Influence of sepsis on minimum alveolar concentration of desflurane in a porcine model

B. Allaouchiche1, F. Duflo1, R. Debon1, J.-P. Tournadre1 and D. Chassard2

1Department of Anaesthesiology and Intensive Care, Hotel Dieu Hospital, Lyon, France. 2Department of Anaesthesiology and Intensive Care, Hotel Dieu Hospital, Lyon and Department of Research EA 18/96, Claude Bernard University, Lyon, France*Corresponding author

Accepted for publication: February 13, 2001


    Abstract
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
The effect of sepsis on the minimum alveolar concentration of desflurane (MACDES) in humans and other animals has not been reported previously. The aim of this study was to test the hypothesis that sepsis might alter MACDES in a normotensive septic porcine model. Twenty-four young healthy pigs were premedicated with ketamine 10 mg kg–1 i.m and then anaesthesia was established with propofol 3 mg kg–1 and the trachea was intubated. Baseline MACDES in each pig was evaluated by pinching with a haemostat applied for 1 min to a rear dewclaw. MACDES was determined by changing desflurane concentrations stepwise until purposeful movement appeared. Pigs were randomly assigned to two groups of 12 animals: the saline group received a 1 h i.v. infusion of saline solution while the sepsis group received a 1 h i.v. infusion of live Pseudomonas aeruginosa. Epinephrine and hydroxyethylstarch were used to maintain normotensive and normovolaemic haemodynamic status. In both groups, MACDES was evaluated 5 h after infusion. Significant increases in heart rate, cardiac output, mean pulmonary artery pressure and pulmonary vascular resistance occurred in the sepsis group. MACDES was 9.2% (95% confidence interval (CI) 6.8–10.6%) for the saline group and 6.7% (95% CI: 4.7–10.4) for the sepsis group (P<0.05). These data indicate that MACDES is significantly decreased in this normotensive hyperkinetic septic porcine model.

Br J Anaesth 2001; 86: 280–3

Keywords: anaesthetics, volatile, desflurane; infection, bacteraemia; pig


    Introduction
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Patients with sepsis syndrome or septic shock may require general anaesthesia for surgical procedures. Ketamine may be clinically usefully because it avoids sudden afterload reduction and is relatively good at preserving sympathetic nervous system activity.1 The rapid pharmacokinetics of desflurane allow rapid haemodynamic control.2 As it has few hepato-renal side effects, desflurane could be an interesting alternative to ketamine in septic patients.3

As for other volatile anaesthetic agents, several factors affect the minimum alveolar concentration of desflurane (MACDES) in pigs, including age, body temperature, additional anaesthetic drugs, acid–base status, concentrations of carbon dioxide and brain electrolytes, type of supramaximal stimulus and haemodynamics.46

The pharmacokinetics of desflurane have been well characterized in humans and other animals,2 but no data are currently available on MACDES requirements in septic animals or patients. The aim of this study was to test whether sepsis can change MACDES requirements in an animal model of sepsis.


    Methods and results
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
With approval of our local animal research committee, 24 healthy young pigs (3–4 months old; mean (SD) weight 23 (2.9) kg) were used. Animals were premedicated with ketamine 10 mg kg–1 i.m., then general anaesthesia was induced with propofol 3 mg kg–1. The trachea was intubated and mechanical ventilation started (Sa 2; Dräger, Lübeck, Germany). The circuit was assembled as an open, non-rebreathing system. Desflurane was administered as the sole anaesthetic agent via a calibrated vaporizer (Devapor, Dräger) in 100% oxygen as the carrier gas with a fresh gas flow of 7.0 litres min–1. Ventilation was adjusted to maintain end-tidal normocapnia. Inspired and expired gas (end-tidal anaesthetic concentrations) were measured using a calibrated infrared gas analyser (PM 8050, Dräger). Hydration was maintained with a 0.9% NaCl solution.

