Effect of sevoflurane on the ex vivo secretion of TNF-alpha during and after coronary artery bypass surgery.

BACKGROUND AND OBJECTIVE: Sevoflurane has been used for the induction and maintenance of anaesthesia during cardiac surgery owing to its favourable haemodynamic effects. It has been suggested that it offers protection against myocardial ischaemia-reperfusion injury. METHODS: We investigated the effect of sevoflurane on plasma concentrations of tumour necrosis factor-alpha (TNF-alpha) after ex vivo stimulation of whole-blood leukocytes by lipopolysaccharide from 20 patients undergoing coronary artery bypass surgery. The patients were randomized to two groups. Group 1 patients were induced and maintained with sevoflurane; those in Group 2 were anaesthetized with moderate doses of midazolam-sufentanil. Blood samples were drawn from the patients on seven occasions from before induction of anaesthesia until 24 h after skin closure. RESULTS: Plasma concentrations of TNF-alpha were lower in Group 1 than in Group 2 after cessation of cardiopulmonary bypass (median (interquartiles): 25 (21-30) versus 37 (28-79) pg mL(-1); P < 0.05) and 24h after skin closure (196 (100-355) versus 382 (233-718) pg mL(-1); P < 0.05). Postoperatively, two cases of myocardial infarction were recorded, one in each group. Six patients in Group 2 needed continued inotropic support after the first morning to maintain haemodynamic stability versus one patient in Group 1 (P < 0.05). The length of stay in the intensive care unit was significantly lower in Group 1 than in Group 2 (mean +/- SD: 25 +/- 16 versus 54 +/- 30 h; P < 0.05). CONCLUSIONS: Sevoflurane reduces production of TNF-alpha more than total intravenous anaesthesia with midazolam-sufentanil during cardiac surgery. This may reduce cardiac morbidity and the length of stay in the intensive care unit.

Dexamethasone decreases the pro- to anti-inflammatory cytokine ratio during cardiac surgery.

BACKGROUND: Cytokines regulate inflammation associated with cardiopulmonary bypass (CPB). Pro-inflammatory cytokines may cause myocardial dysfunction and haemodynamic instability after CPB, but the release of anti-inflammatory cytokines is potentially protective. We studied the effects of dexamethasone on pro- and anti-inflammatory cytokine responses during coronary artery bypass grafting surgery. METHODS: Seventeen patients were studied: nine patients received dexamethasone 100 mg before induction of anaesthesia (group 1) and eight patients acted as controls (group 2). Plasma levels of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, IL-10 and IL-4 were measured perioperatively. RESULTS: TNF-alpha and IL-8 did not increase significantly in group 1 whereas they increased in group 2 to greater than preoperative values (P<0.05). IL-6 increased in both groups, with lower values in group 1 than in group 2 (P<0.05). IL-10 increased in both groups, with higher values in group 1 (P<0.05). IL-4 did not change in group 1 but decreased in group 2 compared with pre-induction values (P<0.05). After surgery, patients in group 2 had tachycardia, hyperthermia, a greater respiratory rate and higher pulmonary artery pressure, and a longer stay in the intensive care unit. CONCLUSION: Dexamethasone given before cardiac surgery changes circulating cytokines in an anti-inflammatory direction. Postoperative outcome may be improved by inhibition of the systemic inflammatory response.

Effect of VIMA with sevoflurane versus TIVA with propofol or midazolam-sufentanil on the cytokine response during CABG surgery.

