The burst-suppression pattern on the electroencephalogram (EEG) was first recognized in barbiturate- and ether-anesthetized dogs by Swank and Watson in 1949.1 There has since been considerable interest in examining both the physiological underpinnings and clinical implications of this EEG phenomenon. The purpose of this narrative review is to present a brief description of the purported mechanisms by which burst-suppression can occur and to provide a comprehensive review of the evidence to date regarding the potential neurological and neurocognitive benefits and harms of burst-suppression in various perioperative clinical settings.
DEFINITION AND PHYSIOLOGY
Burst-suppression is a continuous, quasiperiodic alteration between high-amplitude electrical activity, called “bursts,” and the isoelectric EEG, called “suppression.”2–4 Burst-suppression may result from a wide range of cerebral pathologies, including but not limited to anoxic or epileptic encephalopathy, drug intoxication, hemispheric stroke, and malignant intracranial hypertension.5–11 It may also be the consequence of metabolic activity suppression secondary to either anesthetic drugs or hypothermia.12,13
According to the American Clinical Neurophysiology Society (ACNS), “burst” is defined as slow oscillations (although occasionally they are fast oscillations) of high voltage with at least 4 phases (ie, crossing the midline ≥3 times) lasting for ≥0.5 seconds and up to 30 seconds.4 “Suppression” is a period with electrical activity of <10 µV lasting for ≥0.5 seconds, although the threshold definitions of <5 and <15 µV have also been used in other literature.4,14–16 As per ACNS, the term “burst-suppression” is used only when describing an EEG pattern of which 50% to 99% of the cortical EEG consists of suppression, while the term “discontinuous EEG” should instead be used if an EEG tracing contains <50% suppression. Thus, a 10-second period containing 6 seconds of suppression and 4 seconds of burst activity would be termed “burst-suppression with 60% suppression” (Figure 1). However, this terminology is not universally adopted, and occasionally an EEG tracing with <50% suppression would be described as “burst-suppressed” in other literature.17
One method of quantifying burst-suppression is the burst-suppression ratio (BSR), which is derived from dividing the total suppression duration by total epoch time and then multiplying by 100%.14 An epoch with complete isoelectricity and no burst would therefore have a BSR of 100%, while an epoch with no suppression would have a BSR of 0%. Due to the quasiperiodic pattern of burst-suppression, BSR should be averaged over 15 epochs or a 60-second period for a more accurate representation of the cortical state.16 It is important to note that most commercially available processed EEG (pEEG) monitors record a BSR for an epoch with <50% suppression even when it does not meet the ACNS criteria for burst-suppression. Another method of quantifying burst-suppression is the burst-suppression probability, which is defined as the instantaneous probability of the brain being in the suppressed state.18 Among the 2 indices, BSR is used more commonly by commercial devices, although the proprietary algorithm for which the BSR value is generated is unclear.
At present, the pathophysiological mechanism behind burst-suppression remains poorly understood. Ching et al2 suggest in their neurophysiological-metabolic model of burst-suppression that burst-suppression represents a state of cortical inactivation. It was theorized that the unifying feature across various etiologies for burst-suppression is the reduction of cerebral metabolic rate of oxygen consumption (CMRO2) and the resultant autoregulatory drop in cellular adenosine triphosphate (ATP) production. The decreased intracellular ATP concentration ([ATP]i) leads to increased ATP-gated potassium channels (KATP) conductance, and the opening of KATP causes cellular hyperpolarization, thereby preventing neuronal firing. This electrically quiescent period allows for ATP regeneration and, on reaching a sufficient [ATP]i, the KATP conductance falls, consequently allowing a burst of electrical activity to occur. The repetition of this cycle explains the quasiperiodic nature of the burst-suppression pattern.
Another competing theory by Amzica3 suggests that burst-suppression represents a state of cortical hyperactivity resulting from decreased inhibition. During this state of cortical hyperactivity, the cortex can have “bursts” of electrical activity when prompted by subcortical stimuli, as the subcortical structures remain metabolically and electrically active even when the cortex is displaying a burst-suppressed pattern.19 The “bursts” of electrical activity rapidly deplete the extracellular supply of calcium (Ca2+), which is necessary for synaptic transmission. The depletion of extracellular Ca2+ leads to cessation of electrical activity and the cortex returns to electrical suppression, while the next “burst” occurs when Ca2+ supply is gradually restored and the cortex is once again stimulated by subcortical structures.
