Departments of 1 Vascular Surgery, 2 Biochemistry and 3 Anaesthetics and Intensive Care, Selly Oak Hospital, University Hospital Birmingham NHS Trust, Raddlebarn Road, Selly Oak, Birmingham B29 6JD, UK
*Corresponding author. E-mail: rajiv@vohra.org.uk
Accepted for publication: August 8, 2003
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Abstract |
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Methods. Forty patients were randomized into two groups. The anaesthetic technique was standardized. Lung function was assessed with the PO2/FIO2 ratio, respiratory compliance, chest x-ray and a score for lung injury. Microvascular permeability was determined by measuring microalbuminuria. Neutrophil activation was determined by measurement of plasma elastase.
Results. Four hours after surgery, the median (quartile values) PO2/FIO2 ratio was 40.3 (37.8, 53.1) kPa for the HES-treated patients compared with 33.9 (31.2, 40.9) kPa for the Gelofusine-treated patients (P<0.01, MannWhitney test). The respiratory compliance was 80 (73.5, 80) ml cm1 H2O in the HES-treated patients compared with 60.1 (50.8, 73.3) ml cm1 H2O in the Gelofusine-treated patients (P<0.01, MannWhitney test). The lung injury score 4 h after surgery was less for the patients treated with HES compared with the patients treated with Gelofusine (0.33 vs 0.71, P=0.01, Wilcoxon rank sum test). Mean (SD) plasma elastase was less in the HES-treated patients on the first postoperative day (1.96 (0.17) vs 2.08 (0.24), P<0.05). The log mean microalbuminuria was less in the HES-treated patients (0.41 vs 0.91 mg mmol1, P<0.05). This difference in microvascular permeability was associated with different volumes of colloid required to maintain stable cardiovascular measurements in the two groups of patients studied (3000 vs 3500 ml, P<0.01, MannWhitney test).
Conclusion. Compared with Gelofusine, the perioperative pulmonary function of patients treated with HES after abdominal aortic aneurysm surgery was better.
Br J Anaesth 2004; 92: 616
Keywords: complications, microalbuminuria; enzymes, elastase; lung, pulmonary function; surgery, aneurysm repair; volume replacement, hydroxyethyl starch
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Introduction |
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In the lung, ischaemiareperfusion injury can increase pulmonary capillary permeability,3 affect transendothelial protein and fluid fluxes,4 cause interstitial oedema5 and impair gas exchange. These features are similar to those in adult respiratory distress syndrome (ARDS).6 In this condition, there is an inverse relationship between systemic capillary leak, assessed as microalbuminuria, and pulmonary gas exchange.7 Capillary permeability, assessed as microalbuminuria, can predict pulmonary dysfunction.8
Neutrophils may be a cause of remote lung injury after ischaemiareperfusion.9 Activated neutrophils sequester in the pulmonary circulation, degranulate and generate free radicals that cause lung injury.10 Neutrophil elastase concentrations increase in the plasma of patients with acute lung injury after aortic surgery11 and in the plasma and the bronchioalveolar fluid of patients with ARDS.12 13 Elastase increases vascular permeability10 and experimental leucocyte depletion prevents pulmonary dysfunction.14
The colloid used for intraoperative volume replacement can affect microvascular function and ischaemiareperfusion damage.15 16 Compared with albumin, hydroxyethyl starch (HES) can reduce splanchnic ischaemia and release of circulating adhesion molecules in critically ill patients,17 18 reduce post-trauma capillary leak and improve gas exchange.19 The effects of HES on pulmonary function, capillary permeability and neutrophil activation in patients undergoing aortic surgery have not been compared with those of other low molecular weight colloid solutions.
We set out to study the effect of volume expansion with HES solution compared with Gelofusine solution on pulmonary function, capillary permeability and neutrophil activation in patients undergoing elective aortic aneurysm surgery.
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Methods |
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Determination of respiratory compliance
Static respiratory compliance was measured during mechanical ventilation using an inflation hold during ventilation. The tidal volume, plateau pressure during an end-expiratory occlusion of 5 s, and PEEP were recorded. The respiratory compliance was calculated as the tidal volume divided by the difference between the plateau pressure and the PEEP. Four hours after the end of surgery, a compliance score was determined as follows:20 compliance 80 ml cm1 H2O=0; compliance 6079 ml cm1 H2O=1; compliance 4059 ml cm1 H2O=2; compliance 2039 ml cm1 H2O=3; and compliance <19 ml cm1 H2O=4.
Determination of the degree of non-cardiogenic oedema on chest x-ray
A chest x-ray was taken the day before surgery as part of the routine assessment. Another chest x-ray was taken 4 h after surgery. The x-rays were taken at end-inspiration with a portable machine with the patient propped up. The films were assessed by a radiologist unaware of the patients status in the study and were assigned a score of 04 according to defined criteria, as follows: mild interstitial oedema=1; severe interstitial oedema=2; alveolar oedema in 12 quadrants=3; and alveolar oedema in 34 quadrants=4.
Calculation of the lung injury score
The lung injury score was determined from the PO2/FIO2 ratio, lung compliance, chest x-ray and the amount of PEEP. The PEEP score was assigned as follows: PEEP <5 cm H2O=0; PEEP 68 cm H2O=1; PEEP 911 cm H2O=2; PEEP 1214 cm H2O=3; and PEEP 15 cm H2O=4. A lung injury score was computed 4 h after surgery by dividing the aggregate score by the number of components used.20
Measurement of neutrophil elastase
Plasma concentrations of elastase, measured as the 1-antiproteaseelastase complex, were assayed by the latex-enhanced immunoassay using Ecoline® PNM elastase (Merck Diagnostica, Darmstadt, Germany). The elastase values were measured before surgery, after release of the aortic cross-clamp, four-hourly for the first 12 h and then daily for the next 2 postoperative days.