BACKGROUND AND OBJECTIVE: Cardiac surgery with cardiopulmonary bypass triggers an inflammatory response involving pro-inflammatory cytokines such as tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and interleukin 8 (IL-8). We investigated whether different anaesthetic techniques alter the pro-inflammatory cytokine response to cardiac surgery. METHODS: Thirty patients scheduled for elective coronary artery bypass grafting (CABG) surgery were randomized into three groups of 10 patients. They received either volatile inhalation induction and maintenance (Group 1) or total intravenous anaesthesia with propofol and a minimal dose sufentanil (Group 2) or a moderate dose midazolam-sufentanil (Group 3). The effect of the different anaesthetic techniques on plasma levels of TNF-alpha, IL-6 and IL-8 were examined during and after anaesthesia. RESULTS: Concentrations of TNF-alpha, and IL-8 were comparable in the three groups throughout all measurements. Before the start of cardiopulmonary bypass, IL-6 was significantly higher in Group 1 than in Group 2 (P = 0.009) or Group 3 (P = 0.030), but there were no differences between groups after cardiopulmonary bypass or postoperatively. In the three groups there was a positive correlation between aortic clamping time and serum concentrations of IL-6 (r = 0.54) and IL-8 (r = 0.62). Length of stay in intensive care was correlated with high levels of TNF-alpha (r = 0.78). CONCLUSIONS: Albeit there is difference between the volatile induction and maintenance of the anaesthesia method and the total intravenous anaesthesia technique on the pro-inflammatory cytokine response to surgical stimulation before starting of cardiopulmonary bypass, neither technique can modify the pro-inflammatory cytokine response to ischaemia-reperfusion or extracorporeal circulation.

Liver and renal function after volatile induction and maintenance of anesthesia (VIMA) with sevoflurane versus TIVA with sufentanil-midazolam for CABG surgery.

We compared liver and renal function after volatile induction and maintenance of anesthesia (VIMA) with sevoflurane and minimal dose sufentanil versus total intravenous anesthesia (TIVA) with moderate dose of midazolam and sufentanil in patients undergoing CABG surgery. Eighty nine patients were studied retrospectively after VIMA (44 patients) or after TIVA (45 patients). Liver and renal function were measured before (T0), then 1 (T1), 2 (T2), 5 (T3) days and 6 weeks (T4) after the operation. Serum levels of aspartate aminotransferase (ASAT) and lactate dehydrogenase (LDH) increased in both groups at T1, T2 and T3 and the highest levels were at T1. Levels of total bilirubin (TBil) increased at T1 only in the TIVA group. Levels of g-glutamyl transpeptidase (GGT) and alanine aminotransferase (ALAT), increased in both groups at T3. Serum levels of creatinine (Cr) were high in both groups on T1 and T2. Blood urea nitrogen (BUN) was high in both group at T2, and T3 with the peak levels in T2. Six weeks after the operation all liver and renal functions were normal in both groups. We concluded that VIMA with sevoflurane during cardiac surgery has no untoward effects on liver or renal functions. The transient reversible elevation was comparable in the VIMA and TIVA groups which was most probably due to the effect of the operation itself.

Short-term efficacy of tricyclic antidepressants revisited: a meta-analytic study.

The original data from the placebo-arms and the tricyclic-arms of all parallel randomized controlled three-arm studies, which had been conducted in the period 1979-1991 for a drug under development in order to obtain marketing authorization for the indication major depression, were included in a meta-analysis. Thirty-two placebo-controlled studies including 4314 patients were analyzed. The intention to treat analysis resulted in 46% responders (at least 50% improvement on the Hamilton Depression Rating Scale) in the tricyclic antidepressant group and 31% in the placebo-group (CI(95%-difference) 11.5-17.1%). The number needed to treat for responders was 7 (CI(95%) 5-8). In 10 out of 32 studies, a statistically significant difference in favor of tricyclic antidepressant compared to placebo was found for responders. The responder rate in the placebo-group varied from 6 to 52%. We conclude that tricyclic antidepressants are efficacious in the short-term treatment of major depression. However, the magnitude of the effect is rather modest. Because 69% of the placebo-controlled studies with a tricyclic antidepressant did not show a statistically significant difference in favor of tricyclic antidepressant and the placebo rate varied considerably from study to study, equivalence studies with tricyclic antidepressant as comparator without a placebo-control are not sufficient for demonstrating efficacy. Therefore in major depression, placebo-controlled studies are still necessary to demonstrate efficacy.

Evaluation of techniques for the presentation of laboratory data: support of pattern recognition.

