The Use of Neuromuscular Blockers to Prevent Shivering in the Setting of Postcardiac Arrest Targeted Temperature Management: A Narrative Review of an Off-Label Indication

Abstract

Targeted temperature management (TTM) has become a standard of care over the past two decades for the improvement in neurologic function and mortality in postcardiac arrest patients. There are various mechanisms by which hypothermia helps to improve these outcomes, one of which is by reducing oxygen requirements. Less established is the use of nondepolarizing neuromuscular blockers (NMBs) to prevent shivering during TTM. Shivering can be disadvantageous in this setting as it increases oxygen requirements, which TTM is actively trying to decrease, in an already oxygen-deprived system as well as generates heat making it difficult to maintain hypothermia. Whether NMBs can improve these outcomes is conflicting in the currently available literature and there lacks a consensus on their role in shivering management. The pharmacokinetic and pharmacodynamic responses of these agents may be altered in hypothermic patients, therefore, their standard of monitoring may be unreliable. The accurate dosing and administration of these agents also remain unclear, further complicated by the lack of a standard use protocol. Various studies have been conducted regarding the use of NMBs to prevent shivering in postcardiac arrest patients undergoing TTM; however, it remains an off-label indication requiring further investigation.

Introduction

Targeted temperature management (TTM), sometimes also referred to as therapeutic hypothermia, is a well-established therapy in cardiac arrest patients who remain unresponsive after the return of spontaneous circulation (ROSC) to favorably impact neurologic function and mortality (Bernard and Buist, 2003; Alzaga et al., 2006; Holzer and Behringer, 2008; Soar et al., 2020).

Shivering is the body's attempt at rewarming to combat hypothermia through repetitive muscle contractions. In addition to causing temperature instability, shivering increases the body's metabolic rate resulting in globally higher oxygen consumption. Both of these factors have the potential to complicate and counteract this therapy by increasing the body's temperature and oxygen demand. With postcardiac arrest being a time when oxygen is already in short supply, shivering is counterproductive.

Nondepolarizing neuromuscular blockers (NMBs) have the potential to mediate shivering in the setting of TTM. They act by binding to the nicotinic acetylcholine receptors found on motor endplates causing skeletal muscle paralysis. Paralyzed muscles are unable to repetitively contract, preventing the shivering mechanism altogether. While undergoing paralysis, patients must receive adequate sedation and analgesia to avoid awakening and uncontrolled pain, which they are unable to communicate about while paralyzed.

Currently, nondepolarizing NMBs have an off-label indication for the management of overt shivering during TTM in postcardiac arrest patients. This use comes from the 2016 update of the 2002 Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient that provides a weak recommendation of NMBs being used to manage overt therapeutically induced shivering with no recommendation on their routine use (Murray et al., 2017).

The American Heart Association suggests within their 2015 guidelines that these agents be used at a minimum or avoided completely with regard to this indication as they can confound clinical assessment of neurologic outcomes due to the inability to perform neurologic examination while the patient is adequately sedated and paralyzed (Callaway et al., 2015).

Using NMBs to prevent shivering can improve the outcomes of TTM by decreasing oxygen consumption, shortening the time to target temperature, and potentially decreasing lactate levels (Salciccioli et al., 2013; Tezcan et al., 2019). To date, there is not a comprehensive review of available literature solely regarding this off-label indication of shivering management in postcardiac arrest patients for this class of agents that this narrative review aims to provide.

Search Strategy

A PubMed search using MeSH terms was performed using the following search strategy that yielded 146 results: [(“Circulatory Arrest, Deep Hypothermia Induced”[Mesh] OR “Hypothermia, Induced”[Mesh])] AND [(“Neuromuscular Blocking Agents” [Pharmacological Action] OR “Neuromuscular Blocking Agents”[Mesh])]. A second PubMed search was performed: [(“Circulatory Arrest, Deep Hypothermia Induced”[Mesh] OR “Hypothermia, Induced”[Mesh] OR hypothermia)] AND [(“Neuromuscular Blocking Agents” [Pharmacological Action] OR “Neuromuscular Blocking Agents”[Mesh] OR neuromuscular blocking agents)] that yielded 256 results. An individual search of similar articles and citations was also performed. Articles were screened for relevance and a total of 22 articles were included in this review.

