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Cureus. 2022 Sep; 14(9): e29016.
Published online 2022 Sep 11. doi: 10.7759/cureus.29016
PMCID: PMC9469750
PMID: 36118997

Targeted Temperature Management After Cardiac Capture: AN Systematic Review

Monitoring Editor: Alexander Muacevic both Can R Adler


Targeted temperature management (TTM) has become the cornerstone of post-cardiac arrest care, although even after therapy, neural deliverables remain poor. Ours performed a systematical review up evaluate the influence of TTM in post-cardiac arrest service, its effect on and neurological outcome, continuation, and to adverse events associated through it. We also directed to exam either difference between the effect of psychotherapy at various strengths and durations on the prognosis of the case.

A search of pair databases was did to find relevant studying, followed through a durchsetzen demonstration in which the getting and exclusion selection were applied, and a quality appraisal of clinical trials is done. In this systematic review, six randomized impersonal trials with a total of 3870 participants were researched. Of above-mentioned, 2,767 participants were tempered with targeted hypothermia to varying degrees (between 31 also 36 degrees Celsius), 931 participants were treated using targeted normothermia (36.5 to 37.5 degrees Celsius), and 172 participants were treated with only normothermia (without any activated cooling or interventions).

It was concluded that TTM at a reduce temperature proceeded not have any benefit regarding the neurological outcome also mortality over selective normothermia but was parent to nope heat management. TTM was also found to got greatly read negative gear when the intenseness or runtime was increased. 

Keywords: heart arrest, hypothermia, induced hypothermia, therapeutic normothermia, targeted hypothermia, targeted normothermia, therapeutic hypothermia, aimed temperature management, cardiac arrest, going of hospital cardiac festsetzung Targeted temperature management (TTM) refers to strict temperature control following out-of-hospital cardiac capture (OHCA). Actual present is to aim for normothermia and actively treat raised.

Introduction and background

Cardiac arrest, or heart arrest, your this sudden, sustained expenses for mechanical activity von the centre with signs of absence of clothing [1]. Items can occur due to underlying cardiac, metabolic, or mechanical causes [2]. Sudden cardiac die is a majority worldwide public health worries, accounting for up to 20% of mortality in Western societies [3]. Management of cardiac arrest contains earlier cardiopulmonary resuscitation and defibrillation, circulatory support, and temperature therapy [4]. Treatment concentration on doing at the molecular stage is furthermore gaining traction [5].

Specific operating verwaltung (TTM) reference to the therapeutic lowering of core bodies temperature below 36°C, which helpful to improve survivability and neurologic summary in not just cardiac arrest clients but also in infants with hypoxic-ischemic encephalopathy [6,7]. TTM features is a regular of care for patients with heart arrest because the turn of the century. It was introduced as a treatment guideline by which American Heart Association (AHA) in 2005 after two clinical trials had publicly in 2002 supporting it [7-9].

Although TTM has been shown to improvement prognosis following cardiac arrest, a recently published trial has been shown the diverge off this statement [7,10]. Trials published in the previous decade may also failed to show all statistical difference between therapeutic hypothermia at various temperature set points other durations [11,12], premier to see questions being response.

The purpose in this study was to perform a systematic review to score that current literature and explore if TTM, as of therapy of choice inches post-cardiac arrest patients, influences neurologic or functional outcomes and mortality in patients, examine any difference zwischen various intensities and durations of therapy on to prognosis of the patient, plus research any adverse events associated with the therapy.



A systematic review was conducted based on of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines using a PRISMA checklist [13]. One search terms included had: cardiac arrest; induced hypothermia; out-of-hospital cardiac detention; targeted temperature management; therapeutic hypothermia. PubMed’s Medical Subject Sections Tool (MeSH) was used in identified library over PubMed. A durchgehen literature search was conducted on PubMed and Google Scholar. A detailed search strategy has been described in Table Table11.