Two tabular and two graphical techniques for the presentation of laboratory test results were compared in a reaction-time experiment with 22 volunteers. The experimental setup was designed to determine whether one or more of the presentation techniques facilitated the recognition of four predefined combinations of abnormal test results. Using a conventional, tabular presentation technique as a reference, faster median response times were obtained with each of the other three presentation techniques, irrespective of pattern. The effect on accuracy was less clear, possibly due to the small number of errors made.

Improved reproducibility of measurements with the nerve fiber analyzer.

PURPOSE: This study was undertaken to assess and improve the repeatability and reproducibility of nerve fiber layer (NFL) measurements using the Nerve Fiber Analyzer (NFA I), a scanning laser polarimeter. METHODS: The repeatability of two subsequent measurements was determined in 100 healthy eyes. Four methods of image evaluation were performed. Polarimetric measurements of retinal NFL were obtained along a peripapillary band at the superior and inferior poles of the optic disk and analyzed in a one-pixel band of absolute retardation values (method 1) and relative to the nasal segment (method 2). Method 3 used measurements obtained in a 10-pixel band along the same peripapillary band. Method 4 comprised measurements in selected areas outside the peripapillary band, which did not contain blood vessels. The repeatability (r) and relative reliability coefficient (Rel) were assessed as indices of agreement of repeated measurements. In addition, the reproducibility (R) from day to day for methods 3 and 4 was assessed by taking 10 images on 10 consecutive days from each of 10 subjects. RESULTS: The 95% critical value for r in the superior and inferior segments improved from about 30% for methods 1 and 2, to 23% for method 3, and to 11% for method 4. For the superior and inferior segments, the fourth method of image evaluation yielded a Rel of 98%, as compared with 54% in method 1, 80% in method 2, and 87% in method 3. The 95% critical value for R was 23% for method 3 but only 15% for method 4. CONCLUSIONS: The improved reproducibility of measurements has made the NFA I a promising device. An improved reproducibility (smaller limit for detecting change) does not necessarily indicate good sensitivity and specificity for any instrument. The role of the scanning laser polarimeter in clinical practice requires further study.

Evaluation of techniques for the presentation of laboratory data. I: Time needed for interpretation.

Four tabular and two graphical techniques for the presentation of laboratory test results were evaluated in a reaction-time experiment with 25 volunteers. Artificial variables and values were used to represent sets of 12 laboratory tests to eliminate the possible effects of clinical experience. Analyses focused on reaction times for correctly classified sets of data. For comparable data sets, Presentation Techniques (PT) that use color, always allow faster interpretation than PTs that do not use color, or use only a simple marker. Color-coded tables yielded an improvement in median reaction time of approximately six times or better, as compared to the reference PT (a tabular PT without any hints). For the color-coded graphs, the improvement rate was approximately 2.5 or better.

Evaluation of techniques for the presentation of laboratory data. II: Accuracy of interpretation.

Four tabular and two graphical techniques for the presentation of laboratory test results were evaluated in a reaction time experiment with 25 volunteers. Artificial variables and values were used to represent sets of 12 laboratory tests to eliminate the possible effects of clinical experience. Analyses focused on four types of errors in interpretation. Color-coded tables and one of the color-coded graphs greatly (2.8 times or better) reduced the number of incorrectly classified test results, as compared to the reference presentation technique. This was mainly due to a reduction of the number of abnormal test results that were not noticed by the subjects when using these presentation techniques.

Excessive prolongation of the bleeding time by aspirin in essential thrombocythemia is related to a decrease of large von Willebrand factor multimers in plasma.

