612
Letters to the Editor
Pilot prospective study of therapeutic hypothermia for treatment of post-cardiac arrest patients☆,☆☆,★ Mingwei Ng a, Aaron Sung Lung Wong b, Huck Chin Chew c, Nur Shahidah d, Pin Pin Pek d, Juliana Poh d, Chee Tang Chin b, Terrance Siang Jin Chua b, Marcus Eng Hock Ong d,⁎ a b c d
Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore Department of Cardiology, National Heart Centre, Singapore, Singapore Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore, Singapore Department of Emergency Medicine, Singapore General Hospital, Singapore, Singapore
a r t i c l e
i n f o
Article history: Received 6 February 2014 Accepted 15 March 2014 Available online 21 March 2014 Keywords: Therapeutic hypothermia Cardiac arrest Emergency department Neurological function
Survival to hospital discharge after out-of-hospital cardiac arrest (OHCA) in Singapore is a mere 2.7% [1]. Therapeutic hypothermia (TH) is a method of preserving vital organ and neurological function following global anoxia in cardiac arrest [2], by controlled lowering of core body temperature to improve the oxygen supply-anddemand mismatch and attenuate ischemic–reperfusion injury. The revised 2010 guidelines by AHA stated that initiating TH is now considered as standard post-resuscitation care for comatose cardiac arrest patients [3]. This study aimed to determine if TH can reduce mortality and improve neurological outcomes in post-resuscitated cardiac arrest patients. The study was a before–after phased case–control study comparing survival-to-hospital discharge or 30-days post-arrest and neurological status in cardiac arrest patients before implementation of TH (March 2006–July 2008) and after (October 2008–May 2013). This study was nested within an ongoing prospective randomized controlled trial comparing internal and external methods for TH. All in-hospital cardiac arrest (IHCA) or OHCA patients aged 18–80 years with sustained ROSC for N30 min, comatose with GCS b8 and with systolic BP N90 mm Hg with or without inotropic support were included. Primary outcome was survival-to-discharge or 30-days post-arrest. Retrospective normothermic controls from our cardiac arrest registry were matched based on age and gender on a 1:1 ratio. Since the subjects enrolled were unconscious and unable to provide consent for enrollment, delayed consent was sought by relatives and this was approved by ethics committee of Singapore General Hospital. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ☆☆ Grant supports: This study was supported by grants from the Department of Clinical Research, Singapore General Hospital (DCR/P08/2009) and Singapore General Hospital research grant (SRG#11/2010). ★ Conflict of interest: A/Prof Ong has licensing agreement and patent filing (Application no: 13/047,348) with ZOLL Medical Corporation for a study titled ‘Method of predicting acute cardiopulmonary events and survivability of a patient’. No further conflict of interests for other authors. ⁎ Corresponding author at: Department of Emergency Medicine, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. Tel.: +65 63213590; fax: + 65 62260294. E-mail address: [email protected] (M.E.H. Ong).