Measurement of microalbuminuria
Aliquots of urine were saved preoperatively, after induction of anaesthesia, after clamp release and four-hourly for 12 h and then daily for 3 days. The urinary excretion of microalbumin was determined using automated immunoturbidimetry. The results were expressed as a protein:creatinine ratio in mg mmol1, to correct for variations in urine flow rate. Values in normal subjects were less than 2.3 mg mmol1.
Measurement of plasma oncotic pressure
The plasma oncotic pressure was measured using a Genotec Osmomat 050 (Hants., UK) with 20 kDa membrane. Blood for colloid oncotic pressure measurement was taken before operation, 4 h after release of the aortic cross-clamp (T3), and on each of the first 2 postoperative days (T6 and T7 respectively).
Statistical analysis
Where appropriate, the numerical data were compared using the MannWhitney test. Intragroup data were analysed using ANOVA. Lung injury scores were compared using the Wilcoxon rank sum test. Log transformation was used to normalize the data on plasma elastase and urinary excretion of albumin before statistical analysis. These data were analysed using Students t-test.
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Results |
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Discussion |
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Aneurysm surgery is usually associated with an increase in pulmonary capillary permeability, allowing the extravasation of osmotically active macromolecules, such as albumin, into the interstitial space. Fluid movement across a capillary membrane is governed, according to Starlings law,25 by a balance between the hydrostatic and colloid osmotic forces across the capillary wall and the permeability of the capillary membrane. In the Gelofusine-treated patients there was more systemic loss of albumin, as determined by the microalbuminuria. This shift in protein allows movement of water across the pulmonary endothelium into the interstitial space. This is borne out by studies of permeability oedema in both human subjects26 and experimental animal models.27 Normally, an increase in transendothelial fluid is removed by pulmonary lymph flow.28 Interstitial oedema develops when the colloid leak overwhelms the lymph drainage rate. Previous studies in animal models of ischaemiareperfusion injury have suggested that the use of starch colloids of the right shape and size can reduce capillary permeability and oedema formation. The HES molecules may act as a sealant to the leaky capillary pores.29 While this could explain the differential excretion of urinary albumin and the disparity in lung function, recent studies on the endothelial barrier function would suggest that this mechanism of action is simplistic.30
The 1-antiproteaseelastase complex, a marker of neutrophil activation, was increased in both groups of patients. In animal models of ischaemiareperfusion injury, the increase in microvascular permeability in the pulmonary circulation depended on the pulmonary sequestration of activated neutrophils.31 32 Reperfusion was associated with a transient decrease in neutrophil count, presumably related to the tissue sequestration, followed by an increase in circulating neutrophils. The plasma neutrophil elastase activity was not significantly different between the two groups of patients during the early postoperative period, yet there were significant differences in the pulmonary function during that time. The
1-antiproteaseelastase complex measured in the plasma in the early postoperative period is derived from the degranulation of activated neutrophils from the initial reperfusion and not from primed neutrophils that are sequestered in the pulmonary circulation. Sequestered neutrophils are relatively harmless unless they are activated by a second stimulus,33 such as endotoxins,34 by-products of dead cells that have been affected by the initial ischaemiareperfusion injury, and mediators released after protracted tissue ischaemia. Rittoo and colleagues 35 have shown that microvascular perfusion and splanchnic oxygenation are better preserved with HES infusion than with Gelofusine. Further activation of the neutrophils by a second stimulus, such as endotoxins, could account for the secondary rise in plasma
1-antiproteaseelastase complex in the first 2 days after surgery. Intravital microscopy studies of haemodilution in controlled ischaemia have shown that HES can reduce leucocyte adherence in ischaemic conditions.36 The weak inverse correlation between the PO2/FIO2 ratio and the log
1-antiproteaseelastase complex (rs=0.079) suggests that more than one mechanism may be operational. While HES may modulate the neutrophil endothelial activation,37 the similar plasma elastase values in the two groups do not support this mechanism of lung protection.
COP normally decreases during surgery. In unstable general surgery patients, a low COPpulmonary capillary wedge pressure difference of >3 mm Hg was weakly associated with ADRS and pulmonary oedema.38 However, in the presence of low COP, when the hydrostatic pressure is normal, the lung can resist oedema formation.28 There was no significant difference in COP in the two groups of patients studied, so a beneficial effect of HES is probably not related to the COP.
The treatment of non-cardiogenic oedema is aimed at preventing further damage and improving tissue oxygenation. As it is not always possible to achieve the former, attention has been aimed at improving the rate of extraction or reducing the rate of accumulation of oedema fluid in the lungs. Synthetic colloid solutions such as HES contain a heterogeneous mixture of macromolecules of varying molecular weight. Some of these molecules are too large to escape through the leaky endothelium and can help prevent excessive fluid flux across the endothelial layer. HES, particularly in the narrow molecular weight range, may therefore offer certain advantages over Gelofusine. However, the role of HES molecules may be more than biophysical.39 We found that perioperative pulmonary function was better after HES than after Gelofusine.
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