Anaesthesia with propofol decreases FMLP-induced neutrophil respiratory burst but not phagocytosis compared with isoflurane

J. Heine, K. Jaeger, A. Osthaus, N. Weingaertner, S. Münte, S. Piepenbrock and M. Leuwer

Department of Anaesthesiology, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany*

Accepted for publication: March 8, 2000


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Propofol has been reported to produce a dose-dependent inhibition of phagocytosis and superoxide anion production during the respiratory burst (RB) of polymorphonuclear cells (PMNs) in vitro. In this randomized, blinded study, these two parameters were compared during propofol or isoflurane anaesthesia in patients undergoing elective interventional embolization of cerebral arterio-venous malformations. Anaesthesia was performed with continuous intravenous propofol 6–8 mg kg–1 h–1 (n=15) or isoflurane 0.8–1.0% end tidal (n=15). Heparinized blood was drawn before, and 2 and 4 h after induction of anaesthesia. The RB in isolated leucocytes was measured with the fluorescent dye rhodamine after ex vivo induction by Escherichia coli or tumour necrosis factor {alpha}/N-formyl-methionyl-leucylphenylalanine (TNF-{alpha}/FMLP). Phagocytosis was carried out in whole blood after incubation with fluorescein isothiocyanate (FITC)-labelled, opsonized E. coli and also measured with a flow cytometer. The two groups were similar in terms of biometric data and haemodynamic responsiveness. After 4 h of propofol or isoflurane anaesthesia, the mean (SD) phagocytosis of E. coli was 93.2% (7.0%) and 94.3% (9.2%), respectively, of that before anaesthesia. The percentage of PMN with RB activity following TNF-{alpha}/FMLP stimulation was significantly reduced after 2 h (80.9% (24.2%); P<0.05) and 4 h (53.7% (27.3); P<0.05) of anaesthesia with propofol compared with the values before induction. This effect of propofol anaesthesia was significantly different from the effect of isoflurane anaesthesia. In contrast to published in vitro results, 4 h of anaesthesia with propofol did not reduce the phagocytotic capacity of human blood PMN more than isoflurane anaesthesia.

Br J Anaesth 2000; 85: 424–30

Keywords: anaesthetics i.v., propofol; blood, leucocytes


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Polymorphonuclear cells (PMNs) are the first line of defence against bacterial and fungal infections. Their main function is to protect the host by destroying invading micro-organisms. They play a decisive role in the inflammatory process, which may have already been activated intra-operatively by surgical trauma.1 Therefore, it is feasible that the possible inhibitory effects of anaesthetics on PMN functions may increase the risk posed by microbial infection acquired intra-operatively.

There is evidence that intravenous anaesthetics can influence the immune system.2 In a previous study, we showed that propofol and its lipid carrier, Intralipid, induce concentration-related inhibition of superoxide anion production during the respiratory burst (RB) of PMNs in vitro.3 The RB enzyme in the plasma membrane of neutrophils catalyses the oxidation of NADPH, leading to the production of superoxide anions which, in turn, is responsible for killing the phagocytosed micro-organisms.4 Other authors found similar inhibitory in vitro effects of propofol on different granulocyte functions.5–7 Only a few studies have investigated potential immune-compromising effects of intravenous anaesthetics under clinical conditions.8 9 One reason for this may be the difficulties in differentiating between effects on the immune system associated with the anaesthetic itself or the operative trauma, and other side effects occurring during the operation, such as volume shift, loss of body temperature or infusion of blood components. However, the effects of continuous propofol anaesthesia on blood PMNs are still unknown.

Our aim was to evaluate the time-dependent changes in PMN functions during elective interventional neuroradiological procedures with propofol or isoflurane anaesthesia. In this controlled, randomized, blinded study, the induced RB and the phagocytotic capacity of blood PMNs were investigated after 2 and 4 h of general anaesthesia.

