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Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management
Accepted Manuscript Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management
Dong Hun Lee, Byung Kook Lee, Kyung Woon Jeung, Yong Hun Jung, Yong Soo Cho, Chun Song Youn, Yong Il Min PII: DOI: Reference:
S0883-9441(17)30283-6 doi: 10.1016/j.jcrc.2017.04.026 YJCRC 52493
To appear in: Please cite this article as: Dong Hun Lee, Byung Kook Lee, Kyung Woon Jeung, Yong Hun Jung, Yong Soo Cho, Chun Song Youn, Yong Il Min , Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yjcrc(2016), doi: 10.1016/j.jcrc.2017.04.026
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Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management
Dong Hun Lee, MDa, Byung Kook Lee, MD, PhDa*, Kyung Woon Jeung, MD, PhDa, Yong Hun Jung,
of Emergency Medicine, Chonnam National University Hospital, 42 Jebong-ro,
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aDepartment
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MDa, Yong Soo Cho, MDa, Chun Song Youn, MDb, and Yong Il Min, MD, PhDa
Donggu, Gwangju, Republic of Korea
of Emergency Medicine, College of Medicine, The Catholic University of Korea, 222,
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* Corresponding author. Byung Kook Lee
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Banpo-daero, Seocho-gu, Seoul, Republic of Korea
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bDepartment
Address: Department of Emergency Medicine, Chonnam National University Hospital, 42
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Jebong-ro, Donggu, Gwangju, Republic of Korea
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Tel.: 82 62 220 6809; fax: 82 62 228 7417.
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Funding Sources
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E mail addresses: [email protected]
This work supported by a grant (CRI16024-1) Chonnam National University Hospital Biomedical Research Institute.
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Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management
Abstract Purpose: We examined the association between neuromuscular blockade (NMB) requirements
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and outcomes and lactate clearance in cardiac arrest survivors treated with targeted
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temperature management (TTM).
Methods: We included consecutive adult cardiac arrest survivors treated with TTM between
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2012 and 2015. NMB use was categorized into 3 groups: no NMB, bolus NMB (intermittent
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bolus use), and continuous NMB (continuous infusion). Serum lactate levels were measured on admission and at 12 h, 24 h, and 48 h after admission. The primary outcome was neurologic
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outcome at discharge. The secondary outcomes were in-hospital mortality and lactate clearance. Results: In total, 309 patients were included. Of these, 206 (66.7%) and 73 (23.6%) were
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discharged with poor neurologic outcome and death, respectively. Multivariate analysis
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revealed that continuous NMB, as opposed to no NMB use, was associated with decreased poor neurologic outcomes (odds ratio [OR], 0.317; 95% confidence interval [CI], 0.124–0.815) and decreased in-hospital mortality (OR, 0.414; 95% CI, 0.183–0.941). There were no differences in
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lactate clearance between the NMB groups. Conclusion: Continuous NMB requirement was associated with improved neurologic outcome
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and decreased in-hospital mortality in cardiac arrest survivors treated with TTM. The NMB requirement was not associated with lactate clearance.
Keywords: heart arrest; neuromuscular blockade; lactic acid; prognosis; induced hypothermia Abbreviations1
TTM, targeted temperature management; NMB, neuromuscular blockade; MV, mechanical ventilation; ICU, intensive care unit; CPR, cardiopulmonary resuscitation; GCS, Glasgow Coma Scale; ROSC, restoration of spontaneous circulation; SOFA, sequential organ failure assessment; CPC, cerebral performance category; OR, odds ratio; CI, confidence interval 1
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Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management
1. Introduction Targeted temperature management (TTM) has become a standard treatment for comatose
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cardiac arrest survivors [1,2]. Based on randomized controlled trials, it is recommended that
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the temperature of comatose cardiac arrest survivors be lowered to the target temperature of 33°C or 36°C [3-5]. Shivering is a physiologic response to cooling or decreased body
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temperature; hence, it is one of the most common adverse events encountered during TTM.
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Shivering not only interferes with the achievement of the target temperature by generating heat but also increases metabolic activity, oxygen consumption, and cerebral metabolic stresses [6-8].
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Therefore, shivering should be controlled to preserve the beneficial effect of TTM in cardiac arrest survivors.
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A well-known anti-shivering protocol provides a stepwise strategy against shivering [9]. Non-
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sedatives, including acetaminophen, buspirone, and magnesium are used at the beginning of the intervention. However, opiates, sedatives, and even neuromuscular blockade (NMB) are required in patients with poorly controlled shivering [9]. The 2010 American Heart Association
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guidelines recommended minimal use of NMB during post-cardiac arrest care [10]. A multicenter study investigating the association between NMB use and outcome in cardiac arrest
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survivors undergoing TTM demonstrated that NMB use was associated with an increased probability of survival [11]. Improved lactate clearance, suggested as a surrogate marker for good outcomes in cardiac arrest survivors regardless of TTM, was associated with NMB use [1114]. However, another single center study reported that NMB use during TTM was associated with increased early-onset pneumonia [15]. NMB use is also associated with a risk of developing critical illness polyneuromyopathy [16]. There is limited evidence on NMB use in cardiac arrest survivors and the practice remains controversial. According to changes in our post-cardiac arrest care protocol, we have used NMB in a stepwise
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fashion instead of routine infusion of NMB since 2012. We hypothesized that NMB requirements were associated with improved clinical outcomes and lactate clearance. We evaluated the association between clinical outcomes and NMB requirements in cardiac arrest survivors treated with TTM. Furthermore, we also investigated the association between NMB requirements and lactate levels, lactate clearance, mechanical ventilator (MV) support, and
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intensive care unit (ICU) stay.
2. Materials and Methods
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2.1. Study Design and Population
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We performed a retrospective observational study involving adult comatose cardiac arrest survivors treated with TTM at Chonnam National University Hospital, Gwangju, Republic of
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Korea, between January 2012 and December 2015. This study was approved by the Institutional Review Board of Chonnam National University Hospital.
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Cardiac arrest survivors aged >18 years having completed TTM were included. Patients were
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excluded on the basis of the following criteria: (1) death during TTM, (2) transfer during TTM, (3) receipt of a TTM protocol with a different target temperature (< 32°C or > 34°C) or hypothermia duration (48 h or 72 h); and (4) extracorporeal membrane oxygenation applied
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during post-cardiac arrest care.
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2.2. Targeted Temperature Management protocol Cooling was initiated as soon as possible with ice packs, intravenous cold saline, and one of the following three TTM devices: Arctic Sun® Energy Transfer Pads™ (Medivance Corp, Louisville, KY, USA); Blanketrol® II (Cincinnati Subzero Products, Cincinnati, OH, USA); or COOLGARD3000® Thermal Regulation System (Alsius Corporation, Irvine, CA, USA). Core temperature was monitored using an esophageal temperature probe. Remifentanil and midazolam were routinely used for sedation and analgesia. During the 24-h maintenance phase, a target temperature of 33 ± 1°C was maintained. Upon completion of the maintenance phase, patients were rewarmed
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at a target rate of 0.25°C h−1. Advanced critical care, such as oxygenation, ventilation, glucose control, and hemodynamic optimization, was provided in accordance with the guidelines. Serum lactate levels were obtained on admission and at 12, 24, and 48 h after admission. We have changed the TTM protocol regarding NMB use since 2012 in accordance with the 2010 guidelines [10]. Shivering, which interferes with the achievement of the target temperature and
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with patient-ventilator synchrony, was initially controlled with a bolus infusion of atracurium
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(25 mg). Repeated bolus administration of atracurium was used to control shivering, if required. Poorly controlled shivering, despite repeated bolus administration of atracurium, was controlled
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by continuous infusion of atracurium, with an initial dose of 0.5 mg/kg/h. Continuous infusion
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of atracurium was at the discretion of the attending physician. Based on NMB requirements,
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subjects were divided into three groups: no NMB, bolus NMB, and continuous NMB.
2.3. Data Collection and Outcomes
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The following data were obtained for each patient: age, sex, comorbidities, first monitored
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rhythm, etiology of cardiac arrest, location of cardiac arrest, presence of a witness on collapse, bystander cardiopulmonary resuscitation (CPR), Glasgow Coma Scale (GCS) score after return of spontaneous circulation (ROSC), time to ROSC, epinephrine dose used during the intra-arrest
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period, glucose levels after ROSC, arterial oxygen tension after ROSC, arterial carbon dioxide tension after ROSC, initial temperature, pre-induction time, induction duration, rewarming
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duration, total dose of atracurium used during TTM, time of the first bolus atracurium infusion, time of initiation of continuous atracurium infusion, duration of continuous atracurium infusion, lactate values, lactate clearance (12, 24, and 48 h), weaning from MV, duration of MV, ICU stay, vital status at hospital discharge (alive or dead), and neurologic outcome at discharge. The sequential organ failure assessment (SOFA) score within the first 24 h of admission was used to assess the severity of multiple-organ dysfunction [17]. Neurologic outcome was assessed using the Glasgow-Pittsburgh Cerebral Performance Category (CPC) at discharge and recorded as CPC 1 (good performance), CPC 2 (moderate disability), CPC 3 (severe disability), CPC 4 (vegetative
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state), or CPC 5 (brain death or death) [18]. Neurologic outcome was dichotomized as either good (CPC 1 and CPC 2) or poor (CPC 3 to 5). The primary outcome was neurologic outcome at hospital discharge. The secondary outcomes were in-hospital mortality, serum lactate levels, lactate clearance, duration of MV, and ICU stay.
