Low-Dose Doxapram Therapy in Premature Infants and Its CSF and Serum Concentrations

ABSTRACT. The efficacy of low-dose doxapram therapy (0.2 mg/kg/h) in combination with methylxanthines was evaluated in 20 premature infants with idiopathic apnea unresponsive to methylxanthines alone, and in 13 premature infants with secondary apnea. The serum concentrations of doxapram and, in some infants, the simultaneous cerebrospinal fluid and serum concentrations were measured, and the correlation between cerebrospinal fluid and serum concentrations in the postnatal period was determined. The following results were obtained: 1) In idiopathic apnea of prematurity, low-dose doxapram therapy was as effective as a dose of 1.0-2.5 mg/kg/h and the side effects were few, mild, and reversible. 2) In premature infants over seven days of age, serum concentrations of doxapram were almost stable but were significantly lower than in infants within the first six days of life. 3) The ratio of the cerebrospinal fluid to serum doxapram concentration was 0.48 ± 0.13 (mean ± SD). There was a good correlation between cerebrospinal fluid and serum concentrations ( r = 0.933, p < 0.001). The initial doxapram dose can be set as low as 0.2 mg/kg/h in very young premature infants with idiopathic apnea of prematurity unresponsive to methylxanthines.     

再论中枢神经兴奋药

高效合理使用中枢神经兴奋药的基本观点,近年来有明显的变革。目前,临床上呼吸与循环的抢救与功能的维持,已不再依靠中枢神经兴奋药;昏迷重症的催醒,也不依靠本类药物。另一方面,本类药尤其是苯丙胺和哌醋甲酯等,对小儿的多动贪玩、注意力不集中,常能有所帮助。使用较广的多沙普仑能兴奋呼吸,时效仅10min许,疗效有限。其他过去常用的一些中枢神经兴奋药,现均已无实用价值。     

多沙普仑和哌替啶治疗全麻苏醒期寒战的对比研究

目的：研究多沙普仑和哌替啶对于全麻后寒战患者的治疗效果及对苏醒质量的影响。方法将全麻苏醒期进入术后恢复室后发生寒战的51例全麻病人随机分三组治疗：多沙普伦针1.0 mg/kg （多沙普仑组）、哌替啶针0.5 mg/kg（哌替啶组）及0.9％氯化钠注射液（对照组）,比较三组患者的降低寒战分级、寒战终止率,并观察对镇静、镇痛的影响及不良反应发生率。结果治疗1 min、2.5 min和5 min后多沙普仑组和哌替啶组寒战等级相比对照组均有明显降低,差异均有统计学意义（H分别=18.97、24.96、30.85,P均＜0.05）。治疗1 min后,多沙普仑组和哌替啶组寒战终止率明显高于对照组,差异均有统计学意义（χ2=5.04、11.10,P＜0.05）。而哌替啶组24 h内恶心、呕吐的发生率明显高于多沙普仑组和对照组,经Fisher精确检验,差异均有统计学意义（P均＜0.05）。三组之间术后恢复室停留时间比较,差异无统计学意义（F=8.63,P＞0.05）。结论全麻术后寒战患者使用多沙普仑和哌替啶都有明显中止寒战效果,哌替啶会增加术后恶心呕吐的发生。对已经苏醒的患者,两药对全麻的恢复无明显影响。     

The disposition of intravenous doxapram in man

Summary The pharmacokinetics of intravenous doxapram in healthy individuals is consistent with a three-compartment open model. Doxapram was administered by bolus injection (1.5 mg · kg^–1) and by intravenous infusion (6.5 mg · kg^–1 for 2 h) to 5 subjects on separate occasions. There was no significant difference in mean terminal plasma half-lives (355 and 448 min) or in mean total body clearances (5.9 and 5.6 ml · min^–1 · kg^–1) following i. v. bolus injection or infusion respectively. In 3 subjects plasma doxapram concentrations during and after i. v. infusion agreed with those predicted from pharmacokinetic values obtained from the bolus injection study. Since mean steady-state concentrations (9.9 µg · ml^–1) would be reached only after an extended interval (mean 15.2 h), a variable-rate infusion regimen was calculated to produce and maintain a concentration of 2 µg · ml^–1 from 15–25 min onwards. A regimen in which the infusion rate is reduced step-wise is recommended to achieve early near-constant plasma doxapram concentrations.     

