Influence of Hemorrhagic Shock on Remifentanil: A Pharmacokinetic and Pharmacodynamic Analysis

Background: Hemorrhagic shock is known to alter significantly the pharmacokinetics of fentanyl, an opioid that requires delivery to the liver for metabolism. The authors hypothesized that the pharmacokinetics and pharmacodynamics of remifentanil, an esterase metabolized opioid that does not require delivery to a metabolic organ, would be altered less by hemorrhagic shock that those of fentanyl.

Methods: Sixteen pigs were assigned randomly to control and shock groups. The shock group was bled using an isobaric hemorrhage model. Remifentanil 10 [mu]g [middle dot] kg-1 [middle dot] min-1 was infused for 10 min to both groups. Arterial samples were collected for remifentanil concentration assay. Pharmacokinetic parameters were estimated using a three-compartment model. The electroencephalogram spectral edge was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model.

Results: Remifentanil blood levels were higher in the shocked group. The central clearance was slower and the central compartment was smaller in shocked animals. No difference between groups was observed in the magnitude or time course of the remifentanil-induced decrease in spectral edge.     

Determination of the Potency of Remifentanil Compared with Alfentanil Using Ventilatory Depression as the Measure of Opioid Effect

Background: Remifentanil is a new opioid with properties similar to other mu-specific agonists. To establish its pharmacologic profile relative to other known opioids, it is important to determine its potency. This study investigated the relative potency of remifentanil compared with alfentanil.

Methods: Thirty young healthy males were administered double-blind remifentanil or alfentanil intravenously for 180 min using a computer-assisted continuous infusion device. Depression of ventilation was assessed by the minute ventilatory response to 7.5% CO2 administered via a "bag in the box" system. The target concentration of the study drug was adjusted to obtain 40-70% depression of baseline minute ventilation. Multiple blood samples were obtained during and following the infusion. The concentration-effect relationship of each drug was modeled, and the concentration needed to provide a 50% depression of ventilation (EC50) was determined.

Results: Only 11 subjects in each drug group completed the study; however, there were sufficient data in 28 volunteers to model their EC50 values. The EC50 (mean and 95% confidence interval) for depression of minute ventilation with remifentanil was 1.17 (0.85-1.49) ng/ml and the EC (50) for alfentanil was 49.4 (32.4-66.5) ng/ml.     

单纯靶控输注瑞芬太尼对脑电双频指数（BIS）的影响

目的：观察单纯靶控输注（TCI）瑞芬太尼对患者脑电双频指数（BIS）的影响。方法：40例择期全麻手术患者，按不同的瑞芬太尼预计血浆浓度随机分为4组（R2 、R4、 R6组，、即2、4、4、8ng/ml）。首先靶控输注瑞芬太尼，待瑞芬太尼血浆与效应室浓度达平衡后，记录患者BIS值。随后持续呼唤患者一分钟，并记录呼唤一分钟后患者的BIS值。结果：与基础BIS值相比，R8组患者BIS值明显降低（P〈0.05）,R6、R8组BIS值组间丝袜无统计学差异（P〉0.05）。R6、R8组组内患者对瑞芬太尼反应个体差异很大。结论：当单纯血浆单纯靶控输注瑞芬太尼时，血浆和效应室浓度小于4ng/ml时不会引起起BIS值下降，5－8ng/ml有镇静作用，可以引起BIS值明显下降，但个体间差异较大。     

A Model of the Ventilatory Depressant Potency of Remifentanil in the Non-steady State

Background: The C50 of remifentanil for ventilatory depression has been previously determined using inspired carbon dioxide and stimulated ventilation, which may not describe the clinically relevant situation in which ventilatory depression occurs in the absence of inspired carbon dioxide. The authors applied indirect effect modeling to non-steady state Paco2 data in the absence of inspired carbon dioxide during and after administration of remifentanil.

