Clinical management of patients requiring cardiopulmonary bypass (CPB) for cardiac surgery is complex, and the cardiac anesthesiologist is faced with many challenging management issues as surgical techniques evolve, such as altered cannulation sites, minimally invasive cardiac surgery, profound hypothermic circulatory arrest, and use of mechanical assistance.1 While busy confronting these challenges, the cardiac anesthesiologist must also ensure adequacy of the 3 basic facets of any anesthetic: amnesia, analgesia, and muscle relaxation.2 Objective assessment of these facets is challenging during CPB because traditional clinical variables used to assess “adequacy” of anesthesia, such as heart rate, arterial blood pressure, respiratory rate/pattern, and end-tidal carbon dioxide tension, are either not available or are directly controlled by the perfusionist. A unique aspect of this period is that critical aspects of anesthetic management, such as volatile anesthetic delivery, are transferred entirely to, or at best comanaged with, the perfusionist.
Institution of CPB induces many complex circulatory changes (pressure, flow, distribution) and profoundly alters major organ blood flow to the brain, heart, lung, kidneys, and liver.1 Unique pathophysiologic changes accompany these alterations in circulation and blood volume, such as hemodilution, hypothermia, and the systemic inflammatory response. These alterations profoundly influence the pharmacokinetics and pharmacodynamics of IV and volatile anesthetics.3,4 This systematic review focuses initially on the mechanics of CPB and resulting pathophysiologic alterations, influencing pharmacokinetics and pharmacodynamics of commonly used classes of anesthetics. We then attempt to synthesize high-quality studies and identify gaps in the literature pertaining to the proper maintenance of amnesia, analgesia, and muscle relaxation in patients undergoing CPB. The literature search strategy is presented in the Appendix.
CARDIOPULMONARY BYPASS CIRCUITRY
The CPB circuit (Fig. 1) consists of a venous reservoir, membrane oxygenator, and centrifugal pump designed to drain venous blood and return oxygenated blood to the arterial system.5 Standard CPB circuits use roller pumps for suction, venting, and delivering cardioplegia and are typically equipped with a heat exchanger, filters, real-time blood gas monitors, pressure and flow monitors, and various safety mechanisms. CPB components may be coated with heparin, albumin, or other compounds designed to minimize damage to blood products and to potentially attenuate the systemic inflammatory response.6
During CPB, oxygen and volatile anesthetic are delivered via a membrane oxygenator inflow. Carbon dioxide and waste anesthetic gas are removed via an oxygenator exhaust port. It is important to note that anesthetic vaporizers are added to the CPB circuit by perfusionists after the equipment has been purchased and without any guidance from the manufacturer.7 This lack of standardization in anesthetic vaporizer integration into the CPB circuit may contribute to substantial variability in volatile anesthetic delivery within and between hospitals.
Differences in oxygenator design also influence volatile anesthetic delivery. Table 1 presents the 2 types of membrane oxygenators in common use. Microporous polypropylene (PPL) hollow-fiber membrane oxygenators function via capillary action and countercurrent gas exchange (Fig. 2).8,9 The hollow fibers are fragile, and these oxygenators are only rated by the Food and Drug Administration for a maximum of 6 to 8 hours of use.10,11 Longer durations may be associated with a decreased ability to oxygenate the patient and membrane “weeping,” which usually requires brief separating from CPB to replace the oxygenator. Consequently, PPL membranes are best suited for short-term applications. Although these membranes are the standard oxygenators used during CPB in the operating room, the risk of gas embolism also limits its safety.9 Poly-(4-methyl-1-pentene) (PMP) membrane oxygenators were developed more recently to address some of the limitations of PPL oxygenators. They are also called plasma-tight or diffusion oxygenators.12 The clinical advantages include stability for more than 6 to 8 hours, less risk of gas microembolism, and less plasma leakage across the membrane.11 Given their stability, PMP oxygenators are best suited for long-term applications, and they are used mainly during prolonged extracorporeal membrane oxygenation. Clinical ramifications of differences in CPB circuit or membrane oxygenator design are considered later.
Table 2 lists clinical factors influencing pharmacokinetic alterations during CPB. Previous reviews by Mets4 in 2000 and Hall3 in 2002 address these in detail. Herein, we provide a brief review and update with new information accumulated over the past decade. Table 3 presents an overview of important studies investigating pharmacokinetic changes observed during CPB.