All eligible post-resuscitated OHCA patients in the Emergency Department were randomized to either internal or external cooling by sealed opaque envelopes. Cooling treatment was then commenced at the Medical Intensive Care Unit (MICU) or Coronary Care Unit (CCU). Eligible post-resuscitated patients from MICU/CCU after IHCA were also randomized by contacting the study coordinator. Bladder and esophageal temperature probes were used to monitor patient's temperature. Patients were first sedated and paralyzed to avoid shivering. They were then crash-cooled to target temperature of 34 °C, after which they were maintained at hypothermia for 24 h. Upon completing 24 h of cooling, patients were rewarmed passively by changing the device settings to a target temperature of 36.5 °C at 0.25 °C/h. Once patients achieved 36.5 °C, the treatment was stopped and no further maintenance was required. Internal cooling was achieved using the Intravascular Temperature Management System from ZOLL Medical Corporation, which requires a triple-lumen catheter to be inserted into the central venous system of the patient via the femoral vein. External cooling was achieved with the Arctic Sun® 2000 Temperature Management System from Medivance which uses gel-coated pads to maintain contact with the patient's skin throughout the treatment. Data were entered using Microsoft Excel 2010 and analyzed using SPSS version 17.0 (SPSS, Chicago, IL). Frequency tables and descriptive statistics for all covariates were calculated. Univariate comparisons were conducted to identify differences in distribution of covariates where appropriate. Statistical significance was generally set at a two-tailed P value of less than 0.05. Twenty-five cardiac arrest patients who completed a controlled TH protocol were matched by age and gender to 25 controls who received conventional normothermic treatment. There were no significance in terms of age and gender between the intervention and control groups. Similarly, there was no significance in the initial rhythm of VT/VF between the TH (8%) and control group (12%) (Table 1). Survival-to-discharge trended higher in the intervention group [11 (44.0%) vs control 4 (16.0%), P = 0.06]. Survivors in the intervention group had good neurological recovery [CPC = 1/2: 7/ 11 (63.6%); OPC = 1/2: 6/11 (54.5%)]. Temperature data obtained from temperature probe were used to compare cooling rates and time taken from ROSC to initiation of TH (R2TH), time from initiation of TH to target temperature of 34 °C (T2TT) and time from ROSC to target temperature (R2TT) between the external and internal cooling groups (Table 2). Patients from external group took 5.5 h (330 min [IQR: 204–449 min]) from ROSC to initiation of TH (R2TH), while patients randomized to internal cooling took about 5 h (304 min [IQR: 243–419 min]). Subsequently, patients on external cooling achieved target temperature (T2TT) in a median time of 120 min [IQR: 67–218 min], while internal cooling took a median time of 154 min [IQR: 77–158 min]. Patients on external cooling appeared more likely to have both overcooling (internal 33.3%, external 50.0%) and undercooling (internal 88.9%, external 93.8%). Rebound hyperthermia (defined as temperature overshoot ≥ 38.0 °C) was observed in only 4 patients (16.0%), all of whom were on external cooling.
Letters to the Editor Table 1 Characteristics of study participants. Characteristics
Control N = 25
Intervention P N = 25
Mean age (standard deviation, SD) Gender, male (%) Race (%) Chinese Malay Indian Others Past medical history (%) Diabetes mellitus Hypertension Hypercholesterolemia Stroke Cancer Cardiac conditions Respiratory conditions Renal conditions No past medical history Cardiac arrest location (%) Out-of-hospital In-hospital Witnessed collapse (%) Unwitnessed collapse Bystander Paramedic Hospital staff Bystander CPR (%) Yes No Not applicable (in-ambulance/in-hospital arrest) Prehospital defibrillation (%) Yes No Not applicable (in-hospital arrest) Prehospital and/or ED defibrillation (%) Initial rhythm (%) Asystole Pulseless electrical activity (PEA) VF/VT ROSC en-route Median time in minutes to ROSC (SD)a
61.5 (13.4) 19 (76.0)
