1 The Northern General Hospital, Herries Road, Sheffield S5 7AU, UK E-mail: richardmarks@doctors.org.uk
The choice of agent for anaesthetic maintenance during cardiopulmonary bypass has developed in an arbitrary manner. As a result, strong personal preferences for i.v. or volatile agent anaesthesia are frequently expressed, with a dearth of carefully considered evidence to support either argument. The process of cardiopulmonary bypass itself has complex effects on the pharmacokinetics of i.v. anaesthetic agents, because of haemodilution and altered visceral perfusion.1 The relatively advanced age of the patient population undergoing heart surgery may also increase the variability of effect of i.v. anaesthetics. The coexistence of systemic atheroma further reduces visceral perfusion and may affect the clearance of these drugs. Extracorporeal circulation effectively substitutes for the patients own heart and lungs, and during bypass, gas exchange is achieved via an artificial oxygenator. The normal route of administration of volatile agents by inhalation is not possible. As a result, the administration of volatile anaesthetic agents during bypass must occur directly into the circulating blood from the gas mixture entering the oxygenator.
Cooling has long been used to provide some measure of cerebral and myocardial protection during bypass. Despite the unquestionable protective benefits of cooling, recent concerns have been expressed relating to the potentially harmful effects of rewarming on neurological outcome after hypothermia.2 3 Furthermore, it is now common practice during heart surgery to provide myocardial protection by injecting a cardioplegic mixture of saline and potassium in whole blood into the patients coronary arteries. The blood cardioplegia solution results in a reversible asystole with a high degree of myocardial protection, without the need for cooling.4 As a result, there is a steady increase in the amount of coronary artery bypass surgery being carried out under normothermic bypass conditions. This has perceived advantages for early extubation of cardiac patients with fewer perioperative complications.4 It also avoids any harmful effects of rewarming.
An immediate consequence of normothermic bypass is an increased requirement for anaesthesia. There may be an increased risk of awareness during normothermia. Anaesthesia that is deemed adequate for hypothermic bypass may be inadequate for normothermic bypass.5 A second requirement is for cerebral protection. A high prevalence of cognitive impairment is recognized after cardiac surgery.6 Whilst blood cardioplegia may provide adequate myocardial protection for normothermic bypass, there is no comparable additional cerebral protection during normothermia. The depth of anaesthesia during bypass surgery has not been correlated specifically with neurological outcome. However, under normothermic conditions, it is reasonable to assume that any reduction in cerebral metabolic rate is likely to be beneficial. Despite the growth of normothermic cardiopulmonary bypass, there is a surprising paucity of information on the appropriate dose of anaesthetic agent for either i.v. or volatile agent maintenance in such circumstances.
The administration of a volatile anaesthetic agent via a vaporizer, in series with the fresh gas flow to the bypass oxygenator, offers one means of anaesthetic maintenance. Benefits of volatile agent anaesthesia include the avoidance of the pharmacokinetic variability that affects i.v. agents such as: haemodilution; alterations in tissue blood flow; or variation in body mass. Similarly, the elimination of volatile agents is relatively independent of liver and renal function and offers a potentially rapid, predictable offset.
Using a gas analyser, it is possible to measure the concentration of volatile agent entering or leaving the oxygenator. The administration of around 12 volume percent of volatile agent in combination with i.v. opioid supplements is in common use. The anaesthetic potency of volatile agents administered by inhalation is expressed in familiar terms as a minimum alveolar concentration.7 No equivalent value exists for volatile agent administered via a bypass oxygenator. It has recently been confirmed, however, that the oxygenator exhaust gas tension is a reliable measure of blood isoflurane tension.8 Limited information is available on the concentration of isoflurane that produces adequate depth of anaesthesia (in terms of electroencephalogram (EEG) measurements) during hypothermia,9 10 but no comparable studies relate to normothermia.
