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Severe acidemia on arrival not predictive of neurologic outcomes in post–cardiac arrest patients
American Journal of Emergency Medicine 34 (2016) 425–428
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Severe acidemia on arrival not predictive of neurologic outcomes in post–cardiac arrest patients☆,☆☆ Kenichi Tetsuhara, MD ⁎, Hiroshi Kato, MD, Takashi Kanemura, MD, Ichiro Okada, MD, Nobuaki Kiriu, MD Department of Critical Care Medicine and Trauma, National Disaster Medical Center, 3256 Tachikawa City, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 31 October 2015 Accepted 14 November 2015
a b s t r a c t Purpose: This study aimed to determine whether severe acidemia (pH b 7.2) on arrival at the emergency department (ED) is a predictive factor for neurologic outcomes of post–cardiac arrest patients treated with targeted temperature management (TTM). Materials and methods: Data in the National Disaster Medical Center, a tertiary care hospital, were used to perform a case-control study on post–cardiac arrest patients treated with TTM from January 2013 to April 2015. The case group comprised patients with good neurologic outcomes (cerebral performance categories 1 and 2), whereas the control group comprised patients with poor neurologic outcomes (cerebral performance categories 3-5). Exposure was defined as arterial pH less than 7.2 on arrival at the ED. Results: We identified 32 patients matching our criteria, of which 13 had good outcomes and 19 poor outcomes. Arterial pH on arrival was not significantly associated with neurologic outcomes (P = .47; odds ratio, 0.5; 95% confidence interval, 0.09-2.61). In 24 patients with cardiogenic causes of cardiac arrest, pH on arrival was not significantly associated with neurologic outcomes (P = .68; odds ratio, 0.5; 95% confidence interval, 0.092.73) after matched-pair analysis by age, sex, and presence of light reflex. Conclusion: Severe acidemia on arrival at the ED is not a significant predictive factor for neurologic outcomes in post–cardiac arrest patients treated with TTM, particularly in patients with cardiogenic causes of cardiac arrest. These results suggest that treatment should not be withheld in post–cardiac arrest patients with severe acidemia. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Post–cardiac arrest patients suffer damage to multiple organs, including the brain [1]. Various prognostic factors for poor neurologic outcomes have been reported, including the absence of pupillary light reflexes, corneal reflexes, and motor response [2]. Although severe acidemia frequently occurs in patients during and after cardiac arrest, the prognostic value of severe acidemia for neurologic outcomes is unknown [3,4]. Severe acidemia, defined as arterial pH less than 7.2 [5,6], at the time of initiation of targeted temperature management (TTM) in shockable post–cardiac arrest patients is associated with poor neurologic outcomes [7]. Lower arterial pH in post–cardiac arrest patients upon intensive care unit (ICU) admission is associated with poor neurologic outcomes [8]. The association between arterial pH at the time of arrival at the emergency department (ED) and neurologic outcomes has seldom been reported [9]. ☆ Conflicts of interest: All authors declare no conflict of interest. ☆☆ Source of support: All authors declare no source of support. ⁎ Corresponding author at: Critical Care Medicine and Trauma, National Disaster Medical Center, 3256 Midori-cho, Tachikawa City, Tokyo, Japan. Tel.: +81 42 526 5511; fax: +81 42 526 5729. E-mail addresses: [email protected] (K. Tetsuhara), [email protected] (H. Kato), [email protected] (T. Kanemura), [email protected] (I. Okada), [email protected] (N. Kiriu). http://dx.doi.org/10.1016/j.ajem.2015.11.030 0735-6757/© 2015 Elsevier Inc. All rights reserved.
Targeted temperature management is the recommended treatment for comatose post–cardiac arrest patients [2]. This case-control study aims to determine whether severe acidemia on arrival at the ED is a predictive factor for neurologic outcomes in post–cardiac arrest patients treated with TTM.