Anaesthesia was performed with continuous propofol infusion (1% Disoprivan; Zeneca, Plankstadt, Germany) or isoflurane inhalation (Forene; Abbott, Wiesbaden, Germany). All patients underwent elective interventional neuroradiological procedures for embolization of cerebral arterio-venous malformations (AVM). As the surgical trauma associated with such procedures is minimal compared with that in abdominal or orthopaedic operations, we believe that these procedures are suitable for investigating the potential immune system effects of anaesthetics in humans. Additionally, during embolization there is no significant reduction in body temperature or marked change in blood volume. Infusion of blood components, with possible immune-compromising consequences,10 is unlikely to be necessary.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The study protocol was approved by the institutional ethics committee and written informed consent was obtained from all patients. The patients (12 male, 18 female) had a mean age of 38 yr (range 12–67 yr) and an ASA status of I or II (Table 1). All patients suffered from cerebral AVM and underwent elective super-selective embolization under general anaesthesia in the Neuroradiological Department of the Hanover Medical School. Patients taking potential immune-compromising medication, such as steroids or non-steroidal anti-inflammatory medication, were excluded. Since each embolization was elective, no patient presented with a history of acute infection during the 2 weeks before the procedure.


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Table 1 Patient characteristics, amounts of drugs administered, infused volume, urine output, amount of contrast medium and decrease in rectal temperature 4 h after induction of anaesthesia. The consumption of isoflurane was calculated by weighing the isoflurane vaporizer before and at the end of investigation. Results are mean (SD). There were no significant differences between the groups
 
One hour before induction of anaesthesia, all patients were premedicated with oral midazolam. Patients were randomly assigned to anaesthetic maintenance with propofol (n=15) or isoflurane (n=15). Anaesthesia was induced with propofol 2–2.5 mg kg–1 and alfentanil 15–20 µg kg–1, and oral intubation was carried out after application of atracurium 0.5 mg kg–1. Patients’ lungs were mechanically ventilated with 70% nitrous oxide and 30% oxygen with a fresh gas flow of 1 litre min–1. End-expiratory carbon dioxide was maintained between 4.5% and 5%. Continuous propofol infusion (6–8 mg kg–1 h–1) or isoflurane inhalation (end-expiratory concentration 0.8–1.0% v/v) was supplemented with a bolus application of alfentanil 5–10 µg kg–1 h–1. Continuous relaxation was carried out with atracurium infusion (0.3–0.5 mg kg–1 h–1) and monitored with a peripheral nerve stimulator. The train-of-four quotient obtained was <25%. To compensate for baseline fluid consumption, Ringer’s lactate 6–8 ml kg–1 h–1was infused in both groups. Heart rate, peripheral oxygen saturation, arterial and central venous pressure, rectal temperature, end-expiratory isoflurane concentration, carbon dioxide concentration and degree of muscle relaxation were measured and recorded continuously. Amounts of propofol, atracurium and alfentanil administered, infused volume and amount of X-ray contrast medium (Iopromid, Ultravist-240; Schering, Berlin, Germany) and urine output per hour were measured in all patients during the 4 h study period. The consumption of isoflurane was calculated by weighing the isoflurane evaporator before and at the end of the investigation.

Micro-catheterization was performed through an introducer in the femoral artery. After mapping the AVM with digital subtraction angiography, maize protein (Ethibloc occlusion emulsion; Ethicon, Hamburg, Germany) was injected into the feeding vessels.

Sample preparations
Samples (7.5 ml) of venous blood were collected in disposable blood sampling tubes coated with lithium heparin 15 IU ml–1 (S-Monovette LH; Sarstedt, Nümbrecht, Germany) before and 2 and 4 h after induction of anaesthesia. After fixing with 3% acetic acid, leucocytes from all samples were counted in a Neubauer cell counting chamber.