Methods: Ten volunteers underwent determination of carbon dioxide responsiveness using a rebreathing design, and a model was fit to the end-expiratory carbon dioxide and minute ventilation. Afterwards, the volunteers received remifentanil in a stepwise ascending pattern using a computer-controlled infusion pump until significant ventilatory depression occurred (end-tidal carbon dioxide [Peco2] > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 ng/ml. Remifentanil pharmacokinetics and Paco2 were determined from frequent arterial blood samples. An indirect response model was used to describe the Paco2 time course as a function of remifentanil concentration.

Results: The time course of hypercarbia after administration of remifentanil was well described by the following pharmacodynamic parameters: F (gain of the carbon dioxide response), 4.30; ke0 carbon dioxide, 0.92 min-1; baseline Paco2, 42.4 mmHg; baseline minute ventilation, 7.06 l/min; kel,CO2, 0.08 min-1; C50 for ventilatory depression, 0.92 ng/ml; Hill coefficient, 1.25.     

Determination of the Pharmacodynamic Interaction of Propofol and Remifentanil during Esophagogastroduodenoscopy in Children

Background: Propofol is commonly used to anesthetize children undergoing esophagogastroduodenoscopy. Opioids are often used in combination with propofol to provide total intravenous anesthesia. Because both propofol and remifentanil are associated with rapid onset and offset, the combination of these two drugs may be particularly useful for procedures of short duration, including esophagogastroduodenoscopy. The authors previously demonstrated that the median effective concentration (C50) of propofol during esophagogastroduodenoscopy in children is 3.55 [mu]g/ml. The purpose of this study was to describe the pharmacodynamic interaction of remifentanil and propofol when used in combination for esophagogastroduodenoscopy in pediatric patients.

Methods: The authors studied 32 children aged between 3 and 10 yr who were scheduled to undergo esophagogastroduodenoscopy. Propofol was administered via a target-controlled infusion system using the STANPUMP software based on a pediatric pharmacokinetic model. Remifentanil was administered as a constant rate infusion of 25, 50, and 100 ng [middle dot] kg-1 [middle dot] min-1 to each of three study groups, respectively. A sigmoid Emax model was developed to describe the interaction of remifentanil and propofol.

Results: There was a positive interaction between remifentanil and propofol when used in combination. The concentration of propofol alone associated with 50% probability of no response was 3.7 [mu]g/ml (SE, 0.4 [mu]g/ml), and this was decreased to 2.8 [mu]g/ml (SE, 0.1 [mu]g/ml) when used in combination with remifentanil.     

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.     

Influence of Acute Pain Induced by Activation of Cutaneous Nociceptors on Ventilatory Control

Background: Although many studies show that pain increases breathing, they give little information on the mechanism by which pain interacts with ventilatory control. The authors quantified the effect of experimentally induced acute pain from activation of cutaneous nociceptors on the ventilatory control system.

Methods: In eight volunteers, the influence of pain on various stimuli was assessed: room air breathing, normoxia (end-tidal pressure of carbon dioxide (PETCO2) clamped, normoxic and hyperoxic hypercapnia, acute hypoxia, and sustained hypoxia (duration, 15-18 min; end-tidal pressure of oxygen, approximately 53 mmHg). Noxious stimulation was administered in the form of a 1-Hz electric current applied to the skin over the tibial bone.

Results: While volunteers breathed room air, pain increased ventilation (V with dotI) from 10.9 +/- 1.7 to 12.9 +/- 2.5 l/min sup -1 (P < 0.05) and reduced PETCO2 from 38.3 +/- 2.3 to 36.0 +/- 2.3 mmHg (P < 0.05). The increase in V with dotI due to pain did not differ among the different stimuli. This resulted in a parallel leftward-shift of the V with dotI -carbon dioxide response curve in normoxia and hyperoxia, and in a parallel shift to higher V with dotI levels in acute and sustained hypoxia.     

