C.S. Reilly

Evaluation of the predictive performance of a ‘Diprifusor’ TCI system

The predictive performance of a ‘Diprifusor’ target controlled infusion system for propofol was examined in 46 patients undergoing major surgery, divided into three age groups (18–40, 41–55 and 56–80 years). Measured arterial propofol concentrations were compared with values calculated (predicted) by the target controlled infusion system. Performance indices (median performance error and median absolute performance error) were similar in the three age groups, with study medians of 16.2% and 24.1%, respectively. Mean values for ‘divergence’ and ‘wobble’ were −7.6%.h−1 and 21.9%, respectively. Measured concentrations tended to be higher than calculated concentrations, particularly following induction or an increase in target concentration. The mean (SD) propofol target concentration of 3.5 (0.7) μgml−1 during maintenance was lower in older patients, compared with higher target concentrations of 4.2 (0.6) and 4.3 (0.7) μgml−1 in the two younger age groups, respectively. The control of depth of anaesthesia was good in all patients and the predictive performance of the ‘Diprifusor’ target controlled infusion system was considered acceptable for clinical purposes.

Effectiveness of continuous positive airway pressure to enhance pre-oxygenation in morbidly obese women.

Morbid obesity is associated with a reduction in time to desaturate during apnoea following standard pre‐oxygenation and induction of anaesthesia. We have compared the effects of using 7.5 cmH2O of continuous positive airway pressure (CPAP) for pre‐oxygenation with a standard technique using a Mapleson A breathing system, in 20 morbidly obese women. In a prospective, open, randomised trial, we measured the time taken to desaturate to 90% from time of giving a succinylcholine bolus as part of a rapid induction of anaesthesia. All patients received 3 min pre‐oxygenation prior to induction. Tracheal intubation was confirmed and all patients kept apnoeic until oxygen saturation decreased to 90%. No statistically significant difference in mean time to desaturate to 90% could be demonstrated in the CPAP group compared to the Mapleson A group (240 s and 203 s, respectively). A brief period of lower mean heart rate in the CPAP group was the only statistically significant difference in cardiovascular parameters. There was no significant difference in the volume of gastric gas after induction between groups.

Beneficial microvascular and anti-inflammatory effects of pravastatin during sepsis involve nitric oxide synthase III

BACKGROUND Sepsis induces microvascular inflammation and production of the vasodilator nitric oxide (NO) via endothelial and inducible nitric oxide synthase (eNOS or NOS III and iNOS or NOS II). Statins are cholesterol-lowering drugs; however, they also attenuate inflammation. This study aimed to determine whether pravastatin protected against sepsis-induced hypotension, loss of vascular tone, and microvascular inflammation via NOS pathways. METHODS Male Wistar rats (n=18) were anaesthetized and the mesentery prepared for fluorescent intravital microscopy. Animals received either lipopolysaccharide (LPS; n=6); LPS+pravastatin (18 and 3 h before LPS; n=6), or saline as a control, for 4 h. RESULTS Mean arterial pressure decreased in LPS-treated animals (P<0.05), but not in those also receiving pravastatin. Acetylcholine-induced relaxation of venules was abolished by LPS but improved by pravastatin. Pravastatin also reduced the increase in nitrite concentration and macromolecular leak from venules induced by LPS (P<0.05). The increased leucocyte adhesion seen in LPS-treated rats was also reduced in those also treated with pravastatin. Immunohistochemical analysis showed that pravastatin increased endothelial cell expression of NOS III during sepsis, but had no effect on LPS-induced up-regulation of NOS II. CONCLUSIONS Pravastatin improved NOS III-mediated vessel relaxation and exerted anti-inflammatory effects within the microcirculation after LPS administration in rats. Pravastatin therefore appears to have beneficial effects during sepsis, as a result of increased microvascular expression and function of NOS III.

