Relationship between time to target temperature and outcome in patients treated with therapeutic hypothermia after cardiac arrest
© Haugk et al.; licensee BioMed Central Ltd. 2011
Received: 16 January 2011
Accepted: 25 March 2011
Published: 25 March 2011
Our purpose was to study whether the time to target temperature correlates with neurologic outcome in patients after cardiac arrest with restoration of spontaneous circulation treated with therapeutic mild hypothermia in an academic emergency department.
Temperature data between April 1995 and June 2008 were collected from 588 patients and analyzed in a retrospective cohort study by observers blinded to outcome. The time needed to achieve an esophageal temperature of less than 34°C was recorded. Survival and neurological outcomes were determined within six months after cardiac arrest.
The median time from restoration of spontaneous circulation to reaching a temperature of less than 34°C was 209 minutes (interquartile range [IQR]: 130-302) in patients with favorable neurological outcomes compared to 158 min (IQR: 101-230) (P < 0.01) in patients with unfavorable neurological outcomes. The adjusted odds ratio for a favorable neurological outcome with a longer time to target temperature was 1.86 (95% CI 1.03 to 3.38, P = 0.04).
In comatose cardiac arrest patients treated with therapeutic hypothermia after return of spontaneous circulation, a faster decline in body temperature to the 34°C target appears to predict an unfavorable neurologic outcome.
For patients who have been successfully resuscitated after cardiac arrest, therapeutic mild hypothermia increases the rate of a favorable outcome in comparison with standard life support. Randomized controlled trials, however, have not shown evidence of whether the time to target temperature correlates with neurological outcome [1–4]. Registries about the practical use of therapeutic hypothermia have also not found a significant association between the timing of therapeutic hypothermia and final outcome [5–7]. We expected a strong relationship between the time to target temperature (<34°C) and neurological outcome. Furthermore, we hypothesized that earlier achievement of target temperature would not necessarily improve outcome.
Materials and methods
Characteristics of patients in the study
Time to target temperature
120 to 220 minutes
1st ECG, VF/VTb
ROSC to admission, minutes
ROSC to cool, minutes
ROSC to awakeninge, days
ROSC to discharge, days
ROSC to death, days
Favorable neurologic outcome
Neurologic morbidity (a) and mortality (b) were independently compared with the time to target temperature. Neurologic outcome was measured as a Pittsburgh cerebral performance category (CPC) on a five-category scale [15, 16]. Patients with good recovery or moderate disability had sufficient cerebral function to live independently and work at least part-time (best CPC 1-2). The Pittsburgh CPCs were assessed on a regular basis by means of structured patient interviews.
Temperatures in degrees Celsius in correlation to morbidity and mortality
Best CPC 1-2
Best CPC 3-4
Tty cool start
Tes cool start
Tbl cool start
Minutes to target temperature in correlation to morbidity and mortality
Best CPC 1-2
Best CPC 3-4
ROSC to Tty 1st
ROSC to CoolStart
ROSC to Tty ≤34°C
ROSC to Tty ≤33°C
ROSC to Tes 1st
ROSC to CoolStart
ROSC toTes <34°C
ROSC to Tes <33°C
ROSC to Tbl 1st
ROSC to CoolStart
ROSC to Tbl <34°C
ROSC to Tbl <33°C
CoolStart to Tty <34°C
CoolStart to Tty <33°C
CoolStart to Tes <34°C
CoolStart to Tes <33°C
CoolStart to Tbl <34°C
CoolStart to Tbl <33°C
The exposure of interest was the time needed from restoration of spontaneous circulation to achieve a temperature of less than 34°C. Esophageal temperature was chosen because it is considered to be more reliable than urinary bladder or tympanic temperature in reflecting core body temperature [17, 18]. The primary outcome was a favorable neurological outcome, defined as best CPC 1 (good recovery) or 2 (moderate disability) within 6 months after cardiac arrest. The secondary outcome was all-cause mortality within 6 months of arrest.
