At what level of unconsciousness is mild therapeutic hypothermia indicated for out-of-hospital cardiac arrest: a retrospective, historical cohort study
© Natsukawa et al. 2015
Received: 23 March 2015
Accepted: 1 September 2015
Published: 11 September 2015
Appropriate patient selection is very important when initiating mild therapeutic hypothermia (MTH) for patients following out-of-hospital cardiac arrest, and the extent of unconsciousness at implementation must be defined in such cases. However, there are no clear standards regarding the level of unconsciousness at which MTH would be beneficial. The effects of MTH in patients with different degrees of unconsciousness according to the motor response score of the Glasgow Coma Scale (GCS) were investigated.
The subjects consisted of witnessed non-traumatic adult out-of-hospital cardiac arrest patients admitted to our institute from April 2002 to August 2011. The patients were divided into six groups according to the GCS motor response score: 1 (GCS M1), 2 (GCS M2), 3 (GCS M3), 4 (GCS M4), 5 (GCS M5), and 6 (GCS M6). The neurological outcome was evaluated at 30 days after hospital admission using the Cerebral Performance Category. Chi-squared Automatic Interaction Detection (CHAID) analysis was performed to estimate the threshold GCS M level where therapeutic hypothermia is indicated. Odds ratios were then calculated by multiple logistic-regression analysis using factors including GCS M5–6 and MTH.
A total of 289 patients were enrolled in this study. CHAID analysis demonstrated two points of significant increase in percentage of good recovery at 30 days after admission, dividing the GCS M categories into three groups. Patients classified with a GCS motor response score of 5 or higher had the highest percentage of good recovery. The odds ratio for good recovery (CPC1–2) was 2.901 (95 % CI 1.460–5.763, P = 0.002) for MTH, and that for GCS M5–6 was 159.835 (95 % CI 33.592–760.513, P < 0.001).
MTH may be unnecessary in patients with a GCS motor response score of 5 or higher. Consequently, because there are post cardiac arrest patients with a GCS motor response score of 4 or lower who benefit from MTH, MTH may be limited to patients with a GCS motor response score of 4 or lower.
KeywordsMild therapeutic hypothermia Post cardiac arrest Coma Glasgow Coma Scale Motor response score
The American Heart Association currently recommends mild therapeutic hypothermia (MTH) for out-of-hospital cardiac arrest patients presenting in a coma .
MTH is a therapy capable of improving the neurological outcome of post cardiac arrest patients, but it is also associated with many complications . MTH, which includes precise body temperature management, is a therapy that requires an increase in manpower in the intensive care unit (ICU), thus creating problems due to increased medical costs, including the purchase of equipment and special devices. Therefore, the indications to perform MTH in patients with out-of-hospital cardiac arrest should be examined.
The Glasgow Coma Scale (GCS) is generally used for evaluating the state of consciousness at emergency scenes . There is no definition of the degree of unconsciousness for which MTH is indicated at the present time, although in past reports, a GCS of eight points or less has been reported. However, it is difficult to evaluate eye opening when the patient is in a post cardiac arrest coma. Moreover, tracheal intubation is carried out in almost all cases, thus rendering an evaluation of the verbal response impossible. From the above, when evaluating the state of consciousness in cardiac arrest patients using the GCS, only the motor response is commonly used. Regarding the evaluation of the degree of unconsciousness in out-of-hospital cardiac arrest patients on arrival to the hospital, we have conventionally used the best level of consciousness within 2 h following the return of circulation, before administration of sedatives, using only the GCS motor response score. Patients classified with a GCS motor response score of 3 or lower are considered to be in a comatose state. Meanwhile, although patients classified with a GCS motor response score of 4 or higher may or may not be in a comatose state, it is believed that MTH may have a positive effect on patient outcome.
In this study, the level of consciousness of out-of-hospital cardiac arrest patients on arrival to the hospital was classified according to the GCS motor response score, and the effect of MTH was retrospectively investigated. In addition to identifying the indications for MTH using the GCS motor response score, whether classifying such patients according to their GCS motor response score on arrival to the hospital may be a potentially useful indicator for predicting the outcome was investigated.