盐酸多沙普仑对右旋美托咪定全麻恢复期催醒效果临床观察

[目的]观察盐酸多沙普仑用于右旋美托咪定全麻患者围麻醉期的催醒效果及不良反应.[方法]择期成人骨科全麻手术40例,随机分为两组,每组20例.A组：右旋美托咪定（DEX）＋盐酸多沙普仑（DOX） B组：DEX＋生理盐水.麻醉诱导插管后5 min开始,两组均给予DEX负荷量1 μg/kg,既以 0.6～0.8 μg/（kg·min）泵注维持,术毕前10 min停药.A组术毕拔管后即刻给予DOX 1 mg/kg,B组给予等体积生理盐水.观察两组患者诱导前5 min（T0）、插管后 5 min（T1）、停止所有麻醉药时（T2）、拔管时（T3）、拔管后5 min（T4）时的收缩压（SBP）、舒张压（DBP）、心率（HR） 患者术前（T＇0）、拔管时（T＇1）及拔管后 10 min（T＇2）Riker镇静、躁动评分（SAS） 及术后不良反应情况.[结果]两组患者一般资料具有可比性（P〉0.05） 各时点SBP、DBP、HR组间比较无差异（P〉0.05） SAS评分在T＇2时A组高于B组,差异有显著性（P〈0.05）, 两组患者拔管反应评分及恶心呕吐、寒颤、术中知晓等发生率比较无差异（P〉0.05）.[结论]右旋美托咪定用于麻醉维持可提供良好的血流动力学稳定性和镇静作用,全麻恢复期更平稳 多沙普仑对右旋美托咪定麻醉术后的催醒效果确切,血流动力学波动幅度小,不良反应发生率低.     

Metabolic, ventilatory and circulatory effects of doxapram in anaesthetized pigs during normoxia and hypoxia

Background: In a previous clinical study doxapram was found to improve ventilatory efficacy postoperatively, presumably via effects on hypoxic pulmonary vasoconstriction (HPV). The present study was designed to see whether doxapram induced any changes of arterial oxygenation and pulmonary vascular resistance during normoxia or hypoxia and whether the changes were influenced by the anaesthetic agents. Methods: Seventeen piglets were anaesthetized by combinations of either midazolam + fentanyl + pancuronium + pentobarbital (TIVA, n = 9), or by midazolam + fentanyl + pancuronium + halothane, 0.5% in end-tidal gas (Hal, n = 8). Analyses of expired gas and mixed venous and arterial blood in combination with determinations of central blood flow and pressures allowed for calculations of standard metabolic, ventilatory and circulatory data. Values were obtained at normoventilation using normoxic (FIO₂ = 0.3) and hypoxic (FIO₂ = 0.08) gas mixtures at calculated doxapram plasma concentrations of 1, 2 and 4 μg · ml^-1. Results: With few exceptions doxapram administration affected the investigated variables only moderately during normoxia. In group Hal, PVR and SVR showed a biphasic raise (P< 0.05), CO fell (P< 0.05-P≥ 0.05) and C(a -v)O₂ rose (P<0.05). In group TIVA, PaO₂ fell (P<0.01-0.05) despite unchanged PVR, CO and VD/VT. Hypoxia affected a moderate increase in PVR in group TIVA (P<0.05), which was slightly lower at the lowest and highest plasma levels of doxapram (P<0.05). In group Hal, the induction of hypoxia induced a more pronounced rise in PVR (P<0.05) which showed a biphasic response to increasing dose levels of doxapram, the lowest dose affecting a further rise (P<0.05) and the highest a reduction to values below hypoxia control levels (P<0.05). Pronounced differences between the two groups with respect to values for metabolic and circulatory variables make the interpretation of data difficult. Conclusions: Doxapram administration to anaesthetized animals did not induce any effects indicative of augmentation of the HPV response.     

Serum doxapram and respiratory neuromuscular drive in normal man

Summary To investigate the means by which doxapram affects the control of ventilation, ventilatory function and P_0.1 have been related to serum doxapram concentration during a 45-min infusion of doxapram hydrochloride in 7 healthy, conscious subjects under normoxic conditions.Serum doxapram concentrations increased during the infusion: 1.88, 2.48, 3.42, and 3.97 µg/ml after 5, 10, 30 and 45 min, respectively. The majority of significant changes in the measurements from the baseline were observed at 30 and 45 min: , V_T, P_0.1, P_0.1/end-tidal CO₂ tension, V_T/T_i and blood pressure were increased, and end-tidal CO₂ tension was decreased.No significant changes in Pdi_max, T_i/T_tot, /P_0.1, and P_0.1/(V_T/T_i) were observed. A correlation was observed between the % increases in P_0.1 and and doxapram concentration, and between and P_0.1.The doxapram-induced increase in appears to be caused by increased neural drive. It is related to the serum drug concentration in the conscious subject.     

多沙普仑减轻布托啡诺术后镇痛期嗜睡的临床研究

目的 观察多沙普仑对布托啡诺术后镇痛期嗜睡和VAS评分的影响.方法 全组均行硬膜外麻醉后,随机分为0.01%布托啡诺和0.1%多沙普仑镇痛泵组(组Ⅰ,n=35),0.01%布托啡诺和0.15%多沙普仑镇痛泵组(组Ⅱ,n=35)和0.01%布托啡诺镇痛泵组(组Ⅲ,n=35).比较术后镇痛效果和副作用.结果 3组均获得了满意的术后镇痛效果.镇静评分(OAA/S,术后8 h～24 h):组Ⅲ>组Ⅰ和组Ⅱ(分别P<0.01).SpO2(负荷剂量后0 min～30 min):组Ⅲ分别小于组Ⅰ和组Ⅱ.VAS评分(术后8h～24 h):组Ⅲ<组Ⅰ和组ⅡP<0.05,但3组VAS均≤3分,且D1/D2值3组互比P>0.05.其他副作用无统计学差异.结论 多沙普仑和布托啡诺合用能有效地减轻或消除布托啡诺术后镇痛期的嗜睡副作用,提高临床用药的安全性.