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2.4. Data Analysis
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Continuous variables are described as median values with interquartile ranges according to the results of the normality test for statistical analysis. Mann–Whitney U tests or Kruskal-Wallis
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tests were conducted for comparisons of continuous variables. Categorical variables are
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presented as frequencies and percentages. Comparisons of categorical variables were performed using the chi-square or Fisher exact tests, as appropriate. Multivariate logistic
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regression analysis was used to examine the association between NMB requirements and neurologic outcome at discharge or in-hospital mortality, after adjusting for confounders. All
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variables that were p < 0.2 in univariate analyses were included in the multivariate regression
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model. Backward selection was used to obtain the final model. The goodness-of-fit of the final model was evaluated using the Hosmer-Lemeshow test. A linear mixed model analysis was conducted to assess lactate change over time. Post hoc analysis at each time point was
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performed using the pairwise Mann–Whitney U test with Bonferroni correction. Data were analyzed using PASW/SPSSTM software, version 18 (IBM Inc., Chicago, IL, USA). A two-sided
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significance level of 0.05 was considered.
3. Results 3.1. Patient Population During the study period, 436 adult cardiac arrest survivors were treated with TTM. Thirtyeight patients were treated with extracorporeal membrane oxygenation, 35 died during TTM, 47 were treated with a different TTM protocol, and 7 were transferred (Figure 1). Finally, 309 patients were included in this study.
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Baseline characteristics are shown in Table 1. Poor neurologic outcome at discharge and inhospital mortality were reported in 206 (66.7%) and 73 (23.6%) patients, respectively. Table 1 shows comparisons of baseline characteristics among the NMB groups. There were differences in age, sex, first monitored rhythm, etiology, time to ROSC, epinephrine dose, arterial carbon dioxide tension, SOFA score, and induction duration among the three groups (Table 1). The
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bolus NMB and continuous NMB groups required 0.87 mg/Kg (0.38–1.57 mg/Kg) and 16.15
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mg/Kg (10.97–22.32 mg/kg) of atracurium during TTM, respectively (p < 0.001). The mean first bolus dose of atracurium was infused at 3 h (1–9 h) after initiation of TTM in the bolus NMB
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group, and at 2 h (1–5 h) in the continuous NMB group (p = 0.164). In the continuous NMB
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group, the infusion was started at 5 h (2–9 h) after initiation of TTM and was sustained for 37 h (27–44 h). Poor neurologic outcome at discharge and in-hospital mortality were low in the
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continuous NMB group.
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3.2. Association between Neuromuscular Blockade Requirements and Outcomes
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Table 2 shows the baseline characteristics according to neurologic outcome and in-hospital mortality. After multivariate adjustments, younger age, shockable rhythm, cardiac etiology, shorter time to ROSC, higher GCS, and continuous NMB (adjusted odds ratio [OR], 0.313; 95%
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confidence interval [CI], 0.120–0.815; p = 0.017) remained independently associated with better neurologic outcome (Table 3). After multivariate adjustments, cardiac etiology, higher GCS,
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lower serum lactate, lower serum glucose, lower SOFA score, and continuous NMB (adjusted OR, 0.414; 95% CI, 0.183–0.941; p = 0.035) remained independently associated with lower inhospital mortality (Table 4).
3.3. Serum Lactate Level and Lactate Clearance Figure 2 shows the serum lactate level over time according to NMB groups. The serum lactate level significantly decreased over time (p < 0.001); however, there were no differences in serum lactate level among the three NMB groups (p = 0.658)(Figure 2). Serum lactate levels were
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different between the neurologic outcome groups (p < 0.001) and decreased over time (p < 0.001) (Figure 2). Post hoc analysis showed that serum lactate levels differed between neurologic outcome groups at all time-points. Post hoc analysis showed that serum lactate levels differed between survivors and non-survivors (p < 0.001) and decreased over time (p < 0.001; Figure 2).
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Figure 3 shows the comparison of lactate clearance. Lactate clearance at all time-points did not
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differ among NMB groups (Figure 3). However, lactate clearance at all time-points differed between the good and poor neurologic outcome groups. Differences in lactate clearance at 48 h
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were observed between survivors and non-survivors, although there were no differences in
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lactate clearance at 12 h or 24 h (Figure 3).
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3.4. Weaning from Mechanical Ventilator, Duration of Mechanical Ventilator, and Intensive Care Unit Stay
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We compared the duration of MV and ICU stay in patients with discharge CPC scores of 1 to 3.
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There were 15, 45, and 51 subjects scoring a CPC of 1 to 3 in the no NMB, bolus NMB, and continuous NMB group, respectively. Successful weaning from MV was 13 (86.7%), 43 (95.6%), and 50 (98.0%) in no NMB, bolus NMB, and continuous NMB groups, respectively (p = 0.162).
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The median ICU stay was 14 d (11–24 d), 13 d (10–18 d), and 9 d (7–11 d) in the no NMB, bolus NMB, and continuous NMB group, respectively (p < 0.001). The median duration of MV was 8 d
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(5–4 d), 8 d (6–12 d), and 5 d (3–7 d) in the no NMB, bolus NMB, and continuous NMB group, respectively (p < 0.001). Post hoc analysis revealed that the ICU stay and duration of MV in the continuous NMB group were significantly shorter than in the other groups.
4. Discussion In this retrospective cohort of cardiac arrest survivors treated with TTM, we found that requirements for continuous NMB infusion, rather than requirement for no NMB, were independently associated with a decrease in poor neurologic outcome and lower in-hospital
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mortality. The serum lactate level and lactate clearance were not associated with NMB requirements. Among patients scoring CPC 1 to 3 at discharge, groups with requirements for continuous NMB infusion had a shorter MV duration and ICU stay than groups with no NMB requirements and groups with requirements for bolus NMB. Studies using NMB revealed differing results. In a randomized trial that infused bolus NMB
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every 2 h for a total 32 hours in a hypothermic group, the study showed the median time to
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achieve target temperature was 8 h after ROSC [4]. Whereas, the randomized trial by Bernard et al. infused continuous NMB in a hypothermic group until completion of rewarming, and they
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achieved the core temperature of 33.5°C within 120 min after ROSC [3]. However, another TTM
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trial used NMB as needed according to the discretion of the physician, and showed induction time of around 8 h after initiation of cooling [5]. We applied a stepwise protocol of NMB use and
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achieved target temperature within 2.3 h after initiation cooling. It seems a protocol for the active control of shivering would be helpful to achieve earlier target temperature. However,
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minimum NMB use has been suggested, despite its potent anti-shivering effect in cardiac arrest
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survivors [10]. There are several critical reasons to avoid NMB therapy. NMB use can mask clinical seizures or status epilepticus, devastating adverse events after cardiac arrest. NMB also increases the risk of polymyoneuropathy [16]. In order to reduce NMB use, a stepwise protocol,
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demonstrating effective control of shivering without over-sedation and paralysis, was introduced [9]. In the present study, NMB was used in a stepwise fashion to control shivering.
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Our findings are consistent with those of previous studies demonstrating improved survival with early continuous NMB use in cardiac arrest survivors treated with TTM [11]. However, there are subtle differences between reference groups from previous studies [11,15]. Since we thought that the characteristics would be different between no NMB and bolus NMB groups, in the present study the group with no NMB use was set as a separate reference group; previous studies included both groups into a non-continuous NMB group. Salciccioli et al. hypothesized that NMB could affect the evolution of oxygenation in cardiac arrest survivors and Papazian et al. demonstrated improved long-term survival by amelioration
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of pulmonary gas exchange with early continuous NMB in patients with acute respiratory distress syndrome [11,19]. However, Salciccioli et al. found no difference in the evolution of oxygenation between subjects with or without sustained NMB [11]. NMB allows controlled ventilation to sustain normocapnia. Asynchrony with mechanical ventilation leads to hypocapnia or hypercapnia; in cardiac arrest both are known to be associated with poor clinical
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outcome [20,21]. Shivering can be invisible and emerge as electrocardiographic artifact,
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electromyographic activity, or delayed achievement of target temperature [22]. Continuous NMB might control the invisible shivering that can mitigate the neuroprotective effect of TTM. The
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outcome of cardiac arrest survivors is thought to depend on multiple factors, not just
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oxygenation. Peberdy et al. demonstrated that the early inflammatory marker, interleukin-6, was higher in patients with poor outcomes after out-of-hospital cardiac arrest [23]. Continuous NMB
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use has been associated with a decreased proinflammatory response with decreased levels of interleukin-1β and interleukin-6 [24]. Therefore, the anti-inflammatory effect of NMB may have
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a role in improving outcomes in cardiac arrest. Lascarrou et al. also adopted a four-step protocol
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to control shivering in cardiac arrest survivors treated with therapeutic hypothermia [15]. They found that continuous NMB infusion was associated with improved ICU survival [15]. However, there may be a bias in the baseline characteristics of patients undergoing stepwise NMB infusion.
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In the present study, the continuous NMB group also had more favorable baseline characteristics, in terms of younger age, shockable rhythm, cardiac etiology, shorter time to ROSC, and lower
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SOFA score. It is well established that these variables are associated with good outcomes in cardiac arrest survivors. Nair et al. demonstrated the association between shivering during therapeutic hypothermia and increased chances of good neurologic outcome in cardiac arrest survivors undergoing therapeutic hypothermia [25]. The occurrence of shivering implies an intact thermoregulatory response of the brain against cooling. This, in turn, indicates less severe brain injury. Although a continuous NMB requirement was associated with good outcomes, after adjusting for confounding factors, stepwise NMB use was associated with a critical bias in the baseline characteristics of patients. Therefore, controlled trials are required to demonstrate the
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effect of continuous NMB infusion among cardiac arrest survivors. Serum lactate was suggested as a surrogate marker in cardiac arrest survivors, irrespective of TTM application [12-14,26,27]. Our findings that higher serum lactate values were associated with poor neurologic outcome and in-hospital mortality are concurrent with previous studies. Elevated serum lactate represents not only inadequate tissue perfusion but also increased
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metabolic demands owing to shivering during TTM. Serum lactate levels significantly decreased
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over time during post-cardiac arrest care. The change in serum lactate levels implies lactate clearance. Lactate clearance was suggested as a surrogate marker to predict outcomes among
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cardiac arrest survivors [13,14,26]. Higher lactate clearance is associated with good neurologic
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outcome or survival discharge [13,14,26]. Concurrent with previous studies, effective lactate clearance in the present study was associated with good neurologic outcome at discharge.
