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The effect of lidocaine on neutrophil respiratory burst during induction of general anaesthesia and tracheal intubation

Swanton, B. J.1; Iohom, G.1; Wang, J. H.2; Redmond, H. P.2; Shorten, G. D.1

European Journal of Anaesthesiology: August 2001 - Volume 18 - Issue 8 - p 524-529
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Background and objective Respiratory burst is an essential component of the neutrophil's biocidal function. In vitro, sodium thiopental, isoflurane and lidocaine each inhibit neutrophil respiratory burst. The objectives of this study were (a) to determine the effect of a standard clinical induction/tracheal intubation sequence on neutrophil respiratory burst and (b) to determine the effect of intravenous lidocaine administration during induction of anaesthesia on neutrophil respiratory burst.

Methods Twenty ASA I and II patients, aged 18–60 years, undergoing elective surgery were studied. After induction of anaesthesia [fentanyl (2 μg kg−1), thiopental (4–6 mg kg−1), isoflurane (end-tidal concentration 0.5–1.5%) in nitrous oxide (66%) and oxygen], patients randomly received either lidocaine 1.5 mg kg−1 (group L) or 0.9% saline (group S) prior to tracheal intubation. Neutrophil respiratory burst was measured immediately prior to induction of anaesthesia, immediately before and 1 and 5 min after lidocaine/saline.

Results Neutrophil respiratory burst decreased significantly after induction of anaesthesia in both groups [87.4 ± 8.2% (group L) and 88.5 ± 13.4% (group S) of preinduction level (P < 0.01 both groups)]. After intravenous lidocaine (but not saline) administration, neutrophil respiratory burst returned towards preinduction levels, both before (97.1 ± 23.6%) and after (94.4 ± 16.6%) tracheal intubation.

Conclusion Induction of anaesthesia and tracheal intubation using thiopentone and isoflurane, inhibit neutrophil respiratory burst. This effect may be diminished by the administration of lidocaine.

1Department of Anaesthesia and Intensive Care Medicine, Cork University Hospital, Cork, Ireland

2Department of Surgery, Cork University Hospital, Cork, Ireland

Accepted January, 2001.

Correspondence to: Swanton Department of Anaesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts, MA 02114, USA.

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Introduction

Phagocytic cells including neutrophil polymorphonuclear granulocytes possess an electron-transport system that accepts electrons from NADPH in the cytosol to reduce oxygen to the superoxide radical in the vacuolar lumen. The reactive oxygen species generated are instrumental in killing pathogenic microorganisms [1].

The intravenous (i.v.) anaesthetic induction agent sodium thiopental inhibits neutrophil reactive oxygen species (ROS) production in vitro. This effect is dose dependent and occurs at clinically relevant concentrations [2]. Likewise, the inhalational anaesthetic agent isoflurane has been shown to inhibit ROS production in vitro [3]. The primary objective of this study was to determine whether these in vitro inhibitory effects occur after administration of these agents in a standard clinical induction/tracheal intubation sequence.

During induction of anaesthesia, in the clinical setting, factors other than direct pharmacological effects of the anaesthetic agents may influence neutrophil respiratory burst (NRB). For instance, catecholamines decrease NRB via an agonist effect on neutrophil b-adrenergic receptors [4]. Thiopental administration results in a decrease in plasma catecholamine concentration [5], whereas subsequent laryngoscopy and tracheal intubation cause a significant increase in plasma epinephrine and norepinephrine concentrations as part of the sympathoadrenal response to these manoeuvres [6].

Intravenous lidocaine has been used in clinical practice for the purpose of decreasing the haemodynamic and sympathetic response to laryngoscopy and tracheal intubation [7]. Therefore, the potential exists for lidocaine to decrease any inhibitory effect of laryngoscopy and intubation on NRB. In vitro, lidocaine has a direct inhibitory effect on NRB [8]. A secondary objective of this prospective randomized study was to determine the effect of i.v. lidocaine (1.5 mg kg−1), during induction of anaesthesia, on NRB.

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Methods

After institutional ethical approval, and having obtained written informed consent from each, 20 ASA I–II patients (aged 18–60 years), undergoing elective surgery requiring tracheal intubation were studied. Exclusion criteria were (a) history of allergy to amide local anaesthetic agents, and (b) pre-existing conditions or drug therapy known to influence immune function.