The subjects were adults who were 18 years of age or older who had been admitted to our institute due to witnessed out-of-hospital cardiac arrest from April 2002 to August 2011 with stable post cardiac arrest hemodynamics. Patients with unwitnessed cardiac arrest or patients with injury, cerebral stroke, a poor functional status, in a terminal state, a serious infectious disease, and serious coagulopathy were excluded. There was no clear criterion for the use of MTH in our institute. MTH was conducted when two or more emergency physicians who were in charge of the treatment thought that MTH would be beneficial.
The patients’ data were extracted from medical records, and the data, as well as the outcomes, were retrospectively analyzed as a historical cohort study. The best level of consciousness within 2 h following return of spontaneous circulation (ROSC) was evaluated using the GCS motor response score. Once a decision was made to perform MTH, the administration of a rapid intravenous infusion of 2000 ml of cooling liquid at 4 °C was carried out immediately, along with commencing body surface cooling in most patients. The core body temperature was continuously decreased to 34 °C using the K-TEK III® (Kawasumi, Tokyo), ArcticSun® (IMI, Saitama), or percutaneous cardio-pulmonary support (PCPS), and the core body temperature was then maintained at 34 °C for 24 h, before rewarming over a period of 2 days at 1 °C/day. Furthermore, sedatives, analgesics, and muscle relaxant agents were used in all patients during MTH, and the bladder temperature was monitored as the core body temperature. Meanwhile, sedatives and analgesics were used in patients who were treated without MTH, and although monitoring of the core body temperature was carried out, no active intervention was carried out for temperature management. The outcome, the state of consciousness at 30 days of hospital admission, was evaluated using the Cerebral Performance Category (CPC) . CPC1 and CPC2 were determined to be a good recovery.
The study protocol complied with the guidelines for epidemiologic studies issued by the Ministry of Health, Labour and Welfare of Japan and was approved by the Ethics Committee of the Osaka Saiseikai Senri Hospital. All patients received the standard care available at the hospital, and no subjects underwent any type of experimental intervention. In light of these safeguards, the Ethics Committee approved this study and waived the need for oral or written consent.
Continuous variables, which were not normally distributed, are reported as medians and interquartile ranges. Categorical variables are reported as counts and percentages. Either the chi-square test or Fisher’s exact test, as appropriate, was used to compare neurological outcomes in patients treated and those not treated with MTH. The Mann-Whitney U test was used to compare continuous variables of baseline characteristics between patients with good recovery (CPC1–2) and those with bad recovery (CPC3–5). Chi-squared Automatic Interaction Detection (CHAID) analysis was used to find the threshold of GCS M in patients with good recovery at 30 days after admission. Odds ratios (ORs) were calculated by multivariate logistic-regression analysis to identify the significant factors for good recovery. The significance level was set at P < 0.05. The software program SPSS Statistics 21 for Windows (IBM Japan, Tokyo) was used to analyze the data.
Baseline clinical characteristics
CPC 1–2 (n = 138)
CPC 3–5 (n = 151)
Age (year), median (IQR)
60 (53, 73)
66 (58, 73)
Male, n/total n (%)
Bystander CPR, n/total n (%)
VF or pulseless VT, n/total n (%)
Cardiac cause, n/total n (%)
Time interval between collapse and ROSC (min), median (IQR)
14 (10, 22)
25 (18, 42)
Without prehospital ROSC, n/total n (%)
Glasgow Coma Scale motor response score
pH, median (IQR)
7.27 (7.19, 7.34)
7.09 (6.94, 7.26)
Base excess (mmol/l), median (IQR)
−7.8 (−14.1, −4.9)
−13.7 (−18.7, −10.4)
Lactate (mmol/l), median (IQR)
6.8 (4.8, 9.4)
9.8 (7.3, 12.1)
PCPS, n/total n (%)
IABP, n/total n (%)
The median (IQR) time interval between ROSC and consciousness assessment in each GCS M group was as follows: GCS M1, 66 (36, 89); GCS M2, 48 (33, 77); GCS M3, 52 (36, 80); GCS M4, 49 (34, 83); GCS M5, 77 (32, 113); and GCS M6, 48 (20, 69).