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Salciccioli et al. first demonstrated that NMB use was associated with increased lactate clearance in cardiac arrest survivors treated with TTM and they postulated that NMB may
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reduce metabolic demand by preventing shivering [11]. However, we found no association
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between NMB groups and serum lactate values, although the dose of NMB used was definitely higher in the continuous NMB group. The study by Lascarrou et al. applying a stepwise NMB use also showed no difference in serum lactate values or in variations of serum lactate between
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groups with and without continuous NMB therapy [15]. One potential explanation is that the initiation time of continuous NMB infusion or the duration of bolus NMB administration were
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not consistent across the subjects, while serum lactate levels were obtained regularly at the appointed time in the present study and in the study by Lascarrou et al. [15]. Randomized controlled trials of continuous NMB infusion are required to prove the effect of NMB use on serum lactate and lactate clearance. It is postulated that NMB decreases the clearance of pulmonary secretions and proinflammatory responses, and induces respiratory muscle weakness, eventually increasing the duration of MV [24,28]. However, a randomized controlled trial including 340 patients with acute respiratory distress syndrome demonstrated that continuous infusion of NMB increased
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ventilator-free days and days outside the ICU, and explained that early continuous NMB limited asynchrony-related alveolar collapse and overdistension [19]. In the present study, we investigated the successful weaning from MV, the duration of MV, and ICU stay in subjects with a CPC score of 1 to 3 at discharge. Consistent with the previously reviewed randomized trial the continuous NMB group had a significantly shorter duration of MV and ICU stay, although they
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received higher doses of NMB than the other groups. Therefore, muscular weakness,
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suppression of clearance of pulmonary secretion, or development of pneumonia from NMB use was considered negligible in our cohort. However, we did not evaluate long-term muscular
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weakness or neuropathy. Further studies are required to investigate the significant long-term
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polymyoneuropathy resulting from NMB use.
There are several limitations in the present study. First, this was a single-center retrospective
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study. Therefore, this study lacks generalizability, has potential selection bias, and tested for association, not causation. Exclusion criteria such as death during TTM can cause bias; however,
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the requirement of NMB was not certain in those patients. Second, although continuous NMB
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infusion was used for repetitive or intractable shivering, which interferes with cooling or ventilation, shivering was not assessed objectively. Third, neurologically intact patients were more likely to require continuous NMB infusion. The continuous NMB group showed more
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favorable clinical characteristics than the other groups. The duration and dose of continuous NMB infusion differed in accordance with the subjects’ characteristics. Therefore, to identify the
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true effect of NMB on outcomes, a randomized controlled trial is required. Fourth, withdrawal of life-sustaining therapies is not generally permitted in Korea. This explains the high proportion of poor neurologic outcome in the present study and this may have affected our results. Fifth, there may have been unmeasured and potentially confounding factors that were not considered in our multivariate analysis.
Conclusions The continuous use of NMB as compared to the absence of NMB was associated with improved
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neurologic outcome and survival discharge in cardiac arrest survivors undergoing TTM. However, the serum lactate level and lactate clearance were not associated with NMB requirements. Patients receiving continuous NMB infusion had a shorter duration of MV and a
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shorter ICU stay than those receiving no NMB and those receiving a bolus of NMB.
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therapeutic hypothermia is associated with a good neurologic outcome. Resuscitation
[26] Lee TR, Kang MJ, Cha WC, Shin TG, Sim MS, Jo IJ, et al. Better lactate clearance associated
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with good neurologic outcome in survivors who treated with therapeutic hypothermia after outof-hospital cardiac arrest. Crit Care 2013;17:R260. [27] Lee DH, Cho IS, Lee SH, Min YI, Min JH, Kim SH, et al. Correlation between initial serum levels of lactate after return of spontaneous circulation and survival and neurological outcomes in patients who undergo therapeutic hypothermia after cardiac arrest. Resuscitation 2015; 88:143-9. [28] Leone M, Delliaux S, Bourgoin A, Albanese J, Garnier F, Boyadjiev I, et al. Risk factors for late-onset ventilator-associated pneumonia in trauma patients receiving selective digestive
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decontamination. Intensive Care Med 2005;31:64-70.
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Legends to Figures Figure 1. A schematic diagram showing the selection process of patients for analysis
Figure 2. Comparisons of repeat serum lactate levels. (A) There is no interaction between NMB groups and time (p = 0.658). Serum lactate levels decreased over time (p < 0.001) and did not
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differ among NMB groups (p = 0.440). The included numbers for analyses at 12 h were 88, 118,
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and 91; at 24 h were 91, 118, and 97; and at 48 h were 84, 115, and 90 in no bolus, and continuous NMB groups, respectively. (B) There is no interaction between neurologic outcome
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and time (p = 0.701). There are differences in serum lactate levels between good and poor
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neurologic outcome groups (p < 0.001). Post hoc analysis after Bonferroni adjustment shows that the serum lactate levels at baseline, 12, 24, and 48 h after admission were significantly
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different between the two groups. The included numbers for analyses at 12 h were 100 and 197, at 24 h were 103 and 203, and at 48 h were 100 and 189 in good and poor neurologic outcome
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groups, respectively. (C) There is no interaction between in-hospital mortality and time
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(p = 0.698). Serum lactate level differs between survivors and non-survivors (p < 0.001). Posthoc analysis after Bonferroni adjustment shows that serum lactate levels at baseline, 12, 24, and 48 h after admission were significantly different between the two groups. The included numbers
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for analyses at 12 h were 226 and 71, at 24 h were 235 and 71, and at 48 h were 227 and 62 in
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survivors and non-survivors, respectively.
Figure 3. Comparison of lactate clearance between the groups. (A) Lactate clearances at 12, 24, and 48 h after admission are not different among the NMB groups. The included numbers for analyses at 12 h were 88, 118, and 91; at 24 h were 91, 118, and 97; and at 48 h were 84, 115, and 90 in no, bolus, and continuous NMB groups, respectively. (B) Lactate clearance at 12, 24, and 48 h after admission are different between good and poor neurologic outcome groups. The included numbers for analyses at 12 h were 100 and 197, at 24 h were 103 and 203, and at 48 h were 100 and 189 in good and poor neurologic outcome groups, respectively. (C) No differences
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in lactate clearance at 12 h and 24 h following admission are found between survivors and nonsurvivors. However, differences in lactate clearance 48 h after admission are observed between survivors and non-survivors. The included numbers for analyses at 12 h were 226 and 71, at 24
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h were 235 and 71, and at 48 h were 227 and 62 in survivors and non-survivors, respectively.
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Figure 3
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Table 1. Demographic and baseline characteristics of patients, stratified by neuromuscular blockade use Total
No NMB
Bolus NMB
Continuous
(N = 309)
(n = 93)
(n = 119)
NMB
p
66.0 (54.5–
60.0 (46.0–
57.0 (46.0–
70.0)
76.0)
69.0)
65.5)
Male sex
198 (64.1)
46 (49.5)
77 (64.7)
75 (77.3)
<0.001
Comorbidities ≥ 3
49 (15.9)
20 (21.5)
18 (15.1)
11 (11.3)
0.153
Shockable rhythm
107 (34.6)
16 (17.2)
42 (35.3)
49 (50.5)
< 0.001
Cardiac etiology
175 (56.6)
41 (44.1)
64 (53.8)
69 (71.1)
0.001
OHCA
248 (80.3)
70 (75.3)
99 (83.2)
79 (81.4)
0.334
Witnessed
229 (74.1)
69 (74.2)
93 (78.2)
67 (69.1)
0.317
Bystander CPR
192 (62.1)
54 (58.1)
79 (66.4)
59 (60.8)
0.440
Downtime, min (IQR)
27.0 (15.0–
30.0 (19.0–
25.0 (13.0–
25.0 (13.5–
0.035
38.0)
40.0)
37.0)
36.5)
2.0 (1.0–
3.0 (2.0–
2.0 (1.0–
2.0 (0.0–4.0),
4.0)
6.0)
4.0), 117*
95*
Glasgow Coma Scale
3 (3–3)
3 (3–3)
3 (3–3)
3 (3–4)
0.113
Lactate, mmol/L (IQR)
7.2 (4.0–
7.7 (4.2–
6.5 (4.0–
7.4 (4.2–10.2)
0.495
10.2)
10.4)
10.0)
226 (169–
233 (170–
217 (176–
232 (161–289)
0.374
293)
307)
286)
130 (80–
132 (80–
134 (85–
120 (76–208)
0.825
204)
218)
195)
36.0 (30.0–
39.0 (30.3–
34.0 (28.3–
38.0 (31.2–
0.044
during
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CPR, mg (IQR)
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Epinephrine
Glucose, mg/dL (IQR)
PaO2, mmHg (IQR)
PaCO2, mmHg (IQR)
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Age, yr (IQR)
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61.0 (50.0–
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(n = 97) <0.001
0.001
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45.0)
9 (7–12)
11 (8–13)
8 (7–12)
7 (6–11)
<0.001
36.0 (35.0–
35.5 (34.4–
36.1 (35.3–
36.2 (35.3–
0.006
36.7)
36.5)
36.6)
36.9)
210 (154–
215 (163–
210 (163–
205 (132–283)
291)
323)
291)
2.3 (1.3–
1.5 (1.0–
2.3 (1.5–
3.5)
2.8)
3.3)
12.5 (12.0–
13.0 (12.0–
12.5 (12.0–
12.0 (12.0–
14.9)
15.0)
15.0)
14.0)
206 (66.7)
81 (87.1)
78 (65.5)
47 (48.5)
<0.001
24 (20.2)
15 (15.5)
0.002