Patients did not receive premedication. Prior to induction of anaesthesia, standard monitoring was established with a pulse oximeter, electrocardiograph and non-invasive arterial pressure monitoring (Datex AS/3, Datex Corp., USA). A 20-gauge intravenous cannula, for the purpose of drug administration, was inserted in one forearm and an infusion of Hartmann's solution 1000 mL commenced. An 18-gauge cannula was inserted in the contralateral arm to facilitate venous sampling and blood (4 mL aliquots) withdrawn for estimation of total white cell and neutrophil counts. Pulse rate and non-invasive arterial pressure were recorded at 1-min intervals from immediately prior to the induction of anaesthesia until 3 min after tracheal intubation. After preoxygenation, fentanyl (2 μg kg−1) was administered. One minute later, general anaesthesia was induced using sodium thiopental (4–6 mg kg−1), and vecuronium (0.1 mg kg−1) was administered to facilitate laryngoscopy and tracheal intubation. Anaesthesia was maintained with isoflurane (end-tidal concentration 0.5–1.5%) in nitrous oxide (66%) and oxygen. According to random allocation, patients received either i.v. lidocaine (1.5 mg kg−1) (group L) or an equal volume of 0.9% saline (group S), 2 min after induction of anaesthesia, administered over 5 s. Laryngoscopy and tracheal intubation were performed 1 min after lidocaine/saline administration.

For the measurement of neutrophil respiratory burst, venous blood samples were withdrawn from the dedicated sampling cannula (a) prior to induction of anaesthesia and fentanyl administration, (b) after induction of anaesthesia and immediately prior to administration of lidocaine/saline, (c) 1 min after administration of lidocaine/saline, immediately prior to laryngoscopy and (d) 5 min after administration of lidocaine/saline (but prior to surgical skin incision).

In order to measure ROS production, 5 mL of blood was mixed with heparin (10 IU mL−1) in a sterile plain tube, stored at room temperature and analysed within 2 h. The amount of intracellular oxygen radical production was determined using a commercially available kit (Bursttest®, Orpegen Pharma, Heidelberg, Germany) [9]. Three samples (100 μL each) were incubated (10 min, at 37°C) in dihydrorhodamine123 with phosphate buffered saline (PBS), chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP), or opsonized Escherichia coli bacteria. In this time, the dihydrorhodamine123 was taken up by the neutrophils and, in the presence of ROS from the respiratory burst, was converted to rhodamine 123, a green fluorescent compound. Erythrocytes were lysed and leucocytes fixed with Bursttest® lysing solution (Orpegen Pharma, Heidelberg, Germany). DNA staining was performed with propidium iodide (red fluorescence, FL-3) to enable exclusion of cell debris or dead cells. Five thousand cells were gated and analysed with a laser flow cytometer (FACScan/Lysis II, Becton Dickinson, Heidelberg, Germany) using blue/green excitation light (488 nm argon laser). For characterization of the fluorescence distribution, the geometric mean values (FL-1) (E. coli cells minus PBS cells) were used, indicating the amount of rhodamine 123 per cell.

The data thus obtained were analysed using unpaired two tailed Student's t-tests or repeated measures ANOVA, as appropriate. P < 0.05 was considered significant.

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Results

Twenty patients were studied (nine in group L and 11 in group S). The two groups were similar with respect to age, gender, body weight, total white cell and neutrophil counts (Table 1). The type of surgery performed was similar in group L [laparoscopy (3), bladder neck suspension (2), hysterectomy (2), inguinal hernia repair (1) and laparascopic cholecystectomy (1)] and group S [laparoscopy (4), inguinal hernia repair (3), hysterectomy (2), laparascopic cholecystectomy (1) and lipoma excision (1)].

Table 1

Table 1

Respiratory burst activity decreased significantly after induction of anaesthesia (to 87.4 ± 8.2% and 88.5 ± 13.4% of preinduction level in groups L and S, respectively, P < 0.01 both groups) (Figure 1). In group S, respiratory burst activity remained depressed at 1 min (83.9 ± 14.3% of preinduction level) and 5 min (82.5 ± 15.6% of preinduction level) after administration of saline. In group L, respiratory burst activity returned towards preinduction levels at 1 min (97.1 ± 23.6% of preinduction level) and 5 min (94.4 ± 16.6% of preinduction level) after administration of lidocaine. At these time points the difference between the groups approached but did not achieve statistical significance (P = 0.07 and 0.06 for 1 and 5 min after lidocaine/saline administration respectively).

Figure 1.

Figure 1.

After induction of anaesthesia, systolic and diastolic arterial pressure decreased significantly in both groups (Figure 2). After tracheal intubation, systolic arterial pressure increased significantly in group S (145 ± 16 mmHg postintubation vs. 115 ± 10 mmHg preintubation) but not group L (115 ± 17 mmHg postintubation vs. 105 ± 14 mmHg preintubation). Diastolic arterial pressure increased in both groups after tracheal intubation (73 ± 13 mmHg group L, 98 ± 14 mmHg group S) compared with preintubation (60 ± 11 mmHg group L, 70 ± 10 mmHg group S). There were no significant changes in heart rate in either group (Figure 3).

Figure 2.

