S. De Hert

Effects of postural changes on cardiac function in healthy subjects

Aims: To analyse the response of Doppler measurements to increased venous return in middle-aged healthy subjects. Methods and Results: Left ventricular pulsed Doppler parameters, colour M-mode of early left ventricular filling and septal mitral annulus velocities were measured at baseline and after leg lifting ðn ¼ 24Þ. Leg lifting resulted in increased stroke volume (69 � 14 to 74 � 14 ml, P < 0:01) and peak systolic annulus velocity (6.8 � 1.3 to 7.3 � 1.1 cm/s, P < 0:01). Leg lifting enhanced peak early (E) mitral flow (74 � 13 to 80 � 14 cm/s, P < 0:01), flow propagation (53 � 10 to 59 � 13 cm/s, P < 0:01) and E 0 diastolic mitral annulus velocity (10.8 � 2.2 to 11.7 � 2.0 cm/s, P < 0:01). There was a shortening of E wave deceleration time (178 � 27 to 163 � 27 ms, P < 0:01) and isovolumic relaxation time (76 � 11 to 68 � 10 ms, P < 0:01). However, individual changes in Doppler parameters differed among subjects.

Counter statement to open letter to the Executive Director of the European Medicines Agency concerning the licensing of hydroxyethyl starch solutions for fluid resuscitation

Editor—We were surprised to read the letter of Bellomo and colleagues criticizing the Co-ordination Group for Mutual Recognition and Decentralised Procedures-human (CMDh) position related to the benefit/risk evaluation of hydroxylethyl starch (HES)-containing solutions. Since the conclusion of these EU Article 31 and 107i procedures is based on a review of all available safety and efficacy data, including recent data from clinical studies, meta-analyses, postmarketing experience, and stakeholders’ opinions, it should be respected. Notably, the safety signals reported in the three investigator-initiated trials VISEP, 6S, and CHEST – 4 have all been reported in the setting of critically ill patients in general and mostly in patients with sepsis. These facts have been acknowledged and will be included in the product information, as proposed by the PRAC and endorsed by the CMDh by majority vote. On the contrary, in surgical and trauma patients, the benefit/risk ratio has been evaluated as positive. This is in line with the results of many clinical trials and the recent review article by Van der Linden and colleagues, showing, for example, a decreased requirement of blood transfusion and no difference in mortality and need for renal replacement therapy (RRT). These results confirm that the use of modern HES solutions is safe in the perioperative setting and are congruent with other reports. The judgement of a positive benefit/risk ratio is also in agreement with the majority of stakeholders, who have alreadyexpressed theiropinion during the EU Article 107i procedure. However, the PRAC has recommended conducting additional clinical studies in the surgical and the trauma setting. In the letter by Bellomo and associates, it is important to note that many articles are misquoted like the CRISTAL study. In fact, this clinical trial showed that colloids—when given in patients with hypovolaemic shock—are life-saving (significantly reduced 90 day mortality). In this study, 70% of the patients have been treated with HES. The subgroup analysis confirmed a significantly reduced 90 day mortality in HEStreated patients when compared with patients treated with 0.9% saline. Withdrawing HES would therefore not decrease but increase the risk for patients. Another example of a misquotation is linked to the reference James and colleagues, which is misleadingly cited to suggest that HES ‘. . . increases the risk of bleeding and need for blood products in patients . . . following blunt trauma’. Notably, the study results do not support the statement of Bellomo and colleagues. In fact, organ function was better in penetrating trauma patients treated with 6% HES 130/0.4 when compared with 0.9% saline. Owing to baseline imbalances among groups, no firm conclusion on the treatment effects in patients with blunt trauma was possible. In general, Bellomo and colleagues do not differentiate between HES types with different molecular substitutions and physicochemical properties. The references cited toreflect negative effects of HES in part used outdated solutions, for example, Cittanova and colleagues (6% HES 200/0.62), Brunkhorst and colleagues (VISEP-study, 10% HES 200/0.5), and the metaanalyses including starch solutions of older generations. On the contrary, there is increasing evidence showing that there are relevant differences between the effects of the different products, with the best profile for the latest generation of starches. This is supported by recent data of the RaFTinG registry that have been evaluated by PRAC in the Article 107i procedure. In their letter, Bellomo and colleagues did not discuss the major limitations of the three investigator-initiated studies VISEP, 6S, and CHEST. – 4 In this context, it is important to note that many patients were already treated before randomization and were not hypovolaemic at the time of study inclusion. Accordingly, there was no need of volume therapy in at least this subset of patients. It is also important to consider that many patients with contra-indications to HES have been included in the studies. In addition, dose limitations have not been respected in the VISEP trial. Overdosing and use outside the indication of hypovolaemia were associated with increased mortality. These criticisms have been expressed by the scientific community. Most importantly, data from the CHEST trial are used incorrectly, although the letter was written and signed by a number of CHEST investigators: ‘In CHEST, increased use of renal replacement therapy in intensive care patients occurred after a total cumulative dose of 5 ml/kg, one tenth of the maximal dailydose of 50 ml/kg’. This cannot be correct, since on the first treatment day, a mean dose of 980 ml was administered, which amounts to 12 ml kg. Moreover, the cumulative HES dose within the first 4 days of treatment was 26.5 ml kg. Thus, the cumulative HES dose was greater than five times more than acknowledged by Bellomo and colleagues. It is also important to consider that the difference in the use of RRT was only of borderline significance between groups and that no rules for initiating and stopping RRT were defined. There are also major concerns about study designs and data analyses in VISEP, 6S, and CHEST. Analyses by independent third parties are needed to clarify the open issues. We would also like to express that although some physicians signed the open letter, it is a minority not taking the current status of knowledge of the risk–benefit assessment of HES into account. In addition, we would like to emphasize that the conduct of further clinical studies is of high value to gain BJA Correspondence

