Luc Barvais

Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass

Proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-6, and interleukin-8, and anti unflammatory cytokines, such as interleukin-10, may play an important role in patient responses to cardiopulmonary bypass. We sought to define whether the myocardium and the lungs serve as important sources of these cytokines under conditions of cardiopulmonary bypass. Ten patients (age 64 +/- 3 years, mean +/- standard error of the mean) undergoing elective coronary artery bypass grafting were monitored with an arterial catheter, a coronary sinus catheter, and pulmonary artery catheter. Plasma levels of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured simultaneously in peripheral arterial blood, coronary sinus blood, and mixed venous blood before heparin administration, 1 minute before aortic crossclamping, 5 minutes after aortic declamping, and at 0.5, 1, 1.5 and 2 hours after aortic declamping. The durations of cardiopulmonary bypass and aortic crossclamping were 114 +/- 9 and 64 +/- 5 minutes, respectively. Levels of tumor necrosis factor-alpha and interleukin-6 were significantly higher in coronary sinus blood than in arterial blood after aortic declamping. Tumor necrosis factor-alpha and interleukin-6 levels were also higher in mixed venous blood than in arterial blood within 1 hour after declamping. There were no significant differences among the three sampling sites with respect to interleukin-8 and interleukin-10 levels. In one patient who had postoperative myocardial infarction, however, interleukin-8 levels were three times as high as in coronary sinus blood than in arterial blood. These data indicate that the myocardium is a major source of tumor necrosis factor-alpha and interleukin-6 in patients undergoing cardiopulmonary bypass. The lungs may consume rather than release proinflammatory cytokines in the early phase of reperfusion. The source under these conditions of the antünflammatory cytokine interleukin-10 remains to be determined.

Corticosteroids increase blood interleukin-10 levels during cardiopulmonary bypass in men

BACKGROUND Interleukin (IL)-10 is a potent antiinflammatory cytokine inhibiting the release of tumor necrosis factor--alpha (TNF-alpha) and IL-8 by activated macrophages and polymorphonuclear leukocytes. Cardiopulmonary bypass (CPB) represents a unique situation where an inflammatory reaction is predictably induced. The present study examined the influence of CPB on the release of TNF-alpha, IL-1 beta, IL-8, and IL-10 and also defined the effects of pretreatment with corticosteroids on the release of these cytokines. METHODS The study included 22 patients undergoing coronary artery bypass graft operations, including eight control patients and seven patients who received dexamethasone, and seven patients who received methylprednisolone 4 hours before the operation. Cytokines were measured with the enzyme-linked immunosorbent assay technique before treatment, before anesthesia induction, immediately before heparin administration, before aorta declamping, 10 minutes and 90 minutes after aorta declamping, and 4 hours after the end of CPB. RESULTS In the control patients the TNF-alpha levels and especially the IL-8 levels increased during CPB and reached their maximal levels 4 hours after CPB. IL-10 levels rose moderately and transiently, reaching peak values 90 minutes after aorta declamping. Notably, administration of corticosteroids prevented IL-8 release but increased IL-10 levels, which were tenfold higher than in the control group 90 minutes after aorta declamping (dexamethasone, 271 +/- 128 pg/ml; methylprednisolone, 312 +/- 213 pg/ml; control, 17 +/- 12 pg/ml, p < 0.05). IL-1 beta was not detected in any group of patients. CONCLUSIONS The present data indicate that IL-10 is released together with proinflammatory cytokines during and after CPB and that pretreatment with corticosteroids markedly enhances this release. The release of IL-10 may play an important role in the antiinflammatory effects of corticosteroids.

Titration of propofol for anesthetic induction and maintenance guided by the bispectral index: closed-loop versus manual control: a prospective, randomized, multicenter study.

Background: This report describes a closed-loop titration of propofol target control infusion based on a proportional-differential algorithm guided by the Bispectral Index (BIS) allowing induction and maintenance of general anesthesia and compares this to manual propofol target control infusion. Methods: One hundred sixty-four patients scheduled to undergo elective minor or major surgery were prospectively randomized in a multicenter study into the closed-loop (n = 83) or manual target control infusion group (n = 81). The goal was to reach a BIS target of 50 during induction and to maintain it between 40 and 60 during maintenance. For both groups, remifentanil target control infusion was adjusted manually, and ventilation was without nitrous oxide. Results: Closed-loop control was able to provide anesthesia induction and maintenance for all patients. During induction, propofol consumption was lower in the closed-loop group (1.4 ± 0.5 vs. 1.8 ± 0.6 mg/kg; P < 0.0001), but the duration was longer (320 ± 125 vs. 271 ± 120 s; P < 0.0002). Adequate anesthesia maintenance, defined as the BIS in the range of 40–60, was significantly higher in the closed-loop group (89 ± 9 vs. 70 ± 21%; P < 0.0001), with a decrease of the occurrence of BIS less than 40 (8 ± 8 vs. 26 ± 22%; P < 0.0001). Time from discontinuation of propofol infusion to tracheal extubation was shorter in the closed-loop group (7 ± 4 vs. 10 ± 7 min; P < 0.017). Unwanted somatic events and hemodynamic instability were similar. Conclusion: Automatic control of consciousness using the BIS is clinically feasible and outperforms manual control.