MACDES was assessed in each pig as described previously,5 beginning with a 10% end-tidal concentration of desflurane. A haemostatic clamp was placed on the hind limb and moved cranially and caudally for 1 min. If no purposeful response was obtained, the desflurane expired concentration was decreased by 20%. Fifteen minutes were allowed to achieve equilibration and the stimulus was repeated. The end-tidal desflurane concentration was decreased further, step by step, until there was purposeful movement. The desflurane concentration was then increased by 0.3% steps, and after the equilibration period, the stimulus was repeated. The desflurane concentration midway between that allowing and that preventing movement was taken to be the MACDES. Once MACDES had been determined, haemodynamics, end-tidal carbon dioxide concentration and core temperature were recorded. Arterial blood samples were simultaneously collected for gas analysis and measurement of plasma lactate concentrations. Pigs were randomly allocated to two groups with carefully prepared opaque sealed envelopes. The saline group received a 1 h infusion of saline solution (1 ml kg–1) and the sepsis group a 1 h i.v. infusion of live Pseudomonas aeruginosa. In keeping with previous studies,7 0.3 ml of bacteria (5x108 cfu ml–1) were infused per 20 kg bodyweight per minute. In both groups, haemodynamic status and core temperature were assessed 30, 60, 120, 180, 240 and 300 min after infusion of bacteria or saline. Hydroxyethylstarch and epinephrine were used shortly after the infusion to maintain a pulmonary artery occlusion pressure (PAOP) between 8 and 15 mm Hg and a mean systemic arterial pressure (MAP) between 60 and 70 mm Hg.7 MACDES was assessed again 5 h after the end of the infusion. One physician assessed MAC before and after infusion and was not aware of the nature of the infusion or of haemodynamic status; another physician was enrolled to administer the infusion and to manage potential sepsis.

MACDES data are expressed as median (95% confidence intervals) and were compared using the Mann–Whitney test. Haemodynamic data were compared using the Friedman test. No statistically significant differences in MACDES were observed between the groups before saline and bacterial infusion: the median (95% confidence interval) MACDES before infusion was 9.7% (8.7–10.4%) in the saline group and 9.5% (8.6–10.3%) in the sepsis group (Figure 1). MACDES for the saline group was 9.2% (6.8–10.6%) after saline infusion and that for the sepsis group was 6.7% (4.7–10.4%) after bacterial infusion (P<0.05) (Figure 1). The mean pulmonary arterial pressure (MPAP) in the sepsis group was significantly (170%) higher 30 min after the end of perfusion, and then decreased gradually to a steady state with persistent pulmonary hypertension for the remainder of the study when compared with the saline group. Pulmonary vascular resistance had increased significantly (by 333%) in the sepsis group 30 min after the end of the bacterial infusion, then declined but remained significantly higher than that in the saline group (+96%). Heart rate increased continuously 1 h after the end of bacterial infusion (+18%) and increased by the end of the study (+23%). Cardiac output had significantly increased in the sepsis group (+23%) 1 h after the end of bacterial infusion and remained elevated until the end of the study (+60%).



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Fig 1 MACDES (as a percentage) before (control) and after infusion (saline and sepsis) expressed as median and 95% confidence intervals. *Not significantly different from control after saline infusion. {dagger}Significantly different (P<0.05) from saline and control after bacterial infusion.

 
No statistically significant differences in MAP, PAOP, systemic vascular resistance, end-tidal carbon dioxide, arterial gas values, core temperature or plasma lactate concentration were observed. None of the measurements in the saline group after infusion were statistically significantly different from those before infusion.


    Comment
 Top
 Abstract
 Introduction
 Methods and results
 Comment
 References
 
Septic animals had a lower MACDES than those in the control group. Minimum alveolar concentration has three components: a nociceptive stimulus, a response and an end-tidal anaesthetic concentration.6 Eger and colleagues defined two types of stimulus for determining MAC in pigs: clamping the dewclaw or clamping the tail.5 The MAC obtained by clamping the tail was more variable and lower than the that obtained by clamping the dewclaw. The supramaximal stimulus that was applied in our study was dewclaw clamping; purposeful response was said to have been achieved when contralateral movement was obtained.

