a b s t r a c t

Introduction: The recommended target temperature in the treatment of comatous patients after cardiac arrest has recently changed. We analyzed the impact on the neurological outcome of a change in the target temperature from July 2021.

Material and methods: This was a retrospective analysis comparing the discharge status of 78 patients with a tar- get temperature of 33 ?C (group 1) with that of 24 patients with a target temperature of 36.5 ?C (group 2). Pear- son chi-square and Mann-Whitney U tests were used.

Results: The initial rhythm was defibrillable in 65% of group 1 and 71% of group 2, and cardiac arrest was witnessed in 93% of group 1 and 96% of group 2. There was an adverse outcome (death or vegetative state) in 37 patients in group 1 (47%) compared to 18 in group 2 (74%) (Pearson chi-square 5.612, p = 0.018).

Conclusions: In our series of patients, the Temperature control target temperature change from 33 ?C to 36.5 ?C was associated with worse neurological outcome. Further studies are needed to evaluate the outcome of a gen- eralized modification of temperature control targets in comatose patients after cardiac arrest in our postpandemic era.

(C) 2023

1. Introduction

Improving the prognosis and neurological outcome of patients who remain in coma after recovery from cardiac arrest is still a challenge today, and control of temperature plays a key role. Hyperthermia during the first hours is associated with a worse Neurological prognosis, with an odds ratio of 2.2 for every 1 ?C increase in temperature [1]. In 2002, the publication of two studies demonstrating a significant improvement in prognosis by applying a protocol of Mild hypothermia at 32-34 ?C had a rapid impact on clinical recommendations and guidelines [2-4]. Years later, some studies have questioned the usefulness of hypother- mia as a therapeutic tool, focusing more on the control of hyperthermia. In June 2021, the results of the TTM2 study were published, demonstrat- ing the equality in terms of neurological outcomes of a mild

Abbreviations: CPC, Cerebral performance category; TTM, target temperature management trial; ROSC, recovery of spontaneous circulation; ECMO, extracorporeal membrane oxygenation.

* Corresponding author at: Coronary Unit, University Hospital Virgen Macarena, Avenida Doctor Fedriani sn, Sevilla, Spain.

E-mail address: Grubira1@gmail.com (J.C. Garcia-Rubira).

hypothermia protocol versus a temperature control protocol below

37.8 ?C [5]. We present the clinical outcomes of our patients treated with active control of temperature in relation to the change in temper- ature target.

1. Material and methods

A retrospective analysis of patients admitted to our coronary unit between December 2012 and December 2022 was performed. During this period, 230 patients were admitted to our coronary unit for resusci- tated cardiac arrest. The period after February 2020 was considered the postpandemic period. Patients who presented with a motor Glasgow score less than 6 and received therapeutic hypothermia were included in the analysis. The target temperature of the protocol between 2012 and June 2021 was 33 ?C, and from July 2021 onwards, it was 36.5 ?C. To maintain temperature control, a specific device (Coolgard^R or Artic Sun^R) was preferably used, or if no device was available, protected ice packs and cold saline were used. After maintaining the target tempera- ture for 24 h, patients were slowly rewarmed to 37 ?C in 12 h, and sub- sequently, the temperature was maintained below 37.6 ?C until 72 h. The patients treated with therapeutic hypothermia during the first

https://doi.org/10.1016/j.ajem.2023.06.004

0735-6757/(C) 2023

period constituted group A, and the patients in the second period con- stituted group B. Awakening was defined as a Glasgow motor scale of

6. In patients who did not recover consciousness in the first 72 h after completion of the hypothermia protocol (108 h after returning of spon- taneous circulation), the neurological prognosis was established with the collaboration of a neurologist. Clinical examination, repeated elec- troencephalograms, somatosensory evoked potentials, and computed axial tomography were considered, as described in the TTM study pro- tocol (1). brain magnetic resonance imaging and neurospecific enolase were used systematically from 2016, and since 2021, prognostic evalu- ation began to be considered as early as 72 h after the recovery of spon- taneous circulation after cardiac arrest, according to the guidelines of the European Resuscitation Council (2). In the absence of motor re- sponse, when the multidisciplinary evaluation clearly established a poor neurological prognosis, the withdrawal of life support measures was offered to the patient’s family. We compared the clinical character- istics, resuscitation data and clinical outcomes between the two groups. For clinical outcome, we used the CPC scale, which ranges from 1 (com- plete neurological recovery or with minimal disability) to 5 (death) [6]. A CPC scale of 4 (Persistent vegetative state) or 5 was considered a poor outcome, and a CPC scale of 1 or 2 was considered a good outcome. Qualitative variables are presented as percentages and were compared using the Pearson chi-square test. Quantitative variables are presented as the median and interquartile range and were compared using the Mann-Whitney U test, with values of p < 0.05 considered significant.