Neurological outcome at 30 days after hospital admission by MTH
Furthermore, one GCS M5 case with CPC5 that had not undergone MTH was admitted to the hospital due to malnutrition and died in hospital due to an inability to control the primary disease. In this case, it was difficult to believe that MTH would have improved the CPC at 30 days after hospital admission. Moreover, one GCS M6 case with CPC5 that underwent MTH was a case in which death was caused without recovery due to pump failure due to acute myocardial infarction, and one case with CPC3 that had not undergone MTH was a case in which decreased activity was due to extended critical illness hospitalization caused by old age. Regarding these two cases as well, it was difficult to believe that implementing MTH would have improved the CPC at 30 days after hospital admission.
Odds ratio for a good recovery
Odds ratio for a good recovery
Good recovery (CPC 1–2)
Odds ratio (95 % CI)
Odds ratio (95 % CI)
Odds ratio (95 % CI)
Age (1 year)
VF or pulseless VT
Time interval between collapse and ROSC (1 min)
Without prehospital ROSC
GCS Motor response score 5–6
Base Excess (1 mmol/l)
Lactate (1 mmol/l)
In multivariate 1, significant factors associated with a good recovery were age (1 year) (OR 0.955, P < 0.001, 95 % confidence interval 0.931 to 0.980), bystander CPR (OR 2.064, P = 0.043, 95 % confidence interval 1.022 to 4.169), GCS M5–6 (OR 123.272, P < 0.001, 95 % confidence interval 26.842 to 566.123), and MTH (OR 2.980, P = 0.004, 95 % confidence interval 1.414 to 6.281).
In multivariate 2, significant factors associated with a good recovery were age (1 year) (OR 0.958, P < 0.001, 95 % confidence interval 0.934 to 0.979), VF or pulseless VT (OR 2.492, P = 0.010, 95 % confidence interval 1.247 to 4.980), without prehospital ROSC (OR 0.330, P = 0.025, 95 % confidence interval 0.125 to 0.867), GCS M5–6 (OR 159.835, P < 0.001, 95 % confidence interval 33.592 to 760.513), lactate (1 mmol/l) (OR 0.830, P < 0.001, 95 % confidence interval 0.752 to 0.916), and MTH (OR: 2.901, P = 0.002, 95 % confidence interval 1.460 to 5.763).
The GCS is a useful indicator for evaluating the level of consciousness in emergency situations, which is also suitable for evaluating the level of consciousness post cardiac arrest. Specifically, the motor response score reflects an abnormal reflex and integrated movement, thus reflecting the degree of encephalopathy. However, it is difficult to evaluate eye opening when the patient is in a post cardiac arrest coma. For example, we sometimes find post cardiac arrest patients who present with open eyes, but they cannot obey an order to close their eyes. Thus, they do not truly have an eye opening score of 4 in the GCS. In our opinion, it would be better not to take the eye opening score of the GCS into account. Moreover, tracheal intubation is carried out in almost all cases and even if using the modified verbal score, it would be difficult to evaluate the GCS verbal response score as usual. Therefore, the verbal response score is obscure in most post cardiac arrest patients. From the above, when evaluating the state of consciousness in cardiac arrest patients, it is believed that evaluating such patients using only the motor response is most appropriate.
Definition of coma
Definition of coma
Mckean et al. 
GCS ≤ 8 and E1 and M ≤ 5
Testori et al. 
GCS ≤ 8
Hörburger et al. 
GCS < 8
GCS < 8
Hachimi-Idrissi et al. 
GCS < 7
Shah et al. 
GCS E1 or M1
HACA study group 
GCS M ≤ 5
Bernard et al. 