Patients with essential thrombocythemia (ET), who frequently have bleeding complications, may manifest an excessive prolongation of the bleeding time (BT) after ingestion of aspirin (ASA). The reason for this excessive prolongation of the BT is unknown, but it is attributed to qualitative platelet defects. Since patients with ET may also have acquired abnormalities of plasma and platelet von Willebrand factor (vWF), we questioned whether the excessive prolongation of the BT by ASA was related to changes in either plasma or platelet vWF. To that end, we studied BT and plasma and platelet vWF in ten ET patients, ten patients with reactive thrombocytosis (RT), and ten normal individuals, both before and after administration of 500 mg ASA for 7 days. In a second study, the effect of DDAVP infusion on plasma vWF in relation to the BT was studied in ten normal individuals and ten ET patients after treatment with 100 mg ASA for 3 days. In the first study, treatment with ASA resulted in a significant prolongation of the BT in normal subjects, RT patients, and ET patients. However, in five ET patients an excessive (> 2 SD) prolongation of the BT by ASA was observed. Although ASA induced no direct changes in either plasma or platelet vWF levels in either normal subjects, RT patients, or ET patients, all five ET patients who showed an excessive prolongation of the BT by ASA had significantly decreased levels of large vWF multimers in plasma. In the second study, infusion with DDAVP resulted in a significant increase in plasma large vWF multimers, paralleled by a normalization of (excessively) prolonged BT. Our data suggest that in ET inhibition of platelet function by ASA in the presence of concurrently decreased levels of large vWF multimers in plasma may have provoked the excessive BT prolongation.

Decreased half-life time of plasma von Willebrand factor collagen binding activity in essential thrombocythaemia: normalization after cytoreduction of the increased platelet count.

Patients with essential thrombocythaemia (ET) exhibit a decrease of large von Willebrand factor (VWF) multimers in plasma, which is inversely related to the platelet count. In the present study we investigated whether the decrease of large VWF multimers in plasma with increasing platelet counts is the consequence of increased turnover of large VWF multimers in vivo. To that end we measured the half-life times of endogenously released VWF:Ag and VWF:CBA (collagen binding activity) after intravenous administration of desmopressin (DDAVP) to nine ET patients and nine control subjects (N). In addition, the half-life times of VWF:Ag and VWF:CBA were also measured in four ET patients after cytoreduction of the increased platelet count to normal or nearly normal values. Estimated half-life times of VWF:Ag did not differ between ET patients and normals (11.0+/-4.0 h v 12.4+/-2.5 h, P>0.05). Estimated half-life times of VWF:CBA were significantly lower in ET patients as compared with normal individuals (6.1+/-2.0 h v 8.4+/-2.5 h, P<0.05). After cytoreduction of the increased platelet count to (nearly) normal values in all four ET patients the half-life time of VWF:CBA significantly (P=0.014) increased from 5.2+/-1.2 h to 8.7+/-2.0 h. Our data suggest that platelets may play a role in the homeostasis of circulating von Willebrand factor, which may compromise normal haemostasis at fairly increased platelet counts.

Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation.

Erythromelalgia, a characteristic aspirin-responsive microvascular thrombotic complication in essential thrombocythemia (ET), may develop despite oral anticoagulant treatment or treatment with heparin, suggesting that the generation of thrombin is not a prerequisite for its development. To study this, a cross-sectional comparison of the plasma levels of thrombomodulin (TM), platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), prothrombin fragment 1 + 2 (F1 + 2) and total degradation products of fibrin(ogen) (TDP) was made between 5 ET patients suffering from erythromelalgia, 16 asymptomatic ET patients and 20 control subjects, and after treatment with aspirin, respectively. Furthermore, 2 ET patients with a history of erythromelalgia were studied at regular time intervals after discontinuation of aspirin until erythromelalgia recurred. As compared with asymptomatic ET patients and control subjects erythromelalgia was characterized by significantly higher beta-TG and TM levels but no significant differences were detected in either F1 + 2 or TDP levels. Treatment of erythromelalgia with aspirin resulted in disappearance of erythromelalgic signs and symptoms, which was paralleled by a significant decrease of beta-TG and TM levels. Histopathologic and immunohistochemical analysis of biopsies derived from erythromelalgic skin areas of 2 ET patients showed that erythromelalgic thrombi stained positively for von Willebrand factor opposed to only a weak fibrin staining. Our data suggest that erythromelalgia is caused by the intravascular activation and aggregation of platelets with subsequent sludging or occlusion of the acral arterial microvasculature. The generation of thrombin appears not to be essential for the formation of these platelet thrombi, thereby giving a plausible explanation for the inefficacy of coumadin derivatives and heparin in the prevention and treatment of erythromelalgia in essential thrombocythemia.