Pharmacodynamic Interaction between Propofol and Remifentanil Regarding Hypnosis, Tolerance of Laryngoscopy, Bispectral Index, and Electroencephalographic Approximate Entropy

Background: The purpose of this investigation was to describe the pharmacodynamic interaction between propofol and remifentanil for probability of no response to shaking and shouting, probability of no response to laryngoscopy, Bispectral Index (BIS), and electroencephalographic approximate entropy (AE).

Methods: Twenty healthy volunteers received either propofol or remifentanil alone and then concurrently with a fixed concentration of remifentanil or propofol, respectively, via a target-controlled infusion. Responses to shaking and shouting and to laryngoscopy were assessed multiple times after allowing for plasma effect site equilibration. The raw electroencephalogram and BIS were recorded throughout the study, and AE was calculated off-line. Response surfaces were fit to the clinical response data using logistic regression or hierarchical response models. Response surfaces were also estimated for BIS and AE. Surfaces were visualized using three-dimensional rotations. Model parameters were estimated with NONMEM.

Results: Remifentanil alone had no appreciable effect on response to shaking and shouting or response to laryngoscopy. Propofol could ablate both responses. Modest remifentanil concentrations dramatically reduced the concentrations of propofol required to ablate both responses. The hierarchical response surface described the data better than empirical logistic regression. BIS and AE are more sensitive to propofol than to remifentanil.     

The Adequacy of Fragmin as a Single Bolus Dose with Reused Dialyzers

Abstract: Thirty-four hemodialysis patients were studied in a crossover fashion to compare the effectiveness of bolus-dose Fragmin (a low molecular weight heparin) with regular heparin usage in hemodialysis. For each anticoagulant, 3 dialyzes were studied for each patient; the first sessions involved a new dialyzer, and the subsequent sessions involved dialyzers reprocessed with peracetic acid. To assess the effectiveness of the anticoagulation regimens, the following were measured: the dialyzer fiber bundle volume and the instantaneous dialyzer clearances for urea (1 h into the second session). In addition, factor Xa levels were measured in 5 patients during the first and second sessions at 0 min, 30 min, and 4 h. Fiber bundle volumes were (in ml) 75.4 ± 8.8, 73.0 ± 8.9, and 73.5 ± 7.6 on first, second, and third uses with Fragmin (p = ns); and 77.8 ± 9.0, 73.4 ± 8.1, and 73.8 ± 8.1 with heparin (p < 0.001 second and third vs. first). Thus, there were no significant differences between Fragmin and heparin. Instantaneous dialyzer clearances were 165.8 ± 12.6ml/min with Fragmin and 163.8 ± 9.8 with heparin (p = ns). Factor Xa levels were 0 predialysis, 0.81 ± 0.17 U/ml at 30 min on first use, and 0.92 ± 0.09 U/ml on second use (p = ns); they were 0.51 ± 0.21 U/ml at 4 h on first use and 0.61 ± 0.16 U/ml on second use (p = ns). Thus, bolus-dose Fragmin provided similar results to constant infusion heparin and is not deleteriously influenced by reprocessing dialyzers with peracetic acid.     

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.     

Pharmacodynamic Modeling of Muscle Relaxants: Effect of Design Issues on Results

Background: Pharmacodynamic studies of muscle relaxants use different dosing regimens (such as administration by bolus vs. infusion and doses that produce complete vs. incomplete paralysis). The authors used published data to evaluate the effect of modeling assumptions on pharmacodynamic estimates.

Methods: The authors used a pharmacokinetic-pharmacodynamic dataset in which patients received cisatracurium, 75 or 300 [mu]g/kg (1.5 or 6 x ED95), to generate plasma concentration (Cp) and twitch depression (effect) curves. They then evaluated the impact of the following: assuming that Cp decreased monotonically versus increasing initially before decreasing monotonically; misrecording effect data by 6 s or less; and doses targeting incomplete versus complete paralysis. Parameters evaluated were the steady state Cp depressing twitch tension 50% (C50) and the rate constant for equilibration between plasma and effect site concentrations (ke0).

