Early- versus late-initiation of therapeutic hypothermia after cardiac arrest: Preliminary observations from the experience of 17 Italian intensive care units

doi:10.1016/j.resuscitation.2011.12.002

Resuscitation

Volume 83, Issue 7, July 2012, Pages 823-828

https://doi.org/10.1016/j.resuscitation.2011.12.002 Get rights and content

Abstract

Objectives

Mild therapeutic hypothermia (TH) has been shown to improve neurologic outcome in patients experiencing cardiac arrest after return of spontaneous circulation (ROSC). The best timing to initiate TH is currently not known. The aim of this study by the ICE (Italian Cooling Experience) group was to investigate the relationship between the timing of initiation of therapeutic hypothermia (TH) and both patient survival and neurologic outcome.

Methods

In this observational prospective clinical study we collected data on cardiac arrest patients admitted, after ROSC, to any of the 17 participating Italian intensive care units. Patients were managed according to routine clinical practice, including, in a group of patients, therapeutic hypothermia. Patients who underwent TH were classified, arbitrarily, into an early-initiation group (TH started <2 h since cardiac arrest) and a late-initiation group (TH started >2 h since cardiac arrest).

Results

Intensive care unit (ICU) mortality was 47.4% for the early-initiation group and 23.8% for the late-initiation group (P = 0.01). Six-month mortality was 60.8% for the early-initiation group and 40.5% for the late-initiation group (P = 0.04). Cerebral performance category (CPC, a measure of neuro-cognitive outcome) at ICU discharge was 1 [1–2] for the early-initiation group and 1 [1–3] for the late-initiation group (P = 0.57). At 6 months, CPC was 1 [1–1] for the early-initiation group and 1 [1–2] for the late-initiation group.

Discussion

Despite similar neurologic outcomes at every time point, mortality was significantly higher when therapeutic hypothermia was started within 2 h of cardiac arrest than when it was started later. Due to the lack of possibility to control several putative confounding factors, such results should be considered as preliminary observations warranting further research.

Introduction

Mild therapeutic hypothermia has been shown to improve the neurologic outcome of patients experiencing return of spontaneous circulation (ROSC) after an episode of cardiac arrest.1, 2 Therapeutic hypothermia is therefore an important and clinically useful measure to implement during the immediate post-resuscitation care period.3, 4

Several laboratory trials have suggested that neurologic outcome might be improved by a rapid initiation of therapeutic cooling5, 6, 7, 8 but, despite the results of several clinical trials, the best timing to start therapeutic hypothermia remains unknown.9, 10, 11, 12

In this observational prospective multicentre study (ICE study), we aimed at investigating, in a population of cardiac arrest patients admitted to several Italian intensive care units after experiencing return of spontaneous circulation, the effects of the timing of initiation of therapeutic hypothermia on both survival and neurologic outcome.

Section snippets

Study design

The ICE (Italian Cooling Experience) study was designed as an observational prospective clinical study. The main aim of the study was to investigate the relationship between the timing of initiation of therapeutic hypothermia (TH) and both patient survival or neurologic outcome.

It was conceived as multicentre study conducted at 17 intensive care units (ICU) in Italy. All patients (not matching exclusion criteria) admitted to these units after an episode of cardiac arrest were included in the

Cardiac arrest patient population

Between January 2009 and September 2009, 174 patients experiencing return of spontaneous circulation (ROSC) after an episode of cardiac arrest were admitted to the 17 intensive care units participating in the study. Return of spontaneous circulation (ROSC) was attained a median of 20 [10–30] min after cardiac arrest. Out-of-hospital cardiac arrest had occurred in 73.7% of cases.