Effects of Hemodilution
Hemodilution is a consequence of crystalloid or colloid volume priming of the CPB circuit. This decreases blood concentrations of all IV and volatile anesthetics on initiation of CPB.13–24 The choice of priming fluid may be important because anesthetics are less soluble in crystalloid and albumin than in blood.25,26
The amount of prime impacts degree of anesthetic dilution. Techniques to reduce transfusion, such as autologous priming,27–30 aim to minimize hemodilution by restricting volume of crystalloid or colloid. Similarly, minimal extracorporeal circulation (MECC) is a new technology that aims to reduce transfusion requirements and potentially attenuate the systemic inflammatory response.31,32 In short, MECC uses smaller CPB circuits (less blood-circuit interface), which require smaller priming volumes. “MECC” is a generic term, and each MECC circuit setup varies among individual perfusionists. MECC is not the standard of care in the United States because of the numerous clinical disadvantages of this technique, which include decreased safety (many safety devices are eliminated), inability to manipulate large volumes of fluid in and/or out of the patient, and sometimes lack of a volatile anesthetic vaporizer. Autologous priming and MECC (typical prime approximately 400 mL, in contrast to “standard” prime of 750–1000 mL) both decrease the volume of prime solution and may attenuate the effect of hemodilution on anesthetic blood concentrations. However, these techniques have only recently been introduced. Thus, their impact on anesthetic blood concentrations during CPB has not been adequately studied. Essentially, all the literature forming the basis of our understanding of the effects of hemodilution was published during the era of standard priming volumes (750–1000 mL). However, one study demonstrated that smaller priming volumes (300–360 mL vs 750–1000 mL) resulted in less hemodilution of fentanyl during pediatric cardiac surgery.33
Altered Plasma Protein Binding
Priming volume at onset of CPB decreases blood concentrations of albumin,17,18,33α1-acid glycoprotein,13 and red blood cells,3,14,25 all of which bind anesthetics. This is of particular relevance for IV drugs that are highly protein bound, with high hepatic extraction ratios or low therapeutic indices.34 Consequently, propofol, midazolam, and opioids exhibit increased free fractions of drug during CPB.17,18,20,22,33 The free unbound component of drug is what diffuses across the blood-brain barrier, producing anesthetic effect.35–37 The increased free fraction offsets the decrease in overall drug concentration from hemodilution (Fig. 3). Several studies have revealed that unbound drug concentrations are unaffected by initiation of CPB and in many cases may exceed pre-CPB levels, despite significant decreases in total drug concentration.18,20,22 Decreased hepatic and renal clearance may also contribute to higher levels of unbound drug.38,39 Thus, anesthetic depth may be preserved or even enhanced, despite decreases in total anesthetic blood concentration. Finally, given the substantial proportion of critically ill patients undergoing cardiac surgery, it is also important to consider the potential pharmacologic impact of hypoalbuminemia on concentrations of active, unbound drug. Higher levels of unbound propofol have been observed in critically ill patients with hypoalbuminemia,40 possibly resulting in decreased propofol requirements (Fig. 4).
Heparin, particularly in the large amounts required for CPB, also affects free drug blood concentrations by initiating the release of lipoprotein lipase and hepatic lipase, each of which hydrolyzes plasma triglycerides into nonesterified fatty acids.4,41 These bind competitively to plasma proteins, displacing protein-bound drugs and increasing free fraction of drug. This effect of heparin has been well described for many drugs,42–46 and amounts as low as 50 International Units have been shown to increase the free fraction of propranolol.45 This principle also likely applies to protein-bound anesthetics, with increasing free fractions potentially deepening anesthetic level. However, many of these studies were performed decades ago, and the clinical impact of heparin administration on modern anesthetics is unclear. Of note, protamine reverses heparin’s impact on unbound drug blood concentrations.23
Volume of Distribution
Drugs with a high volume of distribution such as propofol and fentanyl distribute widely throughout blood and tissues. A high volume of distribution likely attenuates the clinical impact of hemodilution on anesthetic blood concentrations because drug distributed into tissues will rapidly re-equilibrate with plasma concentrations after initiation of CPB. Re-equilibration occurs over the course of a few minutes and has been demonstrated for many anesthetic17,20 and nonanesthetic47,48 drugs.
Altered Drug Clearance
Drug clearance is profoundly affected by hypothermia. Animal studies reveal that enzymatic efficiency is impacted by changes in temperature.49,50 In humans, hypothermia-induced decreased Hoffman elimination occurs with cisatracurium51,52 and remifentanil.22 Degree of hypothermia also impacts rate of drug clearance.52,53 A decrease in body temperature of as little as 2°C may double the duration of neuromuscular blockade.54
Over the years, substantial change in the clinical management of hypothermia during CPB has occurred, with a shift toward “mild” hypothermia (“drifting” to 32–34°C range) and, to a lesser degree, normothermic CPB.55 Much of the literature forming the basis of our understanding of the pharmacokinetic impact of CPB was published before this change in practice (e.g., at colder temperature). In addition, the terms “mild,” “moderate,” “deep,” and “profound” hypothermia are often vaguely defined and vary across studies. Thus, the effects of hypothermia on drug clearance in contemporary clinical practice may not be as significant as initially reported at colder temperatures.
Drug clearance is also affected via altered organ perfusion/microcirculatory flow during CPB. Blood flow to the liver and kidney is decreased by hypothermic CPB.3,4 This is particularly relevant for drugs with high liver extraction ratios, such as propofol.13 However, these conclusions are based on data extrapolated from animal studies56,57 and indirect measurements of hepatic function in humans.58–60 Several studies have challenged these assumptions and suggest that normothermic and mild to moderate hypothermic CPB may have only minimal effects on hepatic blood flow and function.61–64 Thus, the clinical impact of contemporary temperature management practices on hepatic and renal perfusion/function may be less than previously thought.