61.6 (12.4) 19 (76.0)
0.99 1.00
20 (80.0) 2 (8.0) 2 (8.0) 1 (4.0)
20 (80.0) 4 (16.0) 1 (4.0) 0 (0.0)
0.57
9 (36.0) 14 (56.0) 8 (32.0) 3 (12.0) 1 (4.0) 14 (56.0) 5 (20.0) 7 (28.0) 5 (20.0)
11 (44.0) 12 (48.0) 13 (52.0) 2 (8.0) 4 (16.0) 12 (48.0) 5 (20.0) 7 (28.0) 4 (16.0)
0.77 0.78 0.25 1.00 0.35 0.78 1.00 1.00 1.00
20 (80.0) 5 (20.0)
19 (76.0) 6 (24.0)
1.00
4 (16.0) 13 (52.0) 4 (16.0) 4 (16.0)
3 (12.0) 16 (64.0) 1 (4.0) 5 (20.0)
4 (16.0) 13 (52.0) 8 (32.0)
5 (20.0) 14 (56.0) 6 (24.0)
5 (20.0) 14 (56.0) 6 (24.0) 14 (56.0)
7 (28.0) 12 (48.0) 6 (24.0) 13 (52.0)
10 (40.0) 10 (40.0) 12 (48.0) 8 (32.0) 3 (12.0) 2 (8.0) 0 (0.0) 5 (20.0) 33.0 (20.5) 32.4 (20.4)
0.50
0.81
613
We found that it took a longer time (330 min) from ROSC to actual initiation of TH for patients randomized to external cooling, compared to those who were randomized to internal cooling (304 min). The longer time taken to initiate external TH might be explained by greater urgency of the medical team for the more invasive endovascular catheterization procedure, compared to cooling gel pads which are not that different from cooling by ice packs and cold saline. As patients with a shorter R2TH timing tended to have a higher pretreatment core body temperature and therefore a longer T2TT timing, we feel that R2TT (time taken from ROSC to target temperature of 34 °C) is a more intuitive and accurate reflection of time taken to cool. Internal cooling was superior in this respect with R2TT of 404 min, about 2 h faster compared to external cooling. The difficulties faced in recruiting post-cardiac arrest patients with ROSC-to-admission affected our ability to reach statistical power. In particular, we are unable to specifically compare outcomes between patients of cardiac arrest from VT/pulseless VF as the sample size is too small. We recommend that future studies could be designed or powered to investigate which cooling technique and variables are optimal in the implementation of TH for post-cardiac arrest patients. A therapeutic hypothermia protocol was safely implemented and the trend suggests that it could increase survival to hospital discharge and improve neurological outcomes even in non-VT/VF patients. References
0.78 1.00
0.15
[1] Heart Save Singapore Programme. Singapore: Singapore Heart Foundation; 2013 [Available in: http://www.myheart.org.sg/our-programmes/heart-safe-singapore/4/9]. [2] Felberg RA, Krieger DW, Chuang R, et al. Hypothermia after cardiac arrest: feasibility and safety of an external cooling protocol. Circulation 2001;104:1799–804. [3] Sayre MR, Kosta RW, Botha M, et al. Part 5: adult basic life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010;122:S298–324.
–
ROSC = return of spontaneous circulation, ED = emergency department, CPC = Cerebral Performance Category, OPC = Overall Performance Category, VF/VT = ventricular fibrillation/ventricular tachycardia. a Data from 22 cases and 21 controls as these were unwitnessed arrests with no “down-time” documented.
Table 2 Comparison of outcomes and cooling phase between interventions.
Survival (%) CPC 1–2 (%) OPC 1–2 (%) Pretreatment T°C, median (IQR)a R2TH in minutes, median (IQR)a T2TT in minutes, median (IQR)b R2TT in minutes, median (IQR)b
Intervention cases (N = 25)
P
11 (44.0) 7 (28.0) 6 (24.0) 35.97 (34.20–37.31) 320 (216–444) 151 (67–169) 453 (324–705)
0.06 0.14 0.25 – – – –
Intervention cooling technique
P
Internal (N = 9)
External (N = 16)
5 4 3 37.27 304 154 404
6 (37.5) 3 (18.8) 3 (18.8) 35.33 (33.83–36.67) 330 (204–449) 120 (67–218) 514 (247–743)
(55.6) (44.4) (33.3) (35.11–37.32) (243–419) (77–158) (353–560)
0.43 0.21 0.63 – – – –
IQR = interquartile range, R2TH = time from ROSC to initiation of therapeutic hypothermia. R2TT = time from ROSC to target temperature of 34 °C, T2TT = time from initiation of therapeutic hypothermia to target temperature of 34 °C. a Data from 24 cases; 1 patient who received external cooling could not be retrieved due to technical glitches. b Data from 17 cases (9 external; 8 internal); 6 external cases and 1 internal case started off below target temperature of 34 °C (T2TT = 0 min) and were thus excluded in the analysis.
