Department of Anaesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Akademisches Lehrkrankenhaus der Universität Mainz, D-67063 Ludwigshafen, Germany*Corresponding author
Accepted for publication: June 6, 2001
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Abstract |
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Br J Anaesth 2001; 87: 699705
Keywords: arterial pressure, controlled hypotension; blood, acute normovolaemic haemodilution; blood, protein S-100; enzymes, neuron-specific enolase
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Introduction |
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In recent years, specific brain-originated proteins have gained particular attention in the identification of central nervous system (CNS) dysfunction.12 Protein S-100 serum levels and neuron-specific enolase (NSE) have been studied in various clinical settings as specific biochemical markers for the evaluation of cerebral damage.1315 The S-100 protein is a small (molecular weight 21 000 Da) acidic calcium-binding protein and is predominantly found in astrocytes and Schwann cells. It exits in various isoforms, depending on alpha or beta subunit configuration. The beta subunit is highly specific to the brain. Its appearance in the blood indicates brain cell damage and an increased permeability of the bloodbrain barrier.12 NSE is an isoenzyme of the glycolytic enzyme enolase, which is present primarily in the cytoplasm of neurones and cells of the amine precursor uptake and decarboxylation system. This protein is a prognostic indicator of hypoxic brain damage after cardiac arrest and resuscitation. Furthermore it may be a useful tool for monitoring brain infarction and intracerebral haemorrhage.16
As information is lacking as to how combined CH and ANH modifies serum levels of S-100 protein and neuron-specific enolase, we tested the hypothesis that this hypotensive anaesthetic technique might be associated with a disturbance of neuronal cell integrity and subsequent higher serum concentrations of these brain-originated proteins in comparison with normotensive general anaesthesia. Furthermore, we have investigated whether combining CH with ANH would result in greater blood sparing effects than CH alone.
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Methods |
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Times from discontinuation of anaesthetics to eye opening, to trachea extubation, and to orientation (giving ones name and date of birth on request) were recorded. After surgery all patients were observed in the postanaesthesia care unit (PACU) and the time to eligibility to discharge from the PACU according to Aldrete scoring17 was also recorded.
Peripheral venous blood samples for S-100 protein and NSE measurements were obtained at induction of anaesthesia (T0), at the end of surgery (T1), 2 (T2), and 24 h (T3) postoperatively. Serum S-100 protein was analysed with the use of a commercially available monoclonal two-site immunoluminometric assay (Lia-matTM SangtecTM 100, AB Sangtec Medical, Bromma, Sweden). The SangtecTM 100 assay uses three monoclonal antibodies to detect the beta subunit of the S-100 protein. The functional detection limit of the assay is 0.02 µg litre1. Normal values as derived from apparently healthy blood donors were found to be less than 0.12 µg litre1. The intra-assay coefficient of variation was less than 6%. NSE (normal value <15.2 µg litre1) was measured with the use of a solid phase enzyme immunoassay (CobasTM Core NSE EIA II, Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany). The assay uses two highly specific monoclonal antibodies that bind to the -subunit of the enzyme. The lower limit of detection of sensitivity of the assay and intra-assay coefficient of variation was 0.1 µg litre1 and less than 4%, respectively. Samples with haemolysis were rejected. Plasma concentrations of cardiac troponin T (TnT; using a commercial monoclonalmonoclonal double antibody and one-step sandwich enzyme immunoassay; Boehringer Mannheim, Germany; normal value <0.1 µg litre1) were measured as a marker of myocardial ischaemia. During surgery and in the PACU, arterial blood samples were analysed at 30 min intervals for haemoglobin concentration, PaO2, PaCO2, and pH.