Results: With the large dose, increasing the time at which Cp peaked from 0.0 to 1.5 min decreased C50 and increased ke0 markedly; with the small dose, changes in both were small. Misrecording the timing of effect had a larger impact with the large dose compared with the small dose. Doses smaller than ED50 or those producing prolonged, complete twitch depression yielded biased and variable estimates.     

单次静注氯胺酮qEEG的θ波特点分析

目的:通过对单次静注氯胺酮(Ket)的定量脑电图(qEEG)分析来进一步加深认识此药的麻醉性能,探求可以反映其麻醉深度的指标.方法:9例ASAⅠ～Ⅱ级,年龄22～27岁,Ket 4mg/kg单次静脉注射,分术前、ket静注后第5分钟及第20分钟三个时段作qEEG监测并采集各项参数值,行前后自身对照.结果:①REL:可见术前各导联均以α波为主,θ波成份最小.但给药后5分钟却完全以θ波为主,至第20分钟仍以θ波为主.②δ比率:术前处于低比率状态,给药5分钟后比率显著上升(P＜0.01),第20分钟时比率回落,其中F7、F8导联已与术前无显著差异.③θ比率:术前低,给药第5分钟时比率骤升,20分钟时回落不显著,维持时间长于δ比率.而用反θ比率则更能清楚地显示这一特征,术前的高比率在给药第5分钟时骤然崩解,第20分钟时略有上升趋势.结论:EEG持久高功率的θ波活动是单次静注Ket 4mg/kg麻醉的特征表现;δ比率的变化趋势能反映患者的临床初醒状态,而"θ比率"与"反θ比率"较δ比率能更实际地反映大脑意识变化情况.     

Effect of the Milwaukee Brace on Vital and Ventilatory Capacity of Scoliotic Patients

The vital capacity (VC) and the maximal voluntary ventilation (MVV) were studied in 29 patients with scoliosis (predominantly idiopathic). The results obtained confirmed earlier observations that scoliotic patients have decreased VC and MVV. The immediate effect of the application of the Milwaukee brace was a slight though statistically significant decrease in MV, whereas there was no significant effect on VC. Treatment with the Milwaukee brace for a mean period of 15 months did not appreciably influence the VC or MW, as a percentage of the predicted normal values of the patients, when measured without the brace applied.     

Effect of the Milwaukee Brace on Vital and Ventilatory Capacity of Scoliotic Patients

The vital capacity (VC) and the maximal voluntary ventilation (MVV) were studied in 29 patients with scoliosis (predominantly idiopathic). The results obtained confirmed earlier observations that scoliotic patients have decreased VC and MVV. The immediate effect of the application of the Milwaukee brace was a slight though statistically significant decrease in MV, whereas there was no significant effect on VC. Treatment with the Milwaukee brace for a mean period of 15 months did not appreciably influence the VC or MW, as a percentage of the predicted normal values of the patients, when measured without the brace applied.     

Effect of Dexmedetomidine Compared to Remifentanil During Bariatric Surgery on Postoperative Nausea and Vomiting: a Retrospective Study

Purpose

Postoperative nausea and vomiting (PONV) occurs frequently after bariatric surgery and is a major cause of adverse outcomes. This retrospective study investigated whether opioid-restricted total intravenous anesthesia using dexmedetomidine as a substitute for remifentanil can reduce PONV in bariatric surgery.

Materials and Methods

The electronic medical records of adult patients who underwent laparoscopic bariatric surgery between January and December 2019 were reviewed. The patients were divided into two groups according to the agents used for anesthesia: Group D, propofol and dexmedetomidine; Group R, propofol and remifentanil.

Results

A total of 134 patients were included in the analyses. The frequency of postoperative nausea was significantly lower in Group D than that in Group R until 2 h after discharge from the postanesthesia care unit (PACU) (P?=?0.005 in the PACU, P?=?0.010 at 2 h after PACU discharge) but failed to significantly reduce the overall high incidence rates of 60.5% and 65.5%, respectively (P?=?0.592). Postoperative pain score was significantly lower in Group D until 6 h after PACU discharge. The rates of rescue antiemetic and analgesic agent administration in the PACU were significantly lower in Group D than those in Group R.