Drug clearance after CPB is also affected, as prolonged elimination half-lives and elevated blood drug concentrations of propofol13,65 and midazolam66 have been reported. While the mechanism is unclear, reduced elimination resulting from hypothermia and/or altered organ perfusion/microcirculatory flow are commonly cited as potential causes.59
Initiation of nonpulsatile hypothermic CPB alters microcirculatory blood flow, potentially creating physiologic areas of hypoperfusion and acidosis.67 Basic drugs may become trapped in acidic cellular microenvironments and recirculate once perfusion improves and acidosis resolves.4 Thus, during hypothermic CPB, there is the potential for “trapping” of basic drugs and their “release” after separation from CPB. This hypothesis is based on an old study of deltoid muscle gas tensions demonstrating decreased perfusion of muscle during hypothermic CPB,67 and more current research on alterations in microvascular deltoid muscle blood flow during cardiac surgery supports these findings.68 However, neither of these investigations actually confirmed that basic drugs were trapped in these cellular microenvironments because they did not measure muscle drug concentrations.
Pulmonary blood inflow almost completely ceases during CPB yet continues via bronchial artery blood flow; thus the lungs are almost isolated from the systemic circulation. Opioids and neuromuscular blocking drugs are highly sequestered in the lungs during this period and are not metabolized.23,69–71 Consequently, resumption of ventilation and reinitiation of pulmonary blood flow allow these drugs to recirculate, and increased serum concentrations of fentanyl20 and sufentanil19 have been demonstrated during separation from CPB (Fig. 5).
Drug Sequestration by the Cardiopulmonary Bypass Circuit
Opioids,72 propofol,73–76 and volatile anesthetics8 bind tightly to the plastic components of the CPB circuit and membrane oxygenator. As much as 75% of administered propofol is absent from plasma after 120 minutes of a simulated in vitro CPB run.75 However, CPB circuits are now routinely “coated” with a variety of substances such as heparin,73 which decreases platelet adhesion, and phosphorylcholine,77 which may more closely mimic the vascular wall, in an attempt to decrease damage to blood elements and attenuate the systemic inflammatory response. In vitro analyses on the impact of these coatings on propofol have not demonstrated any effect on pharmacokinetics.23,77 There is a growing list of new “biocompatible circuit coatings”78–81 with unknown pharmacologic implications. Thus, additional advances in CPB technology may affect pharmacokinetics. Also, the amount of drug sequestration would be expected to decrease with MECC because of smaller circuit surface area and less blood-circuit interface; however, this has yet to be studied.
Systemic Inflammatory Response
CPB induces a profound systemic inflammatory response, leading to dysregulation of cytokines, interleukins, and the cytochrome P-450 enzymatic system responsible for liver drug clearance. In addition, downregulation of enzymatic systems located in the brain may reduce drug clearance and prolong anesthetic action centrally.3 MECC, corticosteroids,82 complement inhibitors,83 and other techniques used to reduce inflammation may impact anesthetic pharmacology by such attenuation, yet this has not been formally studied. The systemic inflammatory response induced by CPB is a broad topic beyond the scope of this review, and the reader is referred elsewhere.84–86 In general, the clinical impact of individual inflammatory mediators is poorly understood.3 By extension, the sum effect of the inflammatory response on pharmacokinetics is even less well defined. Interestingly, a recently published small (n = 14 animals) porcine model study hints at the potential ability of anesthetic technique to alter the systemic inflammatory response.87 Pigs administered isoflurane, in contrast to propofol, during CPB exhibited a greater increase in fluid extravasation from the intravascular to the interstitial space, resulting in dilution of interstitial fluid and a decrease in interstitial colloid osmotic pressure, implying that perhaps propofol is better than volatile anesthetics at systemic inflammatory response attenuation during CPB.
The use of volatile anesthetics during CPB was first described in 1974.88 In addition to the factors discussed above, the pharmacokinetics of volatile drugs are impacted by 3 additional factors: altered blood/gas partition coefficient,24,26,89–96 altered tissue solubility,90,97,98 and oxygenator design.8,9,12,89,97,99 An important consideration when evaluating clinical studies in this arena is how the volatile anesthetic was measured. One method measures plasma concentration, which requires storage at controlled temperature and transport to a laboratory. Rapid results are not available, preventing applicability for intraoperative management. Another method is to sample the membrane exhaust port (end-tidal anesthetic concentration [ETAC]), which may offer real-time data to help guide intraoperative management.
Altered Blood/Gas Partition Coefficient
Hemodilution and hypothermia are competing physiologic factors influencing volatile anesthetics by virtue of their opposite effects on the blood/gas coefficient (hemodilution decreases, hypothermia increases). During hypothermic CPB, they act to counterbalance each other.90 During rewarming, however, the blood/gas partition coefficient decreases.91 Regarding desflurane and isoflurane, substantial increases in temperature during rewarming (30.4–37.5°C), with small increases in hematocrit (21%–22%), resulted in the lowest blood/gas partition coefficient measured (approximately 75% of preinduction levels for all 3 drugs).91 This results in more rapid washin or washout of volatile anesthetic during separation from CPB and implies that anesthetic titration (changing levels) during hypothermia is slowed.100 However, slower titration of volatile anesthetic can be partially overcome by increasing the fresh gas flow in the CPB circuit.17,99 Practice variations regarding hemodilution and temperature management strategies will impact blood/gas partition coefficients of volatile anesthetics.