http://dx.doi.org/10.1016/j.ijcard.2014.03.132 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Letters to the Editor
Pilot prospective study of therapeutic hypothermia for treatment of post-cardiac arrest patients☆,☆☆,★ Mingwei Ng a, Aaron Sung Lung Wong b, Huck Chin Chew c, Nur Shahidah d, Pin Pin Pek d, Juliana Poh d, Chee Tang Chin b, Terrance Siang Jin Chua b, Marcus Eng Hock Ong d,⁎ a b c d
Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore Department of Cardiology, National Heart Centre, Singapore, Singapore Department of Respiratory and Critical Care Medicine, Singapore General Hospital, Singapore, Singapore Department of Emergency Medicine, Singapore General Hospital, Singapore, Singapore
a r t i c l e
i n f o
Article history: Received 6 February 2014 Accepted 15 March 2014 Available online 21 March 2014 Keywords: Therapeutic hypothermia Cardiac arrest Emergency department Neurological function
Survival to hospital discharge after out-of-hospital cardiac arrest (OHCA) in Singapore is a mere 2.7% [1]. Therapeutic hypothermia (TH) is a method of preserving vital organ and neurological function following global anoxia in cardiac arrest [2], by controlled lowering of core body temperature to improve the oxygen supply-anddemand mismatch and attenuate ischemic–reperfusion injury. The revised 2010 guidelines by AHA stated that initiating TH is now considered as standard post-resuscitation care for comatose cardiac arrest patients [3]. This study aimed to determine if TH can reduce mortality and improve neurological outcomes in post-resuscitated cardiac arrest patients. The study was a before–after phased case–control study comparing survival-to-hospital discharge or 30-days post-arrest and neurological status in cardiac arrest patients before implementation of TH (March 2006–July 2008) and after (October 2008–May 2013). This study was nested within an ongoing prospective randomized controlled trial comparing internal and external methods for TH. All in-hospital cardiac arrest (IHCA) or OHCA patients aged 18–80 years with sustained ROSC for N30 min, comatose with GCS b8 and with systolic BP N90 mm Hg with or without inotropic support were included. Primary outcome was survival-to-discharge or 30-days post-arrest. Retrospective normothermic controls from our cardiac arrest registry were matched based on age and gender on a 1:1 ratio. Since the subjects enrolled were unconscious and unable to provide consent for enrollment, delayed consent was sought by relatives and this was approved by ethics committee of Singapore General Hospital. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ☆☆ Grant supports: This study was supported by grants from the Department of Clinical Research, Singapore General Hospital (DCR/P08/2009) and Singapore General Hospital research grant (SRG#11/2010). ★ Conflict of interest: A/Prof Ong has licensing agreement and patent filing (Application no: 13/047,348) with ZOLL Medical Corporation for a study titled ‘Method of predicting acute cardiopulmonary events and survivability of a patient’. No further conflict of interests for other authors. ⁎ Corresponding author at: Department of Emergency Medicine, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. Tel.: +65 63213590; fax: + 65 62260294. E-mail address: [email protected] (M.E.H. Ong).