Respiratory burst
The protocol of Rothe and colleagues11 12 was used. NADPH oxidase activity was assayed by measuring the intracellular oxidation of dihydrorhodamine 123 (DHR; MoBiTec, Göttingen, Germany) to the green fluorescent dye rhodamine 123 in a flow cytometer. The assay depends upon the incorporation of DHR into the cell. After cell activation, NADPH oxidase catalyses the reduction of oxygen to superoxide anions which are further transformed by dismutation to hydrogen peroxide. The non-fluorescent DHR is oxidized intracellularly in a peroxidase-dependent reaction to rhodamine 123. The amount of rhodamine 123 is proportional to the hydrogen peroxide generated. To isolate leucocytes, 3 ml of heparinized whole blood was layered on to 3 ml of Ficoll Hypaque (density 1.077 g dl–1; Biochrom, Berlin, Germany). Nucleated blood cells in the supernatant were harvested without centrifugation. To 1 ml of phosphate-buffered saline (PBS) pH 7.2, without Ca2+ and MgCl2 (Gibco-BRL, Eggenstein, Germany), heated to 37°C, 30 µl of the leucocyte supernatant (containing an average of 5x105 cells ml–1) was added; the mixture was incubated with 15 µl of 1 mM DHR. RB was induced by 20 µl of Escherichia coli HB-101 (1x109 ml–1; Sigma) or by priming with 10 ng (10 µl of a 1 µg ml–1 solution) of recombinant tumour necrosis factor alpha (TNF-{alpha}; Sigma) for 5 min followed by receptor stimulation with 10 µl of 0.01 mM N-formyl-methionyl-leucylphenylalanine (FMLP; Sigma). After incubation (20 min, 37°C), the reaction was terminated by transferring the samples on to ice. To determine viability, dead cells were counterstained with 1 mM propidium iodide (Serva, Heidelberg, Germany). Samples were stored on ice and subjected to flow cytometry within 30 min (see below). Negative controls without stimulation were included to detect possible preactivation of neutrophils.

Phagocytosis assay
A commercial test kit (Phagotest; Orpegen, Heidelberg, Germany) was used to determine the phagocytotic activity of PMNs. Briefly, 50 µl of heparinized whole blood was incubated (10 min, 37°C) with 5 µl of opsonized and fluorescein isothiocyanate (FITC)-labelled E. coli (1x109 ml–1). Negative controls were kept on ice. After addition of 50 µl of quenching solution (Orpegen) and 3 ml of PBS, the samples were centrifuged (5 min, 250g, 4°C). Fifty microlitres of lysis solution (Optilyse; Immunotech, Krefeld, Germany) was added and the mixture incubated for 10 min. Two millilitres of distilled water was added; the samples were then incubated for another 10 min and centrifuged. After washing of the remaining cell pellet and addition of propidium iodide (50 µl, 1 mM), the samples were analysed by flow cytometry.

Flow cytometry adjustment and acquisition
Both of the flow cytometric assays used allow quantification of PMN responses at the single-cell level. The flow cyto meter (Epics XL; Beckman-Coulter, Krefeld, Germany) was equipped with an argon ion laser adjusted to a wavelength of 488 nm. Twenty thousand events were measured for each sample. The rhodamine emission of the RB assay and the FITC emission of the labelled E. coli in the phagocytosis test were measured with the photomultiplier in the green fluorescence channel (FL1; 515–545 nm). A photomultiplier for red fluorescence (FL3; 650 nm) was used to measure propidium iodide emission in order to discriminate between living and necrotic cells, or between bacteria and leucocytes. Sideways scatter (SSC) and forward scatter (FSC) were assessed in linear mode, and FL1 and FL3 in logarithmic mode without compensation. The photomultiplier voltage and gains of FSC, SSC, FL1 and FL3 were adjusted for each negative control and remained constant for the matched samples. Data files were stored in list mode and analysed in dot plots using a PC software package (EXPO 2.0; Beckman-Coulter). An example of data processing is shown in Figure 1.



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Fig 1 Adjustment of the acquisition dot plots for analysis of the neutrophil respiratory burst due to the green rhodamine fluorescence. (A) Forward scatter (FSC) versus sideward scatter signals (SSC) were depicted as acquired on the flow cytometer. Neutrophils were localized and gated based on their high SSC signals. Only neutrophils from this region were used in the next dot plot. (B) SSC versus red propidium iodide fluorescence (photomultiplier FL3) for gating of necrotic neutrophils (‘dead cells’) based on their strong red fluorescence. Cells from this gate were excluded in the following dot plots. (C and D) SSC versus green rhodamine fluorescence (photomultiplier FL1) for gating of rhodamine-positive cells using the gate combination ‘granulocytes’ of dot plot A but not ‘dead cells’ of dot plot B. (C) is an example for a negative control without stimulation, whereas (D) depicts RB-positive PMNs after E. coli stimulation.

