Cerebral effects and blood sparing efficiency of sodium nitroprusside-induced hypotension alone and in combination with acute normovolaemic haemodilution

S. W. Suttner*, S. N. Piper, K. Lang, I. Hüttner, B. Kumle and J. Boldt

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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The combined reduction of oxygen-carrying capacity and perfusion pressure during the combination of acute normovolaemic haemodilution (ANH) and controlled hypotension (CH) raises concerns of hypoperfusion and ischaemic injury to the brain. Forty-two patients undergoing radical prostatectomy were prospectively allocated to receive CH induced by sodium nitroprusside (mean arterial pressure (MAP) 50 mm Hg), a combination of CH+ANH (post-ANH haematocrit 29%; intraoperative MAP 50 mm Hg), or standard anaesthesia (control). Serum levels of the brain-originated proteins neuron-specific enolase (NSE) and protein S-100, blood loss, transfusion requirements, adverse effects, and postoperative recovery profile were compared among the three groups. Intraoperative blood loss in the CH group (mean (SD)) (788 (193) ml) and CH+ANH group (861 (184) ml) was significantly less than in the control group (1335 (460) ml). Significantly fewer total units of allogeneic packed red blood cells (PRBC) were transfused in the patients receiving hypotensive anaesthesia (CH, 3 units; CH+ANH, 2 units; control, 17 units). There was no difference in immediate postoperative recovery profile among the three groups as determined by the emergence from anaesthesia and time to discharge from the postanaesthesia care unit. Serum S-100 protein concentrations increased significantly in all groups from baseline to peak concentrations 2 h postoperatively (CH 0.25 (0.11) µg litre–1; CH+ANH 0.31 (0.12) µg litre–1; control 0.31 (0.10) µg litre–1). A return to baseline values was seen within 24 h postoperatively in all patients. No changes in NSE concentrations were seen. Our observations suggest that CH and CH+ANH were effective in reducing blood loss and transfusion requirements in patients undergoing radical prostatectomy. Increased serum S-100 protein concentrations imply a disturbance in astroglial cell membrane integrity and an increased endothelial permeability of the blood–brain barrier. There were no associations between serum S-100 protein or NSE and adverse cognitive effects. Further work needs to be done to determine the prognostic importance of S-100 protein and NSE as surrogate variables of postoperative cerebral complications.

Br J Anaesth 2001; 87: 699–705

Keywords: arterial pressure, controlled hypotension; blood, acute normovolaemic haemodilution; blood, protein S-100; enzymes, neuron-specific enolase


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Alternatives to the use of allogeneic blood products are increasingly being sought. Controlled hypotension (CH), using continuous infusion of sodium nitroprusside (SNP) and acute normovolaemic haemodilution (ANH) have been proven effective in decreasing operative blood loss and the need for transfusion of allogeneic blood.13 Combining CH with ANH may further reduce the requirements for allogeneic blood.4 However, the combined use of CH and ANH remains under-utilized, because of the fear that a coexistence of reduced oxygen content and perfusion pressure might lead to hypoperfusion and ischaemic injury to vital organs. The organ most susceptible to hypoxia is the brain. The physiology and limits of cerebral perfusion have been investigated in a variety of clinical and experimental studies.59 Both blood-saving strategies were well tolerated without apparent organ damage, provided that an adequate circulatory volume was maintained. Compensatory mechanisms during normovolaemic anaemia, such as increased cardiac output and the redistribution of blood flow to areas of high metabolic demand, provide sufficient blood flow to other organs and preserve tissue normoxia over a wide range of haematocrit.10 Vital organs such as the brain are characterized by a well functioning pressure-flow autoregulation. It is generally accepted that cerebral blood flow (CBF) remains constant at a mean arterial pressure (MAP) ranging from 50 to 150 mm Hg in normotensive patients. Studies in animals, however, provided some evidence that the superimposition of drug-induced hypotension to severe haemodilution might decrease cardiac output and organ blood flow.11 Therefore, the adequacy of cerebral perfusion might be affected and ischaemic damage to the brain might occur.

