531314 research-article2014
PRF0010.1177/0267659114531314PerfusionMcMullan et al.
Review
Volatile anaesthesia during cardiopulmonary bypass
Perfusion 1–11 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0267659114531314 prf.sagepub.com
V McMullan,1 RP Alston1 and J Tyrrell2
Abstract Since its inception, administering and ensuring anaesthesia during cardiopulmonary bypass has been challenging. Partly because of the difficulty of administering volatile agents during cardiopulmonary bypass, total intravenous anaesthesia has been a popular technique used by cardiac anaesthetists in the last two decades. However, the possibility that volatile agents reduce mortality and the incidence of myocardial infarction by preconditioning the myocardium has stimulated a resurgence of interest in their use for cardiac anaesthesia. The aim of this review is to provide an overview of the administration of volatile anaesthetic agents during cardiopulmonary bypass for the maintenance of anaesthesia and to address some of the practical issues that are involved in doing so. Keywords cardiopulmonary bypass; inhalational anaesthesia; volatile agents; awareness; oxygenator
Introduction Since its introduction into clinical practice over sixty years ago, cardiopulmonary bypass (CPB) has allowed surgery to be safely undertaken on the heart. Currently, around the world, several hundred thousand patients undergo heart surgery with CPB each year. However, since its inception, administering and ensuring anaesthesia during CPB has been challenging. One of the challenges is that the administration of volatile anaesthetic through the lungs is prevented by their exclusion from the circulation. In addition, the main clinical signs of the depth of anaesthesia, including heart rate, respiratory rate and systemic blood pressure, are rendered useless by CPB. Further hindrances to using volatile anaesthetic agents during CPB include the need for scavenging waste gases from the oxygenator’s exhaust to prevent occupational exposure of operating room staff from their potentially harmful effects and a reliance on the perfusionist to administer the volatile anaesthetic agent. Partly because of the difficulty of administering volatile agents during CPB, total intravenous anaesthesia (TIVA) has been a popular technique used by cardiac anaesthetists in the last two decades. However, the possibility that volatile agents reduce mortality and the incidence of myocardial infarction by preconditioning the myocardium has stimulated a resurgence of interest in
their use for cardiac anaesthesia. Therefore, the aim of this review is to provide an overview of the administration of volatile anaesthetic agents during CPB for the maintenance of anaesthesia and to address some of the practical issues that are involved in doing so.
Volatile anaesthetics A commonly used alternative name for volatile anaesthetic agents is ‘inhalational anaesthetic agents’. During CPB, these agents are not administered by inhalation so, for the purposes of this review, the term volatile
1Anaesthesia,
Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, UK 2Perfusion, Royal Infirmary of Edinburgh, UK Corresponding author: RP Alston Department of Anaesthesia, Critical Care and Pain Medicine Royal Infirmary of Edinburgh 51 Little France Crescent Edinburgh EH16 4SA UK Email: [email protected]
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Table 1. Physical properties of volatile anaesthetic agents. Characteristics
Sevoflurane
Isoflurane
Desflurane
N2O
Xenon
Boiling point (°C) Blood:gas partition coefficient (37°C) Oil:gas partition coefficient (37°C) Minimum alveolar concentration (MAC) Metabolism (%)
59 0.68 47 2.0 5
48 1.4 91 1.15 0.2
23 0.4 26 6.0 0.02
−89 0.47 1.4 104 0
−108 0.12 1.9 71 0
anaesthetic agents will used to describe this group of anaesthetic drugs. Volatile anaesthetic agents are supplied as liquids that are vaporised or as compressed gases and administered into the gas that is then inhaled by the patient. The agent is then taken up by the blood and transported to the central nervous system where its action produces anaesthesia. However, during CPB, the lungs are largely isolated from the circulation, rendering them useless as a means of delivering volatile agents. In this situation, volatile agents are vaporised into the sweep gas supplied to the oxygenator where they are transferred to the blood flowing through the CPB machine and, so, to the brain. The ideal agent should be chemically stable in the presence of heat or light, have a long shelf-life, be nonflammable and be unable to support combustion. In addition, it should be non-corrosive and not adsorbed on to rubbers or plastics. The saturated vapour pressure of the agent should be high enough to be able to produce clinically useful concentrations of anaesthetic.1 A speedy onset and offset of anaesthesia is aided by a low blood:gas partition coefficient.2 Moreover, the agent should be sufficiently potent to produce anaesthesia at low inspired concentrations. Minimal alveolar concentration (MAC) is defined as the concentration at steady state of inhaled anaesthetic at one atmospheric pressure that prevents movement in response to a standard surgical midline incision in 50% of a test population and is used to compare the potency of different agents.2 The concept of MAC is irrelevant to CPB where blood concentrations of anaesthetic agent are more important. Currently, the most common volatile anaesthetic agents in use in the United Kingdom are sevoflurane, isoflurane, desflurane and nitrous oxide. Their physical properties are described in Table 1.2
History of volatile anaesthesia during CPB The technique of CPB was researched and developed in animals by Gibbon in the 1930s and introduced into clinical practice for heart surgery in 1953.3 At this time, general anaesthetic techniques for surgery were universally based on volatile agents. Diethyl ether (ether) had
been used for general anaesthesia for over a hundred years, having first been used for anaesthesia by a dentist, Crawford L Long, in 1842, but was only brought to public attention in 1846 by William TG Morton.4 When Kirklin wrote about Gibbon’s CPB machine in 1955, ether was the anaesthetic that was used.5 In his early experimental work with cats, Gibbon had described his CPB equipment and had noted difficulty in maintaining anaesthesia during CPB.6 To overcome this problem, he passed ether vapour through the oxygenator, so establishing, in 1937, the use of a volatile anaesthetic technique during CPB. An alternative to ether was cyclopropane which had been discovered in 1929 and was also popular in thoracic anaesthesia when CPB was introduced. Despite being explosive, cyclopropane was also used to maintain anaesthesia in the early years of CPB.6 Initial problems experienced with CPB in humans included haemolysis associated with the original disc/ bubble oxygenators and explosions due to contact between the ether or cyclopropane and the motors.1,6 For this reason, volatile anaesthesia was frequently lightened or even stopped when the patient was placed on CPB.6 This practice gradually fell out of fashion with the introduction of halothane in 1956, which was nonexplosive and, therefore, safe when used during CPB.6 However, halothane brought its own problems, including myocardial depression, arrhythmogenicity, myocardial resistance to defibrillation and jaundice.6 Since then, every new volatile agent that has been introduced into general anaesthetic practice has been applied to CPB. Isoflurane has been particularly popular, but, as discussed later, there have been concerns that it causes coronary steal and myocardial ischaemia.1 These findings were based on animal research and were subsequently proven to be unsubstantiated by outcome studies, such as the one by Slogoff and Keats.7 Despite this, disquiet over coronary steal was another motivator for the widespread adoption of TIVA for cardiac anaesthesia in the 1990s. Like new volatile agents previously introduced into cardiac anaesthesia, TIVA was embraced with little investigation into its effect on outcome from cardiac surgery. TIVA has remained popular over the last 20 years, but, recently, there has been a resurgence of interest in the use of volatile agents during CPB. This is
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Figure 1. Position of vaporiser within cardiopulmonary bypass circuit.
because current best evidence indicates that volatile anaesthetic agents precondition the myocardium, thus, reducing the incidence of myocardial infarction and mortality associated with heart surgery.8
Administration of volatile anaesthetics during cardiopulmonary bypass During CPB, the circulating blood bypasses the lungs and their function is mechanically replaced by an oxygenator. Volatile anaesthetics may be administered by placing an anaesthetic vaporiser into the sweep gas supply to the oxygenator. Through a mechanism similar to that employed by the lungs, the agent diffuses in the oxygenator from the sweep gas into the blood which then transports it to the brain (Figure 1). When bubble oxygenators were used, there was a direct interface between gas and blood so that the transfer of
volatile anaesthetic was very efficient. However, bubble oxygenators have been superseded by membrane oxygenators as these generate far fewer gaseous microemboli9 and the transfer characteristics of modern membrane oxygenators are much more limited than the lungs or bubble oxygenators. For this reason, a relative overpressure concentration of the volatile anaesthetic agent has to be applied compared to that which is required when administered by inhalation into the lungs so as to ensure the adequate transfer across the membrane of the oxygenator and, so, a sufficient depth of anaesthesia. Moreover, the transfer characteristics of oxygenators differ, depending on the materials from which they are constructed, so that the degree of overpressure required to speed up achieving sufficient levels of anaesthesia varies from oxygenator to oxygenator. For anaesthetists who use a volatile technique during CPB, this needs to be carefully considered when a new oxygenator is introduced into their institution.
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filling with the anaesthetic agent eliminates the risk of damage resulting from potential spillages.