2. Methods 2.1. Study population We used a prospective database of all patients admitted to the ICU of the National Disaster Medical Center, a tertiary care hospital in Tokyo, Japan. This database included data on age, sex, date of admission, diagnosis, and management. From the database, we chose patients who were treated with TTM after a nontraumatic, out-of-hospital cardiac arrest between January 2013 and April 2015. We excluded patients who did not complete TTM. For all patients, we extracted data regarding arterial blood gas analysis (pH, pCO2, and base excess) on arrival at the ED and on admission to the ICU, whether cardiac arrest was witnessed, bystander cardiopulmonary resuscitation, shockable or nonshockable rhythm on initial cardiac electrogram, return of spontaneous circulation (ROSC) before or after arrival at the hospital, cause of cardiac arrest, Glasgow Coma Scale (GCS) between ROSC and initiation of TTM,
426
K. Tetsuhara et al. / American Journal of Emergency Medicine 34 (2016) 425–428 Table 1b Baseline characteristics (n = 31)
Cardiac arrest patients n = 826
Patients treated with TTM n = 32
Cardiogenic
n = 24
Non-cardiogenic
n=4
Unknown
n=4
Initial cardiac rhythm = shockable
Good outcome (n = 13)
Poor outcome (n = 18)
P
10 (76.9)
10 (55.6)
.275
Values are expressed as number (percentage).
2.2. Targeted temperature management
pH < 7.2 on arrival n = 18
CPC 1,2 n=6
CPC 3-5 n = 12
pH ≥ 7.2 on arrival n = 14
CPC 1,2 n=7
CPC 3-5 n=7
Figure. Flow chart of patients.
tympanic temperature on arrival, existence of light reflex within 24 hours after ROSC, lactate on arrival, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and cerebral performance categories (CPC) on discharge from the hospital. Cerebral performance categories are defined as follows: CPC1, good cerebral performance, conscious, alert, and able to work and lead a normal life; CPC 2, moderate cerebral disability, conscious with sufficient cerebral function for part-time work in a sheltered environment or independent activities of daily life; CPC 3, severe cerebral disability, conscious but dependent on others for daily support because of impaired brain function; CPC 4, comatose, vegetative state; and CPC 5, death [10]. The primary end point was the CPC measured on discharge from the hospital. Causes of cardiac arrest were determined by emergency physicians and cardiologists to be cardiogenic, noncardiogenic, or unknown based on medical history and findings of laboratory data and coronary arteriography. When we could not determine whether the cause of arrest was cardiogenic, it was categorized as “unknown.” This study was approved by the institutional review board of the National Disaster Medical Center.
Table 1a Baseline characteristics (n = 32)
Age (y) Sex (male) Witness of faint Performed bystander CPR ROSC at prehospital pH on arrival PaCO2 on arrival (mm Hg) Base excess on arrival (mmol/L) Lactate on arrival (mmol/L) pH on ICU admission GCS after ROSC Existence of light reflex within 24 h from ROSC Tympanic temperature (°C) APACHE II PCPS
Good outcome (n = 13)
Poor outcome (n = 19)
P
53 (49.0-64.0) 10 (76.9) 10 (76.9) 5 (38.5) 10 (76.9) 7.22 (6.87-7.32) 49.3 (39.9-67.3) −10.6 (−15.8 to −7.8) 6.6 (4.9-9.9) 7.40 (7.32-7.43) 3 (3.0-5.0) 13 (100.0)
66 (48.0-76.5) 11 (57.9) 11 (57.9) 6 (31.6) 10 (52.6) 7.12 (6.92-7.30) 44.6 (31.1-67.6) −12.5 (−19.3 to −9.9) 5.9 (3.5-8.9) 7.36 (7.26-7.40) 3 (3.0-4.5) 7 (36.8)
.388 .399 .768 b.001
35.4 (34.7-35.7) 20.0 (18.0-23.0) 3 (23.1)
35.3 (34.8-36.0) 22.0 (19.0-24.5) 3 (15.8)
.848 .441 .666
.134 .450 .450 .721 .267 .759 .578 .527
Values are expressed as number (percentage) and median (interquartile range), as appropriate. Abbreviations: CPR, cardiopulmonary resuscitation; PCPS, percutaneous cardiopulmonary support device.