Conclusion

Opioid-restricted total intravenous anesthesia using dexmedetomidine reduces postoperative nausea, pain score, antiemetic, and analgesic requirements in the immediate postoperative period after bariatric surgery.

Graphical abstract

     

瑞芬太尼的心血管作用研究进展

瑞芬太尼可有效地抑制心血管应激反应,但其引起心动过缓和低血压的不良反应亦不容忽视。其机制可能既有对神经系统的作用;又有对血管的内皮及非内皮依赖性作用。     

The Circulatory Response to Specific Ventilatory Patterns Using a Tidal Volume Ventilator

The circulatory response to different ventilatory patterns during artificial ventilation was examined in 17 sternotomized piglets. A constant CO2-tension level was maintained in all investigations by reference to analyses of the end-tidal infra-red CO2 fraction and arterial CO2-tension. The greatest variation in mean values for end-tidal CO2-tension was 0.2 kPa. Total compliance and lung compliance were lower at a ventilator volume/pressure quotient of 20 compared to those at 80 ml/kPa, and at f = 30 compared to f = 11 cycles/min. Higher cardiac output, lower pulmonary vascular resistance and systemic vascular resistance were measured at f = 11 (inspiration 20%) than at f = 30 (inspiration 50%). An increase in inspiration time by about 100% at the lower ventilatory frequency (f = 11) resulted in a significant but uncompensated decrease in cardiac output and stroke volume. These results demonstrate the value of a rapid insufflation in order to give longer expiration time per minute for the benefit of the venous return and cardiac output.     

The Influence of Remifentanil on the Dynamic Relationship between Sevoflurane and Surrogate Anesthetic Effect Measures Derived from the EEG

Background: The authors modeled the influence of remifentanil on the dynamics of sevoflurane using three parameters derived from the electroencephalogram: 95% spectral edge frequency (SEF), canonical univariate parameter (CUP), and Bispectral Index (BIS).

Methods: Thirty-six patients with American Society of Anesthesiologists physical status class I or II were recruited, of which 12 received a target remifentanil concentration of 0 ng/ml, eight 2 ng/ml, eight 4 ng/ml, and another eight 8 ng/ml. Next (before surgery), several step-wise changes in the end-tidal sevoflurane concentration (FET,sevo) were performed. A data acquisition system simultaneously recorded FET,sevo, the raw electroencephalogram, BIS, and SEF. The authors used a combination of an effect compartment and an inhibitory sigmoid EMAX model to describe the relation between FET,sevo and BIS, SEF, and CUP. Model parameters (t1/2ke0, EMAX, EMIN, C50, [gamma], CUP weight factors) were estimated using the population data analysis program NONMEM. Significant remifentanil model parameter dependencies (P < 0.01) were determined.

Results: Determined from SEF, remifentanil had no effect on t1/2ke0 (1.91 +/- 0.26 min [mean +/- standard error]) but caused an increase in C50 (baseline = 1.48 +/- 0.12%; 80% increase at 8 ng/ml) and decrease in EMIN (baseline = 10.8 +/- 0.6 Hz; 80% reduction at 8 ng/ml). Determined from CUP, remifentanil caused a dose-dependent decrease in t1/2ke0 (baseline = 4.31 +/- 1.00 min; 60% decrease at 8 ng/ml), with no effect on C50 (baseline = 0.88 +/- 0.13%). Determined from BIS, remifentanil caused a dose-dependent decrease in t1/2ke0 (baseline value = 3.11 +/- 0.32 min; 40% decrease at 8 ng/ml), without affecting C50 (baseline = 1.12 +/- 0.05%). Median R2 values of the pooled data set were 0.815 for SEF, 0.933 for CUP (P < 0.01 vs. SEF), and 0.952 for BIS (P < 0.01 vs. SEF and CUP). Addition of remifentanil increased the R2 values for CUP only.