The effect of volatile anaesthetics on oxygenator gas transfer The gas transfer characteristics of most microporous polypropylene oxygenator membranes are not significantly affected by the presence of volatile anaesthetic agents. However, manufacturers’ guidelines specify that, above concentrations of 1.3% and 2.6% for isoflurane and sevoflurane, respectively, adjustments of inspired oxygen concentration and gas flow rates may be needed to achieve the desired gas transfer performance.11
Responsibility for administering volatile agents during cardiopulmonary bypass
Figure 2. Isoflurane vaporiser placed within cardiopulmonary bypass circuit.
Choice of vaporiser The choice of vaporiser on CPB is probably unimportant, but logic would dictate that the make and model of vaporiser should be the same as that used on the anaesthetic machine. Thus, there is shared knowledge about their use among operating room personnel. Whichever vaporiser is mounted on the CPB machine, there needs to be ready access to additional anaesthetic agent and the appropriate filler for the vaporiser in case it becomes exhausted.
Positioning of vaporiser Care should be taken to position the vaporiser on the CPB machine where it is clearly visible so that its filling level can be observed to ensure that it contains sufficient agent (Figure 2). The level of anaesthetic agent within the vaporiser needs to be monitored throughout the case. The vaporiser should be full and turned on before the patient is established on CPB to prevent awareness. Additionally, incorrect mounting on the back bar can result in the loss of the sweep gas before it enters the oxygenator, resulting in inadequate depth of anaesthesia, with patient awareness, hypoxia and hypercapnia. Filling a vaporiser on a CPB machine is not without hazard. Spillage of isoflurane onto the oxygenator causes cracking of the polycarbonate casing, so it is essential to position the vaporiser away from the oxygenator.10 Removing the vaporiser from the CPB machine before
In some countries, such as Australia and France, anaesthetists are directly responsible for the conduct of CPB so, often, they simultaneously manage the administration of volatile anaesthetics. However, in the majority of countries around the world, non-medically qualified perfusionists, who have no anaesthetic training, manage the CPB machine and often undertake the practical administration of volatile anaesthetics during CPB. Nevertheless, most anaesthetists would believe that they, rather than perfusionists, have responsibility for ensuring that the patient is anaesthetised throughout surgery and, therefore, that it is they who should ensure that the vaporiser is adequately filled, connected in series in the sweep gas supply to the oxygenator, set at an appropriate concentration and that the monitoring of volatile agent concentration is connected. Whoever is practically administering the anaesthetic agent, there needs to be close co-operation and communication between the anaesthetist and the perfusionist during CPB.
Scavenging There are concerns about the polluting effects of volatile anaesthetic agents on the atmospheric ozone and on operating theatre staff, including a suggestion of a higher rate of spontaneous abortion among female anaesthetists exposed to anaesthetic gases and a higher incidence of congenital abnormalities in children of anaesthetists.12 Therefore, systems that reduce occupational exposure to volatile anaesthetic agents are recommended and, during CPB, this is done with a scavenging system at the oxygenator gas exhaust outlet (Figures 3 & 4).13,14 However, care needs to be taken with such systems as, if excessive negative pressures are generated by a scavenging system then, consequently, these can produce a negative pressure gradient across membrane
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Figure 3. Scavenging system at the oxygenator gas exhaust outlet.
Figure 4. Anaesthetic gas scavenging system.
oxygenators, which may result in disruption of the oxygenator membrane. Therefore, it has been recommended that this pressure gradient be monitored to avoid oxygenator failure.15 As no specific proprietary equipment exists for these purposes, scavenging systems need to be constructed individually, bearing in mind the potential risks of using such systems. (Figure 3)
Monitoring depth of anaesthesia Clinical signs. During CPB, the clinical signs of the depth of anaesthesia are, for the most part, absent. Cardiovascular signs that might indicate light levels of
anaesthesia, such as hypertension and tachycardia, are diminished. Possibly because of haemodilution when the prime mixes with the circulating blood volume, hypotension commonly occurs at the onset of CPB. Whilst the hypotension gradually resolves during CPB, it renders systemic arterial pressure useless as an indication of the depth of anaesthesia. For the duration of aortic cross-clamping on CPB, the heart is isolated from the circulation and made asystolic with cardioplegia so the heart rate cannot be used a sign of the depth of anaesthesia during this time. In addition, many patients undergoing coronary artery bypass graft (CABG) surgery with CPB are receiving heavy beta-adrenergic blockade. Therefore, tachycardia does not occur, even if a patient’s depth of anaesthesia is light, so the heart rate is unreliable for detecting awareness. Patient movement in response to noxious stimuli is a sign of light anaesthesia and is completely obliterated by neuromuscular blocking (NMB) agents. Many anaesthetists use large doses of long-acting NMB agents, such as pancuronium, for cardiac anaesthesia and, consequently, this contributes to difficulty in detecting light levels of anaesthesia. One pragmatic approach that has been employed by one of the authors for over two decades is to use short- or medium- rather than long-acting NMB agents, in the form of rocuronium, to allow detection of excessive lightening of the level of anaesthesia by patient movement. Clinical experience indicates that patient movement is most likely to occur during the rewarming phase of CPB when the brain rewarms more rapidly than the rest of the body. If physical movement occurs then the anaesthetist needs to take prompt action to deepen the level of anaesthesia and administer additional NMB agent to protect the patient from self-harm in their vulnerable situation. Oxygenator exhaust concentrations. As clinical signs of the depth of anaesthesia are of no value on CPB, alternative means of determining when a sufficient depth of anaesthesia has been achieved are important. In patients receiving a volatile anaesthetic agent, end-tidal measurements of its concentration have long been used as an estimate of blood and, therefore, brain concentration. This measurement is then compared to the MAC for that agent to help assess the adequacy of anaesthesia. End-tidal measurement can also be used to ensure that the agent is actually being delivered to the patient; for example, if the vaporiser becomes exhausted of agent during a long CPB run. In an analogous situation to end-tidal levels, concentrations of volatile anaesthetics in the gas exhausted from the oxygenator should represent concentrations in the blood and, so, the brain. A small study has shown that the oxygenator exhaust gas tension is a
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reliable measure of blood isoflurane tension.16 Therefore, monitoring anaesthetic concentrations in the oxygenator exhaust gas may be a useful adjunct to monitoring the depth of anaesthesia during CPB.17 However, there is no established equivalent to MAC that exists for volatile anaesthetic agents measured in the oxygenator exhaust.18 There is a further problem in that present day oxygenators are not as efficient as the lungs in transferring volatile anaesthetic agents. They, like the lungs, must have a large surface area and be highly permeable to ensure efficient gas exchange. This has been aided by microporous hollow-fibre oxygenators,19 but different oxygenators have different and undefined transfer characteristics which affect the transfer of the volatile agent. Furthermore, systemic hypothermia, which is commonly induced during CPB, diminishes the requirement for anaesthesia and, thus, the concentration of volatile agent required to maintain anaesthesia. So, whilst monitoring oxygenator exhaust levels of anaesthetic agent can be used to ensure that the volatile agents are actually being delivered to the patient, the levels that constitute adequate anaesthesia during the induction of hypothermia, stable hypothermia and rewarming phases of CPB are unclear. Electroencephalographic monitors. Electroencephalographic (EEG) monitoring has been used in patients undergoing CPB in the hope of detecting early cerebral ischaemia. The raw EEG can provide an indication of the depth of anaesthesia as, when burst suppression occurs, one can be assured that there is insufficient cerebral activity to allow awareness. Processed EEGs allow a more basic examination of the brain’s electrical activity, such as the spectral edge, to judge the depth of anaesthesia. More recently, proprietary depth of anaesthesia monitors that are based on processed EEG, such as bispectral index (BIS) and Entropy, have helped to assess the depth of anaesthesia during CPB. However, the use of advanced methods is limited, particularly in cardiac anaesthesia, as measurements of the depth of anaesthesia do not reflect the synergistic sedative effects of opioids. The B-Aware trial did include high-risk cardiac surgery and off-pump CABG patients in their study group, but did not specifically differentiate between patients on- and off- CPB and, therefore, the value of BIS in the specific setting of CPB was not demonstrated.20 In addition, systemic hypothermia is sometimes used during CPB for organ protection, which has profound effects on the electrical activity of the brain to such an extent that it ceases at about 29oC.6 This impact of hypothermia complicates the interpretation of the effects of anaesthetic agents on EEG and it is unclear how it affects the interpretation of the depth of anaesthesia monitors such as BIS or Entropy.
Insufficient and excessive anaesthesia There is an increased incidence of awareness in patients undergoing cardiac surgery. This is due to several risk factors, including the nature of surgery, limited haemodynamic reserve, the use of muscle relaxants and equipment failure with inadequate delivery of anaesthetic agent, whether inhalation or intravenous.21 Undoubtedly, a proportion of awareness, explicit or implicit, is not reported following surgery and this is precluded by post-operative delirium and cognitive dysfunction which are common in cardiac surgery patients. Awareness with recall has been reported between 1.1-4.7% of patients undergoing CPB22,23 compared with 0.1-0.2% undergoing non-cardiac surgery.24,25 The true incidence in the UK will be clearer after the publication of the findings of the 5th National Audit Project of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland concerning accidental awareness during general anaesthesia. However, clearly, the incidence of awareness is lowest when there is conscientious and continual administration of anaesthetic agent before, during and after CPB.26 Despite the importance of maintaining an adequate depth of anaesthesia on CPB to prevent awareness, there are potential risks of giving too much anaesthetic. Along with systemic hypotension, cumulative deep hypnotic time has been shown to have an independent effect on mortality in the setting of non-cardiac surgery.27 It is uncertain whether this is applicable to patients on CPB and, if it is, what constitutes excessive depth of anaesthesia with a volatile anaesthetic agent during CPB.