Knafelj et al. 
Derwall et al. 
Petrovic et al. 
There were several reasons why we decided on GCS M5 as the optimal motor score threshold for MTH. Firstly, the result of the CHAID analysis indicated that an optimal GCS motor score threshold for MTH was GCS M5. Secondly, the percentage of patients with a good recovery in the GCS M5 and M6 groups was around 100 %, and for the patients with a bad recovery in the GCS M5 and M6 groups, it was difficult to believe that implementing MTH would have improved the CPC at 30 days after hospital admission. Thirdly, the ORs of GCS M5 and GCS M6 for good recovery were significantly higher, whilst the percentages of patients with a good recovery in the GCS M4, M3, M2, and M1 were lower than 60 %. Fourthly, MTH improved CPC at 30 days after hospital admission in the GCS M2 and M4 groups.
As for the reason why no significant difference on CPC at 30 days after hospital admission between with MTH and without MTH was observed in the GCS M1 and M3 groups, though the patients treated with MTH had a significantly better neurological outcome at 30 days after hospital admission in the GCS M2 and GCS M4 groups, we postulated that the GCS M1 group included patients whose neurological outcome was poor regardless of whether the patients were treated with MTH, and the GCS M3 group had a small number of patients. Because the OR of MTH for good recovery was 2.901 (P = 0.002), there may be patients whose neurological outcome was good because of MTH in the GCS M1 group.
From the above, because there are post cardiac arrest patients who receive a beneficial effect from MTH among those with a GCS motor response score of 4 or lower, we suggest that the definition regarding the degree of unconsciousness for which MTH is indicated in post cardiac arrest patients is a GCS motor response score of 4 or lower. Furthermore, when discussing the efficacy of MTH, “the percentage of patients with a GCS motor response score of 5 or higher” should be clarified.
In this study, patients with a GCS motor score of 4 or lower had relatively lower percentage of good recovery than earlier trials [13, 14]. The reason was that we included patients with out-of-hospital arrests of presumed non-cardiac cause, non-shockable rhythms and we had fewer exclusion criteria. Another published study  involving patients with cardiac arrest who were admitted to the ICU demonstrated baseline characteristics and mortality that are in keeping with our findings.
Regarding the limitations of this study, the number of patients evaluated was insufficient to make any definitive conclusions. This was a retrospective study at a single institute, and there were some differences in the patient background between patients who were treated with MTH and patients who were treated without MTH. Moreover, the presence of higher brain dysfunction was not evaluated in CPC1 patients at 30 days after hospital admission, so from the standpoint of preventing higher brain dysfunction, the efficacy of MTH in patients classified according to a GCS motor response score of 5 or higher cannot be discussed. We hope this study will be seen as a pilot study leading to a prospective, randomized, multi-center study in the future.
MTH may be unnecessary in patients with a GCS motor response score of 5 or higher. Consequently, because there are post cardiac arrest patients who receive a beneficial effect from MTH among patients with a GCS motor response score of 4 or lower, the degree of unconsciousness in out-of-hospital cardiac arrest patients for which MTH is indicated may be limited to patients with a GCS motor response score of 4 or lower. Furthermore, when discussing the efficacy of MTH, “the percentage of patients with a GCS motor response score of 5 or higher” should be clarified.
Out-of-hospital cardiac arrest patients with a GCS motor response score of 5 or higher showed good neurological outcomes, whether or not MTH was performed.
MTH for post cardiac arrest syndrome may be performed in patients with a GCS motor response score of 4 or lower.
Cerebral Performance Category
Glasgow Coma Scale
- GCS M1:
patients classified with a GCS motor response score of 1
- GCS M1–4:
patients classified with a GCS motor response score of 4 or lower
- GCS M2:
patients classified with a GCS motor response score of 2
- GCS M2-4:
patients classified with a GCS motor response score from 2 to 4
- GCS M3:
patients classified with a GCS motor response score of 3
- GCS M4:
patients classified with a GCS motor response score of 4
- GCS M5:
patients classified with a GCS motor response score of 5
- GCS M5–6:
patients classified with a GCS motor response score of 5 or higher
- GCS M6:
patients classified with a GCS motor response score of 6
intensive care unit
mild therapeutic hypothermia
percutaneous cardio-pulmonary support
return of spontaneous circulation
The authors are greatly indebted to all of the personnel at the Senri Critical Care Medical Center.