The reduction of large von Willebrand factor multimers in plasma in essential thrombocythaemia is related to the platelet count.

We have investigated the relationship between platelet count and large VWF (von Willebrand factor) multimers in the plasma of 36 patients with essential thrombocythaemia (ET) and 26 patients with reactive thrombocytosis (RT). In both ET and RT patients an inverse relationship could be established between platelet count and large VWF multimers in plasma as well in relatively decreased ristocetin cofactor/von Willebrand factor antigen and collagen binding activity/von Willebrand factor antigen ratios. A normalization of the platelet count was accompanied by restoration of a normal plasma VWF multimeric distribution. Our data suggest that increasing numbers of platelets circulating in blood result in increased removal of large VWF multimers from plasma.

The effect of cigarette smoking on the survival of free vascularized and pedicled epigastric flaps in the rat.

Microsurgeons suspect that cigarette smoking reduces the survival of free vascularized flaps and replantations, but this has never been proven. This experimental study investigates the effect of smoking on free-flap survival. A fasciocutaneous epigastric flap was used in 30 rats as a free flap and in 30 rats as a pedicled flap. Of each group, 10 rats were smoked 6 weeks before and 2 weeks after surgery, 10 rats were smoked only 6 weeks before surgery, and 10 rats underwent the sham smoking procedure. Also, a distally based dorsal skin flap was cut in all rats, representing a random vascularized flap. Vitality and size of both flaps and patency of the vascular anastomoses were assessed 14 days after surgery. The epigastric flaps were monitored by laser Doppler flowmetry and thermometry during the experiment. Survival of the free vascularized epigastric flaps was significantly lower in smoking rats. All pedicled flaps except one survived. The epigastric flaps only necrosed or survived completely, exactly correlating to the patency of the vascular anastomoses. The mean surviving area of the dorsal flaps was best for nonsmoking rats, worse for only preoperatively smoking rats, and worst for preoperatively and postoperatively smoking rats. The differences were statistically significant. Postoperative laser Doppler flow differed significantly between surviving and dying flaps, affirming the value of laser Doppler flow monitoring in microvascular surgery. In conclusion, this study proves that smoking of cigarettes is detrimental to the survival of free vascularized flaps.

Why leg crossing? The influence of common postures on abdominal muscle activity.

STUDY DESIGN: Abdominal muscle activity is recorded in the supine position, unconstrained standing, and in the sitting position on an office chair with the use of backrest and armrests, with and without crossed legs. OBJECTIVES: To assess the role of oblique abdominal muscles in relation to the stability of lumbar spine and pelvis in commonly adopted unconstrained postures. SUMMARY OF BACKGROUND DATA: Cross-legged sitting is very common for men and women. No solid evidence exists for either a beneficial or a detrimental effect of this posture. No electromyographic study deals with the activity of abdominal muscles in this commonly adopted unconstrained posture. METHODS: In healthy subjects, electromyographic activity of the rectus abdomini and external and internal oblique abdominals was recorded bilaterally during commonly adopted unconstrained postures. RESULTS: The activity of the internal oblique muscle was significantly higher in the sitting position than in supine position. For the external and internal oblique abdominals, the activity was significantly higher in the standing position than in the sitting position. When sitting, the activity of the oblique abdominals is significantly lowered by crossing the legs in the preferred way (either upper legs cross or ankle on knee). In contrast, the activity of the rectus abdominis is not significantly altered by leg crossing. CONCLUSIONS: From these remarkable findings, we conclude that leg crossing is physiologically valuable. It should be studied whether leg crossing can be implemented in the design of the workplace.

Platelet consumption in thrombocythemia complicated by erythromelalgia: reversal by aspirin.