All appropriate ethical guidelines for the use of human subjects were followed, and we obtained approval from the ethics committee of the University Hospital Virgen Macarena.

1. Results

A total of 102 patients were included in the study, 78 in group A (tar- get 33 ?C) and 24 in group B (target 36.5 ?C). The median age was 66 years (52, 74); 30 were women (29%), and 72 were men (71%). Car- diac arrest was out-of-hospital in 76 patients (75%), witnessed in 93 pa- tients (91%), not witnessed in 6 patients, and not recorded in 3 patients. We recorded the time to recovery of spontaneous circulation (ROSC) in 45 patients with a median of 25 min (20, 40). The first rhythm was defibrillable in 68 patients (67%), and ST-segment elevation was present on admission in 26 patients (26%). A specific hypothermia device was used in 92 patients (90%). None of our patients had COVID-19 infection on admission. No patients in this series received ECMO assistance.

Table 1 shows the comparison of groups A and B. There were no dif- ferences in clinical characteristics, except for the initial Glasgow scale, which was more frequently worse than 6 in group A than in group B. All the patients in group B belonged to the postpandemic period, com- pared to 8 (10%) in group A. Awakening occurred in 58% of group A pa- tients, and in 29% of group B patients (p = 0.015). Ten patients awoke later than 7 days after admission, 9 of them in group A, 1 in group B, all but one awoke in the coronary unit. Patients in group A had more fre- quently good outcome (49% vs 25%, p 0.040) and less frequently bad outcome (47% vs 75%, p 0.018, Fig. 1).

1. Discussion

The publication of the TTM-2 study, which found that there was no benefit in a reduction of body temperature to 33? versus active control avoiding a temperature greater than 37.8 ?C [7], prompted our group to modify the target temperature, setting it at 36.5?, with the confidence of not worsening neurological prognosis. Our protocol was equally rig- orous after the target temperature change. The only additional change was the elimination of Neuromuscular blockade, which with the previ- ous protocol we administered systematically. However, analysis of the cases included up to December 2023 demonstrates that with the new protocol, the results are significantly worse, reaching statistical signifi- cance despite the number of patients being relatively small. The clinical

Table 1

Comparison of characteristics, management and clinical outcome according to the target temperature.

MI: myocardial infarction; ROSC: Time to return of spontaneous circulation, in minutes; CPC: cerebral performance category; WOLST: withdrawal of life-sustaining therapy; ICU: intensive care unit.

characteristics, type of rhythm, and ROSC time were similar between both groups, except for the Glasgow score, which was somewhat worse in group A, which nevertheless had a better neurological out- come. There was a trend toward a higher percentage of patients who were withdrawn from life support measures in the ICU in group B (Table 1). However, it is difficult to think that this could influence our outcome, as all patients who were withdrawn from life support mea- sures had established evidence of poor neurological prognosis. Our re- sult also cannot be attributed to greater deviation in the temperature target. Only three patients had hyperthermia in the first 72 h, all of whom were in group A (Table 1).

There are two other confounding factors whose relevance we cannot clarify with our study: neuromuscular blockade and the postpandemic era. A recent meta-analysis suggests that the routine use of neuromus- cular blocking agents during temperature control after cardiac arrest improves the prognosis and neurological outcome of patients [8]. On the other hand, the pandemic has had an adverse influence on the car- diac arrest Chain of survival, and several studies have demonstrated this [9], which may have some influence on whether patients arriving at the hospital might benefit from a lower temperature target and not just control to 37.7 ?C, as recommended by the European Resuscitation Council [10].

The publication of the TTM study, which found no difference be- tween temperature control at 33 ?C versus 36 ?C [11], had a major im- pact on protocols for the care of comatose patients after cardiac arrest. However, some studies found worse temperature control in hospitals that had modified the target to 36 ?C and a trend toward worse neuro- logical outcomes, while numerous hospitals had maintained the thera- peutic target at 32 to 34 ?C [12,13]. It is to be expected that the publication of the TTM2 study and the new recommendations of the European Resuscitation Council [7,10] will bring about an important change in the protocols for the care of patients recovered after cardiac arrest. Our study highlights that caution should be exercised, as the

Fig. 1. Differences in the adverse outcome according to the change in the target temperature.

change in target temperature may be accompanied by other protocol changes that could have a significant influence on neurological out- come. In addition, patients in the postpandemic era may differ from those included in prepandemic studies [8], so we do not know whether the results may be fully applicable. Moreover, experience from previous years suggests that a modification of the target temperature toward higher values may be accompanied by a relaxation in temperature con- trol, with a higher incidence of fever during the first 24 h, which may have deleterious effects on neuronal survival [14].