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- Peberdy M, Callaway C, Neumar R, Geocadin R, Zimmerman J, Donnino M, et al. American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Part 9 post-cardiac arrest care. Circulation. 2010;122:S768–S786.
- Erb JL, Hravnak M, Rittenberger JC. Therapeutic hypothermia after cardiac arrest. Am J Nurs. 2012;112:38–44.View ArticlePubMedGoogle Scholar
- Teasdale G, Maas A, Lecky F, Manley G, Stocchetti N, Murray G. The Glasgow Coma Scale at 40 years: standing the test of time. Lancet Neurol. 2014;13:844–54.View ArticlePubMedGoogle Scholar
- Phelps R, Dumas F, Maynard C, Silver J, Rea T. Cerebral performance category and long-term prognosis following out-of-hospital cardiac arrest. Crit Care Med. 2013;41:1252–7.View ArticlePubMedGoogle Scholar
- McKean S. Induced moderate hypothermia after cardiac arrest. AACN Adv Crit Care. 2009;20:343–55.View ArticleGoogle Scholar
- Testori C, Sterz F, Behringer W, Haugk M, Uray T, Zeiner A, et al. Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms. Resuscitation. 2011;82:1162–7.View ArticlePubMedGoogle Scholar
- Testori C, Sterz F, Behringer W, Haugk M, Uray T, Zeiner A, et al. Mild therapeutic hypothermia improves outcomes compared with normothermia in cardiac-arrest patients. A retrospective chart review. Crit Care Med. 2012;40:1–5.Google Scholar
- Nielsen N, Wetterslev J, al-Subaie N, Andersson B, Bro-Jeppesen J, Bishop G, et al. Target temperature management after out-of-hospital cardiac arrest—a randomized, parallel group, assessor-blinded clinical trial—rationale and design. Am Heart J. 2012;163:541–8.
- 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.
- Hachimi-Idrissi S, Corne L, Ebinger G, Michotte Y, Huyghens L. Mild hypothermia induced by a helmet device: a clinical feasibility study. Resuscitation. 2001;51:275–81.View ArticlePubMedGoogle Scholar
- Hachimi-Idrissi S, Zizi M, Nguyen DN, Schiettecate J, Ebinger G, Michotte Y, et al. The evolution of serum astroglial S-100 β protein in patients with cardiac arrest treated with mild hypothermia. Resuscitation. 2005;64:187–92.
- Shah MP, Zimmerman L, Bullard J, Yenari MA. Therapeutic hypothermia after cardiac arrest: experience at an academically affiliated community-based veterans affairs medical center. Stroke Res Treat. 2011;2011:1–8.View ArticleGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Holzer M, Cerchiari E, Roine R, Sterz F, Eisenburger P, Havel C, et al. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549–56.
- Knafelj R, Radsel P, Ploj T, Noc M. Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial infarction. Resuscitation. 2007;74:227–34.View ArticlePubMedGoogle Scholar
- Derwall M, Stoppe C, Brücken D, Rossaint R, Fries M. Change in S-100 protein serum levels in survivors of out-of-hospital cardiac arrest treated with mild therapeutic hypothermia: a prospective, observational study. Crit Care. 2009;13:R58. doi:10.1186/cc7785.PubMed CentralView ArticlePubMedGoogle Scholar
- Petrović M, Panić G, Jovelić A, Canji T, Srdanović I, Popov T, et al. Therapeutic hypothermia and neurological outcome after cardiac arrest. Vojnosanit Pregled. 2011;68:495–9.View ArticleGoogle Scholar