Neurologic Function, Mortality, and Other Outcomes

TTM can improve neurologic function and mortality outcomes in cardiac arrest patients. However, the results of clinical trials and observational studies are conflicting regarding the role NMBs play in improving these outcomes. All studies, unless indicated otherwise, maintained a target hypothermia temperature of 33°C for 24 hours. The majority of cardiac arrests were ventricular fibrillation or documented as a shockable rhythm.

A multicenter randomized placebo-controlled trial enrolled 81 comatose out-of-hospital cardiac arrest (OHCA) patients undergoing TTM to receive either continuous infusion rocuronium or placebo for 24 hours (Lee et al., 2018). The placebo group was permitted to receive bolus NMB doses for patient safety, intractable shivering, or asynchrony with mechanical ventilation. Rocuronium was utilized as the continuous infusion agent; however, rocuronium, vecuronium, and atracurium were used for bolus doses. A total of nine patients died during the intervention period, four in the intervention group and five in the placebo group, with no cause of death listed.

All outcomes of the study were determined not statistically significant between the two groups and included serum lactate levels 24 hours after drug infusion, in-hospital mortality, neurologic outcome, and muscle weakness. The authors of this trial concluded that NMBs have a limited scope in this area. However, they suggested the small sample size limited the power to detect differences among the outcomes and recommended a larger trial be conducted before implementing any changes in practice.

A phase 2 multicenter randomized superiority trial was performed analyzing 80 patients randomized to receive either 24 hours of continuous infusion rocuronium, titrated to one to two of four twitches on train-of-four (TOF), or usual care, no neuromuscular blockade, postcardiac arrest in the United States (Moskowitz et al., 2020). It was determined that the impact on lactate levels after 24 hours was no different between the groups as well as there being no effect on hospital survival or survival with good neurologic outcome.

The authors noted that this study may be limited in its generalizability as 21% of the usual care group received some NMB and this may have biased the outcomes of the study toward being insignificant. Furthermore, 818 patients initially met inclusion criteria, yet were excluded for various reasons such as consent not provided by a legally authorized representative. This may account for the results of this trial differing from previous studies, which was acknowledged by the authors.

A post hoc analysis of a multicenter prospective cohort study of comatose OHCA patients assessed the exposure of neuromuscular blockade for 24 hours after ROSC against the lack of exposure (Salciccioli et al., 2013). Of the 111 patients enrolled, 18 received immediate neuromuscular blockade sustained for 24 hours (NMB group), whereas 93 did not (non-NMB group). Including the 18 patients who received sustained blockade, 77 patients received an NMB at some point within the first 24 hours, but it was not always sustained.

In those who received any NMB within the first 24 hours of ROSC, there was an overall survival of 52% compared with 35% in those who received no NMB at all. Lactic acidosis was improved over 48 hours in the NMB group but only significant at 12 and 24 hours, not 36 and 48 hours. The authors concluded that NMBs are associated with an increased probability of survival and improved lactic acid clearance but not with favorable neurologic functional status.

It is worth mentioning that the NMB group experienced an ROSC on average 9 minutes sooner than the non-NMB group before any NMB administration. This large difference at baseline could suggest that the NMB group may have initially had an increased probability of survival as they were able to be resuscitated sooner in addition to a more favorable neurologic outcome as they were without circulation for a shorter period of time. This limitation should be taken into consideration and the authors suggest that further clinical trials need to be done to assess the relationship between NMBs and OHCA outcomes.

An international prospective observational study containing 4267 patients undergoing TTM postcardiac arrest included 20 cardiac centers from 2006 to 2016 following varying protocols assessing neurologic outcomes based on sedation and shivering practices (May et al., 2018). Practices were categorized as minimal or no NMB with escalating doses of sedation, sedation with continuous or scheduled NMB, or sedation with as needed NMB. Names and dosing of specific sedatives and NMBs used across protocols were not collected. The primary outcome of good neurologic function was determined statistically significant and authors hypothesized that improved neurologic outcomes in those who received an NMB could be a result of overall increased bedside monitoring.