Many pathophysiological conditions can affect MACDES, including additional anaesthetic drugs, differences in core temperature, age, acid–base status, concentrations of electrolytes in cerebrospinal fluid, hypotension and prolonged anaesthesia.46 Premedication with i.m. ketamine and induction with propofol affect MACDES. Nevertheless, MACDES values in the two groups were not statistically different before infusion and were close to values reported by Eger and colleagues (10±0.94%).5 There were no statistically significant differences in core temperature between the groups, so the reduction in MACDES in the septic group cannot be explained by changes in temperature. Suspected occult tissue hypoxia associated with sepsis could have produced metabolic acidosis, indicating anaerobic metabolism. This phenomenon is likely to have contributed to the decreased anaesthetic requirement.9 In our study, there was no difference in arterial lactate concentrations or acid–base status. However, lactate is an unreliable indicator of tissue hypoxia in sepsis10 and, in our septic model, tissue hypoxia could have occurred without metabolic changes. Hypotension has been reported to decrease the MAC of volatile anaesthetic agents.6 However, in our study, because of epinephrine and hydroxyethylstarch/saline therapy, septic pigs remained normotensive. In the case of haemodynamic failure, MACDES is likely to be altered more, but this would differ from septic patients undergoing surgical procedures. Another possible explanation of the reduction in MACDES is cerebral electrolyte dysfunction;4 in this study we did not measure electrolyte concentrations in cerebrospinal fluid. Another potential cause of discrepancies in the reduction of MACDES is fluid and drug resuscitation. Hydroxyethylstarch and epinephrine were administered to mimic an anaesthetist’s method of sustaining arterial pressure. Steffey and Eger found that epinephrine had no effect on the MAC of halothane in dogs.11 Our results support the hypothesis that changes in anaesthetic requirement might be related, in part, to the use of hydroxyethylstarch. However, the influence of hydroxyethylstarch on MAC requirements has never been explored. Differences in MACDES can arise from the central nervous system dysfunction associated with sepsis. Encephalopathy, alterations in neurotransmitter levels, changes in receptor function and brain Ca2+ accumulation occur early during sepsis.1 Changes in regional blood flow and in the energy status of skeletal muscle appear during sepsis.12 Thus anaesthetic requirements could be reduced in these models and could possibly explain the lower MACDES in the septic group.1


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Table 1 Haemodynamic characteristics of the population. MPAP, mean pulmonary artery pressure; PVR, pulmonary vascular resistance; SVR, systemic vascular resistance; PAOP, pulmonary artery occlusion pressure; filling, hydroxyethylstarch infusion. Data are mean (SD). *Significantly different (P<0.05) from animals with saline infusion
 

    Acknowledgements
 
We thank P. Y. Gueugniaud, MD, PhD, for critically reading the manuscript and providing useful comments. We also thank Florence Arnal and Philippe Loth for their technical guidance. This work was supported by a grant from the Hospices Civils de Lyon.


    References
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 Abstract
 Introduction
 Methods and results
 Comment
 References
 
1 Baxter F. Septic shock. Can J Anaesth 1997; 44: 59–72[Abstract]

2 Eger EI II. Desflurane animal and human pharmacology: aspects of kinetics, safety, and MAC. Anesth Analg 1992; 75: S3–9[ISI][Medline]

3 Koblin DD. Characteristics and implications of desflurane metabolism and toxicity. Anesth Analg 1992; 75: S10–6[ISI][Medline]

4 Tanifuji Y, Eger EI II. Brain sodium, potassium, and osmolality: effects on anesthetic requirement. Anesth Analg 1978; 57: 404–10[Abstract]

5 Eger EI II, Johnson BH, Weiskopf RB, et al. Minimum alveolar concentration of I-653 and isoflurane in pigs: definition of a supramaximal stimulus. Anesth Analg 1988; 67: 1174–6[Abstract]

6 Quasha AL, Eger EI II, Tinker J. Determination and applications of MAC. Anesthesiology 1980; 53: 315–34[ISI][Medline]

7 Walsh CJ, Surgerman HJ, Mullen PG, et al. Monoclonal antibody to tumor necrosis factor {alpha} attenuates cardiopulmonary dysfunction in porcine Gram-negative sepsis. Arch Surg 1992; 127: 138–45[Abstract]

8 Eger EI II, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965; 26: 756–63[ISI][Medline]

9 Gill R, Martin C, McKinnon T, Lam C, Cunningham D, Sibbald WJ. Sepsis reduces isoflurane MAC in a normotensive animal model of sepsis. Can J Anaesth 1995; 42: 631–5[Abstract]

10 James JH, Luchette FA, McCarter FD, Fisher JE. Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. Lancet 1999; 354: 505–8[ISI][Medline]

11 Steffey EP, Eger EI II. The effect of seven vasopressors on halothane minimum alveolar concentration in dogs. Br J Anaesth 1975; 47: 435–8[Abstract]

12 Illner HP, Shires T. Membrane defect and energy status in rabbit skeletal muscle cells in sepsis and septic shock. Arch Surg 1981; 116: 1302–5[Abstract]





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