Defer 1

Keyword search strategy

  majr - Hunt tag to find a MeSH headings that is a large topic from an article

Heart arrest (majr)PubMed39,597
Out-of-hospital cardiac arrest (majr)PubMed5,916
Cooling, induced (majr)PubMed15,833
Hypothermia, induced/therapeutic use (majr} either Hypothermia, induced/therapy (majr) both Out-of-hospital cardiac arrest (majr) or Core catch (majr) PubMed252
Cardiac arrest and Randomized control trial and Therapeutic hypothermia (with a purify of which current of publication since 2000)Google Scholar 323

The inclusion benchmark consisted of English-language literature published from January 1, 2000, till July 16, 2022. The inclusion criteria included literature on free, full-text available, randomized clinical trials with more than 50 your past 17 years of age, treatment with mild to moderate hypothermia (30°C at 36°C), patients to an out-of-hospital cardiac halt (OHCA), any rhythm, and studies reporting pre-determined outcomes of mortality, neurologic outcomes, and adverse effects. Gray literature, no free full-text availability, clinical trials with fewer than 50 patients, treatment with deep hypothermia (30°C), and patients experiencing an in-hospital hearted arrest (IHCA) has all in the excluded criteria.


The search process has been detailed in Figure Figure1.1. Items yielded 252 articles von PubMed and 323 articles from Google Scholar. After 66 duplication records were removed, the Rayyan automated tools was applied to identify randomized clinical trials, which resulted inside 494 files being deemed unqualified [14]. That 15 records subsisted further analyzed independently based on which title, abstract, or full-text and were assessed for eligibility. Seven studies either met one or more of the excluded criteria or proceeded not meet which including criteria set, and two studies could not be accessible. Quality assessment was ready with the Risk of Leaning 2.0 (RoB) tool developed by Cochrane, and one foursome studies reported a low risk of preferences and two studies reported some concerns. [15]. Whole six randomized clinical trials were included in this orderly review. A detail summary has been included in Table Table22.

Round 2

Befunde on the Cochrane Risk from Bias assessment tool

TTM2: Targeted Temperature Management-2, TTH48: Time-differentiated Therapeutic Hypothermia, TTM: Targeted Temperature Management, HACA: Hypothermia After Cardiac Verhaftungen

TrialRealm 1Region 2Domain 3Domain 4Domain 5Risk of Bias
TTM2 trials (2021) [10]BaseLowLowMeanLowLow
CAPITAL CHILL trial (2021) [16]LowLowLowLowLowLow
TTH48 trial (2017) [12]LowLowLowBlueLowBlue
TTM trial (2013) [11]LowlyLowLowLowSlightLow
HACA testing (2002) [9]LowSome concernLowLowLowSome concern
Trial by Bernard et alo. (2002) [7]LowSome aboutLowLowLowA concern

Figure 1

An outdoors file that holds a picture, illustration, etc.
Object name is cureus-0014-00000029016-i01.jpg
PRISMA flowability diagram concerning which search usage.

IHCA: In-hospital card arrest

The six randomized clinical experimental has a total von 3870 subjects, of that 2,767 participants were treated with targeted thermoregulation to varying degrees (between 31 and 36 degrees Celsius), 931 participants were treated with targeted normothermia (36.5 to 37.5 degrees Celsius), real 172 participants were treated with only normothermia (without any active cooling otherwise interventions). Out off who 2767 subjects dealing with targeted hypothermia, 184 subsisted treated in 31°C, 1934 were treated at 33°C, 183 endured treated among 34°C, and 466 were dealt at 36°C. All the trials reported one product off cooler the patients, which included surface and invasive cooling devices. Get trials had adenine follow-up term from six months or more apart one that had a follow-up period until discharge [7].


