吸抑制的效应室浓度分别降至(3.2±1.0)、(2.9±1.3)和(2.2±1.0)ng/ml.     

Respiratory depression following diazepam: reversal with high-dose naloxone

The authors compared the effects of naloxone and saline solution on the respiratory changes following diazepam in a double-blind crossover trial in six subjects. Following baseline measurements of respiration, each subject was given diazepam, 15 mg, intravenously. Sixty and ninety-five minutes later each subject received either two doses of naloxone, 15 mg, intravenously, or two doses of the equivalent volume of saline solution. Forty-five minutes after diazepam administration the slopes of the curves of the ventilatory responses to rebreathing carbon dioxide (VE/PETCO2) were depressed to 53 per cent of control (P < 0.05). Following the two doses of naloxone, the slopes of VE/PETCO2 recovered, until, 120 minutes after the second dose of naloxone, slopes had returned to control values. After saline solution, however, slopes remained depressed at 68 per cent of control (P < 0.05). A similar recovery following naloxone was observed in the PETCO2 intercept of the VE/PETCO2 response curve and in the slope of the mouth-occlusion-pressure response curve to rebreathing carbon dioxide. End-tidal carbon dioxide during quiet breathing and during inspiratory resistive-loaded breathing (80 cm H2O/l/s) showed small increases after diazepam, which were not significantly reduced by naloxone. The results of this study show that diazepam produces respiratory depression, and that this may be relieved by large doses of naloxone.     

Respiratory depression following epidural morphine: a clinical study

Thirteen post-thoracotomy patients were entered into a double-blind, randomized clinical trial comparing the effects of epidural morphine (Group E) and intravenous morphine (Group I) on postoperative respiratory depression. Postoperative respiratory depression was assessed for 24 hours by (a) PaCO2 at 2, 6, 12 and 24 hours (b) hourly assessment of respiratory rate (RR) (c) presence of respiratory rate of less than ten breaths per min for greater than 5 min (SRR) (d) hypopnoea/apnoea (H/A). RR, SRR, and H/A were measured using respiratory inductive plethysmography. PaCO2 was significantly elevated at 2, 6 and 12 hours in Group E and only at two hours in Group I. One of five patients in Group I had a single episode of SRR whereas five of eight patients in Group E had multiple episodes of SRR. None of the patients in Group I had H/A episodes, in contrast to six of eight in Group E who had numerous H/A episodes post-operatively. This difference was statistically significant. Multiple doses of epidural morphine produce an insidious and unpredictable change in respiratory pattern. Electronic monitoring is useful to assess those at risk of overdose and possible respiratory arrest.     

Modulation by verapamil of hormonal action on the Henle's loop of mice

In order to know the role of cytosolic calcium in the modulation of the hormone action on sodium chloride transport across the thick ascending limbs of Henle's loop, we examined whether verapamil, a blocker of cellular calcium entry, can modulate the effects of arginine vasopressin (AVP) or glucagon in stimulating transepithelial voltage (Vt) and cyclic AMP generation in the mouse medullary thick ascending limb (MAL). The pretreatment of the renal tubule with 5 X 10(-5)M verapamil reduced the Vt stimulated with 200 microU/mliter AVP from 1.7 +/- 0.3 mV to 0.4 +/- 0.4 mV (N = 7, P less than 0.05). The changes in Vt were well correlated with those of unidirectional Cl flux from the lumen to the bath. However, verapamil did not influence the Vt stimulated with 10(-3) M dibutyryl cyclic AMP. The pretreatment of the MAL with 10(-5) M verapamil also inhibited the cyclic AMP generation in the MAL from 72.1 +/- 17.9 to 50.6 +/- 13.6 fmoles/mm/7 min (N = 7, P less than 0.05) as well as in the medullary collecting tubule from 147.6 +/- 46.6 to 121.2 +/- 41.6 fmoles/mm/7 min (N = 4, P less than 0.05). The effect of verapamil in inhibiting the AVP-stimulated cAMP was dose-dependent: the cAMP generation was inhibited by 28.9 +/- 6.8 and 61.1 +/- 9.3% with 10(-5) M and 10(-4) M verapamil, respectively. When verapamil was added to the medium simultaneously with AVP, the generation of cyclic AMP was unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)     

硬膜外阻滞辅以丙泊酚闭环靶控镇静

目的对硬膜外阻滞中以脑电双频指数(BIS)作为反馈的闭环靶控输注丙泊酚镇静的效果和性能进行评价。方法11例ASAⅠ～Ⅱ级择期行下腹部或下肢手术患者，男5例，女6例，年龄28～67岁。硬膜外阻滞期间采用以BIS作为反馈的闭环靶控输注(CLTCI)丙泊酚进行镇静，开始的靶浓度设定为1．5μg／ml，然后每分钟逐步增加或减少0．5μg／ml，直到患者的镇静深度稳定于OAA／S评分3分以下，这时候的BIS值作为反馈变量，通过CLTCI系统自动输注丙泊酚。每5分钟记录血压、心率、BIS和OAA／S评分。记录诱导时间及丙泊酚诱导剂量、丙泊酚总用量、苏醒时间及不良反应，并评价CLTCI系统的性能。结果所有患者镇静期间血液动力学平稳，无严重呼吸抑制。OAA／S评分3分时平均BIS值76．6。CLTCI系统的偏离性1．9％，精确度7．1％，摆动度4．1％。结论在硬膜外麻醉期间以BIS为反馈的闭环靶控输注丙泊酚进行清醒镇静是可行的。该系统性能稳定，有临床推广价值。     

The effect of low-dose ketamine on fentanyl-induced respiratory depression

This study evaluated if adding low-dose ketamine to fentanyl could offer a haemodynamically stable drug combination with little respiratory side-effects. Eight healthy, consenting male volunteers received in a random, cross-over and double-blind fashion both fentanyl 2 μgkg⁻¹ + ketamine 0.25 mgkg⁻¹ and fentanyl 2 μgkg⁻¹ + placebo. The fentanyl and placebo reduced minute ventilation, alveolar ventilation and oxygen consumption ( p < 0.05), with little effect on haemodynamics. After fentanyl and ketamine, the decrease in minute ventilation and alveolar ventilation was attenuated compared to the placebo-containing combination ( p < 0.05), but with a simultaneous increase in oxygen consumption ( p < 0.05) and stimulation of haemodynamics ( p < 0.05). Both treatments decreased oxygen saturation and arterial oxygen pressure similarly. Ketamine thus attenuated the fentanyl-induced reduction in ventilation without preventing the decrease in blood oxygenation. In conclusion, combining low-dose ketamine to fentanyl offers no benefits in terms of preventing respiratory depression.