Effect of midazolam pretreatment on induction dose requirements of propofol in combination with fentanyl in younger and older adults

In a double‐blind, randomised trial, we compared the effects of pretreatment with midazolam at two different doses (0.025 and 0.05 mg.kg−1), with placebo, on the induction dose requirements of propofol in two different age groups. We enrolled 120 patients: 60 younger patients (aged 18–35 years) and 60 older patients (aged over 60 years). All patients received 0.75 µg.kg−1 of fentanyl, plus a blinded pretreatment with either saline or one of two doses of midazolam. Induction continued with a fixed rate infusion of propofol. Propofol dose requirement was recorded, as were cardiovascular parameters and the occurrence of significant apnoea (> 60 s). Midazolam pretreatment was associated with a significant reduction in propofol dose requirement in both younger and older patients. The reduction in older patients was significantly greater than the equivalent response in younger groups. There was no demonstrable benefit in terms of improved cardiovascular stability or reduction in the incidence of apnoea. Caution is advised in the use of midazolam as an agent for co‐induction with propofol in the elderly.

Statins for all: the new premed?

The use of statins is widespread and many patients presenting for surgery are regularly taking them. There is evidence that statins have beneficial effects beyond those of lipid lowering, including reducing the perioperative risk of cardiac complications and sepsis. This review addresses the cellular mechanisms by which statins may produce these effects. Statins appear to have actions on vascular nitric oxide through the balance of inducible and endothelial nitric oxide synthase. The clinical evidence for these benefits is also briefly reviewed with the objective of clarifying the current status of statin use in the perioperative period. There is reasonably strong evidence that patients already taking statins should continue on them perioperatively. However, the evidence for the prophylactic use of statins perioperatively is weak and lacks prospective controlled studies.

Development of a portable closed-loop atracurium infusion system: systems methodology and safety issues.

Safety of closed-loop drug infusion systems is an issue often raised as a matter of concern. As a result, many closed-loop control systems are reported in the literature merely as computer simulation studies and few ever reach the stage of physical realisation and formal clinical evaluation. We address the safety issues involved with such systems by describing the development of a portable closed-loop control system for atracurium-induced muscle relaxation. This is a safety-critical system particularly when applied to brain and eye surgery where movement could have serious deleterious effects. The benefits of closed-loop muscle relaxation in providing stable surgical operating conditions over a wide range of patient sensitivities while infusing the minimum amount of drug makes this a worthwhile aim and serves to demonstrate safety issues which are generally applicable to other closed-loop drug infusion systems. It is hoped that the described methodology will facilitate and encourage the clinical application of closed-loop drug infusion systems so that clinical staff and patients may receive the benefits of closed-loop drug therapy.

Response of the rat cremaster microcirculation to hemorrhage in vivo: differential effects of intravenous anesthetic agents.

Anesthetic agents are known to have differential effects on both the systemic circulation and the microcirculation. The aim of this study was to compare the effects of several intravenous (i.v.) agents on the microcirculatory response to hemorrhage. Male Wistar rats (n = 52) were anesthetized i.v. either with propofol and fentanyl (propofol/fentanyl), ketamine, or thiopental. Cardiovascular variables were monitored. The cremaster muscle was observed by using fluorescent intravital microscopy. FITC-BSA was administered (0.25 mL/100 g, i.a.) to determine macromolecular leak, an index of vessel integrity. Animals were further allocated into control (C), 10% hemorrhage (H), or hemorrhage re-infusion (H-R, removal of 10% blood volume and then re-infusion of saline and blood) groups. When systolic arterial pressure (SAP) was maintained after hemorrhage, constriction of A3 and A4 arterioles (5–30 &mgr;m) was accompanied by no change in the diameter of A1 (80–130 &mgr;m): most frequent with ketamine (A1: −1.7 ± 1.2; A4: −13.9 ± 2.7%; H and H-R: n = 9/11). With lower SAP, dilation of the A3 and A4 was accompanied by constriction of the A1: most frequent with propofol/fentanyl (A1: −8.0 ± 2.5; A4; 35.1 ± 9.4%; H and H-R: n = 6/11). No increases in macromolecular leak occurred with any anesthetic agent or in H or H-R groups. The response of cremaster muscle microcirculation to hemorrhage differs with different i.v. anesthetic agents. Dilation of small arterioles is the predominant response with propofol/fentanyl and constriction of small arterioles with ketamine.

Postoperative analgesia with transdermal fentanyl following lower abdominal surgery

In a randomised, placebo‐controlled, double‐blind study involving 81 patients undergoing total abdominal hysterectomy, the postoperative analgesia provided by transdermal fentanyl given at 25, 50, or 75μg.h‐1 for 72h was compared with a placebo group. The efficacy of the Transdermal Therapeutic System was related to the rate of fentanyl delivery, higher rates being associated with significantly lower visual analogue pain scores (24, 20, 17 and 13, for placebo, 25, 50 and 75μg.h‐1 respectively) and reduced patient controlled analgesia morphine requirements (44, 38, 33 and 31 mg respectively). Patients’overall sedation scores were not increased by transdermal fentanyl, but respiratory rates decreased with higher transdermal fentanyl dosage.