Different volatile anaesthetic agents Nitrous oxide, as discussed below, has rarely been used during CPB because of its physical properties. Currently, the most commonly used volatile agents during CPB are sevoflurane and isoflurane. Xenon is not used clinically in the UK because of its extremely high cost, but will be discussed because of its interesting properties.
Nitrous oxide Despite being an analgesic, the use of nitrous oxide for the maintenance of anaesthesia during CPB is potentially dangerous. Nitrous oxide is highly insoluble in blood and has the capability to enlarge air bubbles, which can cause gaseous emboli to expand.28 For this reason, nitrous oxide is avoided in cardiac anaesthesia during bypass and after weaning from bypass. Although today’s membrane oxygenators generate far fewer gaseous microemboli compared with the old bubble
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oxygenators, they remain common during open heart surgery and nitrous oxide will worsen their adverse effects.9
Isoflurane and sevoflurane Sevoflurane and isoflurane are fluorinated ethers which are supplied as liquids. They are non-flammable and non-corrosive although isoflurane dissolves certain plastics. Sevoflurane has a low blood:gas partition coefficient of 0.68, resulting in a rapid onset and offset of anaesthesia and has a MAC of about 2.0.2 As with other volatile agents, it is distributed to organs with a high blood flow, such as the brain first and later to less-well perfused organs. About 5% of sevoflurane is metabolised by the liver while the rest is excreted by the lungs in the non-CPB setting. Compared to sevoflurane, isoflurane has a higher blood:gas partition coefficient of 1.4, resulting in a slightly slower onset of action.2 It has a MAC of 1.15 due to its high oil:gas partition coefficient and only 0.2% of the drug is metabolised in the liver.29 All fluorinated agents reduce cardiomyocyte calcium influx, causing depressed cardiac contractility and cardiac output.2 A reduction in systemic vascular resistance (SVR) due to vasodilatation is greatest with isoflurane and sevoflurane. These agents depress sympathetic activity although a compensatory tachycardia in response to vasodilatation is more commonly seen with isoflurane.9 Older volatile agents, particularly halothane, were responsible for frequent dysrhythmias potentiated by acidosis, hypokalaemia, hypocalcaemia and sensitisation of the myocardium to catecholamines.6 These adverse effects are less common with newer volatile agents. Most agents induce a degree of coronary vasodilation, but isoflurane demonstrates a phenomenon known as coronary steal in animal models. This is the diversion of blood from poorly perfused areas of myocardium to those already adequately perfused by coronary arteriolar vasodilatation. Despite this finding, the association of coronary steal with isoflurane has not been demonstrated in humans and, as discussed later, isoflurane may have myocardial protective properties in patients with ischaemic heart disease.
Xenon Xenon is an inert, odorless, noble gas which is manufactured from the distillation of air. Unlike other volatile agents, it has no occupational or environmental hazards. Its high cost, as well as the need to use scavenging with a recycling system for its administration, has meant it is not routinely used for patients in the UK. Xenon’s low blood:gas partition coefficient of 0.115 ensures a more rapid onset and offset than sevoflurane, but it has a
MAC of 71%.30 It is not metabolised and is eliminated by the lungs. In addition, xenon is also not thought to be a trigger for malignant hyperthermia.30 Xenon produces less cardiovascular depression than other agents30,31 and, in animals, it has been shown not to worsen preexisting ventricular dysfunction and even reduces infarct size when used during reperfusion after coronary artery occlusion.30 Furthermore, it has the benefit of producing analgesia through antagonism at N-methyld-aspartate (NMDA) receptors and it has been shown to be neuroprotective in rats on CPB.30 However, its low solubility may lead to enhanced diffusion into enclosed gas spaces.28 During CPB, xenon anaesthesia produces a small increase in gas bubble size compared to nitrogen, but much smaller bubbles than nitrous oxide.28 Unfortunately, xenon is extremely expensive so there would be a need to scavenge and recycle the gas during CPB, making it technically challenging to administer and, as yet, an economically impractical option. Finally, although much lower than nitrous oxide, the high MAC of xenon might limit the oxygen concentration that could be used in the sweep gas through the oxygenator and so promote hypoxia.
Anaesthetic requirements on cardiopulmonary bypass During CPB, there is a risk of awareness due to pharmacokinetic variations such as haemodilution and drug sequestration in the CPB circuit - particularly with fentanyl.32 This is balanced by a reduction in protein binding, reduced elimination and hypothermia,9 all of which protect against awareness. As CPB continues, anaesthetic requirements fall.24 The uptake of volatile agents administered by the oxygenator is dependent on:9 • Blood:gas solubility: solubility in blood increases as temperature falls • Tissue:gas solubility: solubility in tissues increases as temperature falls • Oxygenator uptake: resulting in extracorporeal sequestration As is the case in the intact circulation, the uptake and elimination of volatile anaesthetic agents during CPB is inversely proportional to blood:gas solubility.9 While increasing gas flow to the oxygenator increases uptake of volatile agents, changes in pump flow rate have no impact on uptake – possibly due to a relatively small blood volume and large pump flow at the oxygenator.33 This is quite different from the intact circulation where cardiac output has a major impact on the pulmonary uptake of volatile anaesthetic agents.
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Benefits of using volatile anaesthetic agents on CPB A benefit of volatile agent anaesthesia is the simplicity of administering the agent and the fact that the concentration of administered volatile agent does not have to be adjusted for bodyweight. Additionally, the elimination of volatile agents is relatively independent of liver and renal function and offers a potentially predictable offset.34
Myocardial conditioning There is evidence from animal experiments that using volatile agent anaesthesia is associated with myocardial protection in the ischaemic heart through anaesthetic preconditioning.35 This phrase is adapted from the broader term, ischaemic preconditioning (IPC), whereby a period of mild ischaemia protects tissue against subsequent injury.8 Volatile anaesthetics have been shown to directly precondition or indirectly enhance IPC, resulting in cardioprotection against myocardial infarction, with the KATP channel playing a key role.36 There have been a number of randomized controlled trials (RCTs) comparing outcome from TIVA and volatile anaesthetics in humans undergoing cardiac surgery that have been subject to systematic review and metaanalysis. Landoni and colleagues found that the use of the desflurane and sevoflurane reduced the incidence of myocardial infarction in cardiac surgery patients by over 50% from 5.1% in those patients receiving TIVA to 2.4% (odds ratio (OR) 0.51 [95% confidence intervals (95% CI) 0.32-0.84]).37 Importantly, volatile anaesthesia was associated with a reduction in all-cause mortality from 1.6% in the TIVA group to 0.4% (OR 0.31 [95% CI 0.12-0.80]).37 In addition, volatile anaesthesia was associated with significantly less troponin release and requirement for cardiovascular support with positive inotropes and shorter durations of mechanical ventilation, intensive care unit and hospital stay compared to TIVA.37 Whilst the authors note that there were a number of limitations to their study and call for an adequately powered RCT, the meta-analysis would suggest that, compared to TIVA, the best evidence to date indicates that the use of volatile anaesthetics for cardiac anaesthesia is associated with sizeable reductions in important adverse outcomes from cardiac surgery.
Cerebral protection Anaesthetic drugs, such as barbiturates, propofol, xenon and most volatile anaesthetics, show neuroprotective effects against cerebral apoptosis, degeneration, inflammation and energy failure.31 Both propofol and
isoflurane have been shown to reduce cerebral metabolic demand for oxygen when EEG burst suppression is achieved. Whilst these effects are potentially beneficial, no effect of EEG burst suppression on neurological outcome has been demonstrated by either agent during hypothermic CPB.18 An important study by Yoshitani and colleagues38 examined the dose of propofol required to produce EEG burst suppression during normothermic CPB. They found that plasma propofol concentrations of the order of 2.2 µg.ml–1, when given with fentanyl, were associated with measurable EEG burst suppression. Interestingly, the plasma concentrations were considerably less than those needed to produce EEG burst suppression in non-cardiac patients. One RCT has shown that sevoflurane is associated with better short-term post-operative cognitive performance compared with propofol in on-pump cardiac surgery.39 However, currently, there is insufficient outcome evidence to support the use of volatile anaesthetic agents over TIVA to reduce cerebral dysfunction after CPB. If the pragmatic aspects of its delivery during CPB could be overcome then xenon might have a role as a neuroprotectant.