Altered Tissue Solubility
Hypothermia increases solubility of volatile anesthetics in tissues, such as the brain, resulting in increased anesthetic depth.4 However, with alterations in the blood/gas partition coefficient noted earlier, titration (changing levels) of volatile anesthetics occurs more slowly during hypothermic conditions,89,90,97,101 and it may take more time to reach a deeper anesthetic state.
Oxygenator design profoundly affects anesthetic uptake. Oxygenators either absorb volatile anesthetic8,99 or prevent passage of the agent altogether (Fig. 6).9,12 In vitro comparison of PPL and PMP membranes confirms that while volatile anesthetics cross the PPL membrane, virtually no volatile anesthetic diffuses across the PMP membrane.9 This finding has been confirmed using gas chromatographic measurement of blood isoflurane concentrations in vivo.12 While PMP oxygenators are widely used for extracorporeal membrane oxygenation given their superior stability to fragile PPL oxygenators, they may also be used during CPB in the operating room if total IV anesthesia is the planned technique, which is common throughout Europe. Despite such issues, manufacturers of membrane oxygenators (PPL or PMP) are not required to test the impact of their design on anesthetics; they are only required to ensure biocompatibility with membrane components.10 Consequently, the impact of membrane oxygenators on anesthetics may not be apparent until after the device comes to market.11
We are still far from a complete understanding of how anesthetics initiate and maintain the anesthetic state. This fact limits our knowledge of pharmacodynamic alterations induced by CPB. Furthermore, the relative impact of hypothermia alone or CPB on pharmacodynamic alterations cannot always be separated. Altered pharmacokinetics due to hypothermia or CPB and lack of an objective assessment of adequacy of anesthesia during this time also confound evaluation of anesthetic depth. Despite these issues, several studies indicate that hypothermia and impaired cerebral function resulting from pathophysiology associated with CPB play major roles in the pharmacodynamics of IV and volatile anesthetics (Table 4).
Hypothermia clearly impacts anesthetic requirements. Studies on the effect of temperature reveal that less propofol is required to maintain a constant bispectral index (BIS) level during normothermic CPB.102 Patients exposed to hypothermic CPB require even less propofol,23,103 suggesting that hypothermia increases its potency.14,15 Studies on volatile anesthetics assessing anesthetic depth with electroencephalography or ETAC report decreased anesthetic requirement during hypothermia15,104,105 and increased anesthetic requirement during rewarming.106,107 This has been consistently demonstrated in adult patients for sevoflurane106 and isoflurane,107,108 in pediatric patients,108,109 and in animals.110 One investigation in children measured isoflurane minimum alveolar concentration requirements and isoflurane lipid solubility and suggested that anesthetic solubility alone is not enough to explain the decreased minimum alveolar concentration requirement observed during cooling. These investigators postulate that their results imply a potential amnestic effect of hypothermia.108
Hypothermia induces both pharmacokinetic and pharmacodynamic alterations. Some investigators have attempted to control these pharmacokinetic changes to delineate the potential impact of hypothermia alone on pharmacodynamics, by assessing isoflurane lipid solubility, not blood concentration, yet this is challenging.108 In reality, it remains quite difficult to distinguish clinically whether changes in anesthetic depth are due to altered pharmacokinetics or pharmacodynamics (or both).
Hypothermia also confounds studies that rely on BIS monitoring to assess anesthetic depth because BIS independently decreases with hypothermia103,104,111–114 and increases during rewarming.14,17,107,114 It is unclear whether these electroencephalographic changes represent the anesthetic state or are an artifact of changing temperature. In addition, the response of BIS to changes in temperature is highly variable among patients.109,115–117 This information, along with the demonstration of decreased minimum alveolar concentration requirement during hypothermia,108,110 would propose that electroencephalographic changes in response to hypothermia may indeed reflect changes in anesthetic depth, potentially lending validity to studies reliant on electroencephalographic monitoring.
Hypothermia also impacts analgesia and the density of neuromuscular blockade. Analgesia may be affected via decreased morphine binding at opioid receptors under hypothermic conditions.118 Neuromuscular blockade density is enhanced during hypothermia; muscle strength is impaired by as much as 10% with each decreasing degree Celsius in the absence of muscle relaxant.54 Whether the result of pharmacokinetic or pharmacodynamic alterations (or both), studies clearly demonstrate that decreased doses of vecuronium119,120 and rocuronium121 are required during hypothermic CPB.
