Inadequate Sedation During Therapeutic Paralysis: Use of Bispectral Index in Critically Ill Patients

Approximately 9 in 10 patients with BIS™ <60 during therapeutic paralysis were unarousable to lightly sedated (RASS −5 to −1) upon emergence from paralysis. These results suggest a potential role for BIS in critically ill patients for whom therapeutic paralysis may otherwise mask inadequate sedation. BIS™ <60 was shown to be highly sensitive for identifying patients with deeper levels of sedation (RASS −5 to −2) and provides some reassurance that these patients may experience less awareness while paralyzed. Conversely, our study only observed three patients with BIS™ >60, limiting our ability to comment on the ability of BIS™ to identify inadequate sedation reliably. Where applicable, this is reflected in the wide confidence intervals and reflects our uncertainty of the sensitivity and specificity of the total population based on our observations in this study population. While we narrowly defined inadequate sedation as RASS −1 to +4, no attempt was made to further define the optimal level of sedation during therapeutic paralysis nor does this study attempt to address the target BIS™ range to mitigate over-sedation.

There was a weak correlation observed between BIS during paralysis and RASS upon emergence from paralysis but statistical significance was not achieved as we were not powered to detect such a small magnitude of correlation (Fig. 4). The correlation observed in this study was weaker than that found in most previously published studies conducted in non-paralyzed ICU patients [13‐16]. The likely explanation is the difference in the ability of RASS and BIS™ to detect differences in level of sedation throughout the entire spectrum of sedation and agitation. BIS™ quantifies levels of deep sedation and anesthesia, whereas RASS is designated to differentiate levels of agitation. A study conducted in 72 volunteers given varying doses of propofol, midazolam, isoflurane, and alfentanil found the relationship between the probability of recall or consciousness and BIS™ to be sigmoidal across the entire range of BIS™ [21]. Thus, at lower BIS™ values, which were observed in the majority of this cohort, there does not appear to be a strong correlation between BIS™ and behavioral measures of sedation.

The apparent discrepancy between sensitivity and correlation results may be explained by fundamental differences between the tests. Sensitivity examined the probability of correspondence between ranges of BIS™ and RASS scores (e.g., BIS™ <60 vs RASS −2 to −5) whereas correlation tested the correspondence between scores (e.g., BIS™ 40 vs RASS −4) throughout the range. Therefore, BIS™ does not appear to be capable of precisely predicting the level of sedation; however, in clinical terms, the sensitivity of BIS™ <60 for predicting light to deep sedation (RASS −2 to −5) suggests a reasonable initial goal and target for monitoring and sedation titration.

These findings may also illustrate a limitation to BIS™ monitoring in critically ill patients. BIS™ was initially derived from multivariate statistical models based on data from EEG and behavioral scales in subjects receiving various hypnotic agents and anesthetic protocols [18, 22, 23]. However, the patient population used to derive BIS™ comprised healthy volunteers and surgical patients; thus, cautious, skeptical extrapolation to the ICU patient is necessary. Cerebral ischemia, hypoxemia, and sepsis are factors that may cause diffuse cerebral slowing resulting in lower BIS and RASS [22]. Patients with intracranial hypertension or a persistently obtunded state were excluded to reduce the effects of neurologic injury on the findings. Moreover, there is evidence that administration of endotoxin in healthy volunteers (eliciting elevations in body temperature, tumor necrosis factor-α, cortisol, and interleukin-6) resulted in increased non-rapid-eye-movement (delta) sleep and decreased wakefulness [24]. It is highly plausible that a similar state of inflammation and acute phase reactant release is present in the critically ill patient. The implications of these effects on the relationship between RASS and BIS™ and the probability of awareness or wakefulness in this patient population remain unclear.

Nine patients in the study had discordant RASS and BIS™ values (RASS −3 to +4 despite BIS™ <60). Three patients were unique for large burn wounds and for receiving relatively low doses of sedative and analgesic medications. The former factor may account for their falsely depressed BIS™, while the latter factor likely accounts for lighter levels of sedation on emergence from paralysis. Another common finding was that four of these nine patients had history of alcohol or drug abuse, which may represent an unknown risk factor for BIS™ and RASS discordance.