Pre-induction time, min (IQR) Induction duration, h (IQR) Rewarming duration, h (IQR) Poor
neurologic
In-hospital mortality
73 (23.6)
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outcome
34 (36.6)
3.0 (2.0–4.3)
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(IQR)
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42.5)
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Initial temperature, °C
47.0)
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SOFA score (IQR)
45.0)
0.315
<0.001
0.387
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NMB, neuromuscular blockade; IQR, interquartile range; OHCA, out-of-hospital cardiac arrest;
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CPR, cardiopulmonary resuscitation; SOFA, sequential organ failure assessment
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* included number for analysis
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Table 2. Demographic and baseline characteristics between outcome groups Good
Poor
(n = 103)
(n = 206)
p
Survivors
Non-
(n = 236)
survivors
p
(n = 73)
Male sex
64.0
(44.0–
(52.0–
62.0)
72.3)
74 (71.8)
124
<
59.0 (47.0–
65.0 (51.0–
0.001
69.0)
73.5)
0.044
152 (64.4)
artery
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Comorbidities Coronary
0.011
46 (63.0)
0.828
36 (15.3)
12 (16.4)
0.807
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(60.2)
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54.0
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Age, yr (IQR)
20 (19.4)
28 (13.6)
Heart failure
8 (7.8)
21 (10.2)
0.490
20 (8.5)
9 (12.3)
0.324
Hypertension
35 (34.0)
91 (44.2)
0.086
92 (39.0)
34 (46.6)
0.249
Diabetes
14 (13.6)
<
52 (22.0)
30 (41.1)
0.001
Renal disease
Hepatic disease First
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13 (6.3)
0.040
9 (3.8)
5 (6.8)
0.332
8 (7.8)
29 (14.1)
0.107
20 (8.5)
17 (23.3)
0.001
4 (3.9)
10 (4.9)
0.781
13 (5.5)
1 (1.4)
0.201
1 (1.0)
5 (2.4)
0.668
4 (1.7)
2 (2.7)
0.629
1 (1.0)
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CVA
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disease
68 (33.0)
0.001
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Pulmonary
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disease
0.183
monitored
<
rhythm
0.006
0.001
VF/pulseless VT
66 (64.1)
41 (19.9)
93 (39.4)
14 (19.2)
PEA
22 (21.4)
53 (25.7)
54 (22.9)
21 (28.8)
Asystole
14 (13.6)
110
86 (36.4)
38 (52.1)
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(53.4) Unknown
1 (1.0)
2 (1.0)
0 (0.0)
<
<
0.001
0.001
84 (81.6)
91 (44.2)
145 (61.4)
30 (41.1)
Other medical
12 (11.7)
57 (27.7)
47 (19.9)
22 (30.1)
Asphyxia
3 (2.9)
39 (18.9)
34 (14.4)
8 (11.0)
Drug overdose
4 (3.9)
17 (8.3)
10 (4.2)
11 (15.1)
Drowning
0 (0.0)
2 (1.0)
0 (0.0)
2 (2.7)
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0.312
OHCA
86 (83.5)
162
50 (68.5)
17 (16.5)
44 (21.4)
37 (16.1)
23 (31.5)
Witnessed
86 (83.5)
143
0.008
177 (75.0)
52 (71.2)
0.521
0.214
149 (63.1)
43 (58.9)
0.515
<
25.0 (15.0–
32.0 (16.0–
0.041
35.0)
42.5)
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IHCA
0.004
198 (83.9)
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(78.6)
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Location
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Cardiac
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Etiology
3 (1.3)
Time to ROSC, min
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(69.4)
21.0
30.0
(IQR)
(15.0–
(16.5–
30.0)
40.3)
1.0 (0.0–
3.0 (2.0–
<
2.0 (1.0–
4.0 (2.0–
3.0)
5.0), 202*
0.001
4.0), 233*
6.0), 72*
3 (3–6)
3 (3–3)
3 (3–4)
3 (3–3)
<0.001
6.7 (3.9–
8.7 (5.3–
0.001
9.5)
12.7)
Bystander CPR
69 (67.0)
123
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(59.7)
Epinephrine,
mg
(IQR) Glasgow Coma Scale (IQR) Lactate, (IQR)
0.001
<
<0.001
0.001 mmol/L
6.2 (3.8–
7.7 (4.5–
8.9)
11.0)
0.004
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(IQR) PaO2, mmHg (IQR)
PaCO2, mmHg (IQR)
SOFA score (IQR)
212 (157–
236 (180–
279)
300)
117 (77–
136 (82–
190)
211)
35.4
37.9
(31.0–
(29.0–
42.3)
46.8)
7 (6–10)
10 (7–12)
0.039
0.056
0.293
<
time,
min (IQR) Induction duration, h (IQR)
h (IQR)
202)
217)
36.1 (30.6–
35.8 (28.7–
44.0)
47.4)
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11 (9–15)
35.7 (34.5–
(35.7–
(34.6–
36.8)
36.4)
37.0)
36.4)
200 (145–
224 (160–
221 (155–
206 (143–
283)
300)
290)
303)
2.5 (1.5–
1.8 (1.0–
3.6)
3.0)
12.5 (12.0–
12.3 (12.0–
14.0)
15.8)
3.0 (2.0–
2.0 (1.0–
4.3)
3.0)
12.0
13.0
(12.0–
(12.0–
13.5)
15.0)
0.087
<0.001
0.075
0.047
0.955
0.993
< 0.001
36.1 (35.1–
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Rewarming duration,
124 (79–
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Pre-induction
133 (80–
<0.001
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(IQR)
317)
35.8
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°C
289)
36.4
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temperature,
255 (187–
8 (6–11)
0.001 Initial
218 (166–
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mg/dL
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Glucose,
0.044
0.626
0.014
0.574
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IQR, interquartile range; CVA, cerebrovascular accident; VF, ventricular fibrillation; VT, ventricular tachycardia; PEA, pulseless electrical activity; OHCA, out-of-hospital cardiac arrest; IHCA, in-hospital cardiac arrest; CPR, cardiopulmonary resuscitation; ROSC, restoration of spontaneous circulation; SOFA, sequential organ failure assessment * included number for analysis
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Table 3. Factors associated with poor neurologic outcome at discharge Odds ratio (95% CI)
p
1.040 (1.017 – 1.065)
0.001
Shockable rhythm
0.345 (0.159 – 0.749)
0.007
Cardiac etiology
0.232 (0.101 – 0.532)
0.001
Time to ROSC, min
1.054 (1.028 – 1.080)
<0.001
Glasgow Coma Scale
0.542 (0.407 – 0.721)
<0.001
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Bolus (n = 119)
0.433 (0.169 – 1.107)
0.080
Continuous (n = 97)
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Reference
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Neuromuscular blockade No (n = 93)
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Age, yr
0.313 (0.120 – 0.815)
0.017
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CI, confidence interval; ROSC, restoration of spontaneous circulation
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Table 4. Factors associated with in-hospital mortality Odds ratio (95% CI)
p
0.504 (0.262 – 0.971)
0.041
Glasgow Coma Scale
0.644 (0.433 – 0.958)
0.030
Lactate, mmol/L
1.098 (1.015 – 1.189)
0.020
Glucose, mg/dL
1.003 (1.000 – 1.006)
0.032
SOFA
1.234 (1.122 – 1.358)
<0.001
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Bolus (n = 119)
0.546 (0.271 – 1.100)
0.091
Continuous (n = 97)
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Reference
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Neuromuscular blockade No (n = 93)
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Cardiac etiology
0.414 (0.183 – 0.941)
0.035
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Highlights NMB requirement is related with good neurologic outcome in cardiac arrest patients.
Lactate clearance has no association with neuromuscular blockade requirement.
NMB use is deemed not to increase the duration of mechanical ventilation
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Dong Hun Lee, Byung Kook Lee, Kyung Woon Jeung, Yong Hun Jung, Yong Soo Cho, Chun Song Youn, Yong Il Min PII: DOI: Reference:
S0883-9441(17)30283-6 doi: 10.1016/j.jcrc.2017.04.026 YJCRC 52493
To appear in: Please cite this article as: Dong Hun Lee, Byung Kook Lee, Kyung Woon Jeung, Yong Hun Jung, Yong Soo Cho, Chun Song Youn, Yong Il Min , Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yjcrc(2016), doi: 10.1016/j.jcrc.2017.04.026
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Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management
Dong Hun Lee, MDa, Byung Kook Lee, MD, PhDa*, Kyung Woon Jeung, MD, PhDa, Yong Hun Jung,
of Emergency Medicine, Chonnam National University Hospital, 42 Jebong-ro,
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aDepartment
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MDa, Yong Soo Cho, MDa, Chun Song Youn, MDb, and Yong Il Min, MD, PhDa
Donggu, Gwangju, Republic of Korea
of Emergency Medicine, College of Medicine, The Catholic University of Korea, 222,
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* Corresponding author. Byung Kook Lee
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Banpo-daero, Seocho-gu, Seoul, Republic of Korea
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bDepartment
Address: Department of Emergency Medicine, Chonnam National University Hospital, 42
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Jebong-ro, Donggu, Gwangju, Republic of Korea
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Tel.: 82 62 220 6809; fax: 82 62 228 7417.
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Funding Sources
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E mail addresses: [email protected]
This work supported by a grant (CRI16024-1) Chonnam National University Hospital Biomedical Research Institute.
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Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management
Abstract Purpose: We examined the association between neuromuscular blockade (NMB) requirements
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and outcomes and lactate clearance in cardiac arrest survivors treated with targeted
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temperature management (TTM).
Methods: We included consecutive adult cardiac arrest survivors treated with TTM between
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2012 and 2015. NMB use was categorized into 3 groups: no NMB, bolus NMB (intermittent
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bolus use), and continuous NMB (continuous infusion). Serum lactate levels were measured on admission and at 12 h, 24 h, and 48 h after admission. The primary outcome was neurologic
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outcome at discharge. The secondary outcomes were in-hospital mortality and lactate clearance. Results: In total, 309 patients were included. Of these, 206 (66.7%) and 73 (23.6%) were
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discharged with poor neurologic outcome and death, respectively. Multivariate analysis
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revealed that continuous NMB, as opposed to no NMB use, was associated with decreased poor neurologic outcomes (odds ratio [OR], 0.317; 95% confidence interval [CI], 0.124–0.815) and decreased in-hospital mortality (OR, 0.414; 95% CI, 0.183–0.941). There were no differences in
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lactate clearance between the NMB groups. Conclusion: Continuous NMB requirement was associated with improved neurologic outcome
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and decreased in-hospital mortality in cardiac arrest survivors treated with TTM. The NMB requirement was not associated with lactate clearance.