Vasodilation Systemic hypertension during CPB is dangerous as it places excessive stress on the aorta, which may precipitate aortic dissection or rupture at the cannulation sites. For this reason, vasodilation is commonly employed to control excessive hypertension. The vasodilatory effects of isoflurane can be used to control systemic hypertension during CPB, but usually require doses in excess of those required to produce anaesthesia.
Disadvantages of using volatile anaesthetic agents on CPB Whilst the use of volatile anaesthetic agents on CPB may reduce pharmacokinetic variability, their administration is not without technical problems. During CPB, both the gas and blood flow rates are altered independently to maintain the acid–base balance. Adjustment of these flows, particularly fresh gas flow, affects blood concentrations of anaesthetic agents by their impact on agent uptake at the oxygenator.40 Some oxygenators may, themselves, influence volatile agent uptake and elimination, depending on their composition – this has been demonstrated with isoflurane.41 Isoflurane is a vasodilator under the abnormal conditions of hypothermic CPB, but has no beneficial effect on systemic oxygen uptake.40 Comparatively, propofol also causes a fall in SVR, but reduces systemic oxygen uptake on hypothermic CPB.42 So, unlike isoflurane,
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McMullan et al. Table 2. Benefits of using volatile anaesthetic agents and total intravenous anaesthesia (TIVA). Volatile anaesthetic agents
TIVA
Cerebral protection Improved myocardial contractility after revascularisation Reduced myocardial infarction rates and reduced mortality
Cerebral protection Avoidance of inhalational agent uptake at the oxygenator Reduced systemic oxygen uptake on hypothermic cardiopulmonary bypass Free-radical scavenger benefits of propofol No need to ensure vaporiser correctly mounted on CPB machine
Does not rely on patent, connected, reliable venous access Avoids effects of haemodilution and alterations in concentration due to body mass
propofol may, in common with hypothermia, enhance organ protection.
TIVA versus volatile anaesthesia A survey published in 2005 showed that, amongst consultant members of the Association of Cardiothoracic Anaesthetists in the UK, there is roughly equal use of propofol and isoflurane for the maintenance of anaesthesia on CPB.43 This highlights a slightly increased usage of volatile agents for the maintenance of anaesthesia on CPB compared with the previous national survey in 1993 when usage was reported by only approximately one third of respondents.44 This reversion from TIVA back to a volatile technique may reflect an increasing awareness by cardiac anaesthetists of their potential to precondition the myocardium. Propofol is known to have free radical scavenging properties,34 but there is no convincing evidence that it specifically confers myocardial protection. Unlike volatile anaesthetics, it does not appear to have any effect on mitochondrial potassium channels.18 Additionally, myocardial contractility following coronary revascularisation is better preserved in patients receiving volatile anaesthesia than those with propofol.45,46 Both propofol and all the volatile agents apart from xenon cause vasodilatation with a reduction in SVR. The potential benefits of each method are presented in Table 2.
The future It is important to emphasise that many of the studies to date on administering volatile anaesthetic agents during CPB have been conducted on animals or invitro and, therefore, are not directly applicable to patients undergoing CPB. Future work is needed to determine the administered concentrations of volatile anaesthetic agent during CPB that are sufficient to ensure anaesthesia and also give maximum myocardial and cerebral protection. With regard to myocardial protection during cardiac surgery, an adequately powered, randomized, controlled study is
required to confirm that volatile anaesthesia results in less myocardial infarction and lower mortality than TIVA. Additionally, the development of emulsified volatile agents, such as isoflurane, for intravenous administration might circumvent the problem of administering volatile anaesthetic agents through the oxygenator on CPB.47 Furthermore, studies on the uptake of volatile agents administered through the various oxygenators that are currently in use and the impact this apparatus has on plasma concentrations of volatile agents would help to clarify the clinical use of volatile agents during CPB.
Conclusion Since the foundation of CPB, volatile anaesthetic agents have been used to maintain anaesthesia. However, their use during CPB fell out of favour in the 1990s because of the increasing popularity of TIVA for cardiac anaesthesia. In recent years, there has been a move back to volatile anaesthesia during CPB. Most probably, the reason for this resurgence of use is anaesthetic preconditioning of the myocardium by volatile anaesthetic agents and an associated improved myocardial outcome and reduced mortality following cardiac surgery. However, the administration of volatile anaesthetic agents during CPB requires a sound understanding of the pharmacodynamics and pharmokinetics of volatile anaesthetic agents during CPB and overcoming a number of practical difficulties, not least of which are assessing depth and ensuring adequate anaesthesia. Acknowledgements The photographs were supplied by the Department of Medical Photography, Royal Infirmary of Edinburgh.
Declaration of conflicting interest The authors declare that there are no conflicts of interest.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
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References 1. Yentis SM, Hirsch NP, Smith GB. Anaesthesia and Intensive Care A-Z: An Encyclopedia of Principles and Practice, 4th ed. China: Churchill Livingstone, 2009. 2. Khan KS, Hayes I, Buggy DJ. Pharmacology of anaesthetics II: inhalation anaesthetic agents. Contin Educ Anaesth Crit Care Pain Epub ahead of print 25 Sept 2013. DOI: 10.1093/bjaceaccp/mkt038. 3. Gibbon JH. Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med 1954; 37: 171–185. 4. Long C. An account of the first use of sulphuric ether by inhalation as an anesthetic in surgical operations. South Med Surg J 1849; 3: 705–721. 5. Kirklin JW, Dushane JW, Patrick RT, et al. Intracardiac surgery with the aid of mechanical pump-oxygenator system (Gibbon type): report of eight cases. Proc Staff Meet Mayo Clin 1955; 30: 201–206. 6. Alston RP. Anaesthesia and cardiopulmonary bypass: an historical review. Perfusion 1992; 7: 77–88. 7. Slogoff S, Keats AS, Dear WE, et al. Occupational hazards of anaesthesia. Contin Educ Anaesth Crit Care Pain 2006; 6: 182–187. 8. Symonds JA, Myles PS. Myocardial protection with volatile anaesthetic agents during coronary artery bypass surgery: a meta-analysis. Br J Anaesth 2006; 97: 127– 136. 9. Mackay JH, Arrowsmith JE, eds. Core Topics in Cardiac Anesthesia, 2nd ed. Cambridge: Cambridge University Press, 2012. 10. Lim HS, Cho SH, Kim DK, et al. Isoflurane cracks the polycarbonate connector of extra-corporeal circuit: a case report. Korean J Anesth 2010; 58: 304–306. 11. Medtronic. Medtronic manual. User manual: Medtronic affinity fusion oxygenator, 2012. 12. Corbett TH, Cornell RG, Endres JL, et al. Birth defects among children of nurse-anesthetists. Anesthesiology 1974; 41: 341–344. 13. Hoerauf K, Harth M, Wild K, et al. Occupational exposure to desflurane and isoflurane during cardiopulmonary bypass: is the gas outlet of the membrane oxygenator an operating theatre pollution hazard? Br J Anaesth 1997; 78: 378–380. 14. Mierdl S, Byhahn C, Abdel-Rahman U, et al. Occupational exposure to inhalational anesthetics during cardiac surgery on cardiopulmonary bypass. Ann Thorac Surg 2003; 75: 1924–1927. 15. Hessel EA, Hill AG. Circuitry and cannulation techniques. In: Gravlee GP, Davis RF, Kurusz M, Utley JR, eds. Cardiopulmonary bypass: principles and practice, 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2000. 16. Lockwood GG, Sapsed-Byrne SM, Adams S. A comparison of anaesthetic tensions in arterial blood and oxygenator exhaust gas during cardiopulmonary bypass. Anaesthesia 1999; 54: 434–436. 17. Liu E, Dhara S. Monitoring oxygenator expiratory isoflurane concentrations and the bispectral index to guide isoflurane requirements during cardiopulmonary bypass. JCVA 2005; 19: 485–487.