Data are shown as mean (SD). The assumption of normality was checked using the KolmogorovSmirnov test. Continuous, normally distributed data were compared using paired and unpaired Students t-test or analysis of variance (ANOVA) for repeated measures. When multiple comparisons were made the Bonferroni correction was applied. Continuous, non-normally distributed data were compared using the Wilcoxon test. Binominal data were compared using chi-squared analysis and Fishers exact test. Correlations between biochemical marker and variables of postoperative recovery were calculated by using Spearmans rank correlation coefficient. Before the study, the number of patients required in each group was determined after a power calculation according to data obtained from previous studies on the release pattern of protein S-100.18 19 Although there is no generally accepted normal range for this biochemical marker during CH or combined haemodilution and hypotension, we felt that a 50% increase of protein S-100 concentrations from baseline might be of clinical importance. The approximate SD of protein S-100 values has been found to be 0.13 µg litre1. The alpha error was set at 0.05 (two-sided) and type II (beta) error was at 0.2. Based on this assumption, 14 patients per group were required.
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Results |
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Discussion |
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Comparison with the results of other studies is difficult, because data on the combined effects of CH and ANH are scarce. Studies dealing with this blood-saving technique are often flawed in design and execution, because they fail to compare patients who have undergone the combined technique with contemporaneous controls.22 23 Addition ally, no precise data on transfusion practice are given in most of these studies. We decided to withdraw a fixed amount of 2 units of autologous blood (1000 ml) for ANH, resulting in a post ANH haematocrit of approximately 29%. The limited effectiveness of haemodilution in this setting might be a result of the fact that the efficacy of ANH as a blood-saving strategy is proportional to the amount of blood withdrawn during the ANH procedure.1 24 Further dilution by accepting lower limits of post ANH haematocrit would produce disproportionately larger blood savings.24 Data on minimal acceptable limits of haemodilution are derived from several studies.10 24 25 ANH to a target haemoglobin concentration of 7 g dl1 may be performed safely in patients with intact myocardial function and without cerebrovascular disease.10 Anaesthetized patients with known coronary and cardiac disease tolerated ANH to a target haemoglobin concentration of 10 g dl1 without signs of myocardial ischaemia.24 25 However, as there is no established safe lower limit of packed red cell volume, the blood sparing benefits of this technique must be weighed against the risk of inadequate tissue oxygenation.
Although the combination of CH and ANH was not associated with intraoperative haemodynamic instability or an increased incidence of adverse effects, the combined reduction of oxygen-carrying capacity and perfusion pressure raises concerns of hypoperfusion and ischaemic injury to the brain, heart, or other vital organs. Perioperative cerebral complications such as delayed awakening, cognitive dysfunction and stroke were associated with increased levels of brain-originated biochemical markers such as protein S-100 or neuron-specific enolase.12 16 We found a small, but significant increase of serum S-100 protein in all our patients, irrespective of group assignment. Maximum levels occurred 2 h postoperatively, and concentrations declined to baseline values within 24 h. No previous clinical study has investigated serum levels of this specific biochemical marker for brain cell damage after CH or combined haemodilution and hypotension. The majority of studies on the release of protein S-100 was performed in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB).12 High levels of S-100 protein were recorded at the end of CPB, followed by a continuous decline to pre-CPB values within 48 h in patients who did not develop neurological signs or symptoms.18 26 A similar pattern of release was observed in our patients. However, maximum values of S-100 protein measured in our study were only 10% of these found after CPB without complications. In patients undergoing off-pump coronary artery bypass grafting, a small but significant increase in S-100 protein levels was found during surgery.27 Earlier studies using less sensitive analysis techniques for protein S-100 (threshold of detection: 0.2 µg litre1) found that anaesthesia alone or thoracic surgery without CPB did not initiate any release of S-100 protein into the serum.28 29 In the present study, S-100 protein levels were analysed using a recently developed immunoluminometric assay with enhanced sensitivity, which can measure S-100 protein to 0.02 µg litre1. The conflicting results between our study and previous investigations might be explained by the fact that earlier studies using a less sensitive assay may have missed smaller increases of S-100 protein.