Nicotine protects kidney from renal ischemia/reperfusion injury through the cholinergic anti-inflammatory pathway.

Kidney ischemia/reperfusion injury (I/R) is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the α7 nicotinic acetylcholine receptor (α7nAChR). Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the α7nAChR, as attested by the absence of protection in α7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-α and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic α7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.

Microcirculatory Alterations in Cardiac Surgery: Effects of Cardiopulmonary Bypass and Anesthesia

BACKGROUND Heterogeneity in microvascular perfusion is associated with impaired tissue oxygenation. We hypothesized that cardiac surgery with or without cardiopulmonary bypass (CPB) could induce microvascular alterations. METHODS We used an orthogonal polarization spectral imaging technique to evaluate the sublingual microcirculation in patients undergoing cardiac surgery with (n = 9) or without (n = 6) CPB. We also included, as a control group, 7 patients undergoing thyroidectomy with the same anesthetic procedure. Hemodynamic and microcirculatory variables were obtained the day before surgery, after induction of anesthesia, during CPB, on admission to the intensive care unit or the recovery room, and 6 and 24 hours after the end of the surgical procedure. Data are presented as median (25th to 75th percentile). RESULTS No differences in hemodynamic variables were observed between the two cardiac surgery groups. The proportion of perfused vessels was similar in all three groups at baseline (89% [87% to 90%]), and decreased similarly after induction of anesthesia to 71% (69% to 74%). It decreased further during CPB to 53% (50% to 56%). On admission to the intensive care unit or recovery room, alterations were more severe in CPB than in off-pump patients (60% [59% to 62%] versus 64% [61% to 65%]; p = 0.03), whereas they had already normalized in thyroidectomy patients (89% [86% to 90%]; p = 0.0005 versus cardiac surgery). In both cardiac surgery groups these microcirculatory alterations decreased with time, but persisted at 24 hours. The severity of microvascular alterations correlated with peak lactate levels after cardiac surgery (y = 11.5 - 0.15x; r(2) = 0.65; p < 0.05). CONCLUSIONS Microcirculatory alterations are observed in cardiac surgery patients whether or not CPB is used. Anesthesia contributes to these alterations, but its effects are transient.

Different Anesthetic Techniques Associated with Different Incidences of Chronic Post-thoracotomy Pain: Low-Dose Remifentanil Plus Presurgical Epidural Analgesia is Preferable to High-Dose Remifentanil with Postsurgical Epidural Analgesia

OBJECTIVE To investigate the relationships between 2 anesthetic techniques, or the extent of allodynia around the surgical wound, and the occurrence of chronic post-thoracotomy pain. DESIGN Prospective, randomized study. SETTING A single-institution, university hospital. PARTICIPANTS Thirty-eight patients who underwent elective thoracotomy under general anesthesia. INTERVENTIONS High-dose remifentanil (average effect-site concentration 5.61 +/- 0.84 ng/mL) with epidural analgesia started and at the end of surgery or low-dose remifentanil (average effect site concentration 1.99 +/- 0.02 ng/mL) with epidural analgesia with 0.5% ropivacaine started at the beginning of anesthesia. MEASUREMENTS AND MAIN RESULTS Pain intensity and the extent of allodynia around the wound were measured during the hospital stay. The presence and intensity of residual pain were assessed 1, 3, and 6 months after surgery and at the end of the study (6-13 months, average 9 months). A DN4 neuropathic pain diagnostic questionnaire was conducted at the same times. In the high-dose group, the area with allodynia was three times larger than the area in the low-dose group. The increased allodynia was associated with a higher incidence of chronic pain (RR: 2.7-4.2) 3 and 6 months after surgery and at the end of the study (median follow-up: 9.5 months). CONCLUSIONS High-dose remifentanil (0.14-0.26 microg/kg/min) without epidural analgesia during surgery is associated with a large area of allodynia around the wound. These patients develop a much higher incidence of chronic pain than those receiving low-dose remifentanil with epidural analgesia during surgery.

Hepatic release of interleukin-10 during cardiopulmonary bypass in steroid-pretreated patients☆☆☆★★★♢

With its antiinflammatory properties, interleukin (IL)-10 may play an important role in limiting complications associated with cardiopulmonary bypass (CPB). We previously demonstrated that pretreatment with steroids can significantly increase IL-10 production during CPB, but neither the heart nor the lung was found to be its main source. To define whether the liver is the source of IL-10, hepatic venous cannulation was performed in 12 patients undergoing CPB. Each patient received 30 mg/kg of methylprednisolone before operation. Plasma levels of IL-10 were simultaneously measured in peripheral arterial blood and hepatic venous blood before heparin administration, before aortic cross-clamping, and 5, 30, 60, 90, and 120 minutes after aortic declamping. The duration of CPB and aortic cross-clamping was 113 +/- 7 minutes and 75 +/- 6 minutes (mean +/- SEM), respectively. IL-10 levels 30 minutes after declamping were significantly higher in hepatic venous blood than in arterial blood (1187 +/- 573 pg/ml vs 911 +/- 405 pg/ml, p < 0.01 by Wilcoxons signed-rank test). To determine whether steroids can also induce the release of another antiinflammatory cytokine, IL-4, plasma IL-4 levels were measured simultaneously. IL-4 was detected in the arterial blood of only 4 of the 12 patients, transiently after aortic declamping. IL-4 was not detected in hepatic venous blood. In conclusion, the liver is a major source of IL-10 during CPB. However, steroid-treated patients do not show an increase in IL-4, and the liver is not the source of IL-4 during and after CPB.