In the perioperative setting, where general anesthesia is routinely achieved with either an ether-based or intravenous anesthetic with gamma-aminobutyric acid (GABA)ergic-potentiating properties, the first observable change is an increase in the power of fast oscillations. With the deepening of anesthesia, fast oscillations gradually decrease in power as slow-delta oscillations progressively come to dominate the EEG. Concurrently, alpha oscillations, initially observed in the occipital region when the patient is relaxed with eyes closed, shift to the frontal region in a process known as alpha anteriorization. Further deepening of anesthesia increases the power of slow-delta oscillation, and a burst-suppression pattern could then eventually appear. With even further increases in anesthetic depth, the electrical “bursts” would become more spread out until an isoelectric pattern (ie, flat EEG) is established13 (Figure 2).
CEREBRAL PROTECTION IN CARDIAC SURGERY
The concept of neuroprotection via pharmacological burst-suppression was born out of the early works of Michenfelder et al,20,21 who demonstrated that the dose-dependent suppression of cerebral metabolic activity by thiopental provided protection against cerebral ischemia in animal models. There has since been considerable interest in the potential neuroprotective effects of burst-suppression, both in the setting of focal ischemia caused by cerebral embolization during cardiovascular (CV) surgery or iatrogenic vascular occlusion during neurosurgery, as well as in the setting of global ischemia caused by malignant intracranial hypertension.
The postulated mechanisms behind possible cerebral protection via burst-suppression in CV surgery include both the reduction of cerebral blood flow (CBF) by flow-metabolism coupling with the intent of decreasing embolization during cardiopulmonary bypass (CPB) and the reduction of CMRO2 with the intent of improving cerebral tolerance to the ischemic insult of emboli.22 Despite promising results from animal studies, findings from early human studies were less encouraging. Two randomized controlled trials (RCTs) involving barbiturate-induced burst-suppression for neuroprotection—one involving open-heart surgery and one involving coronary bypass surgery—yielded conflicting results23,24 (Supplemental Digital Content, Table 1, https://links.lww.com/AA/D723). Of note, the “positive” study by Nussmeier et al23 used several CPB techniques that have since been abandoned in clinical practice due to the known increased risk of cerebral embolization, and this heightened risk for postoperative neurological complications could have potentially exaggerated the small (if even existent) neuroprotective effect of thiopental-induced burst-suppression that was not observed in Zaidan et al’s24 “negative” study that used CPB techniques more consistent with modern practice. With the mixed results from early human studies and the unfavorable pharmacokinetic and pharmacodynamic profile of barbiturates, the focus was shifted toward identifying an alternative anesthetic agent for neuroprotection.
In a single-centered RCT by Newman et al25 in which 30 patients undergoing valvular surgery were randomized to receive either propofol infusion titrated to 80% BSR or no propofol infusion during maintenance, patients who achieved propofol-induced burst-suppression had a statistically significant reduction in CMRO2 and CBF. This observation laid the groundwork for Roach et al,26 who aimed to examine the neuroprotective effect of propofol-induced burst-suppression in a multicenter, assessor-blinded RCT with patients undergoing valvular surgery. In the study, patients between 21 and 79 years of age were randomized to receive either a sufentanil infusion or a computer-assisted propofol infusion titrated to burst-suppression with 60 seconds between bursts from the time of aortic cannulation to chest closure in addition to a sufentanil infusion. Standardized neurological and neuropsychiatric tests were performed by blinded assessors preoperatively and on postoperative days (PODs) 1 and 2, PODs 5 to 7, and PODs 50 to 70. With 225 patients enrolled and randomized, the authors found no statistically significant difference in the incidence of neurological deficits or neuropsychiatric outcomes between the 2 groups across all timepoints. On the contrary, there was a nonstatistically significant increase in the incidence of early neurological deficits in the burst-suppression group compared to the control group (POD 1%–40% vs 25%; P = .06; POD 6%–18% vs 8%; P = .07), raising the question of whether pharmacological burst-suppression may in fact have an unfavorable neuropsychiatric effect in CV patients. After Roach et al’s26 study, the notion of pharmacological burst-suppression for neuroprotection in CV surgery largely fell out of favor.