IMPAIRED CEREBRAL FUNCTION
Exposure to CPB alone (with or without hypothermia) has been implicated as a reason for decreased minimum alveolar concentration requirement. While the mechanism is unclear, impaired cerebral function as a consequence of CPB has been the focus of many animal studies.110,122–126 However, such observational studies have lacked control groups and report inconsistent results. Several human studies during hypothermic CPB implicate CPB as an independent factor responsible for decreased anesthetic requirements.103,107,127 Specifically, initiation of CPB decreases the magnitude of propofol requirements, and the effect of hypothermic CPB is significantly more than that of normothermic CPB.103 Isoflurane requirements are also reduced during hypothermic CPB107 and isoflurane requirements are reduced after, compared with before, hypothermic CPB.127
One randomized, controlled trial assessed minimum alveolar concentration of rats exposed to normothermic CPB.126 Ten rats were cannulated and exposed to CPB and compared with a control group that underwent sham cannulation without CPB. Although isoflurane requirements remained unchanged in the sham CPB group, minimum alveolar concentration after 20 minutes in the CPB group was 10% lower than pre-CPB measurements and remained below baseline at the last measurement 2 hours after CPB. This is consistent with a study in goats demonstrating a 20% decrease in minimum alveolar concentration requirements after CPB exposure.110
Other investigations have sought to compare anesthetic requirements in patients during CPB and off-pump coronary artery bypass patients to determine the potential hypnotic impact of CPB. One study showed no difference in propofol requirements between CPB and off-pump coronary artery bypass patients.128 However, the off-pump coronary artery bypass procedures took significantly longer, and equivalent propofol consumption was only noted after correcting for time. More recently, other investigators have compared CPB with off-pump coronary artery bypass procedures and found that less propofol is required during CPB to maintain a constant BIS.129 However, these investigators did not measure serum propofol concentrations and were unable to account for the effects of altered pharmacokinetics due to CPB.
Although it appears that anesthetic requirements decrease during CPB, the mechanism of such an effect remains unclear. Numerous models of CPB-induced neurologic injury, such as microembolic load, cerebral edema, brain inflammation, decreased brain cytochrome P-450 activity, or increased intracranial pressure, have all been invoked to explain why anesthetic requirements may decrease.3,130–132 New avenues of study have identified surgical trauma as a potential source of exaggerated and persistent neuroinflammation, perhaps leading to postoperative cognitive dysfunction in elderly patients.133,134 While the etiology of postoperative cognitive dysfunction is certainly multifactorial, the systemic inflammatory response observed during cardiac surgery has also been used to explain the frequent incidence of postoperative cognitive dysfunction in this surgical population.135
HOW DO THESE ALTERATIONS AFFECT ANESTHETIC MANAGEMENT?
To the novice, initiation of CPB is the start of a mandatory “downtime” for anesthesiologists, when workload appears to diminish. However, the experienced cardiac anesthesiologist appreciates that initiation of CPB begins a unique period in which management of the patient’s physiologic and anesthetic state is shared with the perfusionist. Given the pharmacokinetic and pharmacodynamic alterations discussed earlier, physiologic controversies related to appropriate mean arterial blood pressure, flow rates, degree of anticoagulation, and absence of traditional clinical variables used to assess adequacy of anesthesia, such as changes in heart rate, pulsatile blood pressure, and the de facto delegation of several key anesthetic processes such as volatile anesthetic delivery to the perfusionist, this should be appreciated as a period of maintained vigilance for the anesthesiologist. Unfortunately, ensuring that the 3 basic tenets of anesthesia are met (amnesia, analgesia, muscle relaxation) during CPB remains challenging.
ENSURING AMNESIA DURING CARDIOPULMONARY BYPASS
Ensuring amnesia requires an accurate assessment of anesthetic depth, which is quite complicated with or without CPB. The use of BIS (discussed later) remains controversial. Monitoring anesthetic depth based on autonomic signs is challenging during CPB because these signs are largely absent. However, hypertension during normal CPB flows may indicate that anesthetic depth or the degree of neuromuscular blockade is inadequate. Traditional methods of measuring ETAC are also impractical because of the minimal blood flow through the lungs during CPB. Several studies suggest measuring the oxygenator membrane exhaust gas for halogenated anesthetic as a surrogate for ETAC.12,90,97,106,107,136 However, this is not a standard practice. Consequently, routine monitoring of patients during CPB cannot ensure that adequate anesthesia to prevent awareness is being delivered or to exclude equipment malfunction such as cracked tubing or damaged vaporizers. With the use of total IV anesthesia during CPB, there is no real-time monitor of IV anesthetic serum concentration. Empiric dosing regimens based on target-controlled infusions are distorted by pharmacokinetic and pharmacodynamic alterations during CPB.18,21,22,53,119,137,138 In addition, cardiac patients may not tolerate traditional amnestic doses without adverse hemodynamic consequences. Finally, practitioners may be hesitant to use appropriate doses of anesthetics while separating from CPB because of perceived depressant effects on the myocardium.139,140
Thus, considering all the above, it may not be surprising that cardiac surgery patients exhibit an increased incidence of recall when compared with other surgical cohorts.141–148 Initial reports of awareness using a high-dose opioid technique during the early days of cardiac surgery were common, and the incidence was reported to be as high as 23%.149 High-dose opioid techniques blunt hemodynamic responses traditionally used to assess anesthetic depth without ensuring amnesia.150 A significant decrease in the incidence of awareness in cardiac surgery occurred once high-dose opioid techniques were supplemented with benzodiazepines or volatile anesthetics.151 More contemporary methods using balanced anesthetic techniques based on the combination of low- to moderate-dose opioids, benzodiazepines, volatile anesthetics, or propofol infusions have decreased the incidence of awareness during cardiac surgery to 0.2% to 2.3%.141,142,144–148 This incidence remains significantly higher than the reported rate in the general surgical population.144,152
However, the 5th National Audit Project on accidental awareness during general anesthesia in the United Kingdom and Ireland published simultaneously in Anaesthesia and the British Journal of Anaesthesia may change our thinking regarding awareness. The incidence of certain/probable and possible accidental awareness cases was much lower than previously reported (approximately 1:19,000). Although cardiac cases remained “high risk” (approximately 1:10,000), most of the reports involved either brief interruption of drug delivery caused by human error or technical problems or the use of intentionally low doses of anesthetic drugs in high-risk patients, such as those with cardiovascular instability. The full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home.