Therapeutic hypothermia

The most relevant characteristics of patients undergoing therapeutic hypothermia are reported in Table 1. In the

Discussion

The ICE study was conducted at a group of intensive care units routinely using therapeutic hypothermia to manage patients experiencing cardiac arrest. In our experience, a large number of comatose cardiac arrest patients – after experiencing return of spontaneous circulation (ROSC) – underwent therapeutic hypothermia (69.7%) within a short time frame (median time to initiate cooling: 90 [50–160] min). The response time of the participating centres was indeed exceptionally short, especially in

Conclusions

In conclusion, while in Italy therapeutic hypothermia is marginally employed as a therapeutic strategy – as noted in a recent survey by Bianchin et al.²⁰ – the centres participating in the ICE study have shown considerable expertise into it with ability to rapidly implement therapeutic hypothermia in cardiac arrest patients admitted to their intensive care units after return of spontaneous circulation. A surprising finding of this study was that starting hypothermia early was associated with

Conflicts of interest

All the authors declare they have no financial or personal conflicts of interest.

Acknowledgements

We are grateful to all physicians and nurses who cared after the patients enrolled in this study.

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Due to TTM's neuroprotective effect,6,7 many researchers have hypothesized that quicker time to target temperature following initiation of TTM would yield better outcomes. Prior studies in animals have supported this hypothesis8–10 but studies in humans have provided mixed results.11–13 One potential explanation for the inconclusive findings in humans is the heterogeneity of the patients included in the studies.
Evaluate the relationship between heat generation during rewarming in post-cardiac arrest patients receiving targeted temperature management (TTM) as a surrogate of thermoregulatory ability and clinical outcomes.
This is a prospective observational single-centre study conducted at an urban tertiary-care hospital. We included post-cardiac arrest adults who received TTM via surface cooling device between April 2018 and June 2019.
Patient heat generation was calculated by multiplying the inverse of the average machine water temperature with time to rewarm to 37 °C and standardized in two ways to account for target temperature variation: (1) divided by number of degrees between target temperature and 37 °C, and (2) limited to when patient was rewarmed from 36 °C to 37 °C. The primary outcome was poor neurologic status, defined as Cerebral Performance Category (CPC) score 3–5, and the secondary outcome was 30-day survival. Sixty-six patients were included: 45 (68%) had a CPC-score of 3–5 and 23 (35%) were alive at 30 days. Besides initial rhythm and arrest downtime, baseline characteristics were similar between outcomes. Heat generation was not associated with poor neurological outcome (CPC 3–5: 6.6 [IQR: 6.1, 7.4] versus CPC 1–2: 6.6 [IQR: 5.7, 7.6], p = 0.89) or survival at 30 days (non-survivors: 6.6 [IQR: 6.6, 7.4] vs. survivors: 6.6 [IQR: 5.7, 8.0, p = 0.78]).
Heat generation during rewarming was not associated with neurologic outcomes. However, there was a relationship between poor neurological outcome and higher median water temperatures. Time to rewarm was prolonged in patients with poor neurological outcome.
Post-cardiac arrest care and targeted temperature management: A consensus of scientific statement from the Taiwan Society of Emergency & Critical Care Medicine, Taiwan Society of Critical Care Medicine and Taiwan Society of Emergency Medicine
2021, Journal of the Formosan Medical Association
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Worse outcome was noted if the targeted temperature was reached faster in a retrospective study. However, there is no intervention study showing that delayed onset or slower rate of cooling can improve outcome.51 The conflicts of results may come from the different severities of brain injury.
Post-cardiac arrest care is critically important in bringing cardiac arrest patients to functional recovery after the detrimental event. More high quality studies are published and evidence is accumulated for the post-cardiac arrest care in the recent years. It is still a challenge for the clinicians to integrate these scientific data into the real clinical practice for such a complicated intensive care involving many different disciplines.
With the cooperation of the experienced experts from all disciplines relevant to post-cardiac arrest care, the consensus of the scientific statement was generated and supported by three major scientific groups for emergency and critical care in post-cardiac arrest care.