The influence of a muscle relaxant bolus on bispectral and datex-ohmeda entropy values during propofol-remifentanil induced loss of consciousness.

Studies investigating the influence of muscle relaxants on the bispectral index have yielded contradictory results. In our prospective, randomized, double-blind experiments, patients received a fixed target concentration of remifentanil along with a target-controlled infusion of propofol, titrated until loss of consciousness. Two minutes after loss of consciousness, the study group received a bolus injection of atracurium, whereas the control group received a placebo. The following variables were recorded: bispectral index, spectral edge frequency, electromyographic activity, state entropy, and response entropy provided by the Datex-Ohmeda Entropy monitor. Similar values were obtained in both groups at loss of consciousness. Placebo administration induced a decrease in bispectral index (P < 0.002), spectral edge frequency (P < 0.05), electromyographic activ-ity (P < 0.02), state entropy (P < 0.05), and response entropy (P < 0.01) compared with the values measured at loss of consciousness. Atracurium administration induced a decrease in bispectral index (P < 0.0001), spectral edge frequency (P < 0.01), electromyographic activity (P < 0.0001), state entropy (P < 0.0001), and response entropy (P < 0.0001) values. Decreases in bispectral index (P < 0.05), electromyographic activity (P < 0.0001), and response entropy (P < 0.01) were larger after atracurium than placebo injection. In lightly anesthetized patients, myorelaxant administration decreases bispectral index and response entropy, but not state entropy values.

Effects of propofol on human microcirculation

BACKGROUND It is increasingly believed that acute microvascular alterations may be involved in the development of organ dysfunction in critically ill patients. Propofol significantly decreases vascular tone and venous return, which can induce arterial hypotension. However, little is known about the microcirculatory effects of propofol in healthy humans. METHODS We conducted a prospective, open-labelled trial in 15 patients anaesthetized by propofol for transvaginal oocyte retrieval. The sublingual microcirculatory network was studied before, during, and after propofol infusion using orthogonal polarization spectral imaging. RESULTS Mean (SD) calculated propofol effect-site concentration was 6.5 (1.8) microg ml(-1). During propofol administration, systemic haemodynamic and oxygenation variables were unchanged, but total microvascular density decreased by 9.1% (P<0.05). The venular density remained unchanged, but the density of perfused capillaries was significantly reduced by 16.7% (P<0.05). Microcirculatory alterations resolved 3 h after discontinuation of the propofol infusion. CONCLUSIONS Propofol infusion for anaesthesia in man reduces capillary blood flow.

Administration of propofol by target-controlled infusion in patients undergoing coronary artery surgery

OBJECTIVES To study the predictive performance of a target-controlled infusion (TCI) system of propofol in patients undergoing coronary bypass graft (CABG) surgery, using a referenced pharmacokinetic set derived from healthy patients. Also, to determine the propofol concentrations required for clinically acceptable induction and maintenance of anesthesia when combined with midazolam as premedication and a continuous alfentanil infusion and to study the hemodynamic stability of this technique. DESIGN Prospective noncomparative study analysis. SETTING Operating room at a university hospital. PARTICIPANTS Twenty-on patients with good left ventricular function undergoing coronary artery surgery. INTERVENTIONS Patients were anesthetized using a continuous infusion of alfentanil (mean infusion rate: 1 microgram/kg/min) and propofol administered by TCI. MEASUREMENTS AND MAIN RESULTS The predictive performance of the TCI system (212 arterial samples) was measured at specified time points before, during, and after bypass. The TCI system underestimated the measured blood propofol concentrations with a bias of +21.2% and +9.6% during the prebypass and the bypass periods, respectively. The predictive inaccuracy, expressed by the median absolute prediction error, was 23% and 18.5%, respectively. Mean target propofol concentrations required to induce and maintain anesthesia before bypass were 0.92 microgram/mL and 3.64 micrograms/mL, respectively. In the period during and after bypass, the mean target concentrations required to maintain anesthesia was 2.22 micrograms/mL. The administration of propofol by TCI was still associated with some short episodes of hemodynamic instability that were easily controlled by adjusting the target concentration in the majority of the patients. Therefore, the overall quality and ease of control of anesthesia were considered as being good or adequate. CONCLUSIONS In this group of patients undergoing CABG surgery, the TCI system used underestimated the measured propofol concentrations. However, the predictive performance of the selected mean pharmacokinetic parameters derived from healthy patients was acceptable during the whole surgical procedure.