In North America, the perfusionist typically delivers volatile anesthetic during CPB. The use of volatile anesthetic during CPB was initiated approximately 20 years ago in an attempt to decrease administration of long-acting opioids and sedatives to allow patients to emerge more rapidly from anesthesia and persists, in part, due to the presumed clinical benefits of volatile anesthetic preconditioning.153,154 An additional factor perhaps favoring volatile anesthetics is the anecdotal reporting of a propofol “biofilm” or “foam” that may develop on the oxygenator membrane after long CPB runs or during low-flow CPB, prompting fears of oxygenator failure and leading to hesitation or even refusal by many perfusionists to deliver propofol directly through the CPB circuit (Robert Groom, MS, CCP, Maine Medical Center, personal communication, December 16, 2013; Joerge Ender, MD, Leipzig Heart Center, University of Leipzig, personal communication, December 19, 2013). However, there is the potential for biofilm development independent of whether propofol is administered IV or directly into the oxygenator. Despite these concerns regarding propofol, we were unable to find any case report(s) or original investigations regarding this potential problem. In contrast, 1 in vitro study supports the use of propofol during CPB, concluding that there is no effect of propofol on gas exchange properties of membrane oxygenators, even at high doses (Fig. 7).77 This study makes no mention of a propofol biofilm or foam accumulating on the membrane oxygenator. Of note, older CPB circuits may not promote adequate mixing. Thus, propofol delivered directly into the CPB circuit may float to the top of the reservoir.155 This can be avoided by delivering propofol IV during CPB.
In contrast to practice in North America, Europeans favor total IV anesthetic techniques during CPB. This preference has been driven by European Council Directive 93/42/EEC, which prohibits the routine use of volatile anesthetics while on CPB.156,157 This directive bans the supplementary incorporation of an anesthetic vaporizer into the extracorporeal circuit because this would add complementary safety and performance-related device features. France and Germany, for instance, use this directive to mandate that any modification performed on CPB circuits must pass a technical approval process to ensure device safety (Joerge Ender, MD, Leipzig Heart Center, University of Leipzig, personal communication, December 17, 2013). This becomes problematic because manufacturers of CPB circuits do not build them with vaporizers, requiring perfusionists to modify them.11 Thus, anesthesiologists in many European countries routinely administer propofol during CPB to avoid the device approval process (Joerge Ender, MD, Leipzig Heart Center, University of Leipzig, personal communication, December 17, 2013). Notably, the application of this directive to CPB circuits is variable across nations. For instance, the United Kingdom does not enforce it (Joerge Ender, MD, Leipzig Heart Center, University of Leipzig, personal communication, December 17, 2013).7 The combination of this directive and the literature regarding the presumed clinical benefits of volatile anesthetic preconditioning153,154 has prompted European practitioners to alternative approaches. For instance, one protocol uses MECC circuits to minimize drug sequestration and PMP membranes (prevent passage of volatile anesthetic) to maximize recirculation of tissue stores of sevoflurane accumulated before CPB in an attempt to achieve the potential benefits of volatile anesthetic preconditioning during CPB.156
In addition to variability in international practice, several hazards associated with the delivery of volatile anesthetic during CPB must be considered. Accumulation of toxic sevoflurane metabolites during CPB has been reported.158 Case reports also describe severe damage to the plastic components of the circuit by spillage of liquid volatile anesthetic (Fig. 8; video supplied on request).159–162Figure 9 demonstrates insertion of a vaporizer on a contemporary CPB machine well away from the plastic CPB components in an effort to reduce this potential hazard. However, there are no specific instructions from device manufacturers ensuring that vaporizers are placed in a safe position. Finally, scavenging systems should be connected to the membrane oxygenator exhaust to reduce occupational exposure to volatile anesthetic (Fig. 10).163,164 Notably, the Occupational Safety and Health Administration does not offer any recommendations for scavenging from the CPB apparatus.165
Guidelines from the medical community regarding occupational safety are also lacking. Several studies and organized initiatives regarding patient safety in the cardiac operating room and systematic reviews166–169 do not address occupational health and safety for operating room personnel.170 Similarly, these publications do not address safety with regard to occupational exposure to volatile drugs during CPB for health care providers. A recent anesthesiologist-led review provides commentary on equipment design and operating room layout yet does not provide design specifications for CPB circuits regarding anesthetic vaporizer placement or scavenging systems for waste anesthetic gas.171
The American Society of Extracorporeal Technology’s recently revised internal standards and guidelines for perfusion practice are the only guidelines available that recommend scavenging waste anesthetic gas and routine maintenance of anesthetic vaporizers.6 Notably absent are details regarding how vaporizers should be integrated into the circuit, scavenging system specifications, recommendations for titration of volatile or IV anesthetics, how and when anesthetic-related issues should be communicated to the anesthesiologist, monitoring adequacy of anesthetic delivery, or assessment of anesthetic depth.