High quality post-cardiac arrest care, including targeted temperature management, early evaluation of possible acute coronary event and intensive care for hemodynamic and respiratory care are inevitably needed to get full recovery for cardiac arrest. Management of these critical issues were reviewed and proposed in the consensus
The goal of the statement is to provide help for the clinical physician to achieve better quality and evidence-based care in post-cardiac arrest period.
Cold fluids for induction of targeted temperature management: A sub-study of the TTH48 trial
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Pre-intensive care unit (ICU) induction of targeted temperature management (TTM) with cold intravenous (i.v.) fluids does not appear to improve outcomes after in out-of-hospital cardiac arrest (OHCA). We hypothesized that this may be due to ineffective cooling and side effects.
A post hoc analysis of a sub-group of patients (n = 352) in the TTH48 trial (NCT01689077) who received or did not receive pre-ICU cooling using cold i.v. fluids. Data collection included patient characteristics, cardiac arrest factors, cooling methods, side effects and continuous core temperature measurements. The primary endpoint was the time to target temperature (TTT, <34 °C), and the secondary endpoints included the incidence of circulatory side effects, abnormal electrolyte levels and hypoxia within the first 24 h of ICU care. A difference of 1 h in the TTT was determined as clinically significant a priori.
Of 352 patients included in the present analysis, 110 received pre-ICU cold fluids. The median time to the return of spontaneous circulation (ROSC) and TTT in the pre-ICU cold fluids group was longer than that of the group that did not receive pre-ICU cold fluids (318 vs. 281 min, p < 0.01). In a linear regression model including the treatment centre, body mass index (BMI), chronic heart failure, diabetes mellitus and time to ROSC, the use of pre-ICU cold i.v. fluids was not associated with a shorter time to the target temperature (standardized beta coefficient: 0.06, 95% CI for B -49 and 16, p  =  0.32). According to the receipt or not of pre-ICU cold i.v. fluids, there was no difference in the proportion of patients with hypoxia on ICU admission (1.8% vs. 3.3%, p =  0.43) or the proportion of patients with electrolyte abnormalities (hyponatremia: 1.8% vs. 2.9% p = 0.54; hypokalaemia: 1.8% vs. 4.5%, p =  0.20). Furthermore, there was no difference in hospital mortality between the groups.
The initiation of TTM with cold i.v. fluids before ICU arrival did not decrease the TTT. We detected no significant between-group difference in mortality or the incidence of side effects according to the administration or not of pre-ICU cold i.v fluids.
Improvement of consciousness before initiating targeted temperature management
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Following cardiac arrest, return of spontaneous circulation (ROSC) in patients may be followed by spontaneous neurological recovery, which may decrease the potential adverse effects of treatments in post-cardiac arrest care, including those of Targeted Temperature Management (TTM). We investigated the percentage of post-arrest patients who experienced spontaneous neurological recovery, and the characteristics and neurological outcomes of these patients.
A total of 540 patients with ROSC were retrospectively enrolled in this single-center observational study. The patients’ motor responses were documented immediately and at 3 h following ROSC. Predictors of spontaneous neurological recovery were assessed by multiple logistic regression analysis.
A total of 221 patients (41%) showed a change in their GCS (Glasgow Coma Score) M score (motor score) during the 3-h interval following ROSC, with improvement evident in 215 patients. Among 96 patients with GCS M6 at 3 h, 83 (86%) were discharged with a favorable neurological outcome. GCS M6 at 3 h post ROSC, was an independent predictor for a favorable neurological outcome, but GCS M6 at ROSC was not. There were four factors predicting the GCS M6 at 3 h; including in-hospital cardiac arrest (OR 3.057; 95% CI: 1.370–6.824, P = 0.006); bystander CPR (OR 13.311; 95% CI: 6.455–27.447, P < 0.0001); the CPR duration (OR, 0.941; 95% CI: 0.91–0.974; P < 0.0001), and the initial shockable rhythm (OR, 4.41; 95% CI: 2.44–7.95; P < 0.0001).
A significant portion of patients had spontaneous neurological recovery to GCS M6 within 3 h post ROSC, and had a favorable neurological outcome. Close monitoring of GCS and later initiation of TTM should be considered in those patients with a substantial likelihood of neurological recovery.
