Thiopental pharmacokinetics in patients with cirrhosis

The effect of cirrhosis on the pharmacokinetics and plasma protein binding of thiopental was studied in eight patients with cirrhosis, aged (mean +/- SD) 42 +/- 11 yr, and nine patients with normal hepatic and renal function, aged 48 +/- 12 yr, undergoing elective abdominal or orthopedic surgery. The total apparent volume of distribution at steady state was of 2.3 +/- 0.5 1 X kg-1 in the controls and of 3.5 +/- 1.9 1 X kg-1 in the patients with cirrhosis. Thiopental plasma clearance based upon total drug concentrations was 3.9 +/- 1.2 ml X min-1 X kg-1 in the normal group and did not differ significantly in the patients with cirrhosis: 4.4 +/- 2.2 ml X min-1 X kg-1. The elimination half-life was of 529 +/- 97 min in the controls and of 714 +/- 252 min in the patients with cirrhosis. The thiopental free fraction was 14.5 +/- 3.4% in the controls and was increased significantly to 25.2 +/- 3.9% in the patients with cirrhosis. Thiopental intrinsic clearance was decreased insignificantly (P = 0.06) from 28.3 +/- 9.0 ml X min-1 X kg-1 in the controls to 18.2 +/- 10.5 ml X min-1 X kg-1 in those with cirrhosis, suggesting that these patients may have a decreased capacity for thiopental metabolism. These results suggest that the risk of a prolonged effect following thiopental administration appears unlikely in patients with cirrhosis.     

Clinical pharmacokinetics of long-term infusion of midazolam in critically ill patients--preliminary results

Seven intensive care patients were sedated with prolonged infusion of midazolam. One patient received a continuous infusion of midazolam for the treatment of status epilepticus. A bolus injection of 5 mg was administered, followed by infusion of 4-14 mg/hour depending on the required level of sedation. The length of infusion varied between 80 and 360 hours. The plasma concentrations of the midazolam during infusion were between 500-1000 ng/ml. All the patients were adequately sedated. The plasma elimination half-life of midazolam and its main metabolite, 1-OH-midazolam glucuronide, after stopping the infusion varied from 4-12 hours.     

The infusion rate of most disposable,non-electric infusion pumps decreases under hypobaric conditions

Purpose

To examine the delivery rates of four disposable, nonelectric infusion pumps during hypobaric conditions.

Methods

Four models categorized by three different driving forces, one vacuum unit (Coopdech Syringector), one spring unit (Linear-fuser), and two elastomeric balloon-powered units (Multirate Infuser LV and Large DIB), were tested. Each infusion pump was placed in an airtight container, and the pressure in the container was decreased to 1,000, 900, and 800 hPa. The catheter tip of each pump was exposed either to atmospheric pressure (1,000 hPa) or to similar hypobaric conditions (800–1,000 hPa).

Results

Under normal atmospheric pressure, each pump showed an accurate delivery rate in the range of ?2% to +8% of the set infusion rate (4.0–5.0 mL·hr^?1). With the catheter tip exposed to atmospheric pressure, the infusion rate of each pump was reduced from 35% in the case of the Large DIB to 64% in the case of the Coopdech Syringector, depending on the magnitude of change in hypobaric pressure. When the pressure acting on the catheter tip was reduced to a level similar to that exerted on the pump body, infusion rate was reduced (by 19%–27%) in all three types of pump, and the Large DIB showed no significant difference in performance compared to normal atmospheric pressure.

Conclusion

The infusion rates of disposable infusion pumps are reduced under hypobaric conditions. Even though we still do not know how the epidural pressure changes under hypobaric conditions, clinicians should be aware that the infusion rate of disposable infusion pumps is decreased under hypobaric conditions.     

The pharmacokinetics of continuous peridural morphine infusion

In patients with cancer pain treated by continuous epidural opiate infusion (4.5-24 mg morphine per day) via implanted or portable pumps (n = 40) plasma levels of morphine were determined during the postoperative period and during regular refill of the pump systems. Concentrations were between 2.6 and 18.8 ng/ml depending on daily dosage and body weight. There were no signs of accumulation. Concentrations in lumbar CSF measured in some of the patients were 15-20 higher but decreased by 10-20% (in relation to daily dosage) in the course of long-term treatment. This may be induced by reduction in permeability of the dura due to fibrosis within the epidural space after chronicle catheterization. Cervical CSF concentrations (during chordotomy) were about 1/6 to 1/7 of the corresponding lumbar CSF levels. It may be assumed that epidural opiate infusion in spite of low blood levels is accompanied by relevant cerebral opiate actions.     