Keywords: heart arrest; neuromuscular blockade; lactic acid; prognosis; induced hypothermia Abbreviations1
TTM, targeted temperature management; NMB, neuromuscular blockade; MV, mechanical ventilation; ICU, intensive care unit; CPR, cardiopulmonary resuscitation; GCS, Glasgow Coma Scale; ROSC, restoration of spontaneous circulation; SOFA, sequential organ failure assessment; CPC, cerebral performance category; OR, odds ratio; CI, confidence interval 1
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Neuromuscular blockade requirement is associated with good neurologic outcome in cardiac arrest survivors treated with targeted temperature management
1. Introduction Targeted temperature management (TTM) has become a standard treatment for comatose
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cardiac arrest survivors [1,2]. Based on randomized controlled trials, it is recommended that
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the temperature of comatose cardiac arrest survivors be lowered to the target temperature of 33°C or 36°C [3-5]. Shivering is a physiologic response to cooling or decreased body
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temperature; hence, it is one of the most common adverse events encountered during TTM.
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Shivering not only interferes with the achievement of the target temperature by generating heat but also increases metabolic activity, oxygen consumption, and cerebral metabolic stresses [6-8].
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Therefore, shivering should be controlled to preserve the beneficial effect of TTM in cardiac arrest survivors.
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A well-known anti-shivering protocol provides a stepwise strategy against shivering [9]. Non-
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sedatives, including acetaminophen, buspirone, and magnesium are used at the beginning of the intervention. However, opiates, sedatives, and even neuromuscular blockade (NMB) are required in patients with poorly controlled shivering [9]. The 2010 American Heart Association
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guidelines recommended minimal use of NMB during post-cardiac arrest care [10]. A multicenter study investigating the association between NMB use and outcome in cardiac arrest
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survivors undergoing TTM demonstrated that NMB use was associated with an increased probability of survival [11]. Improved lactate clearance, suggested as a surrogate marker for good outcomes in cardiac arrest survivors regardless of TTM, was associated with NMB use [1114]. However, another single center study reported that NMB use during TTM was associated with increased early-onset pneumonia [15]. NMB use is also associated with a risk of developing critical illness polyneuromyopathy [16]. There is limited evidence on NMB use in cardiac arrest survivors and the practice remains controversial. According to changes in our post-cardiac arrest care protocol, we have used NMB in a stepwise
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fashion instead of routine infusion of NMB since 2012. We hypothesized that NMB requirements were associated with improved clinical outcomes and lactate clearance. We evaluated the association between clinical outcomes and NMB requirements in cardiac arrest survivors treated with TTM. Furthermore, we also investigated the association between NMB requirements and lactate levels, lactate clearance, mechanical ventilator (MV) support, and
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intensive care unit (ICU) stay.
2. Materials and Methods
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2.1. Study Design and Population
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We performed a retrospective observational study involving adult comatose cardiac arrest survivors treated with TTM at Chonnam National University Hospital, Gwangju, Republic of
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Korea, between January 2012 and December 2015. This study was approved by the Institutional Review Board of Chonnam National University Hospital.
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Cardiac arrest survivors aged >18 years having completed TTM were included. Patients were
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excluded on the basis of the following criteria: (1) death during TTM, (2) transfer during TTM, (3) receipt of a TTM protocol with a different target temperature (< 32°C or > 34°C) or hypothermia duration (48 h or 72 h); and (4) extracorporeal membrane oxygenation applied
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during post-cardiac arrest care.
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2.2. Targeted Temperature Management protocol Cooling was initiated as soon as possible with ice packs, intravenous cold saline, and one of the following three TTM devices: Arctic Sun® Energy Transfer Pads™ (Medivance Corp, Louisville, KY, USA); Blanketrol® II (Cincinnati Subzero Products, Cincinnati, OH, USA); or COOLGARD3000® Thermal Regulation System (Alsius Corporation, Irvine, CA, USA). Core temperature was monitored using an esophageal temperature probe. Remifentanil and midazolam were routinely used for sedation and analgesia. During the 24-h maintenance phase, a target temperature of 33 ± 1°C was maintained. Upon completion of the maintenance phase, patients were rewarmed
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at a target rate of 0.25°C h−1. Advanced critical care, such as oxygenation, ventilation, glucose control, and hemodynamic optimization, was provided in accordance with the guidelines. Serum lactate levels were obtained on admission and at 12, 24, and 48 h after admission. We have changed the TTM protocol regarding NMB use since 2012 in accordance with the 2010 guidelines [10]. Shivering, which interferes with the achievement of the target temperature and
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with patient-ventilator synchrony, was initially controlled with a bolus infusion of atracurium
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(25 mg). Repeated bolus administration of atracurium was used to control shivering, if required. Poorly controlled shivering, despite repeated bolus administration of atracurium, was controlled
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by continuous infusion of atracurium, with an initial dose of 0.5 mg/kg/h. Continuous infusion
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of atracurium was at the discretion of the attending physician. Based on NMB requirements,
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subjects were divided into three groups: no NMB, bolus NMB, and continuous NMB.
2.3. Data Collection and Outcomes
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The following data were obtained for each patient: age, sex, comorbidities, first monitored
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rhythm, etiology of cardiac arrest, location of cardiac arrest, presence of a witness on collapse, bystander cardiopulmonary resuscitation (CPR), Glasgow Coma Scale (GCS) score after return of spontaneous circulation (ROSC), time to ROSC, epinephrine dose used during the intra-arrest
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period, glucose levels after ROSC, arterial oxygen tension after ROSC, arterial carbon dioxide tension after ROSC, initial temperature, pre-induction time, induction duration, rewarming
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duration, total dose of atracurium used during TTM, time of the first bolus atracurium infusion, time of initiation of continuous atracurium infusion, duration of continuous atracurium infusion, lactate values, lactate clearance (12, 24, and 48 h), weaning from MV, duration of MV, ICU stay, vital status at hospital discharge (alive or dead), and neurologic outcome at discharge. The sequential organ failure assessment (SOFA) score within the first 24 h of admission was used to assess the severity of multiple-organ dysfunction [17]. Neurologic outcome was assessed using the Glasgow-Pittsburgh Cerebral Performance Category (CPC) at discharge and recorded as CPC 1 (good performance), CPC 2 (moderate disability), CPC 3 (severe disability), CPC 4 (vegetative
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state), or CPC 5 (brain death or death) [18]. Neurologic outcome was dichotomized as either good (CPC 1 and CPC 2) or poor (CPC 3 to 5). The primary outcome was neurologic outcome at hospital discharge. The secondary outcomes were in-hospital mortality, serum lactate levels, lactate clearance, duration of MV, and ICU stay.
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2.4. Data Analysis
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Continuous variables are described as median values with interquartile ranges according to the results of the normality test for statistical analysis. Mann–Whitney U tests or Kruskal-Wallis
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tests were conducted for comparisons of continuous variables. Categorical variables are
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presented as frequencies and percentages. Comparisons of categorical variables were performed using the chi-square or Fisher exact tests, as appropriate. Multivariate logistic
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regression analysis was used to examine the association between NMB requirements and neurologic outcome at discharge or in-hospital mortality, after adjusting for confounders. All
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variables that were p < 0.2 in univariate analyses were included in the multivariate regression
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model. Backward selection was used to obtain the final model. The goodness-of-fit of the final model was evaluated using the Hosmer-Lemeshow test. A linear mixed model analysis was conducted to assess lactate change over time. Post hoc analysis at each time point was
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performed using the pairwise Mann–Whitney U test with Bonferroni correction. Data were analyzed using PASW/SPSSTM software, version 18 (IBM Inc., Chicago, IL, USA). A two-sided
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significance level of 0.05 was considered.
3. Results 3.1. Patient Population During the study period, 436 adult cardiac arrest survivors were treated with TTM. Thirtyeight patients were treated with extracorporeal membrane oxygenation, 35 died during TTM, 47 were treated with a different TTM protocol, and 7 were transferred (Figure 1). Finally, 309 patients were included in this study.
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Baseline characteristics are shown in Table 1. Poor neurologic outcome at discharge and inhospital mortality were reported in 206 (66.7%) and 73 (23.6%) patients, respectively. Table 1 shows comparisons of baseline characteristics among the NMB groups. There were differences in age, sex, first monitored rhythm, etiology, time to ROSC, epinephrine dose, arterial carbon dioxide tension, SOFA score, and induction duration among the three groups (Table 1). The
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bolus NMB and continuous NMB groups required 0.87 mg/Kg (0.38–1.57 mg/Kg) and 16.15
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mg/Kg (10.97–22.32 mg/kg) of atracurium during TTM, respectively (p < 0.001). The mean first bolus dose of atracurium was infused at 3 h (1–9 h) after initiation of TTM in the bolus NMB
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group, and at 2 h (1–5 h) in the continuous NMB group (p = 0.164). In the continuous NMB
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group, the infusion was started at 5 h (2–9 h) after initiation of TTM and was sustained for 37 h (27–44 h). Poor neurologic outcome at discharge and in-hospital mortality were low in the
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continuous NMB group.
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3.2. Association between Neuromuscular Blockade Requirements and Outcomes
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Table 2 shows the baseline characteristics according to neurologic outcome and in-hospital mortality. After multivariate adjustments, younger age, shockable rhythm, cardiac etiology, shorter time to ROSC, higher GCS, and continuous NMB (adjusted odds ratio [OR], 0.313; 95%
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confidence interval [CI], 0.120–0.815; p = 0.017) remained independently associated with better neurologic outcome (Table 3). After multivariate adjustments, cardiac etiology, higher GCS,
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lower serum lactate, lower serum glucose, lower SOFA score, and continuous NMB (adjusted OR, 0.414; 95% CI, 0.183–0.941; p = 0.035) remained independently associated with lower inhospital mortality (Table 4).