Alteration of left ventricular endocardial function by intracavitary high-power ultrasound interacts with volume, inotropic state, and alpha 1-adrenergic stimulation.

Background. High‐power intracavitary ultrasound abbreviates left ventricular (LV) ejection duration, thereby decreasing mechanical LV performance, presumably by selective impairment of endocardial endothelial function. Methods and Results. Effects of ultrasound were evaluated in the ejecting LV of anesthetized, open‐chest dogs under different conditions of LV volume and contractile state and after mild selective &agr;1‐adrenergic stimulation. LV pressures, left atrial pressures, and regional segment lengths were measured in anterior and posterior midwall. A cylindrical ultrasound probe (0.9 MHz, 25 W) mounted on a catheter was inserted into the LV cavity through the apex and was activated for 4 minutes in each condition. In protocol A (n=7), LV volume was altered with caval vein occlusion and intravenous dextran infusion. The ultrasound probe was activated at low (4.1±0.9 mm Hg), mid (10.6±1.5 mm Hg), and high (17.9±1.8 mm Hg) LV end‐diastolic pressure (EDP). Effects of ultrasound were less pronounced at higher EDP. For example, the time interval from end‐diastole to peak (−)dP/dt decreased by 7.5±2.3% at low, 4.4±2.2% at mid, and 1.9±1.6% at high LVEDP (p<0.001). In protocol B (n=7), LV inotropic state was altered by slow intravenous infusion of low‐dose calcium. The ultrasound probe was activated before and after calcium. Effects of ultrasound were less pronounced after calcium. Time from end‐diastole to peak (‐)dP/dt decreased by 8.4±3.1% at baseline and by 3.5±2.1% after calcium (p<0.001). In protocol C (n=7), activation of the ultrasound probe was performed at baseline and after mild selective &agr;1‐adrenergic stimulation (propranolol plus phenylephrine). Effects of ultrasound were similar at baseline and after propranolol but increased after phenylephrine. Time from end‐diastole to peak (‐)dP/dt decreased by 5.2±2.4% at baseline, by 5.3±1.9% after propranolol, and by 8.9±3.2% after phenylephrine (p<0.05). Conclusions. Effects of intracavitary ultrasound, which are presumably mediated through modulation of endocardial endothelial function, were more important at low volume, lower calcium, and under mild selective &agr;1‐adrenergic stimulation. (Circulation 1993;87:1275‐1285)

Critical oxygen delivery during cardiopulmonary bypass in dogs: pulsatile vs. non-pulsatile blood flow.