All eligible post-resuscitated OHCA patients in the Emergency Department were randomized to either internal or external cooling by sealed opaque envelopes. Cooling treatment was then commenced at the Medical Intensive Care Unit (MICU) or Coronary Care Unit (CCU). Eligible post-resuscitated patients from MICU/CCU after IHCA were also randomized by contacting the study coordinator. Bladder and esophageal temperature probes were used to monitor patient's temperature. Patients were first sedated and paralyzed to avoid shivering. They were then crash-cooled to target temperature of 34 °C, after which they were maintained at hypothermia for 24 h. Upon completing 24 h of cooling, patients were rewarmed passively by changing the device settings to a target temperature of 36.5 °C at 0.25 °C/h. Once patients achieved 36.5 °C, the treatment was stopped and no further maintenance was required. Internal cooling was achieved using the Intravascular Temperature Management System from ZOLL Medical Corporation, which requires a triple-lumen catheter to be inserted into the central venous system of the patient via the femoral vein. External cooling was achieved with the Arctic Sun® 2000 Temperature Management System from Medivance which uses gel-coated pads to maintain contact with the patient's skin throughout the treatment. Data were entered using Microsoft Excel 2010 and analyzed using SPSS version 17.0 (SPSS, Chicago, IL). Frequency tables and descriptive statistics for all covariates were calculated. Univariate comparisons were conducted to identify differences in distribution of covariates where appropriate. Statistical significance was generally set at a two-tailed P value of less than 0.05. Twenty-five cardiac arrest patients who completed a controlled TH protocol were matched by age and gender to 25 controls who received conventional normothermic treatment. There were no significance in terms of age and gender between the intervention and control groups. Similarly, there was no significance in the initial rhythm of VT/VF between the TH (8%) and control group (12%) (Table 1). Survival-to-discharge trended higher in the intervention group [11 (44.0%) vs control 4 (16.0%), P = 0.06]. Survivors in the intervention group had good neurological recovery [CPC = 1/2: 7/ 11 (63.6%); OPC = 1/2: 6/11 (54.5%)]. Temperature data obtained from temperature probe were used to compare cooling rates and time taken from ROSC to initiation of TH (R2TH), time from initiation of TH to target temperature of 34 °C (T2TT) and time from ROSC to target temperature (R2TT) between the external and internal cooling groups (Table 2). Patients from external group took 5.5 h (330 min [IQR: 204–449 min]) from ROSC to initiation of TH (R2TH), while patients randomized to internal cooling took about 5 h (304 min [IQR: 243–419 min]). Subsequently, patients on external cooling achieved target temperature (T2TT) in a median time of 120 min [IQR: 67–218 min], while internal cooling took a median time of 154 min [IQR: 77–158 min]. Patients on external cooling appeared more likely to have both overcooling (internal 33.3%, external 50.0%) and undercooling (internal 88.9%, external 93.8%). Rebound hyperthermia (defined as temperature overshoot ≥ 38.0 °C) was observed in only 4 patients (16.0%), all of whom were on external cooling.
Letters to the Editor Table 1 Characteristics of study participants. Characteristics
Control N = 25
Intervention P N = 25
Mean age (standard deviation, SD) Gender, male (%) Race (%) Chinese Malay Indian Others Past medical history (%) Diabetes mellitus Hypertension Hypercholesterolemia Stroke Cancer Cardiac conditions Respiratory conditions Renal conditions No past medical history Cardiac arrest location (%) Out-of-hospital In-hospital Witnessed collapse (%) Unwitnessed collapse Bystander Paramedic Hospital staff Bystander CPR (%) Yes No Not applicable (in-ambulance/in-hospital arrest) Prehospital defibrillation (%) Yes No Not applicable (in-hospital arrest) Prehospital and/or ED defibrillation (%) Initial rhythm (%) Asystole Pulseless electrical activity (PEA) VF/VT ROSC en-route Median time in minutes to ROSC (SD)a
61.5 (13.4) 19 (76.0)
61.6 (12.4) 19 (76.0)
0.99 1.00