Multivariable logistic regression for favorable outcome
(bootstrapped 95% confidence intervals)
Time to target temperaturea - crude
Time to target temperaturea,b
Time to target temperature adjusted for
Tbl cool start, °Cd
1st ECG, VFe
A total of 2,536 cardiac arrest patients were assessed; 1,948 of these patients were not cooled. Thus, 588 patients following the treatment algorithm were studied; they included (a) a group of 285 (48%) patients with favorable outcomes and (b) a group of 284 (48%) survivors (Tables 1, 2, 3). All patients included in the analysis were available for follow-up neurologic status evaluation; 17 patients died during sedation, analgesia, and paralysis. At baseline, the patients in the group comparing morbidity were generally similar to the group comparing mortality (Table 1). The methods and strategies used for cooling were not different between groups.
Cooling methods in correlation to morbidity and mortality
Best CPC 1-2
Best CPC 3-4
IV + endovascular
IV + surface air
IV + surface ice
IV + surface water
Other or mixed
No IV cooling
IV cooling alone
Our results show a strong relationship between the time to target temperature and neurological outcome among comatose patients in whom spontaneous circulation had been restored after cardiac arrest and therapeutic hypothermia was induced. A shorter time until systemic cooling to an esophageal temperature below 34°C seems to be able to predict unfavorable neurologic outcome. If faster cooling is detrimental or patients with more severe neurological damage show a faster cooling rate has to be further evaluated.
This study has the limitations of a retrospective, observational, and descriptive single-center registry, but the observers of temperature data were blinded to outcome. All eligible patients may not have been cooled, and many factors in regard to patient heat transfer are not available, particularly in the beginning of post-arrest cooling, which lies in the nature of implementing a new therapeutic strategy. Even if a selection bias exists, the time to target temperature over the years remains a factor independent from any bias. To analyze the effect of the time to target temperature on morbidity and mortality, the cohort was evaluated independently in regard to the best-ever-achieved CPC during the follow-up period and in regard to survival. Therefore, it was necessary to exclude the patients dying during sedation, analgesia, and paralysis from the morbidity evaluation.
Though similar to those in other hypothermia trials, the median time intervals in our study were still lengthy. It took more than 80 minutes to commence cooling therapy and around 3 hours to achieve the target temperature. The time to initiation of cooling was not different between groups, showing that it does not correlate with the time to target temperature. Therefore, it appears that patients with a worse responsiveness to cooling are those with a better outcome; however, this cannot be proven without measuring heat transfer in a prospective trial. Along the same lines, the data show that esophageal temperatures at the beginning of cooling were half a degree lower in patients with unfavorable neurologic outcomes in comparison with those with favorable neurologic outcomes. Thus, patients with unfavorable neurologic outcomes could reach target temperature more quickly. The delay in time to target temperature could reflect a stronger natural homeostatic central-nervous physiological response in those with better outcomes; this might also explain the association with improved outcome but not survival.
The standard for temperature monitoring in our patients after cardiac arrest is to get the first temperature at the tympanum and thereafter as soon as possible in the esophagus and bladder. By presenting the temperature data from the three different sites separately, we want to show that our findings are independently the same (Table 2). This and the long time intervals to initiation of cooling and achieving the target temperature justify basing the calculations only on the ones having an esophageal temperature probe and using the initial bladder temperature for the multivariate analysis. Even if temperatures at the beginning of cooling were lower in patients with unfavorable neurologic outcomes, the difference remains with 0.4°C marginal (Table 2) and we have controlled for that variable and other confounders in our adjusted analysis (Table 3). However, many known and possibly still unknown confounders have not been taken care of and therefore our results can be used only for hypothesis generating of future trials necessary to answer this and many other questions related to therapeutic hypothermia. In addition, the time to target temperature from start of cooling, reflecting the cooling rate, proved to be shorter in the group with unfavorable neurologic outcomes. The reason for this surprising result might be of an associative nature and could be explained by the compromised thermoregulation with cerebral insults [12, 19]. The data are important for those planning future prospective studies of early versus delayed cooling.