Furthermore, worse neurologic outcomes could be associated with escalating doses of sedatives due to accumulation in the setting of hypothermia; however, these data were not collected. Sedatives incompletely control shivering in the absence of an NMB and the benefits of shivering prevention are not fully attained. They concluded that centers that utilized NMBs as needed in addition to baseline sedation are associated with good outcomes when compared with centers that instead used escalating doses of sedatives and avoided the use of NMBs to prevent shivering.

A retrospective observational study of the J-PULSE-HYPO study patients was performed to determine neurologic outcomes in those who received neuromuscular blockade (Hifumi et al., 2021). Of the original 452 patients enrolled in the J-PULSE-HYPO study, 21 patients were excluded for either unknown target temperature or unknown NMB use, leaving 431 patients to be included in this analysis. There was no association between NMB use and favorable neurologic outcome and survival rate in this observational study.

The authors acknowledge it is unclear as to why this study found no significant difference in neurologic outcomes compared with previous studies and suggest it could be due to faster temperature induction times or infectious complications in the study. They suggest that the routine use of NMBs in postcardiac arrest TTM be re-evaluated.

Of the five already mentioned studies, only one study determined that NMBs are associated with increased probability of survival and a different study found them to be associated with good neurologic outcomes. The majority of the collected literature did not establish an association between the use of NMBs, morbidity and mortality, and good neurologic outcome. Further trials and analyses should be performed before making a strong recommendation for or against NMB use in shivering prevention during TTM postcardiac arrest.

Protocols

The following two landmark trials established TTM as a treatment for postcardiac arrest patients. They did not specifically study the effect NMBs have on these outcomes; however, all patients who underwent TTM did receive neuromuscular blockade. Although these pivotal trials did not explicitly study their effectiveness on outcomes and their significance in these trials is unknown, it is relevant to briefly mention their protocols and results to achieve similar outcomes in the future. To establish the best protocol for these agents in this setting, replicating the trial protocols to study the effect NMBs have on outcomes would add great value to the existing literature. These protocols could be further investigated to replicate their results and outcomes in relation to NMBs.

The first was the randomized controlled trial enrolling comatose OHCA patients to undergo either hypothermia (34°C), maintained for 12 hours, or normothermia (37°C) with all patients receiving 8 to 12 mg of vecuronium to prevent shivering (Bernard et al., 2002). The authors concluded that hypothermia appears to improve survival to discharge with good neurologic function.

The second study was a multicenter randomized controlled trial that enrolled postcardiac arrest patients to be randomized to target either hypothermia (32°C to 34°C) or normothermia, not defined in the study, for 24 hours with bolus pancuronium administered for the prevention of shivering (The Hypothermia after Cardiac Arrest Study Group, 2002). They concluded that mild TTM increased the rate of favorable neurologic and mortality outcomes within 6 months of discharge.

Although guidelines recommend a protocol be in place, there is no standardized protocol currently recommended for the use of NMBs in this setting. A systematic review spanning 1997 to 2009 identified 44 differing protocols utilized in >60 intensive care units (ICUs) internationally (Chamorro et al., 2010). NMBs were regularly used in 54 ICUs to prevent shivering and in 8 ICUs as treatment of shivering, whereas 1 ICU discouraged the use altogether. Pancuronium, utilized in 24 ICUs, and cisatracurium utilized in 14 ICUs were the most common agents. Only four ICUs employed TOF monitoring and three ICUs used continuous cerebral activity monitoring.

The sedation and analgesic portions of the protocols differed greatly as well. Midazolam was the most commonly used sedative followed by propofol with fentanyl being the most common analgesic and 33 ICUs not requiring any analgesic use. As an example, the Columbia antishivering protocol reserves the use of NMBs as a last line agent, utilizing acetaminophen, buspirone, magnesium, opioids, dexmedetomidine, and propofol before introducing vecuronium (Choi et al., 2011). Evidently, further research is necessary to formulate an optimized protocol for the use of NMBs to manage shivering in TTM postcardiac arrest.