1. Conclusions

In our series of patients, the temperature control target temperature change from 33 ?C to 36.5 ?C was associated with worse neurological outcome. Further studies are needed to evaluate the outcome of a gen- eralized modification of temperature control targets in comatose pa- tients after cardiac arrest in our postpandemic era.

Ethics approval

All appropriate ethical guidelines for the use of human subjects have been followed, and we have obtained approval from the local ethics committee.

Consent for publication

Not applicable.

Availability of data and material

The datasets used during the current study are available from the corresponding author on reasonable request.

Funding

We have received no funds for this investigation.

Authors’ contributions

All authors have contributed to obtaining the data, the discussion and the preparation of this work, and approved the final paper.

Declaration of Competing Interest

There are no competing interests of any author concerning this investigation.

Acknowledgements

We acknowledge the tireless work of all the teams of the Coronary Unit.

References

1. Zeiner A, Holzer M, Sterz F, Schorkhuber W, Eisenburger P, Havel C, et al. Hyperther- mia after cardiac arrest is associated with an unFavorable neurologic outcome. Arch Intern Med. 2001;161:2007-12. https://doi.org/10.1001/ARCHINTE.161.16.2007.
2. 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. 2002;346:557-63. https://doi.org/10.1056/nejmoa003289.
3. The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346: 549-56. https://doi.org/10.1056/NEJMOA012689.
4. Nolan JP, Morley PT, Vanden Hoek TL, Hickey RW, Kloek WGJ, Billi J, et al. Therapeu- tic hypothermia after cardiac arrest. An advisory statement by the advancement life support task force of the international liaison committee on resuscitation. Resuscita- tion. 2003;57:231-5. https://doi.org/10.1016/S0300-9572(03)00184-9.
5. Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullen S, et al. Hypothermia versus Normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384:

2283-43. https://doi.org/10.1056/NEJMOA2100591/SUPPL_FILE/NEJMOA2100591_ DATA-SHARING.PDF.

1. Nielsen N, Wetterslev J, Cronberg T, Erlinge D, Gasche Y, Hassager C, et al. Targeted temperature management at 33?C versus 36?C after cardiac arrest. N Engl J Med. 2013;369:2197-206. https://doi.org/10.1056/NEJMOA1310519/SUPPL_FILE/ NEJMOA1310519_DISCLOSURES.PDF.
2. Nolan JP, Sandroni C, Bottiger BW, Cariou A, Cronberg T, Friberg H, et al. European resuscitation council and European Society of Intensive Care Medicine Guidelines 2021: post-resuscitation care. Resuscitation. 2021;161:220-69. https://doi.org/10. 1016/j.resuscitation.2021.02.012.
3. Jennett B, Bond M. Assessment of outcome after severe brain damage. Pract Scale Lancet. 1975;305:480-4. https://doi.org/10.1016/S0140-6736(75)92830-5.
4. Dankiewicz J, Cronberg T, Lilja G, Jakobsen JC, Levin H, Ullen S, et al. Hypothermia versus Normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021;384: 2283-94. https://doi.org/10.1056/NEJMOA2100591.
5. Lin T, Yao Y, Xu Y, Bin Huang H. Neuromuscular blockade for cardiac arrest patients treated with targeted temperature management: a systematic review and meta- analysis. Front Pharmacol. 2022:13. https://doi.org/10.3389/FPHAR.2022.780370.
6. Husain AA, Rai U, Sarkar AK, Chandrasekhar V, Hashmi MF. Out-of-hospital cardiac arrest during the COVID-19 pandemic: a systematic review. Healthc. 2023:11. https://doi.org/10.3390/healthcare11020189.
7. Sandroni C, Nolan JP, Andersen LW, Bottiger BW, Cariou A, Cronberg T, et al. ERC- ESICM guidelines on temperature control after cardiac arrest in adults. Intensive Care Med. 2022;48:261-9. https://doi.org/10.1007/S00134-022-06620-5.
8. Nolan JP, Orzechowska I, Harrison DA, Soar J, Perkins GD, Shankar-Hari M. Changes in temperature management and outcome after out-of-hospital cardiac arrest in United Kingdom intensive care units following publication of the targeted tempera- ture management trial. Resuscitation. 2021;162:304-11. https://doi.org/10.1016/j. resuscitation.2021.03.027.
9. Bray JE, Stub D, Bloom JE, Segan L, Mitra B, Smith K, et al. Changing target tempera- ture from 33 ?C to 36 ?C in the ICU management of out-of-hospital cardiac arrest: a before and after study. Resuscitation. 2017;113:39-43. https://doi.org/10.1016/j. resuscitation.2017.01.016.