The findings of the present study appear to be contradictory to the notion that achieving mild therapeutic hypothermia earlier and faster helps to reduce hypoxic brain injury and favors a positive neurologic outcome [3, 20, 21]. It is disappointing that no additional clinical data of patients with cardiac arrest and cooling help to explain that discrepancy. Therefore, all discussions of our findings remain speculative and will not be able to answer whether rapid cooling will cause more hemodynamic changes or other cerebral effects that alter neurologic outcome. Alternatively, it appears that sicker patients lack homeostatic mechanisms to maintain normothermia and therefore cool faster. Unfortunately, the question of how soon cooling should be initiated remains unanswered and prospective human studies have yet to define the ideal time to begin cooling patients .
Given the strong effect of therapeutic hypothermia with a protocol chosen on the basis of experimental data, there might be potential to further optimize the treatment and gain an even better neurologic outcome for patients after a global cerebral ischemic event [20, 23]. At present, hypothermia is initiated mainly in-hospital and for arrests with cardiac etiology and a typical clinical presentation. However, there are no data to support whether earlier and faster cooling, already initiated in the out-of-hospital phase, may be better for preserving neurologic function [24–26]. Further studies should attempt to determine the time point at which the initiation of therapeutic hypothermia becomes most beneficial to patients who achieve restoration of spontaneous circulation following cardiac arrest [7, 23]. Additional research is required to explore the best methods for induction of therapeutic hypothermia, including the most appropriate time and location of therapeutic hypothermia initiation and the optimal means to induce temperature reduction.
In comatose cardiac arrest patients treated with therapeutic hypothermia after return of spontaneous circulation, a faster decline in body temperature to the 34°C target appears to predict a less favorable neurologic outcome. A faster decline in body temperature may simply indicate a more severe ischemic insult with resulting impairments in thermoregulation and thus predicts a worse outcome. Nevertheless, prospective studies should be conducted to confirm this observation and, in turn, address whether such a finding is simply a marker for a more severe insult or whether controlling the rate of cooling could favorably alter the outcome.
In cardiac arrest managed with therapeutic hypothermia after resuscitation, reaching the 34°C target faster retrospectively predicts a poor neurologic outcome.
A faster decline in body temperature may indicate a more severe ischemic insult with impaired thermoregulation and thus predicts a worse outcome.
Prospective studies should address whether this finding is simply a marker for a more severe insult or whether controlling the rate of cooling can favorably alter outcome.
cerebral performance category
The following investigators participated in the Time to Target Temperature (T2TT) study group of the Universitätsklinik für Notfallmedizin, Vienna, Austria (temperature data collection, acquisition of data, analysis and interpretation of data, involvement in revising the manuscript critically for important intellectual content, and final approval of the version to be published): Jasmin Arrich, Kewan Bayegan, Philip Eisenburger, Roman Fleischhackl, Christoph Havel, Nina Holzer-Richling, Andreas Janata, Andreas Kliegel, Julia Kofler, Klemens Köhler, Julia Koller, Angela Koppensteiner, Danica Krizanac, Anton N Laggner, Heidrun Losert, Reinhard Malzer, Eva Riedmüller, Andreas Schober, Waltarud Schörkhuber, Hanno Sendler (ethics committee submission), Gottfried Sodeck, Peter Stratil, Thomas Uray, Marianne Vlcek, Christian Wallmüller, Cosima Wandaller, and Andrea Zeiner-Schatzl.
We are indebted to the nurses and staff for their enthusiastic cooperation and to the patients in the study for their trust and support. This study was supported in part by grants from the Biomedicine and Health Programme (BIOMED 2), implemented under the Fourth RTD Framework Programme 1994-1998 of the European Union (BMH4-CD-96-0667), the Austrian Ministry of Science and Transport (GZ 5.550/12-Pr/4/95 and GZ 650.0251/2-IV/6/96), and the Austrian Science Foundation (P11405-MED).
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