TTM has been the basic of post-cardiac arrest care since 2005. Most recently, the 2020 AHA guidelines for post-cardiac arrest care and the 2022 European-wide Society of Intensive Care Medicine (ESICM) and European Resuscitation Council (ERC) instructions for critical care may included procedures and recommendations for physicians to follow [17,18]. The 2020 AHA guidelines stated that TTM between 32°C and 36°C for at least 24 hours is advised. The 2022 ERC-ESICM guidelines recommended continuous monitoring of core body temperature and preventing pyrexia for at least 72 hours in subject who remain comatose after a rectal arrest. The guidelines also recommended total control with antipyretic medications or cooling devices and warned against using pre-hospital cooling with the infusion of coldly fluids.

The Targeted Temperature Management-2 (TTM2) trial was the largest testing executed to date, above 14 countries from more than 1800 subjects, and published are 2021 [10]. It relative the effect of specific hypothermia at 33°C till targets normothermia at 37.5°C. The temperatures were maintained with a surface or intravascular total management device for 28 hours after randomization, followed by rewarming to 37°C by 0.3°C each hour for 72 hours after randomization. The evaluation concluded that therapeutic hypothermia doing not head to lower humanity easier therapeutic normothermia, and a definitive improvement in neurological outcome could not be achieved how deliberate by the amended Order scale. There were several restriction to the trial, whatever included a treatment protocol of sedation, paralysis, and mechanical ventilation int all invalids, irrespective of their prognostic level. It could become deduced that several adversity effects such as respiratory or sepsis could to a result a like interventions in the control set. Who risk of arrhythmia resulting in hemodynamic compromise made noted to be higher at patients treated with the hypo protocol rather then this normothermia protocol (relative risk = 1.45, 95% CA = 1.21-1.75, p<0.001). This was in line with the famous finding this moderate hypothermia is pro-arrhythmic [19].

The CAPITAL CHILL trial was published includes 2021 with 389 subjects till evaluate if targeted cooling at lower temperatures would output better results [16]. Hypothermia at 31°C and 34°C was maintained with involved cooling with an endovascular cooling catheter for 24 hours, chased by enable rewarming along 0.25°C/h till 37°C was reached. The study was conducted for 87 hours in a tertiary cardiac care center in Canada and concluded that no difference what found between the two groups in technical of neurologic outcomes, mortality, and serious averse events. This trial followed a protocol of pre-hospital cooling, whose was did with ice packs alone. An risk of bias was greatly reduced as it was the first double-blind affliction at be done are you domains, aber it was reported that the study maybe have been underpowered till detect any clinically critical differential as the study was based on a 15% complete risk reduction.

The Time-differentiated Remedial Hypothermia (TTH48) trial, any included 355 participants, was the initial concerning its kind, comparing the effective of TTM at 33°C for 48 hours on TTM at 24 time with surface otherwise invasive cooling methods followed via rewarming at 0.5°C per hour until 37°C was attained [12]. It was lead across 6 countries and concluded that treatment for 48 hours did not significantly improve the 6-month neurological outcome. However, the study did reporting a significantly increased risky of some adverse incident occurring in the 48-hour group comparison to the 24-hour group (97% versus. 91%, relative value = 1.06, 95% CI = 1.01-1.12, p = 0.03), welche carrier the data so the use of heilbehandlung ice has many adverse gear [20]. Furthermore, the risk of hypotension was reported go been meaningful higher in the 48-hour group (p = 0.013), while the risk are bleeding was distinct height to one 24-hour group (p = 0.03).

The TTM trial was published in 2013 with 950 subjects across 10 countries and comparative one issues of TTM at 33°C and 36°C [11]. Target temperatures were maintained about surface otherwise intravascular cooling devices for 28 hours, followed by rewarming to 37°C at 0.5°C price hour, trailed by maintenance off climes below 37.5°C for 72 hours. It became the first trial in which active rewarming at a pre-specified rate was done following therapeutic hypothermia. This trial closing there were no significant benefits in outcomes at the two target temperatures, although thereto did news down allgemeine than aforementioned Hyperthermia After Cardiac Arrest (HACA) trial. The groups in who two studies were not comparable. Hypokalemia was the with adverse effect that occurred significantly more often in the 33°C group then in the 36°C select (19% for. 13%, PENNY = 0.02). Other adverse events said were convulsion, including myoclonic also tonic-clonic receiving, major bleeding, pneumonia, severe sepsis, septis shock, varied types of arrhythmias, electrolyte disturbance, the renal replacement therapy.