18. Marks RRD. Editorial II: Which anaesthetic agent for maintenance during normothermic cardiopulmonary bypass? Br J Anaesth 2003; 90: 118–121. 19. Haworth WS. The development of the modern oxygenator. Ann Thorac Surg 2003; 76: S2216-S2219. 20. Myles PS, Leslie K, McNeil J, et al, for the B-Aware trial group. Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomised controlled trial. Lancet 2004; 363: 1757–1763. 21. Orser BA, Mazer CD, Baker AJ. Awareness during anesthesia. CMAJ 2008; 178: 185–188. 22. Phillips AA, McLean RE, Devitt JH, Harrington EM. Recall of intraoperative events after general anaesthesia and cardiopulmonary bypass. Can J Anaesth 1993; 40: 922–926. 23. Wang Y, Yue Y, Sun Y, et al. Investigation and analysis of incidence of awareness in patients undergoing cardiac surgery in Beijing, China. Chinese Medical Journal 2005; 118: 1190–1194. 24. Liu WH, Thorp TA, Graham SG, et al. Incidence of awareness with recall during general anaesthesia. Anaesthesia 1991; 46: 435–437. 25. Sebel PS, Bowdle TA, Ghoneim MM, et al. The incidence of awareness during anesthesia: a multicenter United States study. Anesth Analg 2004; 99: 833–839. 26. Dowd NP, Cheng DC, Karski JM, Wong DT, Munro JA, Sandler AN. Intraoperative awareness in fast-track cardiac anesthesia. Anesthesiology 1998; 89: 1068–1073. 27. Monk TG, Saini V, Weldon BC, et al. Anesthetic management and one-year mortality after noncardiac surgery. Anesth Analg 2005; 100: 4–10. 28. Grocott HP, Sato Y, Homi HM, et al. The influence of xenon, nitrous oxide and nitrogen on gas bubble expansion during cardiopulmonary bypass. Eur J Anaesthesiol 2005; 22: 353–358. 29. Hardman JG. Awareness during anaesthesia. Contin Educ Anaesth Crit Care Pain 2005; 5: 183–186. 30. Sanders RD. Xenon: no stranger to anaesthesia. Br J Anaesth 2003; 91: 709–717. 31. Schifilliti D, Grasso G, Conti A, et al. Anaesthetic-related neuroprotection: intravenous or inhalational agents? CNS Drugs 2010; 24: 893–907. 32. Skacel M, Knott C, Reynolds F, et al. Extracorporeal circuit sequestration of fentanyl and alfentanil. Br J Anaesth 1986; 58: 947–949. 33. Nussmeier NA, Moskowitz GJ, Weiskopf RB, et al. In vitro anesthetic washing and washout via bubble oxygenators: influence of anesthetic solubility and rates of carrier gas inflow and pump blood flow. Anesth Analg 1988; 67: 982–987. 34. Smith S, Scarth E, Sasada M. Drugs in Anaesthesia and Intensive Care, 4th ed. Oxford: Oxford University Press, 2011. 35. Warltier D, Kersten JR, Pagel PS, et al. Anesthetic preconditioning: serendipity and science. Anesthesiology 2002; 97: 1–3. 36. Swyers T, Redford D, Larson D. Volatile anesthetic induced preconditioning. Perfusion 2014; 29: 10–15. 37. Landoni G, Biondi‒Zoccai GGL, Zangrillo A, et al. Desflurane and sevoflurane in cardiac surgery: a
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McMullan et al. meta-analysis of randomized clinical trials. JCVA 2007; 21: 502–511. 38. Yoshitani K. Plasma propofol concentration and EEG burst suppression ratio during normothermic cardiopulmonary bypass. Br J Anaesth 2003; 90: 122–126. 39. Schoen J, Husemann L, Tiemeyer C, et al. Cognitive function after sevoflurane- vs propofol-based anaesthesia for on-pump cardiac surgery: a randomized controlled trial. Br J Anaesth 2011; 106: 840–850. 40. Alston RP, Anes FR, Tierney C, et al. Isoflurane and hypothermic cardiopulmonary bypass: vasodilation without metabolic effects. JCVA 1992; 6: 700–704. 41. Hickey S, Gaylor JD, Kenny GN. In vitro uptake and elimination of isoflurane by different membrane oxygenators. JCVA 1996; 10: 352–355. 42. Laycock GJ, Alston RP. Propofol and hypothermic cardiopulmonary bypass. Vasodilation and enhanced metabolic protection? Anaesthesia 1992; 47: 382–387.
43. Umashankar VD, K Wilkinson, DC Smith. Maintenance of anaesthesia during cardiopulmonary bypass in patients undergoing cardiac surgery – a national survey. Southampton 2006, www.acta.org.uk/store/docs/ abstracts/AbstractsCambridge230606.doc (2006, accessed 25 Oct 2013). 44. Patey R, Alston RP. Anaesthesia and cardiopulmonary bypass: a UK and Ireland survey. Perfusion 1993; 8: 313–319. 45. De Hert SG, Ten Broecke PW, Mertens E, et al. Sevoflurane but not propofol preserves myocardial function in coronary surgery patients. Anesthesiology 2002; 97: 42–49. 46. Haroun-Bizri S, Khoury SS, Chehab IR, Kassas CM, Baraka A. Does isoflurane optimize myocardial protection during cardiopulmonary bypass? JCVA 2001; 15: 418–421. 47. Zhou C, Liu J. A novel intravenous general anesthetic — emulsified isoflurane: from bench to bedside. Front Med 2012; 6: 381–387.
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PRF0010.1177/0267659114531314PerfusionMcMullan et al.
Review
Volatile anaesthesia during cardiopulmonary bypass
Perfusion 1–11 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0267659114531314 prf.sagepub.com
V McMullan,1 RP Alston1 and J Tyrrell2
Abstract Since its inception, administering and ensuring anaesthesia during cardiopulmonary bypass has been challenging. Partly because of the difficulty of administering volatile agents during cardiopulmonary bypass, total intravenous anaesthesia has been a popular technique used by cardiac anaesthetists in the last two decades. However, the possibility that volatile agents reduce mortality and the incidence of myocardial infarction by preconditioning the myocardium has stimulated a resurgence of interest in their use for cardiac anaesthesia. The aim of this review is to provide an overview of the administration of volatile anaesthetic agents during cardiopulmonary bypass for the maintenance of anaesthesia and to address some of the practical issues that are involved in doing so. Keywords cardiopulmonary bypass; inhalational anaesthesia; volatile agents; awareness; oxygenator
Introduction Since its introduction into clinical practice over sixty years ago, cardiopulmonary bypass (CPB) has allowed surgery to be safely undertaken on the heart. Currently, around the world, several hundred thousand patients undergo heart surgery with CPB each year. However, since its inception, administering and ensuring anaesthesia during CPB has been challenging. One of the challenges is that the administration of volatile anaesthetic through the lungs is prevented by their exclusion from the circulation. In addition, the main clinical signs of the depth of anaesthesia, including heart rate, respiratory rate and systemic blood pressure, are rendered useless by CPB. Further hindrances to using volatile anaesthetic agents during CPB include the need for scavenging waste gases from the oxygenator’s exhaust to prevent occupational exposure of operating room staff from their potentially harmful effects and a reliance on the perfusionist to administer the volatile anaesthetic agent. Partly because of the difficulty of administering volatile agents during CPB, total intravenous anaesthesia (TIVA) has been a popular technique used by cardiac anaesthetists in the last two decades. However, the possibility that volatile agents reduce mortality and the incidence of myocardial infarction by preconditioning the myocardium has stimulated a resurgence of interest in
their use for cardiac anaesthesia. Therefore, the aim of this review is to provide an overview of the administration of volatile anaesthetic agents during CPB for the maintenance of anaesthesia and to address some of the practical issues that are involved in doing so.