 
All immune function tests were performed by a single investigator who was blinded to the anaesthetic management.

Statistical analysis
The percentage of activated PMNs (in the RB assay, the percentage of rhodamine-positive PMNs after induction with E. coli or TNF-{alpha}/FMLP; in the phagocytosis assay, the percentage of PMNs containing FITC-labelled E. coli) after 2 and 4 h of anaesthesia with propofol or isoflurane was compared with the percentage before induction of anaesthesia (the latter was set at 100%). This net effect was calculated using the formula:

activated PMN % =


Results are presented as mean (SD). The phagocytotic activity of PMNs is also expressed as the percentage of mean green channel fluorescence per cell. Time-dependent intragroup data were evaluated using a two-tailed, paired t-test. At each time, differences between propofol and isoflurane were evaluated using one-factor (group) analysis of variance (ANOVA) for repeated measurement, followed by Student–Newmann–Keuls multiple comparison test. P<0.05 was considered significant.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
There were no significant differences between the two groups in terms of patient characteristics, the amount of alfentanil or atracurium administered, the infused volume or the amount of contrast medium used after induction of anaesthesia during the 4 h study period (Table 1).

There were no significant differences in the intra-operative parameters of pulmonary and circulatory function (peripheral oxygen saturation, end-expiratory carbon dioxide concentration, heart rate or arterial and central venous pressure; data not shown) or in decrease in rectal temperature and urine output (Table 1).

The number of leucocytes increased in both groups during the investigation period: at 0, 2 and 4 h of propofol anaesthesia there were 4.1 (2.0), 4.7 (3.3) and 5.3 (3.2) x 106 ml–1 leucocytes, respectively; the corresponding values for isoflurane anaesthesia were 4.2 (2.8), 4.7 (2.4) and 5.0 (2.4) x106 leucocytes ml–1. There was no significant difference between the groups. The percentage of propidium iodide-positive PMNs, used as a measure of cell necrosis, was low (<5%) in both groups throughout the investigation period.

After 4 h of anaesthesia, the percentage of phagocytic PMNs that were ingesting opsonized FITC-labelled E. coli was slightly lower (propofol: 93.2% (7.0%), P=0.02; isoflurane: 94.3% (9.2%); P=0.03) than before induction of anaesthesia (Figure 2). The phagocytotic activity of each single cell expressed by the mean channel green FITC fluorescence was also reduced in both groups (propofol: 78.4% (12.7%), P<0.001; isoflurane: 89.4% (28.6%), P=0.002). There was no significant difference between propofol and isoflurane anaesthesia in either measure of phagocytosis (Figure 2).



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Fig 2 Percentage of PMNs phagocytosing opsonized FITC-labelled E. coli (upper panel) and the phagocytic activity in single PMNs expressed by the mean green channel fluorescence (lower panel) in patients given propofol (•) or isoflurane ({triangledown}). *Significantly different from values before induction of anaesthesia (100%). There were no significant differences between propofol and isoflurane anaesthesia in either of the phagocytosis parameters tested. Data are expressed as mean – SD.

 
The percentage of PMNs with RB activity after stimulation with E. coli was reduced during anaesthesia, but without significant difference between the two groups (Figure 3). RB activity induced by TNF-{alpha}/FMLP was 54% lower (P<0.001) after 4 h of anaesthesia with propofol than it was before induction of anaesthesia. In PMNs in patients given isoflurane for the same length of time, RB activity was reduced by 18% (P=0.031). The difference between the propofol and isoflurane groups was significant (P=0.011) (Figure 3). Linear regression analysis also showed a significant time-dependent reduction in TNF-{alpha}/FMLP induced RB activity (r=0.48, P=0.008) under propofol anaesthesia. The power with {alpha}=0.05 was 0.84, which means there is a 16% chance (ß error) that the observed difference between propofol and isoflurane is not significant.



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Fig 3 Percentage of PMNs producing superoxide anions during the respiratory burst after stimulation with E. coli (upper panel) and TNF-{alpha}/FMLP (lower panel) in patients given propofol (•) or isoflurane ({triangledown}). *Significantly different from values before induction of anaesthesia (100%). {dagger}Significant difference between propofol and isoflurane. Data are expressed as mean – SD.