CEREBRAL PROTECTION IN CEREBRAL ANEURYSM SURGERY
Temporary clip (TC) placement is a commonly used technique during microsurgical clipping of cerebral aneurysms, either as an elective maneuver to reduce transmural tension and facilitate permanent clip placement, or as a rescue therapy to gain proximal hemorrhage control of the parent vessel during intraoperative aneurysm rupture (IAR).27 Iatrogenic occlusion of the parent vessel, albeit temporarily, is not without harm, and several intraoperative measures have been explored to reduce the detrimental effect of TC with varying success.28–33 Pharmacological burst-suppression during TC placement, a seemingly sensible maneuver to improve tolerance to focal ischemia by reducing CMRO2, is one such measure that has since been adopted into clinical practice in many institutions despite the absence of any strong clinical evidence supporting its routine use.29,30,34–37 While 2 studies—a post hoc analysis of the Intraoperative Hypothermia for Aneurysm Surgery Trial by Hindman et al38 and a retrospective review with propensity score matching analysis by Kim et al39—explored the effects of pharmacological neuroprotection during TC placement, neither performed a logistic regression analysis with the intraoperative EEG end point as a variable of interest, and thus no inference can be drawn on whether pharmacological burst-suppression was beneficial during TC placement.
Only a handful of human studies specifically examined the therapeutic effects of burst-suppression during cerebral aneurysm surgery.40,41 In a retrospective review of 49 consecutive patients who underwent cerebral aneurysm clipping and required intraoperative TC placements, Lavine et al40 reported that the mean TC duration for patients without postoperative infarct—as defined by new areas of hypodensity in postoperative imaging—was significantly longer for those who received propofol and/or etomidate infusion titrated to burst-suppression during TC placement compared to patients who received isoflurane but without burst-suppression (TC duration without postoperative infarct [mean ± standard deviations] = 13.6 ± 10.6 minutes vs 3.9 ± 2.2 minutes; P < .01).40 The overall rate of postoperative infarct was also lower among patients who received pharmacological burst-suppression (15.8% vs 45.5%), although such an observation could have been confounded by the fact these patients also had a lower incidence of IAR—presumably from improved brain relaxation and surgical exposure—compared to those without burst-suppression. Nonetheless, there was no statistically significant difference in the incidence of good neurological outcome, defined by a Glasgow Outcome Scale (GOS) score of 4 or 5 at 12 months, between the 2 groups.
Mahajan et al41 attempted to address this controversy in a single-centered RCT involving 66 patients with ruptured cerebral aneurysms who required TC placement during aneurysm clipping. Patients were randomly allocated to receive either a standard anesthetic regimen of nitrous oxide, isoflurane, and fentanyl or a propofol infusion titrated to burst-suppression during TC placement in addition to the standard regimen. While there was a lower incidence of IAR in the treatment group compared to the control (5.9% vs 31.3%; P < .01), there was no statistical difference in the incidence of good neurological outcome on discharge as defined by a GOS score of 4 or 5 (87.5% vs 85.2%; P > .05), or in the incidence of postoperative complications including new infarct, vasospasm, and duration of intensive care unit (ICU) stay. While the authors concluded that there was no benefits with pharmacological burst-suppression during TC placement for cerebral aneurysm surgery, the validity of the finding was limited by several caveats including its small sample size, its failure to include relevant patient variables that could potentially impact outcome in the analysis of baseline characteristics, its lack of description on the blinding process, and its relatively outdated perioperative management (eg, the indiscriminate initiation of “Triple-H therapy” for all postoperative patients).