The involvement of platelets in the pathogenesis of erythromelalgia, a frequent and characteristic microvascular thrombotic manifestation in patients with primary thrombocythemia and polycythemia rubra vera, was investigated by measuring the survival and turnover of 51Cr labeled autologous platelets in 10 patients with thrombocythemia complicated by erythromelalgia, in 10 asymptomatic thrombocythemia patients and in 6 subjects with reactive thrombocytosis. The mean platelet survival time of the erythromelalgia patients was 4.2 +/- 0.2 days, which is significantly decreased as compared with asymptomatic thrombocythemia patients (6.6 +/- 0.3 days, p < 0.001) and patients with reactive thrombocytosis (8.0 +/- 0.4 days, p < 0.001). The mean platelet survival time of asymptomatic thrombocythemia patients was significantly decreased (p < 0.01) as compared with reactive thrombocytosis patients. Treatment of erythromelalgia with aspirin increased the mean platelet survival time from 4.0 +/- 0.3 days to 6.9 +/- 0.4 days (p < 0.001) and was associated with an elevation of the platelet count of 216 +/- 30 x 10(9) platelets per liter (p < 0.001). Coumadin failed to improve platelet survival or symptoms caused by erythromelalgia. The increased platelet consumption in erythromelalgia is attributed to the formation of platelet thrombi in the arterial microvasculature. This conclusion is supported by the ability of aspirin to interrupt platelet consumption and clinical features of erythromelalgia.

Comparison of laser Doppler flowmetry and thermometry in the postoperative monitoring of replantations.

Reliable postoperative monitoring in microvascular surgery is necessary to improve the success rate of reexplorations following vascular compromise. Surface thermometry is known as an easy and inexpensive objective postoperative monitor and therefore is used by many microsurgeons. Reliability, however, is not satisfactory, and therefore several other instrumental methods have been tested of which laser Doppler flowmetry shows the most promising results. This study compared laser Doppler flowmetry to thermometry in the postoperative monitoring after replantation surgery. In 34 patients, 45 replantations and revascularizations were monitored by laser Doppler flowmetry and thermometry. A reliable alarm value of 10 PU was defined for replantations and revascularizations, with a sensitivity of 93% and a specificity of 94%. Thermometry showed a sensitivity of 84% and a specificity of 86% at 29 degrees C.

Uveal melanoma: updated considerations on current management modalities.

Published data on growth rates of uveal melanomas and effects of treatment modalities raise important considerations. Dissemination from uveal melanomas starts after the tumour is larger than 7 mm diameter; growth from 7 to 10 mm diameter increases the risk of metastases incrementally to approximately 16%. Estimations of tumour doubling times indicate that metastatic death before 8 years is nearly always due to pre-therapeutic dissemination so that the impact on survival by therapy can only be assessed thereafter. Histopathology on irradiated melanomas reveals that reproductive activity has not been suppressed and the anticipated (and unfavourable) risk of metastases is not balanced by poor post-irradiation visual acuity. Also the psychological well-being of a patient with a functional fellow eye is better after primary enucleation. Conservative management is most appropriate for: small melanomas, patients with a short life expectancy, melanomas in a single functioning eye, and patients refusing enucleation.

The predictive value of the laser Doppler flowmeter for postoperative microvascular monitoring.

Reliable postoperative monitoring in microvascular surgery is necessary to improve the low success rate of reexploration after vascular compromise. The use of laser Doppler flowmetry has been evaluated in this study. From November 1985 to January 1988, 79 microvascular operations were monitored postoperatively. These consisted of 45 replants and revascularizations in 34 patients, as well as 34 free vascularized tissue transfers. In the replant and revascularization group, a statistically significant difference in laser Doppler flowmetry readings has been demonstrated between well-vascularized and circulatory impaired patients (p < 0.001). In this study a reliable critical (alarm) value could be defined for replants and revascularizations with a sensitivity of 93% and a specificity of 94%. This critical alarm value can be adjusted according to the individual surgeon's attitude toward reexploration. Similar laser Doppler flowmetry characteristics were seen in patients with free vascularized tissue transfers; however, the numbers in this part of the study were too small to define reliable critical alarm values. The laser Doppler flowmeter is recommended for the postoperative evaluation of tissue after microvascular anastomoses, as it indicates vascular occlusion at an early stage where reexploration is worthwhile.