连续硬膜外输注利多卡因的临床及药代动力学研究

通过对间断追加药物组与连续输注组的临床及药代动力学的观察比较，了解持续硬膜外输注利多卡因在临床麻醉中应用的可行性。结果表明：采用持续硬膜外输注法同样可维持良好的镇痛与肌松作用，且无明显不良反应。其血浆利多卡因浓度与间断给药组无显著差异。但间断给药组药－时曲线波动明显，而输注组药－时曲线平稳。药代动力学参数除消除半衰期和表观分布容积有显著差异外，余参数无临床生理意义的差异。本研究证实，持续输注法是临床硬膜外阻滞的可行且安全的方法之一。     

Thiopental sodium by single bolus dose compared to infusion for cerebral protection during cardiopulmonary bypass

The authors previously demonstrated that thiopental sodium infused throughout cardiopulmonary bypass (CPB) considerably reduced persistent but not transient neuropsychiatric complications after open-chamber cardiac operations. Based on the probability that emboli released at the time of aortic declamping cause most postoperative central nervous system (CNS) dysfunction, this study was designed to test whether administration of a single bolus dose of thiopental before aortic declamping provided cerebral protection equal to that of infusion throughout bypass as well as a decrease in unwanted side effects. One hundred adult patients undergoing open-chamber cardiac operations with CPB received either thiopental sodium by infusion throughout CPB (n = 52) or thiopental sodium 15 mg/kg by bolus before aortic declamping (n = 48). In 90% of the patients, thiopental sodium 15 mg/kg produced electroencephalographic (EEG) burst suppression, with more than 60 seconds between bursts. Postoperative CNS dysfunction occurred in 3 (6%) of the infusion group patients (thiopental sodium 36 +/- 10 mg/kg) and 2 (4%) of the bolus group patients (thiopental sodium 16 +/- 2 mg/kg). CNS dysfunction persisting to the tenth postoperative day occurred in only one patient, who was in the infusion group. Requirements for inotropic support on separation from CPB did not differ between groups, but average time to extubation was 2.7 hours shorter in the bolus group. The authors conclude that thiopental sodium 15 mg/kg given as a single bolus immediately before aortic declamping without the need for EEG monitoring provided the same brain protection as larger doses given by infusion titrated to burst suppression, but it did not reduce the need for inotropic support during separation from CPB.     

The effects of acute changes in renal function on the pharmacokinetics of midazolam during long-term infusion in ICU patients.

This study investigated the pharmacokinetics of midazolam and its main metabolite, 1-hydroxymethylmidazolam glucoronide, during long-term i.v. infusion in 39 mechanically ventilated ICU patients of whom 6 were in acute renal failure (ARF). The mean infusion rate of midazolam was similar (9.4 vs 8.7 mg/h) in the control patients and those with ARF. The renal clearance of 1-hydroxymethylmidazolam glucuronide was much lower in the ARF group than in the control group (3.9 vs 136 ml/min). Consequently, its plasma elimination half-life after discontinuation was also greatly prolonged, but this shouldn't cause very prolonged sedative effects since this metabolite is much less active than the parent drug. However, the half-life of midazolam itself was also significantly longer in patients with ARF than in the control group (13.2 vs 7.6 h). Apparently, this was caused by a combination of a slightly lower total clearance and a higher volume of distribution. Therefore, regular reassessment of the degree of sedation and appropriate adaptation of the infusion rate of midazolam are recommended in ICU patients with ARF.     

Intraosseous infusion: pressure-flow relationship and pharmacokinetics.

In order to quantitatively investigate the usefulness of intraosseous fluid and drug administration as a resuscitative modality, we studied the infusion flow rates of crystalloid solutions obtainable at varying infusion pressures into the bovine tibial medullary cavity and time to initial as well as 90% of maximal effect of intraosseously administered vasoactive drugs. Mean infusion rates +/- SEM (n = 6) at 300, 200, and 100 torr and atmosphere + 81 cm H2O were 41 +/- 2, 32 +/- 1, 27 +/-2, and 10 +/- 1 ml/min, respectively. The mean time (+/- SEM) to initial effect of intraosseous injections (n = 6) of either 0.5 mg epinephrine or 50 mg ephedrine was 17 +/- 3 seconds and mean time to 90% of maximal effect was 45 +/- 5 seconds. These results provide a quantitative basis for resuscitation by fluid and drug administration via the tibial malleolar intraosseous route and suggest that when performed in appropriate situations, the technique may have clinical utility.     