20 (80.0) 2 (8.0) 2 (8.0) 1 (4.0)
20 (80.0) 4 (16.0) 1 (4.0) 0 (0.0)
0.57
9 (36.0) 14 (56.0) 8 (32.0) 3 (12.0) 1 (4.0) 14 (56.0) 5 (20.0) 7 (28.0) 5 (20.0)
11 (44.0) 12 (48.0) 13 (52.0) 2 (8.0) 4 (16.0) 12 (48.0) 5 (20.0) 7 (28.0) 4 (16.0)
0.77 0.78 0.25 1.00 0.35 0.78 1.00 1.00 1.00
20 (80.0) 5 (20.0)
19 (76.0) 6 (24.0)
1.00
4 (16.0) 13 (52.0) 4 (16.0) 4 (16.0)
3 (12.0) 16 (64.0) 1 (4.0) 5 (20.0)
4 (16.0) 13 (52.0) 8 (32.0)
5 (20.0) 14 (56.0) 6 (24.0)
5 (20.0) 14 (56.0) 6 (24.0) 14 (56.0)
7 (28.0) 12 (48.0) 6 (24.0) 13 (52.0)
10 (40.0) 10 (40.0) 12 (48.0) 8 (32.0) 3 (12.0) 2 (8.0) 0 (0.0) 5 (20.0) 33.0 (20.5) 32.4 (20.4)
0.50
0.81
613
We found that it took a longer time (330 min) from ROSC to actual initiation of TH for patients randomized to external cooling, compared to those who were randomized to internal cooling (304 min). The longer time taken to initiate external TH might be explained by greater urgency of the medical team for the more invasive endovascular catheterization procedure, compared to cooling gel pads which are not that different from cooling by ice packs and cold saline. As patients with a shorter R2TH timing tended to have a higher pretreatment core body temperature and therefore a longer T2TT timing, we feel that R2TT (time taken from ROSC to target temperature of 34 °C) is a more intuitive and accurate reflection of time taken to cool. Internal cooling was superior in this respect with R2TT of 404 min, about 2 h faster compared to external cooling. The difficulties faced in recruiting post-cardiac arrest patients with ROSC-to-admission affected our ability to reach statistical power. In particular, we are unable to specifically compare outcomes between patients of cardiac arrest from VT/pulseless VF as the sample size is too small. We recommend that future studies could be designed or powered to investigate which cooling technique and variables are optimal in the implementation of TH for post-cardiac arrest patients. A therapeutic hypothermia protocol was safely implemented and the trend suggests that it could increase survival to hospital discharge and improve neurological outcomes even in non-VT/VF patients. References
0.78 1.00
0.15
[1] Heart Save Singapore Programme. Singapore: Singapore Heart Foundation; 2013 [Available in: http://www.myheart.org.sg/our-programmes/heart-safe-singapore/4/9]. [2] Felberg RA, Krieger DW, Chuang R, et al. Hypothermia after cardiac arrest: feasibility and safety of an external cooling protocol. Circulation 2001;104:1799–804. [3] Sayre MR, Kosta RW, Botha M, et al. Part 5: adult basic life support: 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2010;122:S298–324.
–
ROSC = return of spontaneous circulation, ED = emergency department, CPC = Cerebral Performance Category, OPC = Overall Performance Category, VF/VT = ventricular fibrillation/ventricular tachycardia. a Data from 22 cases and 21 controls as these were unwitnessed arrests with no “down-time” documented.
Table 2 Comparison of outcomes and cooling phase between interventions.
Survival (%) CPC 1–2 (%) OPC 1–2 (%) Pretreatment T°C, median (IQR)a R2TH in minutes, median (IQR)a T2TT in minutes, median (IQR)b R2TT in minutes, median (IQR)b
Intervention cases (N = 25)
P
11 (44.0) 7 (28.0) 6 (24.0) 35.97 (34.20–37.31) 320 (216–444) 151 (67–169) 453 (324–705)
0.06 0.14 0.25 – – – –
Intervention cooling technique
P
Internal (N = 9)
External (N = 16)
5 4 3 37.27 304 154 404
6 (37.5) 3 (18.8) 3 (18.8) 35.33 (33.83–36.67) 330 (204–449) 120 (67–218) 514 (247–743)
(55.6) (44.4) (33.3) (35.11–37.32) (243–419) (77–158) (353–560)
0.43 0.21 0.63 – – – –
IQR = interquartile range, R2TH = time from ROSC to initiation of therapeutic hypothermia. R2TT = time from ROSC to target temperature of 34 °C, T2TT = time from initiation of therapeutic hypothermia to target temperature of 34 °C. a Data from 24 cases; 1 patient who received external cooling could not be retrieved due to technical glitches. b Data from 17 cases (9 external; 8 internal); 6 external cases and 1 internal case started off below target temperature of 34 °C (T2TT = 0 min) and were thus excluded in the analysis.
http://dx.doi.org/10.1016/j.ijcard.2014.03.132 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