3.3. Serum Lactate Level and Lactate Clearance Figure 2 shows the serum lactate level over time according to NMB groups. The serum lactate level significantly decreased over time (p < 0.001); however, there were no differences in serum lactate level among the three NMB groups (p = 0.658)(Figure 2). Serum lactate levels were
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different between the neurologic outcome groups (p < 0.001) and decreased over time (p < 0.001) (Figure 2). Post hoc analysis showed that serum lactate levels differed between neurologic outcome groups at all time-points. Post hoc analysis showed that serum lactate levels differed between survivors and non-survivors (p < 0.001) and decreased over time (p < 0.001; Figure 2).
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Figure 3 shows the comparison of lactate clearance. Lactate clearance at all time-points did not
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differ among NMB groups (Figure 3). However, lactate clearance at all time-points differed between the good and poor neurologic outcome groups. Differences in lactate clearance at 48 h
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were observed between survivors and non-survivors, although there were no differences in
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lactate clearance at 12 h or 24 h (Figure 3).
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3.4. Weaning from Mechanical Ventilator, Duration of Mechanical Ventilator, and Intensive Care Unit Stay
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We compared the duration of MV and ICU stay in patients with discharge CPC scores of 1 to 3.
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There were 15, 45, and 51 subjects scoring a CPC of 1 to 3 in the no NMB, bolus NMB, and continuous NMB group, respectively. Successful weaning from MV was 13 (86.7%), 43 (95.6%), and 50 (98.0%) in no NMB, bolus NMB, and continuous NMB groups, respectively (p = 0.162).
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The median ICU stay was 14 d (11–24 d), 13 d (10–18 d), and 9 d (7–11 d) in the no NMB, bolus NMB, and continuous NMB group, respectively (p < 0.001). The median duration of MV was 8 d
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(5–4 d), 8 d (6–12 d), and 5 d (3–7 d) in the no NMB, bolus NMB, and continuous NMB group, respectively (p < 0.001). Post hoc analysis revealed that the ICU stay and duration of MV in the continuous NMB group were significantly shorter than in the other groups.
4. Discussion In this retrospective cohort of cardiac arrest survivors treated with TTM, we found that requirements for continuous NMB infusion, rather than requirement for no NMB, were independently associated with a decrease in poor neurologic outcome and lower in-hospital
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mortality. The serum lactate level and lactate clearance were not associated with NMB requirements. Among patients scoring CPC 1 to 3 at discharge, groups with requirements for continuous NMB infusion had a shorter MV duration and ICU stay than groups with no NMB requirements and groups with requirements for bolus NMB. Studies using NMB revealed differing results. In a randomized trial that infused bolus NMB
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every 2 h for a total 32 hours in a hypothermic group, the study showed the median time to
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achieve target temperature was 8 h after ROSC [4]. Whereas, the randomized trial by Bernard et al. infused continuous NMB in a hypothermic group until completion of rewarming, and they
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achieved the core temperature of 33.5°C within 120 min after ROSC [3]. However, another TTM
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trial used NMB as needed according to the discretion of the physician, and showed induction time of around 8 h after initiation of cooling [5]. We applied a stepwise protocol of NMB use and
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achieved target temperature within 2.3 h after initiation cooling. It seems a protocol for the active control of shivering would be helpful to achieve earlier target temperature. However,
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minimum NMB use has been suggested, despite its potent anti-shivering effect in cardiac arrest
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survivors [10]. There are several critical reasons to avoid NMB therapy. NMB use can mask clinical seizures or status epilepticus, devastating adverse events after cardiac arrest. NMB also increases the risk of polymyoneuropathy [16]. In order to reduce NMB use, a stepwise protocol,
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demonstrating effective control of shivering without over-sedation and paralysis, was introduced [9]. In the present study, NMB was used in a stepwise fashion to control shivering.
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Our findings are consistent with those of previous studies demonstrating improved survival with early continuous NMB use in cardiac arrest survivors treated with TTM [11]. However, there are subtle differences between reference groups from previous studies [11,15]. Since we thought that the characteristics would be different between no NMB and bolus NMB groups, in the present study the group with no NMB use was set as a separate reference group; previous studies included both groups into a non-continuous NMB group. Salciccioli et al. hypothesized that NMB could affect the evolution of oxygenation in cardiac arrest survivors and Papazian et al. demonstrated improved long-term survival by amelioration
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of pulmonary gas exchange with early continuous NMB in patients with acute respiratory distress syndrome [11,19]. However, Salciccioli et al. found no difference in the evolution of oxygenation between subjects with or without sustained NMB [11]. NMB allows controlled ventilation to sustain normocapnia. Asynchrony with mechanical ventilation leads to hypocapnia or hypercapnia; in cardiac arrest both are known to be associated with poor clinical
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outcome [20,21]. Shivering can be invisible and emerge as electrocardiographic artifact,
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electromyographic activity, or delayed achievement of target temperature [22]. Continuous NMB might control the invisible shivering that can mitigate the neuroprotective effect of TTM. The
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outcome of cardiac arrest survivors is thought to depend on multiple factors, not just
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oxygenation. Peberdy et al. demonstrated that the early inflammatory marker, interleukin-6, was higher in patients with poor outcomes after out-of-hospital cardiac arrest [23]. Continuous NMB
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use has been associated with a decreased proinflammatory response with decreased levels of interleukin-1β and interleukin-6 [24]. Therefore, the anti-inflammatory effect of NMB may have
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a role in improving outcomes in cardiac arrest. Lascarrou et al. also adopted a four-step protocol
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to control shivering in cardiac arrest survivors treated with therapeutic hypothermia [15]. They found that continuous NMB infusion was associated with improved ICU survival [15]. However, there may be a bias in the baseline characteristics of patients undergoing stepwise NMB infusion.
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In the present study, the continuous NMB group also had more favorable baseline characteristics, in terms of younger age, shockable rhythm, cardiac etiology, shorter time to ROSC, and lower
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SOFA score. It is well established that these variables are associated with good outcomes in cardiac arrest survivors. Nair et al. demonstrated the association between shivering during therapeutic hypothermia and increased chances of good neurologic outcome in cardiac arrest survivors undergoing therapeutic hypothermia [25]. The occurrence of shivering implies an intact thermoregulatory response of the brain against cooling. This, in turn, indicates less severe brain injury. Although a continuous NMB requirement was associated with good outcomes, after adjusting for confounding factors, stepwise NMB use was associated with a critical bias in the baseline characteristics of patients. Therefore, controlled trials are required to demonstrate the
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effect of continuous NMB infusion among cardiac arrest survivors. Serum lactate was suggested as a surrogate marker in cardiac arrest survivors, irrespective of TTM application [12-14,26,27]. Our findings that higher serum lactate values were associated with poor neurologic outcome and in-hospital mortality are concurrent with previous studies. Elevated serum lactate represents not only inadequate tissue perfusion but also increased
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metabolic demands owing to shivering during TTM. Serum lactate levels significantly decreased
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over time during post-cardiac arrest care. The change in serum lactate levels implies lactate clearance. Lactate clearance was suggested as a surrogate marker to predict outcomes among
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cardiac arrest survivors [13,14,26]. Higher lactate clearance is associated with good neurologic
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outcome or survival discharge [13,14,26]. Concurrent with previous studies, effective lactate clearance in the present study was associated with good neurologic outcome at discharge.
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Salciccioli et al. first demonstrated that NMB use was associated with increased lactate clearance in cardiac arrest survivors treated with TTM and they postulated that NMB may
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reduce metabolic demand by preventing shivering [11]. However, we found no association
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between NMB groups and serum lactate values, although the dose of NMB used was definitely higher in the continuous NMB group. The study by Lascarrou et al. applying a stepwise NMB use also showed no difference in serum lactate values or in variations of serum lactate between
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groups with and without continuous NMB therapy [15]. One potential explanation is that the initiation time of continuous NMB infusion or the duration of bolus NMB administration were
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not consistent across the subjects, while serum lactate levels were obtained regularly at the appointed time in the present study and in the study by Lascarrou et al. [15]. Randomized controlled trials of continuous NMB infusion are required to prove the effect of NMB use on serum lactate and lactate clearance. It is postulated that NMB decreases the clearance of pulmonary secretions and proinflammatory responses, and induces respiratory muscle weakness, eventually increasing the duration of MV [24,28]. However, a randomized controlled trial including 340 patients with acute respiratory distress syndrome demonstrated that continuous infusion of NMB increased
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ventilator-free days and days outside the ICU, and explained that early continuous NMB limited asynchrony-related alveolar collapse and overdistension [19]. In the present study, we investigated the successful weaning from MV, the duration of MV, and ICU stay in subjects with a CPC score of 1 to 3 at discharge. Consistent with the previously reviewed randomized trial the continuous NMB group had a significantly shorter duration of MV and ICU stay, although they
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received higher doses of NMB than the other groups. Therefore, muscular weakness,
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suppression of clearance of pulmonary secretion, or development of pneumonia from NMB use was considered negligible in our cohort. However, we did not evaluate long-term muscular
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weakness or neuropathy. Further studies are required to investigate the significant long-term
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polymyoneuropathy resulting from NMB use.
There are several limitations in the present study. First, this was a single-center retrospective
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study. Therefore, this study lacks generalizability, has potential selection bias, and tested for association, not causation. Exclusion criteria such as death during TTM can cause bias; however,
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the requirement of NMB was not certain in those patients. Second, although continuous NMB
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infusion was used for repetitive or intractable shivering, which interferes with cooling or ventilation, shivering was not assessed objectively. Third, neurologically intact patients were more likely to require continuous NMB infusion. The continuous NMB group showed more
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favorable clinical characteristics than the other groups. The duration and dose of continuous NMB infusion differed in accordance with the subjects’ characteristics. Therefore, to identify the
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true effect of NMB on outcomes, a randomized controlled trial is required. Fourth, withdrawal of life-sustaining therapies is not generally permitted in Korea. This explains the high proportion of poor neurologic outcome in the present study and this may have affected our results. Fifth, there may have been unmeasured and potentially confounding factors that were not considered in our multivariate analysis.