Pharmacokinetic Considerations

The kinetic changes of NMBs in the setting of hypothermia can be attributed to decreased acetylcholine metabolism, hypoperfusion of organs responsible for elimination, and decreased concentration of binding proteins (Hemmerling et al., 2008). The most notable kinetic change is prolonged duration of action. Vecuronium and atracurium experience a 3-fold and 1.5-fold increase in duration of action, respectively, whereas rocuronium experiences a 5-minute increase in duration of action per degree Celsius decrease (Leslie et al., 1995; Tortorici et al., 2007). Despite all three agents having different elimination pathways that include renal, hepatic, Hoffman, ester hydrolysis, and bile elimination, they all show a prolonged duration of action in a hypothermic setting.

Organ hypoperfusion as a result of hypothermia is further complicated by the situation of postcardiac arrest when these patients often have multisystem organ failure (Callaway et al., 2015). As these organ systems are operating inefficiently, they are unable to effectively metabolize or eliminate agents. For example, vecuronium and pancuronium have renally eliminated active metabolites that can accumulate as a result of renal dysfunction, causing prolonged duration of action (Chamorro et al., 2010). As a result, it is recommended that doses be reduced and neuromuscular function be monitored to avoid overdosing in this setting (Tortorici et al., 2007). This further demonstrates the need for an optimized protocol under these conditions.

Frequency of Administration

There exists no official recommendation as to the frequency of NMB dosing in this specific patient population and the evidence available is conflicting. The 2016 update of the 2002 Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient lacks a recommendation regarding the difference between continuous infusion and bolus administration of NMBs (Murray et al., 2017). The original 2002 clinical guidelines do make a general statement that bolus administration can limit complications related to prolonged exposure, offer better control of tachyphylaxis, and improve monitoring of accumulation, analgesia, and amnesia even though continuous infusion is more commonly used in ICUs (Murray et al., 2002). Furthermore, the optimal duration of treatment is also unknown (Salciccioli et al., 2013).

A retrospective medical record review of 123 patients undergoing TTM after sudden cardiac arrest compared the effects of continuous infusion with those of intermittent bolus vecuronium (Jurado and Gulbis, 2011). Continuous infusion was administered to 80 patients at a rate of 0.8 mcg/kg per minute beginning 2 hours after cooling or when shivering occurred and intermittent boluses were given to 43 patients at a dose of 0.05 mg/kg every 2 hours. The authors determined intermittent bolus of vecuronium was more effective at reaching adequate neuromuscular blockade sooner compared with continuous infusion by 5.4 hours.

TOF measurements above goal were higher in the continuous infusion group by 17% and measurements below goal were higher in the bolus group by 14%. The intermittent bolus group received lower total daily doses, 51.7 mg compared with 76.9 mg. The median time to return of spontaneous respirations and time to extubation occurred 5 and 60 hours sooner, respectively, in the continuous infusion group than the bolus group. Overall, both dosing strategies are effective; however, intermittent bolus dosing achieves adequate blockade sooner with a lower total daily dose as well as allows for an earlier extubation and return of spontaneous respirations.

A randomized double-blinded double-dummy controlled clinical trial sought to determine whether continuous infusion or bolus administration of rocuronium in 63 patients undergoing TTM postcardiac arrest would cause fewer shivering episodes (Stöckl et al., 2017). Thirty-two patients received continuous infusion rocuronium 0.25 mg/kg per hour with an initial bolus of 0.25 mg/kg, whereas 31 patients received continuous infusion saline supplemented by bolus rocuronium at the same dose. A shivering episode was identified in 94% of the continuous infusion group compared with 25% of the bolus group.

The continuous infusion group received a higher total rocuronium dose by an average of 5.5 mg/kg, experienced an earlier awakening by 2 days, and decreased length of stay by 4 days. Overall, the authors concluded that continuous infusion of rocuronium during the first day after ROSC reduced shivering along with sedative and analgesia requirements and time to awakening and discharge.

A retrospective cohort study in Japan assessed in-hospital mortality and various clinical outcomes in 5584 postcardiac arrest patients undergoing TTM who received either intermittent (27%) or continuous (73%) rocuronium or vecuronium on the day of their admission to the ICU (Takiguchi et al., 2021). Intermittent being defined as between 50 and 250 mg/day of rocuronium or between 10 and 50 mg/day of vecuronium, and continuous defined as ≥250 mg/day of rocuronium or ≥50 mg/day of vecuronium. The group was unable to ascertain whether administration was continuous or intermittent as it was not available from the Japanese Diagnosis Procedure Combination database.