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 blood–brain 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.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The study was approved by the Human Ethics Committee of the hospital and written informed consent was obtained from each patient. We studied prospectively a total of 42 American Society of Anesthesiologists (ASA) class I–III patients undergoing elective radical prostatectomy. Exclusion criteria were ASA class greater than III, liver dysfunction (ALT/AST >40 unit litre–1), renal insufficiency (creatinine >1.5 mg dl–1), haemoglobin concentration less than 12 g dl–1, severe uncontrolled hypertension (systolic pressure >180 mm Hg or diastolic pressure >100 mm Hg receiving medication), a history of myocardial infarction, angina pectoris, and documented coronary artery disease or carotid artery stenosis. All patients were premedicated with midazolam orally 1 h before induction of anaesthesia. Anaesthesia was induced by thiopental, fentanyl and was maintained with fentanyl and desflurane. Rocuronium was used to produce neuromuscular block. The lungs of all patients were ventilated with 50% nitrous oxide in oxygen. Ventilation was adjusted to keep SaO2 greater than 95% (continuous oximetry) and to maintain PCO2 and pH in the physiological range. Routine intraoperative monitoring included continuous invasive measurement of MAP and central venous pressure (CVP). The patients were allocated randomly to one of three groups. Group 1 (CH, n=14) received CH induced by SNP, group 2 (CH+ANH, n=14) received a combination of ANH and CH. Group 3 (control, n=14), without manipulations, served as control group. ANH in group 2 was carried out after induction of anaesthesia by withdrawing 1000 ml of blood into standard blood collection sets containing citrate–phosphate–glucose with adenine (CPDA-1, Kwasumi, Tokyo, Japan). The identical volume of colloid was given in the form of gelatin (Gelafundin, B. Braun, Melsungen, Germany) to replace withdrawn blood isovolaemically according to the patient’s individual CVP before haemodilution. The removed autologous blood was retransfused at the end of the surgical procedure before the patient left the operating room. CH was initiated in groups 1 and 2 at the beginning of bilateral pelvic lymphadenectomy and was completed with wound closure. The SNP doses applied were adjusted to reduce MAP to 50 mm Hg. A threshold of hypotension was defined as a MAP of less than 50 mm Hg in groups 1 and 2, and 70 mm Hg in the control group. Hypotensive episodes were treated by increasing the rate of fluid administration and reducing the concentration of desflurane and/or SNP when necessary. Crystalloids and gelatin were given to maintain CVP at 10–15 mm Hg. A haemoglobin concentration less than 7 g dl–1 was defined as the transfusion trigger and mandated the retransfusion of one unit of autologous blood in group 2 or one unit of allogeneic PRBC in groups 1 and 3. Anaesthesia was provided by anaesthetists who were not involved in data analysis.

Times from discontinuation of anaesthetics to eye opening, to trachea extubation, and to orientation (giving one’s 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 litre–1. Normal values as derived from apparently healthy blood donors were found to be less than 0.12 µg litre–1. The intra-assay coefficient of variation was less than 6%. NSE (normal value <15.2 µg litre–1) 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 {gamma}-subunit of the enzyme. The lower limit of detection of sensitivity of the assay and intra-assay coefficient of variation was 0.1 µg litre–1 and less than 4%, respectively. Samples with haemolysis were rejected. Plasma concentrations of cardiac troponin T (TnT; using a commercial monoclonal–monoclonal double antibody and one-step sandwich enzyme immunoassay; Boehringer Mannheim, Germany; normal value <0.1 µg litre–1) 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 Kolmogorov–Smirnov test. Continuous, normally distributed data were compared using paired and unpaired Student’s 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 Fisher’s exact test. Correlations between biochemical marker and variables of postoperative recovery were calculated by using Spearman’s 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 litre–1. 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.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Of the 48 patients initially screened for the study, six could not be enrolled because they violated one or more of the inclusion and exclusion criteria. Among these were patients with abnormal preoperative laboratory tests (haemoglobin concentration <12 g dl–1) and patients with severe hypertension (diastolic pressure >100 mm Hg). The patients in the three groups were comparable with respect to ASA physical status, biometric data, and to duration of anaesthesia and surgery (Table 1). The duration of hospitalization ranged from 10 to 15 days and was similar among groups (Table 1). Blood loss in the CH group and the CH+ANH group was significantly lower than in the control group (Table 2). Significantly fewer units of allogeneic PRBC were transfused in the patients receiving hypotensive anaesthesia. The amount of gelatin administered was higher in the CH+ANH group than in the two other groups (Table 2). During surgery, the haemoglobin concentration was significantly lower in the CH+ANH group than in the two other groups, but 2 and 24 h postoperatively the lowest haemoglobin values were observed in the control group (Table 3). Haemodynamic data and blood gas values showed no significant differences, except for MAP, which was significantly lower during surgery in the patients receiving hypotensive anaesthesia (Table 3). The duration of CH and the total dose of SNP administered did not differ between the CH group and the CH+ANH group (Table 4). The mean dose of desflurane and the need for additional anaesthetics were similar between the groups. The emergence time from the end of anaesthetic administration to extubation, eye opening, response to simple commands, or orientation were similar in all groups. There was no difference in the postoperative recovery profile and duration of stay in the PACU between the three groups (Table 4). None of the patients showed gross neurological deficits (e.g. stroke) or signs of myocardial ischaemia (TnT plasma levels were <0.1 µg ml–1 in all patients).