CEREBRAL PROTECTION IN CAROTID SURGERY
Carotid cross-clamping during carotid endarterectomy (CEA), although a necessary step in revascularizing the diseased carotid, is not a physiologically benign process. During cross-clamping, the ipsilateral cortex becomes largely dependent on collateral perfusion derived from the contralateral carotid artery, which often has concomitant atherosclerotic disease, and the Circle of Willis, which is frequently incomplete in the general population.42 Cerebral ischemia is assured if the metabolic supply fails to meet the metabolic demand. One solution involves the routine insertion of an intraluminal shunt to provide distal perfusion across the cross-clamp, although indiscriminate shunt insertion is not without harm either.43,44 Another viable alternative involves selective shunting only when there are signs of inadequate collateral perfusion, as guided either by the neurological status of an awake patient or by various neuromonitoring modalities.45–47
A third approach follows a multistep protocol: following the application of carotid cross-clamp, clinicians observe for EEG evidence of cerebral ischemia manifesting as increased slow oscillations and periods of burst-suppression due to cellular ischemia and synaptic transmission failures.11 In response to an ischemic EEG pattern, hypertensive therapy is initiated with the intention of augmenting collateral perfusion to the ipsilateral cortex. Failure to restore cortical EEG to precross-clamp status with hypertensive therapy would prompt the initiation of pharmacological burst-suppression for neuroprotection while avoiding intraluminal shunting altogether.48 Evidence supporting this approach is mostly based on large case series.49–54 To date, there has been no prospective randomized study to compare the efficacy of pharmacological burst-suppression in preventing perioperative stroke to routine shunting and/or selective shunting in the setting of CEA, although these case series have thus far reported seemingly comparable perioperative stroke rates among the different methods.55,56 At this time, the choice of practice appears largely dependent on institutional experience and clinician preference, not on robust clinical evidence. With the perioperative stroke rate of CEA <2% in modern practice, regardless of protection method, a multicenter RCT with sufficiently large sample size would be required to detect even a small statistical difference.57
MANAGEMENT OF MALIGNANT INTRACRANIAL HYPERTENSION
While intravenous sedation has been widely adopted as a component of standard management for malignant intracranial hypertension in the brain-injured patient, it remains unclear whether intracranial pressure (ICP) reduction via pharmacological means actually necessitates achieving burst-suppression, and furthermore, whether achieving burst-suppression confers any additional benefit in ICP reduction when compared to sedation without an EEG endpoint.58–60
Zeiler et al61 aimed to examine the effect of pharmacological burst-suppression on ICP reduction in a systematic review in 2017. By including prospective and retrospective studies of ≥5 patients, the authors identified 7 studies with a total of 108 patients in the systematic review and concluded that no definitive recommendation could be made regarding pharmacologic burst-suppression in the patient population due to conflicting evidence, with GRADE C Level of Evidence both supporting and refuting the therapeutic effects of burst-suppression on ICP reduction. As indicated by the authors, however, there were several limitations to their analysis. First, a meta-analysis was not feasible due to significant heterogeneity in the study designs, and of the 7 studies included in the systematic review, only 1 study—with a total of 7 patients—had a prospective randomized design.62 In addition, the majority of the 7 included studies failed to detail other therapies used for ICP reduction, and the definition and duration of burst-suppression were also not consistently defined. Moreover, 104 of the 108 patients included in the systematic review had severe traumatic brain injury as their presenting pathology and thus no conclusion could be made regarding the generalizability of any recommendation to other patient populations presenting with alternate etiologies of malignant intracranial hypertension. Importantly, the design of any RCT to determine whether pharmacological burst-suppression is associated with ICP reduction may be complicated by the notion that a burst-suppressed patterns can be a manifestation of cerebral ischemia in the context of malignant intracranial hypertension rather than an EEG end point for titration2,63
Postoperative delirium (PD), with a reported incidence as high as two thirds of the “high-risk” surgical population, has been associated with significant morbidity and mortality.64–66 While PD remains a poorly understood neuropsychiatric and neurocognitive phenomenon with a multifactorial etiology, there has been growing interest in examining the possible link between intraoperative burst-suppression (a phenomenon often associated with excessive anesthetic exposure) and PD in the vulnerable brain.67,68
The connection between burst-suppression and PD was initially reported in a number of observational studies (Supplemental Digital Content, Table 2, https://links.lww.com/AA/D723).69–73 In a prospective observational cohort of 81 patients undergoing cardiac surgery, Soehle et al69 reported burst-suppression duration and BSR, as indicated by bilateral Bispectral Index (BIS) (Medtronic), as predictors of PD, with an area under the curve of 0.73 and 0.68, respectively, using receiver operator characteristic curve analysis. A retrospective observational cohort of 159 patients undergoing cardiac surgery reported by Pedemonte et al,73 as part of a substudy of the Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep trial, likewise identified burst-suppression during CPB, determined by visual analysis of both the time and spectral domain of the EEG, as a predictor for PD in a multivariate logistic regression model (odds ratio [OR] = 4.1; 95% CI, 1.5–13.7; P = .012).73 An observational study by Fritz et al70 that included 727 patients undergoing nonneurological surgeries similarly demonstrated an association between intraoperative burst-suppression, as determined by BIS, and PD in a multivariate regression analysis (OR = 1.22 per 1 minute of burst-suppression; 99% CI, 1.06–1.40; P = .0002). Additionally, given the observation that there was a substantial increase in the incidence of PD when cumulative burst-suppression exceeded 4.4 minutes while further increases in burst-suppression duration were not associated with a significant increase in the incidence of PD, the authors suggested the possibility of a “threshold value” for burst-suppression.74 However, this concept of a “threshold value” has not been supported by other observational studies. The association between intraoperative burst-suppression and postanesthetic care unit (PACU) PD was similarly reported in an observational study of 626 patients by Hesse et al.75 Likewise, Andresen et al76 identified an association between burst-suppression, as detected by BIS monitoring, and postcoma delirium in ICU patients who received sedation during mechanical ventilation (OR = 4.16; 95% CI, 1.27–13.62; P = .02).