As a result, the definitions were set based on doses that would be equivalent to a continuous or intermittent administration, making this a limitation of the study. In-hospital mortality did not differ between the groups. However, in a subgroup analysis of patients 65 years of age or older, the use of continuous neuromuscular blockade may be associated with increased in-hospital mortality when compared with intermittent use. The authors of this study point out this could be partially attributed to the changes in the pharmacokinetic and pharmacodynamic profiles of elderly patients, which, as previously mentioned, are further altered during TTM. The authors determined that there was no difference in morbidity and mortality between the two groups.

Given the mentioned trials, there are benefits to both administrations. Jurado et al. determined intermittent bolus to achieve blockade, perform extubation, and experience return of spontaneous respirations sooner than continuous infusion. Stöckl et al. noted a reduction in sedative and analgesic doses, shivering, and time to awakening and discharge when patients were given continuous infusion NMB compared with bolus doses. Takiguchi et al. observed no difference between continuous or intermittent use. Deciding the frequency of administration should be driven by patient-specific factors and individual risk for complications. A standardized protocol would provide a clearer direction regarding this decision as well as improve patient care.

Monitoring

The standard of monitoring neuromuscular blockade is the TOF, also known as peripheral nerve stimulation (PNS), an electrical current of four consecutive impulses delivered to a superficial nerve and muscle movement is observed. Commonly stimulated is the facial nerve resulting in the orbicularis oculi twitch or ulnar nerve resulting in the adductor pollicis twitch (deBacker et al., 2017). TOF ratio is defined as the ratio between the amplitude of the 4th and 1st pulses and can detect residual paralysis, defined as a ratio of <0.9 (deBacker et al., 2017).

In the setting of hypothermia, PNS is slowed due to cooling and can vary, effectively making the TOF response unreliable to detect the depth of muscle paralysis (Chamorro et al., 2010; Tezcan et al., 2019). Clinical signs such as sustained head or leg lift, “normal” respiration pattern, and sustained hand grip commonly occur when the TOF ratio is <0.9 (deBacker et al., 2017). These clinical signs can be of use in this situation when quantitative tests are not fully reliable.

TOF monitoring should be used concurrently with clinical parameters, including minimal or absence of shivering and absence of spontaneous breathing trigger on ventilation (deBacker et al., 2017; Tezcan et al., 2019). A weak recommendation was made in the 2016 update of the 2002 Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient to utilize PNS with TOF monitoring only if it is in conjunction with a more in-depth clinical assessment of the patient and suggest against its use alone in monitoring continuous infusion neuromuscular blockade (Murray et al., 2017).

Clinical parameters can be difficult to measure and monitor in these patients as they are heavily sedated. Adequate sedation can be monitored through behavioral scales, vital signs, bodily movements, diaphoresis, lacrimation, detection of spontaneous breathing, and end-tidal CO₂ waveforms (deBacker et al., 2017). The original 2002 clinical guidelines recommend titrating to one to two of four twitches correlating to 80–90% of receptor occupancy and blockade, whereas the lowest clinically effective dose is also commonly utilized irrespective of TOF (Murray et al., 2002).

NMBs also have the ability to mask seizure activity as it can be extremely difficult to distinguish shivering from myoclonic activity (Chamorro et al., 2010). A prospective 3-year pilot study was performed to determine whether early routine electroencephalogram (EEG) monitoring would be beneficial to detect status epilepticus in comatose postcardiac arrest patients receiving NMBs undergoing TTM (Legriel et al., 2009). For 51 patients, an EEG was performed routinely as soon as TTM was induced. Status epilepticus was identified in 5 patients, 34 died before discharge, and 17 patients were discharged alive.

All patients who were identified with status epilepticus died before discharge. This trial, along with others, suggests it can be beneficial to monitor EEG in this population as NMBs have the potential to mask postanoxic status epilepticus. However, further studies are necessary to determine whether early treatment of status epilepticus during TTM improves outcomes (Legriel et al., 2009; Chamorro et al., 2010).