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Table 1 Patient characteristics and data from the perioperative period. Values are expressed as mean (SD), number of patients [range]
 

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Table 2 Blood loss, use of allogeneic blood, and intraoperative volume replacement. Values are expressed as mean (SD), total [range]. POD 1, first postoperative day.*P<0.05 compared with other groups
 

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Table 3 Haemoglobin (Hgb) concentration, haemodynamic data, and arterial blood gas values. HR, heart rate; PaO2/PaCO2, partial pressure of oxygen/carbon dioxide. T0=baseline, induction of anaesthesia; 90 min=90 min after skin incision; T1=end of surgery; T2= 2 h postoperatively; T3=24 h postoperatively. *P<0.05, significantly different from baseline value. +P<0.05 compared with other groups
 

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Table 4 Duration of hypotension, anaesthetic exposure, consumption of additional anaesthetics, and recovery profile after discontinuation of anaesthetics. Values are expressed as mean (SD). MAC-h, minimum alveolar concentration hours
 
The baseline values of serum S-100 protein and NSE concentrations were normal in all patients and comparable between the groups. Serum S-100 protein concentrations increased significantly in all groups at the end of surgery, with a further increase 2 h postoperatively. Highest mean concentrations of this protein were detected 2 h postoperatively (CH 0.25 (0.11) µg litre–1; CH+ANH 0.31 (0.12) µg litre–1; control 0.31 (0.10) µg litre–1). A return to baseline values was seen at the first postoperative day in all patients (Fig. 1). There were no significant changes in NSE concentrations in any group throughout the whole study period. Peak values were 7.12 (3.44) µg litre–1 in the CH group, 8.02 (2.92) µg litre–1 in the CH+ANH group, and 6.08 (2.70) µg litre–1 in the control group (Fig. 1). No significant correlations were found between NSE, S-100 protein, and variables of postoperative recovery.



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Fig 1 Concentrations of serum S-100 protein (µg litre–1) and neuron-specific enolase (µg litre–1). T0=induction of anaesthesia; T1=end of surgery; T2=2 h postoperatively; T3=24 h postoperatively. Values are mean (SD). *P<0.05, significantly different from baseline value.

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Both CH and ANH have demonstrated their efficacy as blood-saving techniques.2 20 Consequently, one can speculate that the combination of CH and ANH might produce even larger blood savings.4 One of the main findings of our study is that intraoperative blood loss and requirements for allogeneic blood transfusion were significantly reduced in patients receiving either CH or combined haemodilution and hypotension. Data from our study confirmed the results of two earlier investigations comparing CH and ANH alone with a control group.2 21 It was reported by Boldt and colleagues that blood loss and transfusion requirements were lowest in patients receiving CH, with rather disappointing results in the ANH groups. Thus, decreasing MAP seems to be an effective strategy for the reduction of intraoperative blood loss and tranfusion requirements. However, we found no further reduction in intraoperative blood loss or in requirements for allogeneic blood transfusion in patients receiving a combination of CH and ANH.

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 dl–1 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 dl–1 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 litre–1) 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 litre–1. 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 blood–brain 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 blood–brain 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 blood–brain 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.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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3 Sood S, Jayalaxmi TS, Vijaraghvan S, Nundy S. Use of sodium nitroprusside induced hypotension for reducing blood loss in patients undergoing lienorenal shunts for portal hypertension. Br J Surg 1987; 74: 1036–8[ISI][Medline]

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