A causal relationship between intraoperative burst-suppression and PD, however, cannot be established based on observational data. In the absence of other pathophysiological states (eg, hypoxia, hypocapnia, toxic encephalopathy, brain injury, etc), the presence of intraoperative burst-suppression may represent an exceptionally greater sensitivity to an otherwise “normal” plane of anesthesia, and such anesthetic sensitivity may be an indicator of cerebral vulnerability to the development of PD.71 Thus, it has been suggested that a burst-suppressed EEG pattern may in fact be predictive, rather than causal, of PD.
While several prospective RCTs have explored whether pEEG-guided care was associated with reduced incidence of PD compared to routine care, most studies did not explicitly instruct clinicians in the pEEG-guided care group to avoid burst-suppression or specifically record intraoperative burst-suppression as a variable of interest.77–81 The Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study was a single-center, pragmatic, prospective, double-blinded RCT where 1232 patients >60 years of age undergoing major surgery under general anesthesia were randomized to either a pEEG-guided anesthesia protocol or routine care.82 The primary outcome was the incidence of PD on POD 1 to 5. For those patients who were randomized to pEEG-guided care, clinicians were encouraged to avoid intraoperative burst-suppression and BIS values <40, which suggest excessive anesthetic depth. Contrary to findings from prior RCTs, the ENGAGES authors did not find a statistically significant difference in the overall incidence of PD (26.0% vs 23.0%; difference = 3.0; 95% CI, –2.0 to 8.0; P = .22) between the 2 groups.77,79,80 The lack of a statistical difference might partly be explained by the fact that all patients received multicomponent safety interventions to reduce postoperative confusion, and such interventions may have reduced the overall incidence of clinically detectable PD, such that any potentially therapeutic effects of pEEG-guided care could become negated.83 Furthermore, it is important to note that both groups received arguably excessive anesthetic exposure (duration of BIS <40 = 32 vs 60 minutes; difference = 28 minutes; 95% CI, 18.0–38.0; P < .001) and both demonstrated intraoperative burst-suppression (7 vs 13 minutes; difference = 6 minutes; 95% CI, 2.2–9.9; P < .001). Indeed, the durations of both EEG burst-suppression and BIS <40 were significantly longer among patients with delirium compared to those without, but this was not the focus of the ENGAGES study.84 With all of these facts taken together, the primary analysis of ENGAGES does not answer the question of whether the prevention of burst-suppression can reduce PD.