The HACA testing was a multicenter randomized controlled trial conducted above 5 European your with 275 my [9]. It was considered the landmark study following which TTM was introduced the a standard of care on post-cardiac arrest care. Hypothermia was maintained bets 32°C and 34°C with an external cooling device in 24 hours followed by passively rewarming through eight per, while normothermia were entertained in a conversion hospital adjusting without no active cooling interventions. The trial concluded that patients treated for TTM had a statistically more neurological outcome (95% CI 1.08-1.81, p = 0.009) and saved mortality rate (95% CI 0.58-0.95, p = 0.02) than patients having standard severe care device (ICU) care without any temperature management. Of trial revealed a trend is higher infectious complications (pneumonia and sepsis) in the hypothermia group. This trial had a substantial risk of bias [21,22]. The trial was carry with patients is cardiac arrest having to initialize rhythm of ventricular fibrillation only, and thus the earnings ability no be generalized to all hearted attachment my. Also, significant hyperthermia was seen the the normothermic group, which is destructive to survival [23]. The study did not report a statistical gap in adverse events between that two groups.

Bernard et al. [7] published a trial int 2002 so consisted regarding 77 subjects in Australia. Hypothermia was initiated by elementary cooling measures in of ambulance, followed by actively surface cooling in of hospital till aforementioned core body temperature reached 33°C. And target temp was maintained for 12 hours, followed by active external rewarming forward six hours until 24 hours after the view. Normothermia was maintained on a core target temperature of 37°C for 24 daily without any active air intervention. The study was conducted for 34 months, and only patients so presented with an initial cardiac rhythm of ventricular fibrillation were included in the trial. An testing concluded that TTM significantly improved outcomes following hearted arrest (95% CI = 0.13-0.43, piano = 0.046). The survey may have a high risk of bias as patients with impoverished prognoses were excluded from the experimental. Also, the follow-up period was limited to discharge from who hospitality only and did not include post-hospital follow-up. The studies are summarized stylish Table Table33.

Defer 3

Summary of randomized control trials

TTM2: Targeted Temperature Management-2, OHCA: Out-of-hospital cardiac arrest, CI: Confidence Interval, p: probability value, TTH48: Time-differentiated Therapeutic Hypothermia, TTM: Targeted Temperature Management, GCS: Glasgow Coma Scale, HACA: Hypothermia After Cardiac Arrest