Figure 2.

Figure 3.

Figure 3.

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Discussion

The most important finding of this study is that neutrophil respiratory burst is decreased during a standard clinical induction of anaesthesia using fentanyl, sodium thiopental, nitrous oxide and isoflurane. Consistent with previous in vitro findings, we have demonstrated that neutrophil function is impaired acutely and consistently during induction of anaesthesia employing a commonly used clinical regimen. Several studies have shown an inhibitory effect, in vivo, of general anaesthesia induced by thiopental on human neutrophil ROS production [10–12]. These studies differ from ours in that they demonstrated a later effect after the induction of anaesthesia, which was subsequently maintained by an inhalational agent, either halothane [10,11] or enflurane [12]. Other investigators have shown that induction of anaesthesia with the inhalational agents halothane [13,14] and enflurane [14] inhibits ROS production.

The anaesthetic/analgesic agents administered in this study were fentanyl, thiopental, nitrous oxide and isoflurane. Patients did not receive premedication. In vitro, thiopental has been shown to inhibit neutrophil ROS production at clinically relevant concentrations [2,15,16]. In contrast, fentanyl does not influence NRB or phagocytosis [17–19]. In vitro studies of isoflurane and nitrous oxide on neutrophil function are conflicting, showing either no effect [20,21], inconsistent effect [22] or inhibition [3]. As we demonstrated inhibition of NRB 2 min after induction of anaesthesia using these agents, we suggest that thiopental was the agent primarily involved in producing this effect.

In patients who received saline, the inhibition of NRB persisted after tracheal intubation. It is not possible to study the effect of these manoeuvres on neutrophil function in the absence of pharmacological intervention. However, laryngoscopy and intubation are known to cause a significant increase in plasma catecholamine concentrations, due to activation of a sympathoadrenal response [23]. Catecholamines have been shown to inhibit neutrophil ROS production in vitro via an agonist effect on β-adrenoceptors [4]. This effect may have contributed to the persistent inhibition of NRB observed in the saline group after tracheal intubation.

In patients who received lidocaine (1.5 mg kg−1), NRB activity tended to increase from its postinduction level (87.4% of preinduction level) towards baseline (97.1% and 94.4% of preinduction level, 1 and 5 min after lidocaine administration respectively). Lidocaine has been shown to decrease the sympathetically mediated haemodynamic response to laryngoscopy and intubation [7], which is consistent with our findings (Figure 2). By decreasing the catecholamine response to tracheal intubation (and thus the inhibitory effect on NRB), lidocaine administration may account for the differing NRB activity observed after tracheal intubation, in the two groups studied. Although plasma catecholamine concentrations were not measured in this study, both systolic and diastolic arterial pressure were significantly lower after laryngoscopy and intubation in the lidocaine compared with the saline groups (Figure 2).

Surprisingly, the tendency to increased NRB activity after i.v. lidocaine administration was also present prior to tracheal intubation. The effect of lidocaine on neutrophil ROS production in vitro has been investigated in several studies. In general it has been found that it results in a dose-dependant inhibition, but this occurs at concentrations well in excess of those achieved clinically in plasma [8,24,25]. In only one study was a concentration in the clinical range (1 μg mL−1) found to inhibit ROS production measured by chemiluminescence [26]. Overall, a direct inhibitory effect of lidocaine, administered in the dose and setting examined in this study, on neutrophil ROS production appears unlikely. However, the mechanisms by which intravenous and inhalational anaesthetic agents inhibit neutrophil function are poorly understood. An interaction between lidocaine and thiopental on neutrophil function at the cellular level cannot be ruled out.

Neutrophil respiratory burst, which results in ROS production, is essential for the normal microbial killing activity of neutrophils [1]. Patients suffering from chronic granulomatous disease have defective neutrophil ROS production [27]. This disorder results from defects in any of the four genes encoding essential subunits of respiratory burst oxidase, the superoxide-generating enzyme complex in phagocytic leucocytes. The absence of respiratory burst oxidants results in recurrent bacterial and fungal infections and can also be complicated by the formation of inflammatory granulomata [28]. Skin incision is a time associated with a risk of bacterial colonization and wound infection [29]. Factors that reduce neutrophil microbial killing function at this time may play a role in postoperative infection. In conclusion, we have shown that a commonly used anaesthetic induction/intubation sequence is associated with acute inhibition of neutrophil respiratory burst. The significance of this finding for perioperative infection warrants further study.

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Keywords:

ANAESTHETICS, INTRAVENOUS, thiopental, ANAESTHETICS, LOCAL, amide, lidocaine; CELL PHYSIOLOGY, cell respiration, respiratory burst; IMMUNE SYSTEM, leucocytes, granulocytes, neutrophils

© 2001 European Academy of Anaesthesiology