THE BISPECTRAL INDEX
The BIS monitor (Aspect Medical Systems, Natick, MA) is the only U.S. Food and Drug Administration–approved monitor to assess the anesthetic state of the central nervous system. However, its use during cardiac surgery172 and in the general surgical population148 in preventing awareness is unreliable. Patients may report awareness, despite “appropriate” BIS levels (<60).143,173,174 However, in the absence of effect-site concentration monitors or a surrogate such as ETAC, the BIS monitor may have applicability in potentially reducing the incidence of awareness.141,173,175,176Table 5 outlines important studies evaluating the potential applicability of BIS in preventing awareness.
Additional potential clinical applications of BIS monitoring outside the CPB setting have recently been reviewed.149,172 These include more appropriate anesthetic dosing, potentially improving recovery times and facilitating fast-track techniques. Preventing anesthetic overdose and reducing hemodynamic instability from unnecessarily high anesthetic concentrations may also potentially decrease morbidity and mortality. In addition, the BIS monitor may have applicability as a monitor of cerebral ischemia (prevention of catastrophic neurologic events). However, BIS-guided anesthetic dosing has not been shown to decrease extubation/recovery time,177–180 improve morbidity or mortality,149,172,181–183 nor is it an effective monitor of cerebral ischemia.184–186 It may help alleviate postoperative delirium in older patients, by preventing too “deep” an anesthetic state (BIS values <20; noncardiac surgery).187–189
The American Society of Anesthesiologists Practice Advisory on Awareness and Brain Monitoring currently recommends that the decision to use a brain monitor should be made on a case-by-case basis and should not be considered the standard of care.190 In the United Kingdom, the National Institute for Health and Care Excellence recommends that BIS may be useful in guiding anesthetic dosing in patients at high risk for adverse consequences of anesthetics and that BIS is useful for total IV anesthesia.191 However, the National Institute for Health and Care Excellence also states that electroencephalographic-based monitors are not associated with a statistically significant reduction in intraoperative awareness in patients classified at high risk and that available evidence on the impact of these technologies in reducing awareness is limited.192 The American Society of Extracorporeal Technology’s recently revised internal standards and guidelines for perfusion practice recommend the routine use of cerebral oximetry yet do not address use of processed electroencephalographic monitors (BIS) or the assessment of anesthetic depth.6
END-TIDAL ANESTHETIC CONCENTRATION
When volatile anesthetics are used, ETAC may be clinically useful during CPB. This is not routine practice despite being tested and advocated by many investigators, demonstrating that monitoring of ETAC at the membrane exhaust port accurately reflects serum anesthetic concentrations.12,90,97,106,107,136 Others caution against this practice, reporting that exhaust gas concentrations do not correlate with serum concentrations.17 This may be due to room air admixture as a result of new safety mechanisms designed to prevent negative pressure across the oxygenator membrane.17 This conclusion was challenged by an accompanying editorial asserting that the protocol for measuring serum anesthetic concentration was flawed.193 While the sum of the literature advocates monitoring of ETAC during CPB, it is worth noting that evolving CPB circuit technology has the potential to impact the reliability of this practice.
ENSURING ANALGESIA DURING CARDIOPULMONARY BYPASS
While the focus of anesthetic studies during CPB has primarily been directed at amnesia, very little has been published regarding analgesia during CPB. Unlike amnesia, there is no potential monitor of “analgesic depth.”2 Lack of real-time monitoring of plasma drug concentrations forces anesthesiologists to rely on clinical signs of pain, such as tachycardia, hypertension, and tachypnea. These clinical signs are usually unreliable or absent before, during, and after CPB (pacemakers, vasoactive drugs, paralytic drugs). Thus, opioid dosing during CPB is empirically driven. In the past, high-dose opioid techniques likely provided some reliable degree of early postoperative analgesia. However, fast-track early extubation protocols using low-dose opioid supplementation are now the norm in clinical practice. Their implications for postoperative analgesia are complex and may vary with the type of opioid used, as well as adjuvant sedation used (e.g., potential opioid-sparing effects of dexmedetomidine) and other potential nonopioid drugs (e.g., nonsteroidal anti-inflammatory drugs).194,195
ENSURING MUSCLE RELAXATION DURING CARDIOPULMONARY BYPASS
Neuromuscular blockade during CPB may be desirable, yet there is no definitive evidence that it is absolutely required; therefore, there is wide variability in the practice of neuromuscular blockade during cardiac surgery.196–199 Historically, high-dose opioid techniques allowed practitioners to use high doses of long-acting nondepolarizing drugs because patients had return of motor function long before amnestic and analgesic drugs were metabolized. Current fast-track early extubation techniques and the potential association between awareness and neuromuscular blockade200 have encouraged practitioners to use less paralytic drug during CPB. Optimizing neuromuscular blockade becomes even more challenging in the face of the aforementioned pharmacokinetic and pharmacodynamic alterations due to CPB. If neuromuscular blockade is planned, careful dosing should be guided by peripheral nerve stimulation with a twitch monitor. It is important to note that muscle strength decreases substantially during hypothermia, even in the absence of muscle relaxants.54 This is likely to affect the amplitude of muscle twitches seen with peripheral nerve stimulation.