Adverse Effects of General Anaesthetics

SummaryThis review deals with the adverse reactions associated with general anaesthetic agents in current use. These reactions fall into 2 categories; those which are more common, predictable and often closely related, and those which are rare, unpredictable and carry a high mortality.Both inhalational and intravenous anaesthetic agents affect the central nervous and cardiorespiratory systems in a dose-related manner. Neuronal inhibition results in decreasing levels of consciousness and depression of the medullary vital centres which can lead to cardiorespiratory failure. Both groups of agents have some depressant effect on the myocardium and vascular smooth muscle leading to a fall In cardiac output and hypotension. Centrally-mediated respiratory depression is common to both groups and the inhalational agents have a direct effect on lung physiology.The most important idiosyncratic reactions to the volatile agents are malignant hyperpyrexia and ‘halothane hepatitis’. Malignant hyperpyrexia has an incidence of 1: 12 000 with a mortality of about 24%. 12 is triggered most often by halothane together with suxamethonium. Post halothane hepatic necrosis is rare. Evidence points to 2 distinct syndromes; direct toxicity from the products of reductive metabolism, and a more serious illness, immunologically mediated via haptens formed by liver proteins and the products of oxidative metabolism.Prolonged nitrous oxide exposure can cause bone marrow depression and life-threatening pressure effects by expansion of air-filled spaces within the body. The idiosyncratic reactions to the intravenous agents include anaphylactoid reactions (which are rare) and triggering of acute porphyria. Emmidate is immunologicaily ‘clean’, but it inhibits cortisol synthesis.

Intravenous anesthesia inhibits leukocyte-endothelial interactions and expression of CD11b after hemorrhage.

Hemorrhage increases adhesion of leukocytes to the venular endothelium, mediated by increased expression of the Mac-1 integrin complex (CD18/CD11b) present on leukocytes. Anesthetic agents may possess anti-inflammatory properties. Hence, this study determined the effects of i.v. anesthesia on leukocyte adhesion after hemorrhage in relation to expression of CD11b. Methods Male Wistar rats were (n = 57) anesthetized i.v. with propofol (Diprivan) and fentanyl, ketamine, or thiopental. During anesthesia, 10% of total blood volume was removed and intravital microscopy used to observe the rat mesentery and measure leukocyte (neutrophils) rolling and adhesion in postcapillary venules (15 - 25 &mgr;m). Flow cytometry was also used to determine CD11b expression on neutrophils from blood removed at the end of these experiments (n = 25) or blood incubated with anesthetic agents and activated with platelet activating factor ex vivo (0.1 &mgr;mol/L) (n = 24). Results Hemorrhage increased leukocyte adhesion (stationary count per 150 &mgr;m) in rats anesthetized with thiopental (baseline, 3.4 ± 1.2; hemorrhage, 6.7 ± 2.0; P < 0.05) but not in those receiving either ketamine (baseline, 3.6 ± 1.3; hemorrhage, 3.3 ± 1.3) or propofol/fentanyl (baseline, 6.2 ± 2.0; hemorrhage, 5.8 ± 0.8). Neutrophils collected from thiopental-treated rats had elevated CD11b expression with thiopental (mean fluorescence baseline, 67.5 ± 1.3; hemorrhage, 83.6 ± 5.3; P < 0.05) but not with propofol/fentanyl (mean fluorescence baseline, 69.1 ± 1.3; hemorrhage, 65.9 ± 1.6), and ketamine-treated rats (mean fluorescence baseline, 74.3 ± 2.1; hemorrhage, 74.8 ± 1.1). Ketamine also inhibited upregulation of CD11b with platelet activating factor ex vivo. Conclusions After hemorrhage, leukocyte adhesion and CD11b expression increased during thiopental anesthesia, but propofol/fentanyl and ketamine protected against hemorrhage-induced leukocyte adhesion. The anti-inflammatory effect of ketamine was mediated by direct inhibition of CD11b expression on leukocytes.