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The essential role in host defence of phagocytosis and production of superoxide anions during the RB is illustrated by the marked propensity of patients with certain clinical deficiency syndromes like chronic granulomatous disease or congenital disorders of phagocytic activity, to develop infections.13 Phagocytosis and superoxide anion production are mainly responsible for bacterial killing of PMNs. So if anaesthetics were to suppress these functions, this could reduce host defence. We investigated phagocytosis and RB activity during propofol or isoflurane anaesthesia in patients undergoing elective interventional embolization of cerebral AVM.

Phagocytosis
We found a significant reduction in the number of blood PMNs with phagocytotic activity and in the phagocytotic capacity of each single PMN during propofol or isoflurane anaesthesia. It has been shown previously that phagocytosis by blood cells is reduced after anaesthesia and surgery.14 15 Reduced phagocytosis seems to be associated with general anaesthesia as demonstrated by Hole, Unsgaard and Breivik,15 who showed that a decrease in phagocytosis was caused by general anaesthesia but not by epidural anaesthesia.

Recently, Kotani and co-workers reported that the phagocytic capacity of alveolar macrophages decreased during anaesthesia with isoflurane or propofol.16 These findings are complementary to our findings of reduced phagocytosis by blood PMNs after 2 and 4 h of propofol or isoflurane anaesthesia. In both types of anaesthesia, RB activation via viable, non-opsonized E. coli and phagocytosis of opsonized FITC-labelled E. coli were significantly depressed. We can, thus, add to the findings of Kotani et al. by showing that, under general anaesthesia, opsonin-dependent and opsonin-independent phagocytosis is reduced not only in alveolar macrophages but also in blood PMNs. In neither study was this effect dependent on the anaesthetic used; rather, it seems to depend on the conditions of general anaesthesia itself.

Our most notable finding was that propofol anaesthesia did not cause a greater reduction in the phagocytic activity of blood PMNs than isoflurane anaesthesia, as might have been expected from published in vitro results. In two in vitro studies carried out with the same flow cytometric phagocytosis assay applied in the present study, marked inhibition of neutrophil phagocytosis has been demonstrated after incubation with clinically relevant concentrations of propofol.5 17 In both studies the inhibition by propofol was concentration-related. Should this marked in vitro inhibition of phagocytosis by propofol also take place under clinical settings, e.g. after sedation of ICU patients with propofol for several days, this would probably result in reduced microbial killing and an increased risk of infection induced by propofol. In fact, we were unable to show a significant difference in inhibition of PMN phagocytotic capacity after 4 h of intravenous propofol anaesthesia which is, of course, a short time compared with sedation on ICU.

Respiratory burst
In the present study, the RB was measured after challenge with two different stimuli in order to discriminate between phagocytosis- and receptor-dependent activation of RB. The former was carried out assayed by stimulation with phagocytosis of E. coli and the latter by receptor activation with the bacterial peptide FMLP after priming with TNF-{alpha}. Both pathways increase the intracellular Ca2+ content which activates protein kinase C (PKC) and, hence, NADPH oxidase.4 Inhibition of the RB was estimated from the reduction in the number of PMNs recruited for the RB (percentage of activated PMNs).

The bacterial peptide FMLP is an agonist which mediates the response to bacterial formyl products in the inflammatory environment via a specific formyl peptide receptor on the cell surface. The receptor mediates multiple responses, including chemotaxis, exocytosis of certain enzymes, generation of superoxide anions by the NADPH oxidase complex during the RB and phagocytosis of E. coli.18 19 Like other ‘classical’ chemoattractant receptors (e.g. complement factor C5a, platelet activating factor (PAF) or lipopolysaccharide (LPS)), the FMLP receptor is linked to a heterotrimeric G protein, leading via intermediate steps to activation of PKC which, in turn, activates NADPH oxidase.20 Priming with cytokines such as TNF-{alpha} before FMLP activation leads to a high proportion of PMNs being activated. Priming is defined as the exposure of cells to a triggering agent, so that there is a markedly increased response to a second stimulus.21 It has been suggested that priming with TNF-{alpha} increases neutrophil FMLP receptor expression.22 23