患者静脉输注依托咪酯的群体药代动力学

目的 评价患者静脉输注依托咪酯的群体药代动力学.方法 择期全麻患者29例,年龄25～82岁,以60μg·kg-1·min-1速率持续静脉输注依托咪酯,直至脑电双频谱指数值＜40.于输注依托咪酯前、持续输注1、3、5 min及停药即刻、停止输注后1、3、5、7、10、20、30、45、75、120、180、240、300和360 min时取桡动脉血样,测定血浆药物浓度.采用NONMEM软件建立依托咪酯群体药代学模型,分析年龄、身高、体重等协变量的影响.参数个体间变异性和残差变异性分别采用指数模型和相加误差模型描述,模型改善的统计学标准依据目标函数判断.结果 依托咪酯药代学适合用三室模型描述,年龄是系统清除率C L1的影响因素.依托咪酯药代学参数典型值为:V1=4.7 L,V2=11 L,V3=123L,CL1=1.28-0.0119×[年龄(岁)-55] L/min,CL2=1.25 L/min和CL3=1.08 L/min.输注时间敏感性半衰期随年龄和稳态输注时间的增加而升高(P＜0.05).结论 依托眯酯药代学适合用三室模型描述,年龄因素影响系统清除率.     

靶控输注芬太尼对异丙酚药代动力学的影响

目的 探讨靶控输注芬太尼对异丙酚药代动力学的影响。方法 24例行结肠或直肠癌根治术患者,AsAⅠ-Ⅱ级,随机分为异丙酚复合硬膜外组(A组,n=8),异丙酚复合2 ng·ml-1芬太尼组(B组,n=8),异丙酚复合4 ng·ml-1芬太尼组(C组,n=8),三组患者均采用靶控方式输注芬太尼与异丙酚,异丙酚靶浓度均为3μg·ml-1。测定靶控输注中及停止输注后异丙酚的血浆浓度,并拟合得到各项药代动力学参数。结果 异丙酚药代动力学模型符合三室开放模型。药代动力学参数:快速分布半衰期(t1/2α)、慢速分布半衰期(t1/2β)、消除半衰期(t1/2γ)、浓度-时间曲线下面积(AUC)、清除率(CL)及中央室容积(Vc),各组间比较差异无显著性(P>0.05)。结论 靶控输注临床剂量的芬太尼(2ng·ml-1与4 ng·ml-1)并不影响异丙酚的药代动力学特性。     

Bupivacaine crystal deposits after long-term epidural infusion

The case of a 45-year-old male patient (body weight 52 kg, height 1.61 m) with a locally invasive gastric carcinoma infiltrating into the retroperitoneal space is reported. Because of severe cancer pain a tunnelled thoracic epidural catheter (EC) was placed at thoracic spinal level 7/8 and a local anesthetic (LA) mixture of bupivacaine 0.25?% and morphine 0.005?% was infused continuously at 6 ml h^?1. To optimize pain therapy the concentration was doubled (bupivacaine 0.5?%, morphine 0.01?%) 3 months later but the infusion rate was reduced to 3 ml h^?1 thus the total daily dose did not change. The patient died 6 months after initiation of the epidural analgesia from the underlying disease. The total amount of bupivacaine infused was 69 g and of morphine 1.37 g. The patient never reported any neurological complications. The autopsy revealed large white crystalline deposits in the thoracic epidural space which were identified as bupivacaine base by infrared spectrometry. Morphine could not be detected. A histological examination showed unreactive fatty tissue necrosis within the crystalline deposits but nerve tissue could not be identified. It is concluded that the bupivacaine crystalline deposits arose due to precipitation but the clinical significance with regard to sensory level and neuraxial tissue toxicity is unknown.     

Narcotic pharmacokinetics and dynamics: the basis of infusion applications

Morphine, pethidine and fentanyl have similar pharmacokinetic profiles with moderately long elimination half-lives (3 to 4 hours), large steady-state volumes of distribution (2 to 4 l/kg), and high hepatic clearances (10 to 20 ml/kg/min). Alfentanil has a shorter terminal elimination half-life (1 1/2 hours) because of a decreased steady-state volume of distribution (0.5 to 1 l/kg). Physicochemical properties and blood:brain tissue solubility can explain the clinical differences in the rate of onset and dissipation of narcotic effect for these four narcotics. Morphine's low lipid solubility and limited rate of blood:brain barrier penetration results in the slow onset and dissipation of narcotic effect relative to pethidine or fentanyl. Alfentanil's lower blood:brain solubility results in the very rapid onset of narcotic effect when compared to fentanyl. All of the narcotics have a very steep blood concentration:narcotic effect curves. Thus, small changes of narcotic blood concentrations can have profound changes of narcotic effect. Finally, different degrees of perioperative stimuli result in different narcotic blood concentration requirements. Thus, narcotic infusion rates need be varied during surgical procedures to adjust for the varying opiate requirement.     