Volatile anaesthetics A commonly used alternative name for volatile anaesthetic agents is ‘inhalational anaesthetic agents’. During CPB, these agents are not administered by inhalation so, for the purposes of this review, the term volatile
1Anaesthesia,
Critical Care and Pain Medicine, Royal Infirmary of Edinburgh, UK 2Perfusion, Royal Infirmary of Edinburgh, UK Corresponding author: RP Alston Department of Anaesthesia, Critical Care and Pain Medicine Royal Infirmary of Edinburgh 51 Little France Crescent Edinburgh EH16 4SA UK Email: [email protected]
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Table 1. Physical properties of volatile anaesthetic agents. Characteristics
Sevoflurane
Isoflurane
Desflurane
N2O
Xenon
Boiling point (°C) Blood:gas partition coefficient (37°C) Oil:gas partition coefficient (37°C) Minimum alveolar concentration (MAC) Metabolism (%)
59 0.68 47 2.0 5
48 1.4 91 1.15 0.2
23 0.4 26 6.0 0.02
−89 0.47 1.4 104 0
−108 0.12 1.9 71 0
anaesthetic agents will used to describe this group of anaesthetic drugs. Volatile anaesthetic agents are supplied as liquids that are vaporised or as compressed gases and administered into the gas that is then inhaled by the patient. The agent is then taken up by the blood and transported to the central nervous system where its action produces anaesthesia. However, during CPB, the lungs are largely isolated from the circulation, rendering them useless as a means of delivering volatile agents. In this situation, volatile agents are vaporised into the sweep gas supplied to the oxygenator where they are transferred to the blood flowing through the CPB machine and, so, to the brain. The ideal agent should be chemically stable in the presence of heat or light, have a long shelf-life, be nonflammable and be unable to support combustion. In addition, it should be non-corrosive and not adsorbed on to rubbers or plastics. The saturated vapour pressure of the agent should be high enough to be able to produce clinically useful concentrations of anaesthetic.1 A speedy onset and offset of anaesthesia is aided by a low blood:gas partition coefficient.2 Moreover, the agent should be sufficiently potent to produce anaesthesia at low inspired concentrations. Minimal alveolar concentration (MAC) is defined as the concentration at steady state of inhaled anaesthetic at one atmospheric pressure that prevents movement in response to a standard surgical midline incision in 50% of a test population and is used to compare the potency of different agents.2 The concept of MAC is irrelevant to CPB where blood concentrations of anaesthetic agent are more important. Currently, the most common volatile anaesthetic agents in use in the United Kingdom are sevoflurane, isoflurane, desflurane and nitrous oxide. Their physical properties are described in Table 1.2
History of volatile anaesthesia during CPB The technique of CPB was researched and developed in animals by Gibbon in the 1930s and introduced into clinical practice for heart surgery in 1953.3 At this time, general anaesthetic techniques for surgery were universally based on volatile agents. Diethyl ether (ether) had
been used for general anaesthesia for over a hundred years, having first been used for anaesthesia by a dentist, Crawford L Long, in 1842, but was only brought to public attention in 1846 by William TG Morton.4 When Kirklin wrote about Gibbon’s CPB machine in 1955, ether was the anaesthetic that was used.5 In his early experimental work with cats, Gibbon had described his CPB equipment and had noted difficulty in maintaining anaesthesia during CPB.6 To overcome this problem, he passed ether vapour through the oxygenator, so establishing, in 1937, the use of a volatile anaesthetic technique during CPB. An alternative to ether was cyclopropane which had been discovered in 1929 and was also popular in thoracic anaesthesia when CPB was introduced. Despite being explosive, cyclopropane was also used to maintain anaesthesia in the early years of CPB.6 Initial problems experienced with CPB in humans included haemolysis associated with the original disc/ bubble oxygenators and explosions due to contact between the ether or cyclopropane and the motors.1,6 For this reason, volatile anaesthesia was frequently lightened or even stopped when the patient was placed on CPB.6 This practice gradually fell out of fashion with the introduction of halothane in 1956, which was nonexplosive and, therefore, safe when used during CPB.6 However, halothane brought its own problems, including myocardial depression, arrhythmogenicity, myocardial resistance to defibrillation and jaundice.6 Since then, every new volatile agent that has been introduced into general anaesthetic practice has been applied to CPB. Isoflurane has been particularly popular, but, as discussed later, there have been concerns that it causes coronary steal and myocardial ischaemia.1 These findings were based on animal research and were subsequently proven to be unsubstantiated by outcome studies, such as the one by Slogoff and Keats.7 Despite this, disquiet over coronary steal was another motivator for the widespread adoption of TIVA for cardiac anaesthesia in the 1990s. Like new volatile agents previously introduced into cardiac anaesthesia, TIVA was embraced with little investigation into its effect on outcome from cardiac surgery. TIVA has remained popular over the last 20 years, but, recently, there has been a resurgence of interest in the use of volatile agents during CPB. This is
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Figure 1. Position of vaporiser within cardiopulmonary bypass circuit.
because current best evidence indicates that volatile anaesthetic agents precondition the myocardium, thus, reducing the incidence of myocardial infarction and mortality associated with heart surgery.8
Administration of volatile anaesthetics during cardiopulmonary bypass During CPB, the circulating blood bypasses the lungs and their function is mechanically replaced by an oxygenator. Volatile anaesthetics may be administered by placing an anaesthetic vaporiser into the sweep gas supply to the oxygenator. Through a mechanism similar to that employed by the lungs, the agent diffuses in the oxygenator from the sweep gas into the blood which then transports it to the brain (Figure 1). When bubble oxygenators were used, there was a direct interface between gas and blood so that the transfer of
volatile anaesthetic was very efficient. However, bubble oxygenators have been superseded by membrane oxygenators as these generate far fewer gaseous microemboli9 and the transfer characteristics of modern membrane oxygenators are much more limited than the lungs or bubble oxygenators. For this reason, a relative overpressure concentration of the volatile anaesthetic agent has to be applied compared to that which is required when administered by inhalation into the lungs so as to ensure the adequate transfer across the membrane of the oxygenator and, so, a sufficient depth of anaesthesia. Moreover, the transfer characteristics of oxygenators differ, depending on the materials from which they are constructed, so that the degree of overpressure required to speed up achieving sufficient levels of anaesthesia varies from oxygenator to oxygenator. For anaesthetists who use a volatile technique during CPB, this needs to be carefully considered when a new oxygenator is introduced into their institution.
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filling with the anaesthetic agent eliminates the risk of damage resulting from potential spillages.
The effect of volatile anaesthetics on oxygenator gas transfer The gas transfer characteristics of most microporous polypropylene oxygenator membranes are not significantly affected by the presence of volatile anaesthetic agents. However, manufacturers’ guidelines specify that, above concentrations of 1.3% and 2.6% for isoflurane and sevoflurane, respectively, adjustments of inspired oxygen concentration and gas flow rates may be needed to achieve the desired gas transfer performance.11
Responsibility for administering volatile agents during cardiopulmonary bypass
Figure 2. Isoflurane vaporiser placed within cardiopulmonary bypass circuit.
Choice of vaporiser The choice of vaporiser on CPB is probably unimportant, but logic would dictate that the make and model of vaporiser should be the same as that used on the anaesthetic machine. Thus, there is shared knowledge about their use among operating room personnel. Whichever vaporiser is mounted on the CPB machine, there needs to be ready access to additional anaesthetic agent and the appropriate filler for the vaporiser in case it becomes exhausted.
Positioning of vaporiser Care should be taken to position the vaporiser on the CPB machine where it is clearly visible so that its filling level can be observed to ensure that it contains sufficient agent (Figure 2). The level of anaesthetic agent within the vaporiser needs to be monitored throughout the case. The vaporiser should be full and turned on before the patient is established on CPB to prevent awareness. Additionally, incorrect mounting on the back bar can result in the loss of the sweep gas before it enters the oxygenator, resulting in inadequate depth of anaesthesia, with patient awareness, hypoxia and hypercapnia. Filling a vaporiser on a CPB machine is not without hazard. Spillage of isoflurane onto the oxygenator causes cracking of the polycarbonate casing, so it is essential to position the vaporiser away from the oxygenator.10 Removing the vaporiser from the CPB machine before
In some countries, such as Australia and France, anaesthetists are directly responsible for the conduct of CPB so, often, they simultaneously manage the administration of volatile anaesthetics. However, in the majority of countries around the world, non-medically qualified perfusionists, who have no anaesthetic training, manage the CPB machine and often undertake the practical administration of volatile anaesthetics during CPB. Nevertheless, most anaesthetists would believe that they, rather than perfusionists, have responsibility for ensuring that the patient is anaesthetised throughout surgery and, therefore, that it is they who should ensure that the vaporiser is adequately filled, connected in series in the sweep gas supply to the oxygenator, set at an appropriate concentration and that the monitoring of volatile agent concentration is connected. Whoever is practically administering the anaesthetic agent, there needs to be close co-operation and communication between the anaesthetist and the perfusionist during CPB.
Scavenging There are concerns about the polluting effects of volatile anaesthetic agents on the atmospheric ozone and on operating theatre staff, including a suggestion of a higher rate of spontaneous abortion among female anaesthetists exposed to anaesthetic gases and a higher incidence of congenital abnormalities in children of anaesthetists.12 Therefore, systems that reduce occupational exposure to volatile anaesthetic agents are recommended and, during CPB, this is done with a scavenging system at the oxygenator gas exhaust outlet (Figures 3 & 4).13,14 However, care needs to be taken with such systems as, if excessive negative pressures are generated by a scavenging system then, consequently, these can produce a negative pressure gradient across membrane
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Figure 3. Scavenging system at the oxygenator gas exhaust outlet.
Figure 4. Anaesthetic gas scavenging system.