Background and objective: To determine the minimal oxygen delivery and pump flow that can maintain systemic oxygen uptake during normothermic (37°C) pulsatile and non‐pulsatile cardiopulmonary bypass in dogs. Methods: Eighteen anaesthetized dogs were randomly assigned to receive either non‐pulsatile (Group C; n = 9) or pulsatile bypass flow (Group P; n = 9). Oxygen delivery was reduced by a progressive decrease in pump flow, while arterial oxygen content was maintained constant. In each animal, critical oxygen delivery was determined from plots of oxygen uptake vs. oxygen delivery and from plots of blood lactate vs. oxygen delivery using a least sum of squares technique. Critical pump flow was determined from plots of lactate vs. pump flow. Results: At the critical point, oxygen delivery obtained from oxygen uptake was 7.7 ± 1.1 mL min−1 kg−1 in Group C and 6.8 ± 1.8 mL min−1 kg−1 in Group P (n.s.). These values were similar to those obtained from lactate measurements (Group C: 7.8 ± 1.6 mL min−1 kg−1; Group P: 7.6 ± 2.0 mL min−1 kg−1). Critical pump flows determined from lactate measurements were 55.6 ± 13.8 mL min−1 kg−1 in Group C and 60.8 ± 13.9 mL min−1 kg−1 in Group P (n.s.). Conclusions: Oxygen delivery values greater than 7‐8 mL min−1 kg−1 were required to maintain oxygen uptake during normothermic cardiopulmonary bypass with either pulsatile or non‐pulsatile blood flow. Elevation of blood lactate levels during bypass helps to identify inadequate tissue oxygen delivery related to insufficient pump flow.

Oxygen transport and myocardial function after the administration of albumin 5%, hydroxyethylstarch 6% and succinylated gelatine 4% to rabbits

Background and objective: The effects of administering albumin 5%, hydroxyethylstarch 6% and succinylated gelatine 4% on oxygen transport and left ventricular function were prospectively investigated in different experimental conditions: baseline, fluid load, after 10 min of myocardial ischaemia and after reperfusion. Methods: Twenty-seven rabbits received at random one of three colloids in escalating boluses over 10-15 min to achieve left ventricular end-diastolic pressures (LVEDP) between 8 and 10 mmHg. A branch of the left anterior descending coronary artery was then temporarily occluded by a ligature and released after 10 min. Myocardial function was assessed using left ventricular pressure recordings and dimension data obtained from ultrasound crystals inserted onto the ventricular wall. Blood was sampled for the determination of oxygen delivery and consumption, the oxygen extraction ratio, acid-base status, and glucose and lactate concentrations. Results: Administration of the colloids similarly increased oxygen delivery and improved left ventricular function in all groups. Peak rate of pressure development (dP/dtmax) and oxygen delivery were reduced during ischaemia and reperfusion. The decrease in dP/dtmax was more pronounced in the hydroxyethylstarch group. Conclusions: Administration of albumin 5%, hydroxyethylstarch 6% and succinylated gelatine 4% had similar effects on oxygen delivery and myocardial function. After ischaemia and during reperfusion, the decrease in myocardial function was most pronounced with hydroxyethylstarch 6%.

The response of bispectral index to laryngoscopy, comparison between hemispheres in patients with a brain tumour versus a healthy control group

Background and Goal of Study: Electroencephalogram during anaesthesia may be affected by brain tumour.(1) We studied whether patients with a brain tumour have different BIS responses after laryngoscopy (LAR). We compared tumour patients with healthy control patients. Materials and Methods: After EC approval, 40 ASA 1 or 2 patients (control) and 41 intracranial tumour patients(tumour) received standardized anaesthesia while measuring bilateral BIS (BIS VISTAXP4 with bilateral sensor).(Covidien, Dublin, Ireland) Remifentanil was randomized to 3 or 5ng/ml effect‐site concentration (Minto) and maintained throughout the study. Propofol effect‐site concentration(CePROP)(Schnider) was set at 2 μg/ml and increased with incremental steps of 0.5 μg/ml until loss of consciousness was observed. After 3 minutes, laryngoscopy was performed and BIS was monitored during one minute. The median BIS of 1 minute before LAR is subtracted from the median BIS one minute after LAR to obtain delta BIS for each hemisphere. We tested if delta BIS is significantly different between hemispheres in control, between healthy and diseased hemispheres in tumour and between ipsilateral control and tumour hemispheres. Statistical significance was set at p< 0.05. Results and Discussion: No demographic differences were present except for age.(table 1) Delta BIS is not statistically different, neither between hemispheres in control, nor between healthy and diseased hemispheres in tumour groups.(table 2) No significant difference was found in delta BIS between ipsilateral control and pathological hemispheres. Conclusion(s): Bilateral BIS does not provide additional information on responsiveness to a standardized stimulus. We could not observe major differences in bilateral BIS response between control and brain tumour patients. Unilateral BIS monitoring seems to be equally informative in healthy and brain tumour patients compared to bilateral monitoring.