Efficacy of the cooling method for targeted temperature management in post-cardiac arrest patients: A systematic review and meta-analysis
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Only 2 studies reported the time interval from CPR to cooling of TTM; therefore, the effect of earlier cooling on TTM patient outcome was not evaluated in this study. Previous human studies that have assessed the relationship between cooling time and outcomes have shown inconsistent results concerning the benefits of earlier cooling.45–53 Therefore, we postulated that the time to cooling could affect the outcome for TTM patients but not significantly.
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A systematic literature search was conducted using MEDLINE, EMBASE, and the Cochrane Library to identify randomized controlled trials (RCT) and observational studies (OS) comparing mortality and neurological status for patients treated with ECD or SCD.
The meta-analysis comprised 4,401 patients from 2 RCT and 7 OS. For mortality, the overall pooled analysis showed no statistically significant difference between ECD and SCD recipients (RR, 0.93; 95% CI 0.86–1.00; I² = 0%). Further, no statistically significant difference was observed between RCT (RR, 0.80; 95% CI 0.56–1.14; I² = 0%) and OS (RR, 0.94; 95% CI 0.85–1.04; I² = 18%) for in-hospital mortality.
For good neurological status of survivors after TTM, the overall pooled analysis showed no statistically significant difference between ECD and SCD (RR, 1.08; 95% CI 0.99–1.18; I² = 71%). No statistically significant difference was found between ECD and SCD at hospital discharge in RCT (RR, 0.88; 95% CI 0.61–1.28; I² = 0%) and at 6 months in OS (RR, 1.03; 95% CI 0.99–1.09; I² = 32%).
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Relationship between timing of cooling and outcomes in adult comatose cardiac arrest patients treated with targeted temperature management
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Studies examining associations between time to target temperature and outcomes in cardiac arrest patients who underwent targeted temperature management (TTM) have shown inconsistent results. We examined these associations separately for time from restoration of spontaneous circulation to TTM initiation (pre-induction time) and time from TTM initiation to target temperature (induction time). Furthermore, we examined whether critical time thresholds exist if there is an association.
This was a single-centre retrospective observational study including adult cardiac arrest patients treated with TTM from 2008 to 2015. We tested the associations of pre-induction time and induction time with outcomes at hospital discharge using multivariate logistic regression analysis. We then performed additional multivariate analyses, each with the significant timing variable at different binary cutoffs.
A total of 515 patients were analysed. At hospital discharge, 357 patients (69.3%) were alive, of whom 161 (31.3%) had a favourable neurologic outcome. In multivariate analysis, a shorter pre-induction time was independently associated with a favourable neurologic outcome (odds ratio [OR], 1.110; 95% confidence interval [CI], 1.025–1.202), whereas the induction time was not (OR, 0.954; 95% CI, 0.852–1.067). We found two pre-induction time thresholds (120 and 360 min) that were associated with neurologic outcome.
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^☆: A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2011.12.002.

^a: The individual investigators who participated in the study as the Italian Cooling Experience Study Group are listed in Appendix A. Salvatore Alongi, M.D. (U.O. Anestesia e Rianimazione, Fondazione IRCCS – Ospedale Maggiore Policlinico, Milan, Italy, e-mail: [email protected], tel.: +39 02 5503 3232) assumes the overall responsibility for the integrity of the report.

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Clinical paperEarly- versus late-initiation of therapeutic hypothermia after cardiac arrest: Preliminary observations from the experience of 17 Italian intensive care units☆

Abstract

Objectives

Methods

Results

Discussion

Introduction

Section snippets

Study design

Cardiac arrest patient population

Therapeutic hypothermia

Discussion

Conclusions

Conflicts of interest

Acknowledgements

Resuscitation

Resuscitation

Resuscitation

Resuscitation

Int J Cardiol

Lancet

Resuscitation

Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest

N Engl J Med

Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia

N Engl J Med

Hypothermia and neurological outcome after cardiac arrest: state of the art

Eur J Anaesthesiol (Suppl)

Clinical paper
Early- versus late-initiation of therapeutic hypothermia after cardiac arrest: Preliminary observations from the experience of 17 Italian intensive care units☆