oxygenators, which may result in disruption of the oxygenator membrane. Therefore, it has been recommended that this pressure gradient be monitored to avoid oxygenator failure.15 As no specific proprietary equipment exists for these purposes, scavenging systems need to be constructed individually, bearing in mind the potential risks of using such systems. (Figure 3)
Monitoring depth of anaesthesia Clinical signs. During CPB, the clinical signs of the depth of anaesthesia are, for the most part, absent. Cardiovascular signs that might indicate light levels of
anaesthesia, such as hypertension and tachycardia, are diminished. Possibly because of haemodilution when the prime mixes with the circulating blood volume, hypotension commonly occurs at the onset of CPB. Whilst the hypotension gradually resolves during CPB, it renders systemic arterial pressure useless as an indication of the depth of anaesthesia. For the duration of aortic cross-clamping on CPB, the heart is isolated from the circulation and made asystolic with cardioplegia so the heart rate cannot be used a sign of the depth of anaesthesia during this time. In addition, many patients undergoing coronary artery bypass graft (CABG) surgery with CPB are receiving heavy beta-adrenergic blockade. Therefore, tachycardia does not occur, even if a patient’s depth of anaesthesia is light, so the heart rate is unreliable for detecting awareness. Patient movement in response to noxious stimuli is a sign of light anaesthesia and is completely obliterated by neuromuscular blocking (NMB) agents. Many anaesthetists use large doses of long-acting NMB agents, such as pancuronium, for cardiac anaesthesia and, consequently, this contributes to difficulty in detecting light levels of anaesthesia. One pragmatic approach that has been employed by one of the authors for over two decades is to use short- or medium- rather than long-acting NMB agents, in the form of rocuronium, to allow detection of excessive lightening of the level of anaesthesia by patient movement. Clinical experience indicates that patient movement is most likely to occur during the rewarming phase of CPB when the brain rewarms more rapidly than the rest of the body. If physical movement occurs then the anaesthetist needs to take prompt action to deepen the level of anaesthesia and administer additional NMB agent to protect the patient from self-harm in their vulnerable situation. Oxygenator exhaust concentrations. As clinical signs of the depth of anaesthesia are of no value on CPB, alternative means of determining when a sufficient depth of anaesthesia has been achieved are important. In patients receiving a volatile anaesthetic agent, end-tidal measurements of its concentration have long been used as an estimate of blood and, therefore, brain concentration. This measurement is then compared to the MAC for that agent to help assess the adequacy of anaesthesia. End-tidal measurement can also be used to ensure that the agent is actually being delivered to the patient; for example, if the vaporiser becomes exhausted of agent during a long CPB run. In an analogous situation to end-tidal levels, concentrations of volatile anaesthetics in the gas exhausted from the oxygenator should represent concentrations in the blood and, so, the brain. A small study has shown that the oxygenator exhaust gas tension is a
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reliable measure of blood isoflurane tension.16 Therefore, monitoring anaesthetic concentrations in the oxygenator exhaust gas may be a useful adjunct to monitoring the depth of anaesthesia during CPB.17 However, there is no established equivalent to MAC that exists for volatile anaesthetic agents measured in the oxygenator exhaust.18 There is a further problem in that present day oxygenators are not as efficient as the lungs in transferring volatile anaesthetic agents. They, like the lungs, must have a large surface area and be highly permeable to ensure efficient gas exchange. This has been aided by microporous hollow-fibre oxygenators,19 but different oxygenators have different and undefined transfer characteristics which affect the transfer of the volatile agent. Furthermore, systemic hypothermia, which is commonly induced during CPB, diminishes the requirement for anaesthesia and, thus, the concentration of volatile agent required to maintain anaesthesia. So, whilst monitoring oxygenator exhaust levels of anaesthetic agent can be used to ensure that the volatile agents are actually being delivered to the patient, the levels that constitute adequate anaesthesia during the induction of hypothermia, stable hypothermia and rewarming phases of CPB are unclear. Electroencephalographic monitors. Electroencephalographic (EEG) monitoring has been used in patients undergoing CPB in the hope of detecting early cerebral ischaemia. The raw EEG can provide an indication of the depth of anaesthesia as, when burst suppression occurs, one can be assured that there is insufficient cerebral activity to allow awareness. Processed EEGs allow a more basic examination of the brain’s electrical activity, such as the spectral edge, to judge the depth of anaesthesia. More recently, proprietary depth of anaesthesia monitors that are based on processed EEG, such as bispectral index (BIS) and Entropy, have helped to assess the depth of anaesthesia during CPB. However, the use of advanced methods is limited, particularly in cardiac anaesthesia, as measurements of the depth of anaesthesia do not reflect the synergistic sedative effects of opioids. The B-Aware trial did include high-risk cardiac surgery and off-pump CABG patients in their study group, but did not specifically differentiate between patients on- and off- CPB and, therefore, the value of BIS in the specific setting of CPB was not demonstrated.20 In addition, systemic hypothermia is sometimes used during CPB for organ protection, which has profound effects on the electrical activity of the brain to such an extent that it ceases at about 29oC.6 This impact of hypothermia complicates the interpretation of the effects of anaesthetic agents on EEG and it is unclear how it affects the interpretation of the depth of anaesthesia monitors such as BIS or Entropy.
Insufficient and excessive anaesthesia There is an increased incidence of awareness in patients undergoing cardiac surgery. This is due to several risk factors, including the nature of surgery, limited haemodynamic reserve, the use of muscle relaxants and equipment failure with inadequate delivery of anaesthetic agent, whether inhalation or intravenous.21 Undoubtedly, a proportion of awareness, explicit or implicit, is not reported following surgery and this is precluded by post-operative delirium and cognitive dysfunction which are common in cardiac surgery patients. Awareness with recall has been reported between 1.1-4.7% of patients undergoing CPB22,23 compared with 0.1-0.2% undergoing non-cardiac surgery.24,25 The true incidence in the UK will be clearer after the publication of the findings of the 5th National Audit Project of the Royal College of Anaesthetists and the Association of Anaesthetists of Great Britain and Ireland concerning accidental awareness during general anaesthesia. However, clearly, the incidence of awareness is lowest when there is conscientious and continual administration of anaesthetic agent before, during and after CPB.26 Despite the importance of maintaining an adequate depth of anaesthesia on CPB to prevent awareness, there are potential risks of giving too much anaesthetic. Along with systemic hypotension, cumulative deep hypnotic time has been shown to have an independent effect on mortality in the setting of non-cardiac surgery.27 It is uncertain whether this is applicable to patients on CPB and, if it is, what constitutes excessive depth of anaesthesia with a volatile anaesthetic agent during CPB.
Different volatile anaesthetic agents Nitrous oxide, as discussed below, has rarely been used during CPB because of its physical properties. Currently, the most commonly used volatile agents during CPB are sevoflurane and isoflurane. Xenon is not used clinically in the UK because of its extremely high cost, but will be discussed because of its interesting properties.
Nitrous oxide Despite being an analgesic, the use of nitrous oxide for the maintenance of anaesthesia during CPB is potentially dangerous. Nitrous oxide is highly insoluble in blood and has the capability to enlarge air bubbles, which can cause gaseous emboli to expand.28 For this reason, nitrous oxide is avoided in cardiac anaesthesia during bypass and after weaning from bypass. Although today’s membrane oxygenators generate far fewer gaseous microemboli compared with the old bubble
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oxygenators, they remain common during open heart surgery and nitrous oxide will worsen their adverse effects.9
Isoflurane and sevoflurane Sevoflurane and isoflurane are fluorinated ethers which are supplied as liquids. They are non-flammable and non-corrosive although isoflurane dissolves certain plastics. Sevoflurane has a low blood:gas partition coefficient of 0.68, resulting in a rapid onset and offset of anaesthesia and has a MAC of about 2.0.2 As with other volatile agents, it is distributed to organs with a high blood flow, such as the brain first and later to less-well perfused organs. About 5% of sevoflurane is metabolised by the liver while the rest is excreted by the lungs in the non-CPB setting. Compared to sevoflurane, isoflurane has a higher blood:gas partition coefficient of 1.4, resulting in a slightly slower onset of action.2 It has a MAC of 1.15 due to its high oil:gas partition coefficient and only 0.2% of the drug is metabolised in the liver.29 All fluorinated agents reduce cardiomyocyte calcium influx, causing depressed cardiac contractility and cardiac output.2 A reduction in systemic vascular resistance (SVR) due to vasodilatation is greatest with isoflurane and sevoflurane. These agents depress sympathetic activity although a compensatory tachycardia in response to vasodilatation is more commonly seen with isoflurane.9 Older volatile agents, particularly halothane, were responsible for frequent dysrhythmias potentiated by acidosis, hypokalaemia, hypocalcaemia and sensitisation of the myocardium to catecholamines.6 These adverse effects are less common with newer volatile agents. Most agents induce a degree of coronary vasodilation, but isoflurane demonstrates a phenomenon known as coronary steal in animal models. This is the diversion of blood from poorly perfused areas of myocardium to those already adequately perfused by coronary arteriolar vasodilatation. Despite this finding, the association of coronary steal with isoflurane has not been demonstrated in humans and, as discussed later, isoflurane may have myocardial protective properties in patients with ischaemic heart disease.
Xenon Xenon is an inert, odorless, noble gas which is manufactured from the distillation of air. Unlike other volatile agents, it has no occupational or environmental hazards. Its high cost, as well as the need to use scavenging with a recycling system for its administration, has meant it is not routinely used for patients in the UK. Xenon’s low blood:gas partition coefficient of 0.115 ensures a more rapid onset and offset than sevoflurane, but it has a
MAC of 71%.30 It is not metabolised and is eliminated by the lungs. In addition, xenon is also not thought to be a trigger for malignant hyperthermia.30 Xenon produces less cardiovascular depression than other agents30,31 and, in animals, it has been shown not to worsen preexisting ventricular dysfunction and even reduces infarct size when used during reperfusion after coronary artery occlusion.30 Furthermore, it has the benefit of producing analgesia through antagonism at N-methyld-aspartate (NMDA) receptors and it has been shown to be neuroprotective in rats on CPB.30 However, its low solubility may lead to enhanced diffusion into enclosed gas spaces.28 During CPB, xenon anaesthesia produces a small increase in gas bubble size compared to nitrogen, but much smaller bubbles than nitrous oxide.28 Unfortunately, xenon is extremely expensive so there would be a need to scavenge and recycle the gas during CPB, making it technically challenging to administer and, as yet, an economically impractical option. Finally, although much lower than nitrous oxide, the high MAC of xenon might limit the oxygen concentration that could be used in the sweep gas through the oxygenator and so promote hypoxia.