Influence of intraoperative opioid on postoperative pain and recovery after laparoscopic gastroplasty: Sufentanil TCI vs remifentanil TCI in morbid obesity: 9AP4-9

of amitriptyline and TTX. Primary outcome variable was the cell count in culture after 24 hours of incubation. Results and Discussion: Incubation with lidocaine alone decreased the cell count in culture from 314±58 to 118±48 cells (n=5, p<0.01). Adding TTX to cultures did not lead to a significant decrease in cell count (273±124, n=5, p>0.05), while addition of TTX to amitriptyline similarly did not aggravate the neurotoxic effects of amitriptyline. ±58, n=5, p>0.05). Conclusion(s): Adding TTX to amitriptyline did not aggravate amitriptyline neurotoxicity, such that combinations of these two drugs may be employed to achieve long-lasting conduction block. The synergism observed in electrophysiological studies, and the fact that toxicity is not synergistic, may allow to reduce the amitriptyline dose to levels that do not elicit neurotoxic effects.

EEG spectral entropy during sevoflurane anaesthesia in children: influence of age: 10AP1-3

entropy: SE) and frontal electromyogram (response entropy: RE) have been promoted as monitors of anaesthetic depth, but their characteristics in children remain poorly defined. This prospective randomized double-blind study assessed the effects of 50% N20 on SE and RE values during halothane and sevoflurane anaesthesia in children. Materials and Methods: Following institutional Ethics Committee approval and parental written informed consent, 40 ASA I and II children aged 6 months–5 years undergoing general anaesthesia for lower abdominal surgery were studied. Children were randomized to undergo halothane (group H: N 20) or sevoflurane (group S: N 20) All received caudal analgesia (bupivacaine 2 mg/kg) after anaesthetic induction. Entropy values were recorded by a blinded anaesthesiologist at 1 MAC steady state end tidal concentrations, in 50% O2/air and 50% O2/ N20 conditions. Data were compared with a paired Student t test. A p 0.05 was considered significant. Data are presented as mean SD. Results and Discussions: Demographic and surgical characteristics were not different among groups.

Effects of levosimendan in cardiac surgery patients with poor left ventricular function: 4AP7-2

by SDF imaging via an ileostomy in 5 anesthetized pigs. Four sequences of microcirculatory status were recorded on-line at baseline conditions and after first, second and third hour of HHD with Hartmann’s solution (20 mL/kg/h) iv and analyzed off-line. Systolic (SBP), diastolic (DBP) and mean arterial pressures were monitored continuously. One-way ANOVA on ranks was applied to compare changes in FCD during HHD. Results: Data are presented in the table:

Effect of preoperative medication on postoperative outcome in coronary surgery: 4AP5-2

Anesthesiology, Universital Hospital Antwerp, Edegem, Belgium Introduction: Several studies have assessed the potential beneficial effects of chronic pre-operative medication on postoperative outcome. Results of these studies however are conflicting. The present study investigated the effects of pre-operative medication on outcome variables after coronary surgery.(1) Material and methods: In a retrospective study on 1670 coronary surgery (CABG) patients, preoperative risk-factors and medication were related to the following postoperative outcome variables: 30-day mortality, myocardial infarction, low cardiac output, and hemodialysis. Relative risks were calculated for the individual pre-operative data. All significant variables were entered in a backward stepwise regression analysis to identify the independent risk factors. Statistical significance was accepted at p 0.01. Results: Age 70 years, diuretic therapy and low molecular weight heparin therapy were identified as the significant independent predictors of mortality. Unstable angina and clopidogrel therapy were identified as the significant independent predictor for postoperative myocardial infarction. Age 70 years, diuretic therapy, sex, unstable angina and pre-operative myocardial infarction were identified as the significant independent predictors for postoperative low cardiac output. Diuretic and clopidogrel therapy were identified as the significant independent predictors for the need for postoperative hemodialysis. Conclusions: Only pre-operative diuretic, low molecular weight heparin, and clopidogrel therapy were identified as independent risk factors for outcome after coronary surgery. Other chronic pre-operative medication such as -blocking therapy, calcium channel blockers, angiotensin converting enzyme inhibitors, angiotensin II antagonists, acetylsalicylic acid and nitrates did not affect outcome in this particular patient population.