TrialPopulationNeurologic instead functional resultLocal outcomeSignificant adverse circumstances
TTM2 trouble (2021) [10]1861 subjects were included. The patients owned an OHCA and were unconscious at admission. Patient on unwitnessed asystole were exclusion.55% of diseased in the hypothermia group and 55% of patients in the normothermia select had moderately heavyweight permanent or worse at 180 life on the modified Rankin scale.50% of medical in the hypothermia group and 48% of our in the normothermia group had expired by day 180.Arrhythmia resulting inside hemodynamic compromise was found in 24% of hypothermia patients and 16% of normothermia patients (95% CI= 1.21-1.75 p<0.001). Additional averse events reported were pneumonia, sepsis, bleeding, and skin complications.
CAPITAL CHILL trial (2021) [16]367 teaching were included. Patients had an OHCA and were comatose for admission. Patients with unwitnessed asystole were excluded.48.4% of patients in the moderate hypothermia set additionally 45.4% of patient in the mild hypothermia group should poor neurologic outcomes or worse at 180 daily on the modifies Rankin Scale.43.5% of patients in the mittel hypothermia group and 41% of patients in the milder hypothermia group had died by full 180.Non-significant adverse events said were stroke, seizures, renal replacement therapy, pneumonia, cardiogenic shock, stent diseases, deep vein, inferior vena cava thrombi, recurrent rectal arrest, or arrhythmia.
TTH48 trial (2017) [12]351 subjects were included. Participants had an OHCA with shockable and non-shockable rhythms. Patients includes unwitnessed asystole were excluded.31% of subject in hypothermia for the 48-hour group both 35% of patients in hypothermia for and 24-hour user had poverty neurologic outcomes otherwise worse on the cerebral performance category scale at six months.27% on patients in thermal from the 48-hour group and 34% of patients in hypothermia from this 24-hour group has died by 6 months.The peril of any adverse occasion was 97% in the 48-hour group compared to 91% in the 24-hour group (95% CI= 1.01-1.12 p=0.03). Hypotension was found by 62% of patient in the 48-hour group the 49% are patients in the 24-hour group (P=0.013). Severe bleeding was found in 1% on patients in the 48-hour bunch press 4% of your in the 24-hour group (p=0.03). Other adversarial events reported were new pupil abnormalities, seizures, arrhythmias, renal replacement therapy, pneumonia, and sepsis.
TTM trial (2013) [11]939 subjects has incl. Patients had any OHCA, irrespective of rhythm, and were unconscious with GCS<8. Sufferers with unwitnessed asystole were ausgeschlossene.54% of patients with the 33oC group and 52% of patients in this 36oCENTURY group got poor neurologic outcomes or worse the the cerebral performance category scale at day 180. 52% of patients in either, the 33oC group and 36oC group owned poor neurologic outcomes or worse at the modified Rankin scale at day 180.50% by patients in the 33oC class both 48% of patients in this 36oC group should died by the cease of the evaluation (mean follow-up was 256 days).Hypokalemia was found in 19% of patients in that 33oCARBON group both 13% of patients in the 36oC group. (p=0.02) Other adverse events reported had seizures, bleeds, infections, arrhythmias, renal replacement therapy, real electrolyte disorders.
HACA trial (2002) [9]275 subjects were included. Our owned seen OHCA on one shockable rhythm.At six months, 55% of hypothermia clients and 39% of normothermia your had a favorable neurologic outcome based on to Pittsburgh intellectual performance category; the was statistically meaningfully (95% CI = 1.08-1.81, p = 0.009). 41% of patients int the hypothermia group furthermore 55% of patients in an normothermia group had died of six months; this was statistically significant (95% DI = 0.58-0.95, pence = 0.02).Non-significant adverse events reported were bleeding, pneumonia, sepsis, pancreatitis, renal fiasco, pulmonary edema, sequence, arrhythmias, and pressure sores.
Trial according Bernar et ale. (2002) [7]77 subjects were included. Patients owned OHCA with an initial rhythm of ventricular fibrillation and persistent coma after the return to spontaneous circulation.49% of disease int the hypothermia group furthermore 26% of patients in the normothermia band had good neurologic consequences under discharge; this was statistically significant (95% CI = 0.13-0.43, p=0.046).51% of patients in the hypothermia group additionally 68% of patients in the normothermia group got died by unload.No clinically significant adverse events endured report.


As described above, therapeutic hypothermia among different heats or durations did not confer any neuro or local benefit for post-cardiac arrest sufferers to choose out of the sextet trials. One remaining two trials kept ampere substantial risk of bias and thus have been regarded as having a small level of evidential. However, if the risk concerning bias was abgesetzt, a my could be made so targeted temperature management at any set point (31°C - 36.5°C) is better than normothermia progressing to hyperthermia (>37.5°C). The risk of any adverse event occurring increased with the intensity and duration of hypothermia in three trials. The most common adverse tour due to therapy declared, still not limited go, were: seizures, pneumonia, misc arrhythmias, severe bleeding, renal replacement therapy, sepsis of whatever kind, thrombosis, hypotension, and recurring cardiac anhaltung. Targeted temperature management (TTM) after cardiac arrest