Anaesthetic requirements on cardiopulmonary bypass During CPB, there is a risk of awareness due to pharmacokinetic variations such as haemodilution and drug sequestration in the CPB circuit - particularly with fentanyl.32 This is balanced by a reduction in protein binding, reduced elimination and hypothermia,9 all of which protect against awareness. As CPB continues, anaesthetic requirements fall.24 The uptake of volatile agents administered by the oxygenator is dependent on:9 • Blood:gas solubility: solubility in blood increases as temperature falls • Tissue:gas solubility: solubility in tissues increases as temperature falls • Oxygenator uptake: resulting in extracorporeal sequestration As is the case in the intact circulation, the uptake and elimination of volatile anaesthetic agents during CPB is inversely proportional to blood:gas solubility.9 While increasing gas flow to the oxygenator increases uptake of volatile agents, changes in pump flow rate have no impact on uptake – possibly due to a relatively small blood volume and large pump flow at the oxygenator.33 This is quite different from the intact circulation where cardiac output has a major impact on the pulmonary uptake of volatile anaesthetic agents.
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Benefits of using volatile anaesthetic agents on CPB A benefit of volatile agent anaesthesia is the simplicity of administering the agent and the fact that the concentration of administered volatile agent does not have to be adjusted for bodyweight. Additionally, the elimination of volatile agents is relatively independent of liver and renal function and offers a potentially predictable offset.34
Myocardial conditioning There is evidence from animal experiments that using volatile agent anaesthesia is associated with myocardial protection in the ischaemic heart through anaesthetic preconditioning.35 This phrase is adapted from the broader term, ischaemic preconditioning (IPC), whereby a period of mild ischaemia protects tissue against subsequent injury.8 Volatile anaesthetics have been shown to directly precondition or indirectly enhance IPC, resulting in cardioprotection against myocardial infarction, with the KATP channel playing a key role.36 There have been a number of randomized controlled trials (RCTs) comparing outcome from TIVA and volatile anaesthetics in humans undergoing cardiac surgery that have been subject to systematic review and metaanalysis. Landoni and colleagues found that the use of the desflurane and sevoflurane reduced the incidence of myocardial infarction in cardiac surgery patients by over 50% from 5.1% in those patients receiving TIVA to 2.4% (odds ratio (OR) 0.51 [95% confidence intervals (95% CI) 0.32-0.84]).37 Importantly, volatile anaesthesia was associated with a reduction in all-cause mortality from 1.6% in the TIVA group to 0.4% (OR 0.31 [95% CI 0.12-0.80]).37 In addition, volatile anaesthesia was associated with significantly less troponin release and requirement for cardiovascular support with positive inotropes and shorter durations of mechanical ventilation, intensive care unit and hospital stay compared to TIVA.37 Whilst the authors note that there were a number of limitations to their study and call for an adequately powered RCT, the meta-analysis would suggest that, compared to TIVA, the best evidence to date indicates that the use of volatile anaesthetics for cardiac anaesthesia is associated with sizeable reductions in important adverse outcomes from cardiac surgery.
Cerebral protection Anaesthetic drugs, such as barbiturates, propofol, xenon and most volatile anaesthetics, show neuroprotective effects against cerebral apoptosis, degeneration, inflammation and energy failure.31 Both propofol and
isoflurane have been shown to reduce cerebral metabolic demand for oxygen when EEG burst suppression is achieved. Whilst these effects are potentially beneficial, no effect of EEG burst suppression on neurological outcome has been demonstrated by either agent during hypothermic CPB.18 An important study by Yoshitani and colleagues38 examined the dose of propofol required to produce EEG burst suppression during normothermic CPB. They found that plasma propofol concentrations of the order of 2.2 µg.ml–1, when given with fentanyl, were associated with measurable EEG burst suppression. Interestingly, the plasma concentrations were considerably less than those needed to produce EEG burst suppression in non-cardiac patients. One RCT has shown that sevoflurane is associated with better short-term post-operative cognitive performance compared with propofol in on-pump cardiac surgery.39 However, currently, there is insufficient outcome evidence to support the use of volatile anaesthetic agents over TIVA to reduce cerebral dysfunction after CPB. If the pragmatic aspects of its delivery during CPB could be overcome then xenon might have a role as a neuroprotectant.
Vasodilation Systemic hypertension during CPB is dangerous as it places excessive stress on the aorta, which may precipitate aortic dissection or rupture at the cannulation sites. For this reason, vasodilation is commonly employed to control excessive hypertension. The vasodilatory effects of isoflurane can be used to control systemic hypertension during CPB, but usually require doses in excess of those required to produce anaesthesia.
Disadvantages of using volatile anaesthetic agents on CPB Whilst the use of volatile anaesthetic agents on CPB may reduce pharmacokinetic variability, their administration is not without technical problems. During CPB, both the gas and blood flow rates are altered independently to maintain the acid–base balance. Adjustment of these flows, particularly fresh gas flow, affects blood concentrations of anaesthetic agents by their impact on agent uptake at the oxygenator.40 Some oxygenators may, themselves, influence volatile agent uptake and elimination, depending on their composition – this has been demonstrated with isoflurane.41 Isoflurane is a vasodilator under the abnormal conditions of hypothermic CPB, but has no beneficial effect on systemic oxygen uptake.40 Comparatively, propofol also causes a fall in SVR, but reduces systemic oxygen uptake on hypothermic CPB.42 So, unlike isoflurane,
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McMullan et al. Table 2. Benefits of using volatile anaesthetic agents and total intravenous anaesthesia (TIVA). Volatile anaesthetic agents
TIVA
Cerebral protection Improved myocardial contractility after revascularisation Reduced myocardial infarction rates and reduced mortality
Cerebral protection Avoidance of inhalational agent uptake at the oxygenator Reduced systemic oxygen uptake on hypothermic cardiopulmonary bypass Free-radical scavenger benefits of propofol No need to ensure vaporiser correctly mounted on CPB machine
Does not rely on patent, connected, reliable venous access Avoids effects of haemodilution and alterations in concentration due to body mass
propofol may, in common with hypothermia, enhance organ protection.
TIVA versus volatile anaesthesia A survey published in 2005 showed that, amongst consultant members of the Association of Cardiothoracic Anaesthetists in the UK, there is roughly equal use of propofol and isoflurane for the maintenance of anaesthesia on CPB.43 This highlights a slightly increased usage of volatile agents for the maintenance of anaesthesia on CPB compared with the previous national survey in 1993 when usage was reported by only approximately one third of respondents.44 This reversion from TIVA back to a volatile technique may reflect an increasing awareness by cardiac anaesthetists of their potential to precondition the myocardium. Propofol is known to have free radical scavenging properties,34 but there is no convincing evidence that it specifically confers myocardial protection. Unlike volatile anaesthetics, it does not appear to have any effect on mitochondrial potassium channels.18 Additionally, myocardial contractility following coronary revascularisation is better preserved in patients receiving volatile anaesthesia than those with propofol.45,46 Both propofol and all the volatile agents apart from xenon cause vasodilatation with a reduction in SVR. The potential benefits of each method are presented in Table 2.
The future It is important to emphasise that many of the studies to date on administering volatile anaesthetic agents during CPB have been conducted on animals or invitro and, therefore, are not directly applicable to patients undergoing CPB. Future work is needed to determine the administered concentrations of volatile anaesthetic agent during CPB that are sufficient to ensure anaesthesia and also give maximum myocardial and cerebral protection. With regard to myocardial protection during cardiac surgery, an adequately powered, randomized, controlled study is
required to confirm that volatile anaesthesia results in less myocardial infarction and lower mortality than TIVA. Additionally, the development of emulsified volatile agents, such as isoflurane, for intravenous administration might circumvent the problem of administering volatile anaesthetic agents through the oxygenator on CPB.47 Furthermore, studies on the uptake of volatile agents administered through the various oxygenators that are currently in use and the impact this apparatus has on plasma concentrations of volatile agents would help to clarify the clinical use of volatile agents during CPB.
Conclusion Since the foundation of CPB, volatile anaesthetic agents have been used to maintain anaesthesia. However, their use during CPB fell out of favour in the 1990s because of the increasing popularity of TIVA for cardiac anaesthesia. In recent years, there has been a move back to volatile anaesthesia during CPB. Most probably, the reason for this resurgence of use is anaesthetic preconditioning of the myocardium by volatile anaesthetic agents and an associated improved myocardial outcome and reduced mortality following cardiac surgery. However, the administration of volatile anaesthetic agents during CPB requires a sound understanding of the pharmacodynamics and pharmokinetics of volatile anaesthetic agents during CPB and overcoming a number of practical difficulties, not least of which are assessing depth and ensuring adequate anaesthesia. Acknowledgements The photographs were supplied by the Department of Medical Photography, Royal Infirmary of Edinburgh.
Declaration of conflicting interest The authors declare that there are no conflicts of interest.
Funding This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
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