Whilst the volatile agent technique may avoid pharmacokinetic variability during bypass, it is not without technical problems. The fresh gas flow rate to the bypass oxygenator may be considered analogous to ventilation, whereas the bypass blood flow rate may be similarly compared to pulmonary perfusion during inhalation anaesthesia. The effects of altering either the fresh gas flow rate or the blood flow rate on volatile agent uptake from a membrane oxygenator have not been studied in vivo. Both the gas and blood flow rates are altered independently in order to maintain acidbase balance during bypass, and these adjustments may well affect volatile agent administration. Early in vitro work, with the now obsolete but highly efficient bubble oxygenators, does show changes in volatile agent tensions with changing gas and blood flow rates.11 In the same way that blood gas solubility affects the uptake of agents administered by inhalation, it was suggested that it will also have an effect in determining the uptake of volatile agents administered via a bypass oxygenator.11 Finally, it seems that oxygenators themselves may have a varying influence on the uptake of volatile agents.12
In this issue of the BJA, Yoshitani and colleagues13 advance the case for i.v. agent maintenance with a carefully constructed investigation of the effect of three different infusion rates of propofol during normothermic bypass. The study is important in that it includes five plasma propofol concentration measurements taken during bypass surgery, and attempts to correlate propofol infusion rates and plasma propofol concentrations with EEG measurements. Yoshitani and colleagues went to considerable lengths to avoid EEG artefacts. At propofol infusion rates of 56 mg kg1 h1, combined with a fentanyl infusion of 5 µg kg1 h1, plasma propofol concentrations of the order of 2.2 µg ml1 are associated with measurable EEG burst suppression. Interestingly, the plasma concentrations are considerably less than those needed to produce EEG burst suppression in non-cardiac patients.14 Yoshitani and colleagues have tentatively defined a dose of propofol of 56 mg kg1 h1 for their population of cardiac patients, but clearly acknowledge the need for more detailed depth of anaesthesia studies.
The idea of inducing burst suppression as a means of cerebral protection is certainly not a new one. It was suggested that the protective effects of thiopental are twofold; a reduction in cerebral metabolic rate, and a reduction in cerebral blood flow.15 The former minimizes ischaemic damage, whilst the latter could simultaneously reduce the delivery of damaging embolic particles. Both propofol and isoflurane have been shown to reduce cerebral oxygen demands when burst suppression is achieved.10 16 Whilst these effects are arguably beneficial, no effect of burst suppression on neurological outcome has been demonstrated by either agent during hypothermic bypass. However, anaesthesia to the point of EEG burst suppression may well assume greater importance for providing protection during normothermic bypass. There is some laboratory evidence that the depth of anaesthesia required to produce EEG burst suppression may well be in excess of that needed to produce adequate cerebral protection,17 although burst suppression does at least provide a clinically measurable and reproducible end-point.
Despite the limited technical information available on the uptake of volatile agents during bypass, there has been a recent upsurge of interest in volatile agent anaesthesia for coronary artery surgery. This has resulted from the demonstration of a striking myocardial protective effect in animal models of myocardial ischaemia by volatile anaesthetic agents, recently termed anaesthetic preconditioning.18 The phrase is actually an adaptation of the broader term ischaemic preconditioning, whereby a period of mild ischaemia protects tissue against a subsequent major ischaemic insult. In the heart, an adenosine triphosphate (ATP)-dependant potassium channel was first identified from patch clamping.19 In the presence of ischaemia, a decrease in the generation of ATP (and subsequent fall in intracellular ATP) was shown to increase potassium permeability, reducing the force of contraction, and hence reducing subsequent energy expenditure. It would appear that volatile agents all have a similar effect on ATP-dependant potassium channels in myocardial mitochondria, mimicking the phenomenon of ischaemic preconditioning.2022
Although propofol has free radical scavenging properties,23 there is no convincing evidence that it specifically confers myocardial protection. Unfortunately, it does not appear to have any effect on mitochondrial potassium channels either.21 Two recent clinical studies have measured myocardial contractility after coronary revascularization using echocardiography,24 and intraventricular pressure measurements.25 Patients were anaesthetized with either propofol or a volatile agent. In both studies, despite relatively small sample sizes, myocardial contractility is significantly better in those patients anaesthetized with volatile agents. Should it emerge that these results are confirmed by larger studies, and anaesthetic preconditioning is confirmed as a protective mechanism in humans at anaesthetic concentrations of volatile agents, this alone is likely to fuel a large shift towards volatile agent maintenance.
Yoshitani and colleagues13 should be complimented for their work on propofol maintenance. Further information is required on the administration of volatile anaesthetic agents during normothermic bypass. The administered concentration of volatile agent sufficient to give the maximum myocardial and cerebral protection during normothermic cardiopulmonary bypass needs to be determined. Further work is also needed on the uptake of volatile anaesthetic agents administered through oxygenators at a range of fresh gas and bypass flow rates. It is hoped that an increased use of volatile agent concentration measurement,26 and EEG monitoring, will lead to a better understanding of the administration of volatile agents for normothermic cardiopulmonary bypass.
References
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