We found that anaesthesia with propofol, but not isoflurane, decreased RB activity after isolated blood PMNs had been primed with TNF-{alpha}, followed by FMLP stimulation. This finding is in accordance with the results of Nakagawara and colleagues, who demonstrated that volatile anaesthetics do not seem to interfere with the FMLP receptor, because the affinity of the FMLP receptor for radiolabelled FMLP was not altered in the presence of volatile anaesthetics.24 An in vitro study has demonstrated that isoflurane under clinically relevant concentrations had no effect on FMLP-stimulated RB.25 This study, in particular, was carried out with the same flow cytometry method used in our investigation. The results of the present study and of both cited studies emphasize that isoflurane anaesthesia seems to have only minor effects on the RB of human blood PMNs. In contrast to isoflurane, anaesthesia with propofol seems to interfere with the FMLP receptor or downstream regulation of PMNs. Further studies are necessary to confirm this hypothesis.

In vitro effects of propofol
It is probable that the reported in vitro effects of propofol are caused mainly by its lipid carrier, Intralipid, a long-chain triglyceride (LCT) solution which produces concentration-dependent inhibition of different leucocyte functions in vitro.26 In this previous study we showed that LCT lipids inhibit the RB, whereas a mixture of LCT and saturated medium-chain triglycerides (MCT) augments the RB. In a recent in vitro study, we found that a new propofol preparation dissolved in LCT/MCT lipid (Propofol Lipuro; B. Braun, Melsungen, Germany) gave similar results to standard LCT propofol (Disoprivan; Zeneca).17 It is known that polyunsaturated fatty acids like LCT can be rapidly incorporated into cell membranes,27 thereby increasing membrane rigidity.28 Thus, propofol could inhibit the RB because of a direct effect of its lipid carrier, LCT, on NADPH oxidase in the plasma membrane of PMNs. NADPH oxidase has at least six components. In the resting cell, three of these components are in the cytosol and three in the plasma membrane. After activation by PKC, all components combine in the plasma membrane to produce a fully functional enzyme complex.4 The increase in membrane rigidity following incubation with LCT in vitro could explain the delayed formation of the NADPH oxidase enzyme complex as well as the inhibition of phagocytosis. The close contact between few non-circulating PMNs and fat over an incubation period of at least 20 min. Results in rapid incorporation of LCT fat into the cell membrane could explain the in vitro suppression of the RB and phagocytosis after incubation with LCT–propofol and LCT alone.

Other potential influences
When investigating the effect of anaesthesia on immune function, it is very important to estimate the influence of independent contributions such as operative trauma, mechanical ventilation, co-medication, temperature loss, volume shift or transfusion of blood components. All of our patients were subjected to the same time-dependent alterations of immune function induced by general anaesthesia, mechanical ventilation and embolization of cerebral AVM. In our clinical setting, we attempted to keep these interferences to a minimum. Each embolization was elective, and none of our patients was on steroid or non-steroidal anti-inflammatory medication known to interfere with PMN functions and viability.29 We believe that it is safe to assume that the trauma-induced effects, on immune cells, of interventional embolization of cerebral AVMs is only minor compared with the effects of surgical procedures. Furthermore, the patients in our study did not have significant reduction in body temperature, which has been shown to reduce the release of TNF-{alpha} and interleukin-1ß.30 Radiographic contrast medium reduces the percentage of granulocytes involved in phagocytosing E. coli but not the number of pathogenic bacteria.31 Furthermore, the impairment was most pronounced immediately after the injection of radiographic contrast medium and then rapidly returned to baseline.32 In the present investigation, a possible influence of contrast medium cannot be excluded, but there was no significant difference between the two groups in the amount of contrast medium administered, so any effect of the medium should have been equal in the two groups.

In conclusion, the phagocytotic activity of blood PMNs decreased significantly during the investigation period for both of the anaesthetics studied. Production of superoxide anions after FMLP activation was markedly lower during propofol anaesthesia than during isoflurane anaesthesia, suggesting that 4 h propofol anaesthesia may reduce FMLP receptor expression on the PMN surface. Additional investigations are necessary to test the hypothesis that propofol interferes with the FMLP receptor or the downstream regulation of human PMNs.


    Footnotes
 
* Corresponding author Back


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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