Conclusion

The use of NMBs in postcardiac arrest patients to prevent shivering in the setting of TTM exists as an off-label indication. The trials and studies surrounding this topic are limited and contradictory in their collective results that are summarized in Table 1. Whether their use supports better neurologic function and mortality outcomes is unclear and necessitates further research. This lack in quantity and thorough research results in the absence of a standard protocol and strong consistent recommendations among clinical guidelines.

Table 1.

Summary of Agents, Doses, and Conclusions of Included Studies

Study	Study design	Agent(s)	Dose	Adjunct antishivering agents	Conclusions
Lee et al. (2018)	Clinical trial	Rocuronium (continuous infusion and bolus) Vecuronium (bolus) Atracurium (bolus)	Rocuronium (continuous infusion): 0.3–0.6 mg/kg/h Rocuronium (bolus): 0.6 mg/kg Other doses not provided	Midazolam Propofol Remifentanil Morphine	NMBs have a limited scope in this setting. No outcomes were found to be statistically significant.
Moskowitz et al. (2020)	Clinical trial	Rocuronium	Bolus: 1.0 mg/kg Continuous infusion: titrated to one to two/four twitches on TOF	Propofol Midazolam Lorazepam Dexmedetomidine Fentanyl	NMBs do not impact 24-hour lactate levels, hospital survival, or good neurologic outcome.
Salciccioli et al. (2013)	Post hoc analysis of cohort study	Vecuronium Pancuronium	Not reported	Yes, unspecified	NMBs are associated with increased probability of survival and lactic acid clearance but not neurologic function.
May et al. (2018)	Observational study	Not collected	Not collected	Yes, not collected	NMBs should be used in addition to baseline sedation and are associated with good neurologic outcomes.
Hifumi et al. (2021)	Observational study	Various, not collected	Not collected	Yes, not collected	There was no difference in favorable neurologic outcome between NMB and non-NMB use.
Bernard et al. (2002)	Clinical trial	Vecuronium	8–12 mg	Midazolam	Hypothermia appears to improve survival to discharge with good neurologic function.
The Hypothermia after Cardiac Arrest Study Group (2002)	Clinical trial	Pancuronium	Not reported	Midazolam Fentanyl	Mild therapeutic hypothermia increases the rate of favorable neurologic and mortality outcomes within 6 months of discharge.
Jurado and Gulbis (2011)	Retrospective chart review	Vecuronium	Continuous infusion: 0.8 mcg/kg per minute Bolus: 0.05 mg/kg	Midazolam Propofol Fentanyl	Intermittent bolus and continuous infusion dosing is considered equally efficacious with intermittent bolus achieving blockade sooner with quicker time to extubation and return of spontaneous respirations.
Stöckl et al. (2017)	Clinical trial	Rocuronium	Continuous infusion: 0.25 mg/kg per hour Bolus: 0.25 mg/kg	Midazolam Fentanyl	Continuous infusion NMB within 24 hours reduced shivering, time to awakening and discharge, and reduced sedative and analgesia requirements.
Takiguchi et al. (2021)	Retrospective cohort study	Rocuronium Vecuronium	Rocuronium continuous: ≥250 mg/day Rocuronium intermittent: 50–250 mg/day Vecuronium continuous: ≥50 mg/day Vecuronium intermittent: 10–50 mg/day		No significant difference in mortality and morbidity between intermittent and continuous NMB administration. Patients 65 years of age or older may have increased mortality in the setting of continuous NMB use.
Chamorro et al. (2010)	Systematic review	PancuroniumCisatracurium	Not collected	MidazolamPropofolFentanylMorphine	Various protocols for the use of NMBs exist with no singular, standardized protocol

NMBs, neuromuscular blockers; TOF, train-of-four.

Owing to the nature of this setting, the alterations in pharmacokinetics are extremely necessary to take into consideration for dosing and frequency of these medications as they tend to have a prolonged duration of action. Similarly, standard monitoring of this class is complicated due to the cooler body temperatures. The correct monitoring, frequency of administration, proper dosing, and correlation of outcomes are essential pieces of information to further establish this off-label indication as well as aid in the development of protocols and guideline recommendations.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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