Fritz et al85 subsequently performed a preplanned post hoc mediation analysis on 1133 patients from the ENGAGES study to determine the mediated effect size of burst-suppression on the incidence of PD. The authors demonstrated that patients with abnormal cognition preoperatively had a 17.2% (99.5% CI, 9.3–25.1) absolute increase in the incidence of PD, and of the 17.2% increase in PD, an absolute increase of 2.4% (99.5% CI, 0.6–4.8) was mediated by intraoperative burst-suppression. This finding suggests that, while preoperative cognitive status remains the major determinant of the risk of developing PD, one may not rule out a small causal effect that intraoperative burst-suppression may have on PD. Based on the mediated effect size, the numbers-needed-to-treat for preventing one case of PD by completely eliminating burst-suppression in an idealized setting would be 28. One needs to be cognizant of the limitations of a post hoc mediation analysis, however, in which the inference of causality is based on the assumption that there exist no unknown confounders.85
The Anesthetic Depth and Postoperative Delirium Trial-2 (ADAPT-2) study was a single-center, exploratory, double-blinded RCT aimed to determine whether the use of pEEG helped to reduce intraoperative burst-suppression and the incidence of PD.86 A total of 204 patients >65 years of age were randomized to receive either pEEG-guided care, in which clinicians were instructed to target a Patient Safety Index of 35 using the SEDline Brain Function Monitor (Masimo), or standard care where the reading was blinded to the clinicians. The duration of burst-suppression, adjusted by the length of surgery, was found to be lower for the interventional group compared to the standard care group (median duration of burst-suppression = 1.4% vs 2.5%; difference = −0.8%; 95% CI, −2.1 to −0.000009; P = .02). The incidence of PD was not statistically different between the 2 groups, although as an exploratory trial, ADAPT-2 was not powered to detect a difference in the incidence of PD. Nonetheless, ADAPT-2 offered support to the notion that targeted interventions to reduce burst-suppression are indeed possible.
Notably, given the differences in the methodology for which burst-suppression was quantified in the aforementioned observational and randomized studies, it is difficult to draw inferences when comparing the results between these studies.
Ultimately, a monitor is only as useful as its operator. This notion is particularly important when interpreting the evidence that seemingly suggests a lack of benefit for pEEG-guided care.84,87 To determine whether the relationship between intraoperative burst-suppression and PD is one of causation or of association, an exploratory trial of sufficient sample size with interventions aimed at reducing or altogether eliminating burst-suppression would be required.
DELAYED RECOVERY FROM ANESTHESIA
While a 2019 Cochrane review of available RCTs and quasi-RCTs reported faster emergence from general anesthesia and earlier PACU discharge associated with BIS-guided anesthesia compared to routine care (albeit a very modest effect), none of the studies included in the review specifically examined the incidence of intraoperative burst-suppression or its quantitative effect on the speed of anesthetic recovery.88 Indeed, no prospective randomized study to date has examined whether the purposeful avoidance of intraoperative burst-suppression is associated with quicker recovery from general anesthesia or earlier PACU discharge.
In a prospective study of 27 healthy volunteers between 22 and 39 years of age, Shortal et al89 aimed to determine whether an increasing duration of EEG suppression would be associated with delayed anesthetic emergence.89 The time to emergence was measured after participants received 3 hours of isoflurane titrated to an end-tidal (ET) concentration of 1.3 minimum alveolar concentration (MAC), and the duration of burst-suppression was determined by analyzing the spectrogram derived from the F3 lead. Contrary to their hypothesis, the authors failed to identify an association between the duration of burst-suppression and the recovery time. Shortal et al’s89 findings must be interpreted with caution, however, as the experimental condition (ie, using isoflurane as the sole anesthetic agent) deviates from routine perioperative care where a balanced anesthetic technique is used. Furthermore, the demographics of this study limit its external validity, given the higher risk of delayed emergence that is present among a comorbid or older surgical population.
Given the multifactorial etiology of delayed anesthetic emergence and PACU discharge, it is unlikely that the presence or absence of intraoperative burst-suppression alone would have a significant effect, if any at all, on the timing of anesthetic recovery in the clinical setting.90,91
The association between intraoperative depth of anesthesia and postoperative mortality, first reported by Monk et al in 2005, has since been reported by several observational studies.92,93 Other studies have similarly identified an association between deep anesthesia and postoperative mortality, but only when it coincided with intraoperative hypotension, suggesting a phenotype that is exceptionally susceptible to the potentially deleterious effects of deep anesthesia.94–97 However, these studies only examined the anesthetic depth as indicated by pEEG indices but not specifically the incidence of burst-suppression.