Both the exact mechanism of S-100 protein release after cardiac surgery with CPB and the level at which any cerebral complication can be diagnosed are unclear. An increased endothelial permeability of the bloodbrain barrier because of an increased inflammatory response after CPB and neuronal cell damage secondary to diffuse microembolization were used to explain the augmented release of S-100 protein during cardiac surgery.12 16 A more pronounced acute phase response with highly elevated cytokine inflammatory mediators such as interleukin 6 (IL-6) has also been found in patients receiving CH induced by SNP.30 Although we did not measure biochemical markers of inflammatory response in our study, it seems possible that systemic inflammation mediated by elevated cytokine levels could have increased bloodbrain barrier permeability in patients receiving hypotensive anaesthesia. This may also be attributed to the control patients, as inflammation is seen after all types of major surgery depending on the extent of tissue damage.31 The combination of slightly increased levels of protein S-100 and normal concentrations of NSE after surgery suggests a transient disturbance of astroglial cell membrane integrity rather than irreversible neuronal ischaemia or cerebral damage. NSE, which is predominantly found in the cytoplasm of neurons, is not secreted into blood by intact neurons. After brain damage with neuronal injury this enzyme leaks from structurally damaged cells into the blood, where its levels show some correlation with the magnitude of brain cell injury.16
Studies on neuropsychological outcome after cardiac surgery have found a significant negative correlation between protein S-100 release, NSE concentrations and neuropsychologic performance after CBP.32 33 By using simple measures of postoperative recovery, such as times from discontinuation of anaesthetics to extubation and orientation, or duration of stay in the PACU, we found no difference in immediate recovery profile after surgery between patients receiving the hypotensive anaesthesia regimens or control patients. Furthermore, there was no association between these variables and S-100 protein or NSE serum concentrations. This is in agreement with the results of earlier studies on the effects of postoperative cognitive dysfunction.6 34 Eckenhoff and co-workers found no difference in perception and short-term memory in a group of young adults undergoing hypotensive anaesthesia compared with normotensive controls.34 However, in a study by Thompson and colleagues dealing with the effects of hypotensive anaesthesia on cerebral, myocardial, renal, and hepatic function, several patients failed to complete psychomotor tests because of pain, immobility, or sedation.6 These conflicting results might be attributed to the methods used in these studies, because a variety of different psychomotor tests, scores or scales might be applied for the assessment of functional neuropsychological outcome after major surgery. It has been pointed out by Dodds and Allison that the crucial elements in the detection of postoperative cognitive dysfunction are a sensitive test battery and taking learning effects into account.35
One objection to the present study may be that neither NSE nor S-100 protein has a proven relationship with brain injury, such as postoperative stroke, or neuropsychological dysfunction in well controlled outcome studies. Another limitation of this investigation is the relatively small number of healthy adult patients included. With the limited power resulting from both the small number of patients and the large number of interdependent variables measured, it would require a much larger patient population to confirm prognostic importance of NSE and S-100 protein as surrogate variables of cerebral complications outside cardiac surgery.
In conclusion, the present study demonstrated that intraoperative blood loss and requirements for allogeneic blood transfusion were significantly reduced in patients receiving CH or a combination of CH and ANH compared with control patients. No further reductions in blood loss or transfusion requirements were found by comparing patients receiving CH plus ANH with those receiving CH alone. Both CH alone and the combination of CH and ANH did not cause any serious neuronal damage or cerebral dysfunction, as levels of specific brain-originated biochemical markers and variables of immediate postoperative recovery did not show any differences between patient groups. A short-lasting increase of serum S-100 protein levels in all patients implies a transient disturbance of astroglial cell membrane integrity and an increased endothelial permeability of the bloodbrain barrier in otherwise healthy men undergoing radical prostatectomy. Large studies with considerable numbers of patients must be undertaken to fully evaluate the prognostic importance and to define the role of protein S-100 and NSE as a measure of central nervous system dysfunction in the general surgical population.
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