Conclusions The continuous use of NMB as compared to the absence of NMB was associated with improved
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neurologic outcome and survival discharge in cardiac arrest survivors undergoing TTM. However, the serum lactate level and lactate clearance were not associated with NMB requirements. Patients receiving continuous NMB infusion had a shorter duration of MV and a
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shorter ICU stay than those receiving no NMB and those receiving a bolus of NMB.
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References [1] Callaway CW, Donnino MW, Fink EL, Geocadin RG, Golan E, Kern KB, et al. Part 8: Post-cardiac arrest care: 2015 American Heart Association guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation 2015;132:S465-82. [2] Kim YM, Park KN, Choi SP, Lee BK, Park K, Kim J, et al. Part 4. Post-cardiac arrest care: 2015
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Korean Guidelines for cardiopulmonary resuscitation. Clin Exp Emerg Med 2016;3:S27-38.
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[3] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med
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2002;346:557-63.
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[4] Hypothermia after Cardiac Arrest Study G. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549-56.
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[5] Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest. N Engl J Med
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2013;369:2197-206.
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[6] De Witte J, Sessler DI. Perioperative shivering: physiology and pharmacology. Anesthesiology 2002;96:467-84.
[7] Peberdy MA, Donnino MW, Callaway CW, Dimaio JM, Geocadin RG, Ghaemmaghami CA, et al.
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Impact of percutaneous coronary intervention performance reporting on cardiac resuscitation
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centers: a scientific statement from the American Heart Association. Circulation 2013;128:762-
[8] Oddo M, Frangos S, Maloney-Wilensky E, Andrew Kofke W, Le Roux PD, Levine JM. Effect of shivering on brain tissue oxygenation during induced normothermia in patients with severe brain injury. Neurocrit Care 2010;12:10-6. [9]Choi HA, Ko SB, Presciutti M, Fernandez L, Carpenter AM, Lesch C, et al. Prevention of shivering during therapeutic temperature modulation: the Columbia anti-shivering protocol. Neurocrit Care 2011;14:389-94. [10] Peberdy MA, Callaway CW, Neumar RW, Geocadin RG, Zimmerman JL, Donnino M, et al. Part
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9: post-cardiac arrest care: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S768-86. [11] Salciccioli JD, Cocchi MN, Rittenberger JC, Peberdy MA, Ornato JP, Abella BS, et al. Continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients. Resuscitation 2013;84:1728-33.
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[12] Starodub R, Abella BS, Grossestreuer AV, Shofer FS, Perman SM, Leary M, et al. Association
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of serum lactate and survival outcomes in patients undergoing therapeutic hypothermia after cardiac arrest. Resuscitation 2013;84:1078-82.
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[13] Donnino MW, Miller J, Goyal N, Loomba M, Sankey SS, Dolcourt B, et al. Effective lactate
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clearance is associated with improved outcome in post-cardiac arrest patients. Resuscitation 2007;75:229-34.
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[14] Donnino MW, Andersen LW, Giberson T, Gaieski DF, Abella BS, Peberdy MA, et al. Initial lactate and lactate change in post-cardiac arrest: a multicenter validation study. Crit Care Med
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2014;42:1804-11.
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[15] Lascarrou JB, Le Gouge A, Dimet J, Lacherade JC, Martin-Lefevre L, Fiancette M, et al. Neuromuscular blockade during therapeutic hypothermia after cardiac arrest: observational study of neurological and infectious outcomes. Resuscitation 2014;85:1257-62.
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[16] Price D, Kenyon NJ, Stollenwerk N. A fresh look at paralytics in the critically ill: real promise and real concern. Ann Intensive Care 2012;2:43.
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[17] Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on "sepsis-related problems" of the European Society of Intensive Care Medicine. Crit Care Med 1998;26:1793-800. [18] Booth CM, Boone RH, Tomlinson G, Detsky AS. Is this patient dead, vegetative, or severely neurologically impaired? Assessing outcome for comatose survivors of cardiac arrest. JAMA 2004;291:870-9. [19] Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, et al. Neuromuscular
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blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107-16. [20] Roberts BW, Kilgannon JH, Chansky ME, Mittal N, Wooden J, Trzeciak S. Association between postresuscitation partial pressure of arterial carbon dioxide and neurologic outcome in patients with post-cardiac arrest syndrome. Circulation 2013;127:2107-13. [21] Lee BK, Jeung KW, Lee HY, Lee SJ, Jung YH, Lee WK, et al. Association between mean arterial
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blood gas tension and outcome in cardiac arrest patients treated with therapeutic hypothermia.
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Am J Emerg Med 2014;32:55-60.
[22] Seder DB, May T, Fraser GL, Riker RR. Shivering during therapeutic hypothermia after
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cardiac arrest. Resuscitation 2011;82:149.
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[23] Peberdy MA, Andersen LW, Abbate A, Thacker LR, Gaieski D, Abella BS, et al. Inflammatory markers following resuscitation from out-of-hospital cardiac arrest-A prospective multicenter
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observational study. Resuscitation 2016;103:117-24.
[24] Forel JM, Roch A, Marin V, Michelet P, Demory D, Blache JL, et al. Neuromuscular blocking
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agents decrease inflammatory response in patients presenting with acute respiratory distress
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syndrome. Crit Care Med 2006;34:2749-57. [25] Nair SU, Lundbye JB. The occurrence of shivering in cardiac arrest survivors undergoing
2013;84:626-9.
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therapeutic hypothermia is associated with a good neurologic outcome. Resuscitation
[26] Lee TR, Kang MJ, Cha WC, Shin TG, Sim MS, Jo IJ, et al. Better lactate clearance associated
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with good neurologic outcome in survivors who treated with therapeutic hypothermia after outof-hospital cardiac arrest. Crit Care 2013;17:R260. [27] Lee DH, Cho IS, Lee SH, Min YI, Min JH, Kim SH, et al. Correlation between initial serum levels of lactate after return of spontaneous circulation and survival and neurological outcomes in patients who undergo therapeutic hypothermia after cardiac arrest. Resuscitation 2015; 88:143-9. [28] Leone M, Delliaux S, Bourgoin A, Albanese J, Garnier F, Boyadjiev I, et al. Risk factors for late-onset ventilator-associated pneumonia in trauma patients receiving selective digestive
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decontamination. Intensive Care Med 2005;31:64-70.
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Legends to Figures Figure 1. A schematic diagram showing the selection process of patients for analysis
Figure 2. Comparisons of repeat serum lactate levels. (A) There is no interaction between NMB groups and time (p = 0.658). Serum lactate levels decreased over time (p < 0.001) and did not
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differ among NMB groups (p = 0.440). The included numbers for analyses at 12 h were 88, 118,
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and 91; at 24 h were 91, 118, and 97; and at 48 h were 84, 115, and 90 in no bolus, and continuous NMB groups, respectively. (B) There is no interaction between neurologic outcome
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and time (p = 0.701). There are differences in serum lactate levels between good and poor
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neurologic outcome groups (p < 0.001). Post hoc analysis after Bonferroni adjustment shows that the serum lactate levels at baseline, 12, 24, and 48 h after admission were significantly
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different between the two groups. The included numbers for analyses at 12 h were 100 and 197, at 24 h were 103 and 203, and at 48 h were 100 and 189 in good and poor neurologic outcome
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groups, respectively. (C) There is no interaction between in-hospital mortality and time
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(p = 0.698). Serum lactate level differs between survivors and non-survivors (p < 0.001). Posthoc analysis after Bonferroni adjustment shows that serum lactate levels at baseline, 12, 24, and 48 h after admission were significantly different between the two groups. The included numbers
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for analyses at 12 h were 226 and 71, at 24 h were 235 and 71, and at 48 h were 227 and 62 in
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survivors and non-survivors, respectively.
Figure 3. Comparison of lactate clearance between the groups. (A) Lactate clearances at 12, 24, and 48 h after admission are not different among the NMB groups. The included numbers for analyses at 12 h were 88, 118, and 91; at 24 h were 91, 118, and 97; and at 48 h were 84, 115, and 90 in no, bolus, and continuous NMB groups, respectively. (B) Lactate clearance at 12, 24, and 48 h after admission are different between good and poor neurologic outcome groups. The included numbers for analyses at 12 h were 100 and 197, at 24 h were 103 and 203, and at 48 h were 100 and 189 in good and poor neurologic outcome groups, respectively. (C) No differences
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in lactate clearance at 12 h and 24 h following admission are found between survivors and nonsurvivors. However, differences in lactate clearance 48 h after admission are observed between survivors and non-survivors. The included numbers for analyses at 12 h were 226 and 71, at 24
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h were 235 and 71, and at 48 h were 227 and 62 in survivors and non-survivors, respectively.