Watson et al were first to establish an association between burst-suppression and mortality in a post hoc analysis of a prospective observational study involving 125 mechanically ventilated ICU patients. The authors determined, using a multivariate Cox proportional hazards regression model, that ICU patients who experienced burst-suppression had a significantly higher 6-month mortality compared to those who did not (29% vs 25%; hazard ratio [HR] = 2.04; 95% CI [confidence interval], 1.12–3.70; P < .02). Interestingly, no difference in ICU or in-hospital mortality between the 2 groups was observed. Willingham et al98 provided further evidence to support this association in a secondary analysis of 2662 patients enrolled in the B-Unaware and BAG-RECALL studies. By performing propensity matching between the burst-suppressed and non–burst-suppressed group and a multivariate logistic regression to adjust for confounders, the authors reported that patients who simultaneously had cumulative intraoperative burst-suppression >5 minutes and mean arterial pressure (MAP) <55 mm Hg had increased mortality compared to those without burst-suppression and without hypotension (OR = 2.96; 95% CI, 1.34–6.52; P < .007). Interestingly, an association between mortality and burst-suppression without concomitant hypotension was not identified.
Supporting evidence from prospective studies is however limited. In the Balanced Anesthesia Study, an international, multicenter, double-blinded RCT, 6644 patients >60 years of age undergoing major elective surgery were randomized to receive either light anesthesia (BIS target 50) or deep anesthesia (BIS target 35) using volatile anesthetic, and the primary outcome was 1-year all-cause mortality.89 There was no difference in the primary outcome between the 2 groups by either intention-to-treat or per-protocol analysis. However, the incidence of burst-suppression was not reported and the clinicians assigned to either group were not specifically instructed to avoid burst-suppression. Interestingly, in the ENGAGES trial, patients in the pEEG-guided group had a lower 30-day postoperative mortality (a prespecified exploratory end point) compared to patients in the routine care group (0.7% vs 3.1%; difference = −2.42; 95% CI, −4.3 to −0.8; P = .004).82 Given that exploratory end points are intended for hypothesis generation only, and that there was only a very modest difference in median ET MAC of 0.11 between the 2 groups, this particular finding should be interpreted with caution and may represent a type I error. Indeed, a subsequent post hoc analysis by Fritz et al99 demonstrated no statistically significant difference in 1-year mortality between the pEEG-guided group and the routine care group (adjusted 1-year mortality = 9.6% vs 10.3%; difference = −0.7%; 95% CI, −4.3 to 2.8; P = .70), and this finding is in line with the results from the aforementioned Balanced Anesthesia Study.89
At present, there is no robust prospective evidence to support that iatrogenic intraoperative burst-suppression, nor the purposeful avoidance of it, has any bearing on perioperative or long-term mortality. Indeed, it has been suggested that the presence of burst-suppression, at least among critically ill patients, is more likely to be the consequence of disease burden rather than the result of excessive anesthetic exposure and as such, burst-suppression perhaps serve more usefully as a nonmodifiable predictor rather than a modifiable factor of mortality.100
Burst-suppression remains a poorly characterized EEG phenomenon, and our understanding of its pathophysiological implications in the clinical setting remains limited. Despite initial promising findings from preclinical and observational studies, there is currently a paucity of level-1 evidence supporting pharmacological burst-suppression for perioperative neuroprotection.
One notion that may warrant closer examination is whether all burst-suppression is indeed created equally, and whether there truly exists pharmacological equivalence under the proviso that burst-suppression is achieved.101 In fact, subtle electroencephalographic differences have been reported when different sedative agents were used to induce burst-suppression, although the implications of such observations are unclear at present.102–104 A potential future direction of study may involve examining clinical outcomes associated with pharmacological titration to different burst-suppression end points, including isoelectricity. Nonetheless, at the present time, the concept of pharmacological burst-suppression for perioperative neuroprotection remains an elusive objective, and such practice, although remaining popular in many neurosurgical and neurocritical care units, is likely driven by institutional customs rather than robust clinical evidence. At the same time, notwithstanding observational findings, there currently is a paucity of strong clinical evidence from prospective randomized studies to suggest potentially harmful effects of iatrogenic burst-suppression in the perioperative setting. As Cottrell and Hartung105 stated in 1983, “the absence of evidence is not evidence of absence.” The clinician must interpret the evidence available to date with caution, to be cognizant of both the “knowns” and the “unknowns” of its pathophysiological implications, and to make appropriate clinical judgements on an individualized basis.
Name: Kan Ma, MD.
Contribution: This author helped review the literature and compose and revise the manuscript.
Name: John F. Bebawy, MD.
Contribution: This author helped review the literature and compose and revise the manuscript.
This manuscript was handled by: Oluwaseun Johnson-Akeju, MD, MMSc.
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