The effect of hydroxyethylstarch infusion on bupivacaine pharmacokinetics in rats

BACKGROUND: Bupivacaine is the agent most often used for labor analgesia. However, the risk of accidental intravascular injection of this drug and consequent acute systemic toxicity is ever-present. Although hydroxyethylstarch (HES) is preferred over crystalloid for prevention of hypotension during regional anesthesia, the pharmacokinetics of bupivacaine during fluid preloading has not been studied. METHODS: Twenty-four awake Sprague-Dawley rats were randomly allocated to receive the continuous intravenous infusion of HES 70K, 200K or 400K, or normal saline (NS). After 1 hour of prehydration all animals received bupivacaine, 1mg kg(-1), bolus, followed by a continuous infusion, 0.4mg kg(-1) min(-1) for 15 minutes. After the completion of bupivacaine infusion serial arterial blood samples to determine the plasma bupivacaine concentration were obtained. The plasma concentration-time profile of bupivacaine was fitted to a two-compartment open model, and the estimated intercepts and slopes were used for calculation of standard pharmacokinetic parameters. RESULTS: The mean peak bupivacaine concentration during HES 400K infusion was significantly lower than during NS infusion (1488 +/- 302 ng ml(-1) vs 2388 +/- 582 ng ml(-1)). Mean volume of distribution in each of the three HES groups was greater than in NS group. Mean area under curves (AUC) during HES 200K and HES 400K infusions were significantly lower than during NS infusion (32534 +/- 4180 and 29619 +/- 4431 min ng ml(-1), respectively, vs 39802 +/- 6268 min ng ml(-1)). Mean total clearance of bupivacaine during HES 200K and HES 400K infusions was significantly higher than during NS infusion (115 +/- 14 and 132 +/- 15 ml min(-1) kg(-1), respectively, vs 92 +/- 14 ml min(-1) kg(-1)). CONCLUSION: Our results suggest that the increased volume of distribution during HES infusion could be counterbalanced by the increased total clearance, resulting in unchanged half-life or elimination rate constant of bupivacaine.     

Performance of infusion pumps during hyperbaric conditions

BACKGROUND: Many hyperbaric facilities use infusion pumps inside the chamber. It is therefore important to ensure that this equipment will perform accurately during hyperbaric conditions. The authors tested the function and accuracy of the Imed 965 and Infutec 520 volumetric infusion pumps, the Easy-pump MZ-257 peristaltic infusion pump, and the Graseby 3100 syringe pump. METHODS: The authors calculated the deviations of infused volumes at low and high rates (12-18 and 60-100 ml/h) on three different hyperbaric protocols (up to 2.5, 2.8, and 6 atmospheres absolute [ATA]), resembling a standard hyperbaric oxygen treatment and US Navy treatment tables used for decompression illness and for arterial gas embolism. Two examples of each pump model were examined in every experiment. RESULTS: The Easy-pump MZ-257 failed to function completely beyond a chamber pressure of 1.4 ATA, making it unsuitable for use inside the hyperbaric chamber. The Graseby 3100 failed to respond to all keyboard functions at 2.5-2.8 ATA, making it unsuitable for use in most hyperbaric treatments. The Imed 965 performed within an acceptable volume deviation (< or =10%) during most hyperbaric conditions. During the compression phase of the profiles used, and for the low infusion rates only, exceptional volume deviations of 20-40% were monitored. The Infutec 520 demonstrated an acceptable deviation (within 10%) throughout all the hyperbaric profiles used, unaffected by changes in ambient pressure or infusion rate. CONCLUSIONS: Commercially available infusion pumps operating during hyperbaric conditions demonstrate substantial variations in performance and accuracy. It is therefore important that the hyperbaric facility staff make a careful examination of such instruments to anticipate possible deviations in the accuracy of the equipment during use.     

Simultaneous infusion of crystalloid solutions during long-term parenteral nutrition

A safer and more secure technic for the administration of additional solutions during long-term parenteral nutrition is described. This technic has contributed towards a reduction in septicemia.     

Pharmacokinetics of Thiopental in Caesarian Section

Anaesthesia for a planned caesarian section in nine women was induced with an i.v. thiopental injection. The injection was stopped when the ciliary reflex disappeared. 250–300 mg was given over 60–85 seconds. The concentration of thiopental in peripheral venous blood 20 s after the disappearance of the ciliary reflex varied from 4.3 to 33.7 μg/ml. The simultaneously obtained concentrations at delivery (11–25 min after the start of the induction) were 1.7-6.0 μg/ml in venous blood from the mothers and 1.3–5.5 μg/ml in cord vein blood. In two of the newborns, the Apgar scores were 8 and 9, in the other seven it was 10.
The baby with Apgar score 8 was delivered after 25 min and had a concentration in cord vein blood of 3.5 μg/ml. The decline in the concentration of thiopental in the venous blood of the mothers was described by a three-compartment open model. The terminal half-life was relatively short, between 91 and 595 min. The blood levels of thiopental in the newborns were followed for 22–33 h. The terminal half-lives in the babies ranged from 616 to 2560 min.