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Figure 3
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Table 1. Demographic and baseline characteristics of patients, stratified by neuromuscular blockade use Total
No NMB
Bolus NMB
Continuous
(N = 309)
(n = 93)
(n = 119)
NMB
p
66.0 (54.5–
60.0 (46.0–
57.0 (46.0–
70.0)
76.0)
69.0)
65.5)
Male sex
198 (64.1)
46 (49.5)
77 (64.7)
75 (77.3)
<0.001
Comorbidities ≥ 3
49 (15.9)
20 (21.5)
18 (15.1)
11 (11.3)
0.153
Shockable rhythm
107 (34.6)
16 (17.2)
42 (35.3)
49 (50.5)
< 0.001
Cardiac etiology
175 (56.6)
41 (44.1)
64 (53.8)
69 (71.1)
0.001
OHCA
248 (80.3)
70 (75.3)
99 (83.2)
79 (81.4)
0.334
Witnessed
229 (74.1)
69 (74.2)
93 (78.2)
67 (69.1)
0.317
Bystander CPR
192 (62.1)
54 (58.1)
79 (66.4)
59 (60.8)
0.440
Downtime, min (IQR)
27.0 (15.0–
30.0 (19.0–
25.0 (13.0–
25.0 (13.5–
0.035
38.0)
40.0)
37.0)
36.5)
2.0 (1.0–
3.0 (2.0–
2.0 (1.0–
2.0 (0.0–4.0),
4.0)
6.0)
4.0), 117*
95*
Glasgow Coma Scale
3 (3–3)
3 (3–3)
3 (3–3)
3 (3–4)
0.113
Lactate, mmol/L (IQR)
7.2 (4.0–
7.7 (4.2–
6.5 (4.0–
7.4 (4.2–10.2)
0.495
10.2)
10.4)
10.0)
226 (169–
233 (170–
217 (176–
232 (161–289)
0.374
293)
307)
286)
130 (80–
132 (80–
134 (85–
120 (76–208)
0.825
204)
218)
195)
36.0 (30.0–
39.0 (30.3–
34.0 (28.3–
38.0 (31.2–
0.044
during
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CPR, mg (IQR)
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Epinephrine
Glucose, mg/dL (IQR)
PaO2, mmHg (IQR)
PaCO2, mmHg (IQR)
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Age, yr (IQR)
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61.0 (50.0–
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(n = 97) <0.001
0.001
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45.0)
9 (7–12)
11 (8–13)
8 (7–12)
7 (6–11)
<0.001
36.0 (35.0–
35.5 (34.4–
36.1 (35.3–
36.2 (35.3–
0.006
36.7)
36.5)
36.6)
36.9)
210 (154–
215 (163–
210 (163–
205 (132–283)
291)
323)
291)
2.3 (1.3–
1.5 (1.0–
2.3 (1.5–
3.5)
2.8)
3.3)
12.5 (12.0–
13.0 (12.0–
12.5 (12.0–
12.0 (12.0–
14.9)
15.0)
15.0)
14.0)
206 (66.7)
81 (87.1)
78 (65.5)
47 (48.5)
<0.001
24 (20.2)
15 (15.5)
0.002
Pre-induction time, min (IQR) Induction duration, h (IQR) Rewarming duration, h (IQR) Poor
neurologic
In-hospital mortality
73 (23.6)
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34 (36.6)
3.0 (2.0–4.3)
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(IQR)
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42.5)
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Initial temperature, °C
47.0)
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SOFA score (IQR)
45.0)
0.315
<0.001
0.387
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Table 2. Demographic and baseline characteristics between outcome groups Good
Poor
(n = 103)
(n = 206)
p
Survivors
Non-
(n = 236)
survivors
p
(n = 73)
Male sex
64.0
(44.0–
(52.0–
62.0)
72.3)
74 (71.8)
124
<
59.0 (47.0–
65.0 (51.0–
0.001
69.0)
73.5)
0.044
152 (64.4)
artery
NU
Comorbidities Coronary
0.011
46 (63.0)
0.828
36 (15.3)
12 (16.4)
0.807
SC
(60.2)
PT
54.0
RI
Age, yr (IQR)
20 (19.4)
28 (13.6)
Heart failure
8 (7.8)
21 (10.2)
0.490
20 (8.5)
9 (12.3)
0.324
Hypertension
35 (34.0)
91 (44.2)
0.086
92 (39.0)
34 (46.6)
0.249
Diabetes
14 (13.6)
<
52 (22.0)
30 (41.1)
0.001
Renal disease
Hepatic disease First
D
13 (6.3)
0.040
9 (3.8)
5 (6.8)
0.332
8 (7.8)
29 (14.1)
0.107
20 (8.5)
17 (23.3)
0.001
4 (3.9)
10 (4.9)
0.781
13 (5.5)
1 (1.4)
0.201
1 (1.0)
5 (2.4)
0.668
4 (1.7)
2 (2.7)
0.629
1 (1.0)
AC
CVA
PT E
disease
68 (33.0)
0.001
CE
Pulmonary
MA
disease
0.183
monitored
<
rhythm
0.006
0.001
VF/pulseless VT
66 (64.1)
41 (19.9)
93 (39.4)
14 (19.2)
PEA
22 (21.4)
53 (25.7)
54 (22.9)
21 (28.8)
Asystole
14 (13.6)
110
86 (36.4)
38 (52.1)
ACCEPTED MANUSCRIPT
(53.4) Unknown
1 (1.0)
2 (1.0)
0 (0.0)
<
<
0.001
0.001
84 (81.6)
91 (44.2)
145 (61.4)
30 (41.1)
Other medical
12 (11.7)
57 (27.7)
47 (19.9)
22 (30.1)
Asphyxia
3 (2.9)
39 (18.9)
34 (14.4)
8 (11.0)
Drug overdose
4 (3.9)
17 (8.3)
10 (4.2)
11 (15.1)
Drowning
0 (0.0)
2 (1.0)
0 (0.0)
2 (2.7)
SC
0.312
OHCA
86 (83.5)
162
50 (68.5)
17 (16.5)
44 (21.4)
37 (16.1)
23 (31.5)
Witnessed
86 (83.5)
143
0.008
177 (75.0)
52 (71.2)
0.521
0.214
149 (63.1)
43 (58.9)
0.515
<
25.0 (15.0–
32.0 (16.0–
0.041
35.0)
42.5)
D
IHCA
0.004
198 (83.9)
MA
(78.6)
NU
Location
PT
Cardiac
RI
Etiology
3 (1.3)
Time to ROSC, min
PT E
(69.4)
21.0
30.0
(IQR)
(15.0–
(16.5–
30.0)
40.3)
1.0 (0.0–
3.0 (2.0–
<
2.0 (1.0–
4.0 (2.0–
3.0)
5.0), 202*
0.001
4.0), 233*
6.0), 72*
3 (3–6)
3 (3–3)
3 (3–4)
3 (3–3)
<0.001
6.7 (3.9–
8.7 (5.3–
0.001
9.5)
12.7)
Bystander CPR
69 (67.0)
123
AC
CE
(59.7)
Epinephrine,
mg
(IQR) Glasgow Coma Scale (IQR) Lactate, (IQR)
0.001
<
<0.001
0.001 mmol/L
6.2 (3.8–
7.7 (4.5–
8.9)
11.0)
0.004
ACCEPTED MANUSCRIPT
(IQR) PaO2, mmHg (IQR)
PaCO2, mmHg (IQR)
SOFA score (IQR)
212 (157–
236 (180–
279)
300)
117 (77–
136 (82–
190)
211)
35.4
37.9
(31.0–
(29.0–
42.3)
46.8)
7 (6–10)
10 (7–12)
0.039
0.056
0.293
<
time,
min (IQR) Induction duration, h (IQR)
h (IQR)
202)
217)
36.1 (30.6–
35.8 (28.7–
44.0)
47.4)
SC
11 (9–15)
35.7 (34.5–
(35.7–
(34.6–
36.8)
36.4)
37.0)
36.4)
200 (145–
224 (160–
221 (155–
206 (143–
283)
300)
290)
303)
2.5 (1.5–
1.8 (1.0–
3.6)
3.0)
12.5 (12.0–
12.3 (12.0–
14.0)
15.8)
3.0 (2.0–
2.0 (1.0–
4.3)
3.0)
12.0
13.0
(12.0–
(12.0–
13.5)
15.0)
0.087
<0.001
0.075
0.047
0.955
0.993
< 0.001
36.1 (35.1–
CE
Rewarming duration,
124 (79–
NU
Pre-induction
133 (80–
<0.001
MA
(IQR)
317)
35.8
D
°C
289)
36.4
PT E
temperature,
255 (187–
8 (6–11)
0.001 Initial
218 (166–
PT
mg/dL
RI
Glucose,
0.044
0.626
0.014
0.574
AC
IQR, interquartile range; CVA, cerebrovascular accident; VF, ventricular fibrillation; VT, ventricular tachycardia; PEA, pulseless electrical activity; OHCA, out-of-hospital cardiac arrest; IHCA, in-hospital cardiac arrest; CPR, cardiopulmonary resuscitation; ROSC, restoration of spontaneous circulation; SOFA, sequential organ failure assessment * included number for analysis
ACCEPTED MANUSCRIPT
Table 3. Factors associated with poor neurologic outcome at discharge Odds ratio (95% CI)
p
1.040 (1.017 – 1.065)
0.001
Shockable rhythm
0.345 (0.159 – 0.749)
0.007
Cardiac etiology
0.232 (0.101 – 0.532)
0.001
Time to ROSC, min
1.054 (1.028 – 1.080)
<0.001
Glasgow Coma Scale
0.542 (0.407 – 0.721)
<0.001
RI
Bolus (n = 119)
0.433 (0.169 – 1.107)
0.080
Continuous (n = 97)
NU
Reference
SC
Neuromuscular blockade No (n = 93)
PT
Age, yr
0.313 (0.120 – 0.815)
0.017
AC
CE
PT E
D
MA
CI, confidence interval; ROSC, restoration of spontaneous circulation
ACCEPTED MANUSCRIPT
Table 4. Factors associated with in-hospital mortality Odds ratio (95% CI)
p
0.504 (0.262 – 0.971)
0.041
Glasgow Coma Scale
0.644 (0.433 – 0.958)
0.030
Lactate, mmol/L
1.098 (1.015 – 1.189)
0.020
Glucose, mg/dL
1.003 (1.000 – 1.006)
0.032
SOFA
1.234 (1.122 – 1.358)
<0.001
RI
Bolus (n = 119)
0.546 (0.271 – 1.100)
0.091
Continuous (n = 97)
NU
Reference
SC
Neuromuscular blockade No (n = 93)
PT
Cardiac etiology
0.414 (0.183 – 0.941)
0.035
AC
CE
PT E
D
MA
CI, confidence interval; SOFA, sequential organ failure assessment
ACCEPTED MANUSCRIPT
Highlights NMB requirement is related with good neurologic outcome in cardiac arrest patients.
Lactate clearance has no association with neuromuscular blockade requirement.
NMB use is deemed not to increase the duration of mechanical ventilation
AC
CE
PT E
D
MA
NU
SC
RI
PT