The unique pharmacokinetic and pharmacodynamic alterations associated with CPB, lack of traditional clinical signs of “adequate” anesthesia, and lack of a reliable monitor of anesthetic depth make the cardiac anesthesiologist’s job of ensuring amnesia, analgesia, and muscle relaxation during CPB difficult to impossible. Much of our knowledge is based on clinical investigations performed many years ago under much different clinical management strategies (profound hypothermia, profound hemodilution, no circuit coating) than exist today (normal to mild/moderate hypothermia, autologous priming, MECC, circuit coating). Further complicating clinical management is lack of any regulatory oversight regarding after-market modification of the CPB circuit by perfusionists or occupational health and safety concerns. Last, lack of consensus regarding how to deliver anesthetics during CPB is perhaps best highlighted by the difference in clinical practice between North American practitioners (with a strong preference for volatile anesthetics) and European practitioners (generally favoring total IV anesthesia).
Strategic areas for future research include evaluating the pharmacokinetic and pharmacodynamic alterations induced by modern CPB circuitry (smaller, coated) under near-normothermic conditions, clinical ramifications of neuroinflammation associated with CPB, and development of a reliable clinical monitor of anesthetic depth. Finally, regulatory oversight mechanisms need to be developed to standardize not only CPB circuitry but also after-market modifications.
Systematic Literature Review Search Strategy
We performed a systematic review of the effects of cardiopulmonary bypass on pharmacokinetics of anesthetic drugs and unintended awareness during cardiac surgery. A list of pertinent keywords was derived, and a PubMed database search was performed for each topic, anesthetic awareness and pharmacokinetics. To assess the feasibility of this technique, we began with the topic perceived to be more focused: anesthetic awareness and cardiac surgery. Search terms were “Cardiac Surgery” OR “Cardiopulmonary Bypass” AND Awareness OR Recall OR BIS AND Anesthesia NOT “General Anesthesia” NOT Epidural NOT “General Anesthesia” NOT Spinal NOT Epilepsy (12/11/13). Results of this search were reviewed, and titles and abstracts related to the topic were highlighted. Recently published, highly cited, and review articles were considered “high-yield” articles, and the PubMed “related citations” query was applied to each. Articles related to the topic highlighted during this round were added to the list. The “related citations” query was also applied to “high-yield” articles from this round. Any related articles identified during this final round were added to the list. Articles in languages other than English were excluded from our search.
A similar search strategy was used for pharmacokinetics. The only notable difference in technique was restricting the initial screen to articles published from 2000 to the present. Search terms were “Cardiac Surgery” OR “Cardiopulmonary Bypass” OR “Open Heart” AND Pharmacokinetics OR Pharmacodynamics AND Anesthesia OR Anesthetic NOT Cardioprotection NOT Epidural NOT Spinal NOT Non-Cardiac NOT Preconditioning NOT Cardioplegia NOT Transfusion, Filters: Publication date from 2000/01/01 to 2013/12/31; Humans; English (12/17/13).
The search on awareness and cardiac surgery yielded 1349 results. Titles and abstracts related to the topic narrowed the list to 54. Seven “high-yield” articles were identified in this round.149,172,176,179,201–203 As expected, there was significant overlap in studies found using the “related citations” query. However, 35 additional articles were identified. Five articles from during this round were considered “high yield,” and the “related citations” query was applied to each.141,143,175,181,182 Fifteen additional relevant studies were discovered and added to the total. In summary, 104 articles pertinent to the topic of anesthetic awareness during cardiac surgery were identified and obtained for full review.
The same systematic approach was then turned to pharmacokinetics and CPB. The initial screen yielded 1348 results. Titles and abstracts related to the topic narrowed the list to 113. Nine “high-yield” articles were identified in this round.3,4,14,17,18,51,96,103,120 The “related citations” query yielded 99 more articles. Five more “high-yield” articles were analyzed.7,193,204–206 Sixteen additional studies were identified. In summary, 228 articles pertinent to the topic of pharmacokinetics and CPB were identified and obtained for full review. Bibliographies of all articles obtained for review were used to identify seminal papers for historical context.
The search strategy and results are depicted in Figures 11 and 12.
Name: Aaron E. Barry, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Aaron E. Barry approved the final manuscript.
Name: Mark A. Chaney, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Mark A. Chaney approved the final manuscript.
Name: Martin J. London, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Martin J. London approved the final manuscript.
Dr. Martin London is the Section Editor for Perioperative Echocardiography and Cardiovascular Education for Anesthesia & Analgesia. This manuscript was handled by Dr. Steven L. Shafer, Editor-in-Chief, and Dr. London was not involved in any way with the editorial process or decision.
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