Neuromuscular blockade may have also falsely depressed the values observed for BIS as paralysis effectively ablated electromyographic activity. This possibility was reported in a small proportion of volunteers that were paralyzed with rocuronium without sedation [17]. In order to account for possible ‘interference,’ this study was designed without presumption of a correlation or threshold between any BIS value and any level of sedation. Furthermore, pacemakers, heating blankets, and hypothermia have been reported to cause false changes in BIS™ [25]. The administration of opioids has also been demonstrated to have no effect on BIS™, although concurrent use of opioids with propofol has been shown to contribute greatly to loss of consciousness [26‐28]. Since BIS™ technology has been modified to incorporate new data on EEG response and novel anesthetic drugs and drug combinations, it is unknown whether these inaccuracies remain for newer generations of BIS™ [29]. The results of this study highlight the potential effect of these and other practical challenges.

There were a number of limitations to this study. Most notably, it was an observational study design with a small sample size, thus limiting the conclusions that may be drawn from the results. Second, in the absence of a gold standard for measuring level of sedation during therapeutic paralysis, RASS at the time of emergence from paralysis was utilized as a surrogate for level of sedation during paralysis. While imperfect, RASS upon emergence provides a crude indicator of sedation, likelihood of recall, and possibility of awareness. This study does not directly address recall of paralysis; it would be logistically difficult to conduct follow-up interviews given the high mortality rate of the cohort. This study is also limited by the heterogeneity in defining emergence from paralysis. The decision not to rely solely on TOF alone was based on the imprecision and inaccuracy of this tool in critically ill patients; a prospective study design would likely necessitate similar compromises [30]. Including patients that received one-time or increasing dosages of sedatives or analgesics after cessation of NMBAs may have biased the results to suggest deeper levels of sedation on emergence from paralysis than were actually present during paralysis. However, none of the 15 patients with BIS™ <60 during paralysis and constant analgesic and sedative exposure were inadequately sedated (RASS −1 to +4) upon emergence from paralysis. This finding suggests that the inclusion criteria did not significantly impact the results. Lastly, the cohort was a small subset (7.1 %) of all patients receiving NMBAs in the ICU. It is possible that BIS monitoring was ordered for patients that were considered high risk by clinicians that were expressly sensitive to the possibility of inadequate sedation. Therefore, these findings may not be representative of the larger population.

This study highlights the risk of inadequate sedation during therapeutic paralysis. The results further suggest an implied risk of awareness, even in a small cohort. The recent re-emergence of therapeutic paralysis in the context of relative unfamiliarity and infrequent use further increases the probability of poor management. Strategies that may mitigate risk of inadequate sedation include ensuring target sedation prior to paralysis, periodic cessation of NMBAs, amendment of administration instructions for concurrent sedative orders to avoid titration based on behavioral sedation assessment tools, limiting duration of paralysis, and educating staff. Moreover, future studies utilizing NMBAs as an intervention may assess the risk of inadequate sedation and/or recall of paralysis as a safety endpoint.

There appears to be a disquieting discrepancy between the extremely low rate of awareness achieved in the operating room (0.24 %) [31] and the relatively high rate (36 %) [4] observed in critically ill patients that required therapeutic paralysis. Studies guiding the accurate detection and prevention of awareness during paralysis in the ICU patient are severely lacking. Research in this area is complicated by difficulty in measuring adequate levels of sedation, intrinsic complexity in defining achievement of sedation goals in the paralyzed patient, the high mortality and morbidity in this patient population, and the relative infrequency of continuous NMBA use. Prospective, randomized trials are needed to assess the utility of BIS™ for ensuring adequate sedation and reducing recall in patients receiving NMBA in the ICU. Future research may identify risk factors for inadequate sedation or recall of paralysis, risk factors associated with discordance between BIS™ and true level of sedation, and the cost effectiveness of BIS™ in this setting. At present, there is no well defined sedation goal for patients receiving NMBAs in the ICU, and the optimum level of sedation in this population remains to be determined.