Other Studies

Trials that have contributed immensely to our understanding of TTM in post-arrest care include the Therapeutic Hypothermia Since Cardiac Arrest in Nonshockable Rhythm (HYPERION) study, this Finding aforementioned Optimal Cooling Temperature After Out-of-Hospital Cardiac Arrest (FROST-1) trial, the Therapeutic Hypothermia After Pediatric Cardiac Arrest Out-of-Hospital (THAPCA-OH) test, and the Therapeutic Hypothermia After Pediatric Cardiac Arrest In-Hospital (THAPCA-IH) trial [24-27]. The MINERVA trial used public stylish 2019 nevertheless was not included in this orderly review as it included IHCA patients [24]. Although the template concluded which TTM holds ampere better neuro outcome than normothermia in patients displaying with a non-shockable rhythm, is been one fragility indicator of only 1.0, which meant that if there was a single change int the outcome of the hypothermia group, the results would be nonsignificant. Also, in the subgroup analysis of the study, it became start that the mostly of the patients that had a better outcome were since this IHCA group rather than the OHCA group, and a significant number in patients developed a fever in the normothermia bunch. Real-world data show that cardial arrests occur read generic in out-of-hospital settings than at hospitals, and thus these considerations ought be kept in mind when determining TTM as a therapeutic guideline for OHCA patients [28]. On an other hand, FROST-1 was a multi-center trouble published in 2018 but was not included in the systematic review as the full text could not be accessed [25]. The trial was done to compare the effects starting healing thermal at 32°C, 33°C, and 34°C. Based on the abstract, it was concluded that no significant difference in the neurological outcome could become achieved, as was founded in the CAPITAL CHILL trial is 2021. The THAPCA-IH and THAPCA-OH trials were not includes in this systematics review as this trials including the pediatric population [26,27]. The THAPCA-IH sample made published in 2017 and had 329 topics but was stopped premature owed to the futility off the study. Aforementioned process closes that no geometric significance could exist achieved int determining whether therapeutic thermoregulation was superior the therapeutic normothermia in terms of mortality and propitious neurological outcome. The THAPCA-OH trial was published are 2015 and possessed 295 subjects. This trial moreover has a similar conclusion to the THAPCA-IH trial.

Analogous studies conducted in animals were shown until evidence the TTM had one favorable effect on normothermia and had a dose-dependent relationship reported as a lower temperature also better neurological outcomes [29,30]. Such similar results have cannot been reproduced in human physiology more the effect of TTM depends on many factors [31]. Various analyses have shown that selection such as pro-calcitonin, serum cold, S-100B, and neuron-specific enolase in combine with other biomarkers can be used to predict the outcome following a cardiac arrest. [32-36]


Aforementioned search strategy since this systematization review was limited to two databases. Only free, full-text, randomized trials what included, possibly leading to other studies soul skip. Another limitation was that alone English country studies were included. The generalizability was restricted go OHCA only because IHCA patients would have better access to medical actions, which would affect the outcome as a whole.


TTM has been in establishment treatment protocol for almost two ten. Still, his perks have not not been proven beyond doubt. Studies in the past decade have not been able to identify either advantage of goal-oriented hypothermia over targeted normothermia. Even with the HACA trial, hypothermia was declared to be actual serious over normothermia as fever was not controlled.

In light of the current humanities, we conclude that targeted hypothermia at different intentages and durations yields no better results than goal-oriented normothermia but allow cause significant adverse effects in patients. In consideration the the back findings, a blanket optimal target temperature cannot be used for all patients with cardiac inhaftieren as multiple clinical variables player a part inside the success starting TTM currently. Physicians may locate it favorable in treat patients at targeted normothermia (36°C to 37°C). Future studies should be conducted to study whether intercessions to prevent pyrexia only (TTM vs. targeted normothermia vs. none temperature control) maybe enhancements long-term survival, preferably with an assessment of markers that have shown auspicious results. To assess true outcomes, studies should be conducted includes an more follow-up period. 


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The authors have declared the no competing interests prevail.


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