Post–cardiac arrest patients with GCS 8 or less were treated with TTM based on the discretion of emergency physicians. We terminated TTM in cases involving shock requiring large amounts of inotropes, a bleeding tendency, a clotting disorder, excess hypothermia on arrival, and underlying conditions in which bleeding may lead to death. In our TTM protocol, the target temperature of 34°C ± 0.5°C is reached within 6 hours after ROSC using internal and external cooling. The core temperature is monitored using bladder probes. Internal cooling is performed using intravenous cold extracellular fluid. External cooling is performed using a cooling blanket and MEDI-THERM III (Gaymar, Orchard Park, NY). The target temperature is maintained for 24 hours. Patients are rewarmed to 36°C at 0.5°C per hour using the cooling blanket and MEDI-THERM III. 2.3. Laboratory measurements Blood samples for analysis of arterial blood gas and lactate were obtained as soon as possible after arrival at the ED. Arterial blood gas analysis was evaluated using RAPID POINT 500 (Siemens K.K., Tokyo, Japan). Lactate was evaluated using LACTATE PRO 2 LT-1730 (Arkray, Kyoto, Japan). 2.4. Statistical analysis In this case-control study, the case group comprised patients with good neurologic outcomes (CPC 1 and 2), whereas the control group comprised patients with poor neurologic outcomes (CPC 3-5). Exposure was arterial pH less than 7.2. Continuous variables that were not normally distributed were summarized by median and interquartile range. Categorical variables were summarized by counts and percentages. Fisher exact test was used for categorical variables, and the Mann-Whitney U test was used for continuous variables that were not normally distributed. The Mantel-Haenszel test was used for comparisons between the case and control groups. Wilcoxon signed rank test was used for comparisons between arterial pH on arrival and at ICU admission, as these variables were not normally distributed. P b .05 was considered statistically significant. We used EZR version 1.27 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) for data analysis. EZR is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [11]. 3. Results 3.1. Baseline characteristics The patient flow chart is shown in the Figure. Of 826 cardiac arrest patients, 37 patients who survived had started TTM on admission. Targeted temperature management was discontinued in 5 of these patients for the following reasons: shock requiring large amounts of inotrope (n = 1), bleeding tendency (n = 1), clotting disorder (n = 1), excess hypothermia (n = 1), and aortic dissection (n = 1). Targeted temperature management was completed in 32 patients. Of 18 patients with arterial pH less than 7.2 on arrival, at the time of hospital discharge, 6 were CPC 1 or 2, whereas 12 were CPC 3 to 5. Of 14 patients with pH
K. Tetsuhara et al. / American Journal of Emergency Medicine 34 (2016) 425–428 Table 1c Baseline characteristics (n = 28)
Cause of cardiac arrest, cardiogenic
Table 3 Association of arterial pH and neurologic outcome in all causes after matched pair on age, sex, and existence of light reflex
Good outcome (n = 11)
Poor outcome (n = 17)
P
11 (100)
13 (76.5)
.132
Values are expressed as number (percentage).
greater than or equal to 7.2 on arrival, 7 were CPC 1 or 2, and 7 were CPC 3 to 5 at the time of hospital discharge. Baseline characteristics of the patients are shown in Tables 1a, 1b, and 1c. Arterial pH on arrival did not differ significantly between the case and control groups. The presence of the light reflex differed significantly between the case and control groups. The arterial pH on arrival was significantly lower than that at ICU admission (P b .001). The causes of cardiac arrest were as follows: cardiogenic (n = 24), noncardiogenic (n = 4), and unknown (n = 4). 3.2. Primary end point 3.2.1. Patient group with all causes of cardiac arrest Arterial pH on arrival was not significantly associated with neurologic outcomes in the 32 patients with cardiogenic, noncardiogenic, or unknown causes on Fisher exact test (P = .47; odds ratio [OR], 0.5; 95% confidence interval [CI], 0.09-2.61) (Table 2). After matched-pair analysis on age, sex, and presence of light reflex, arterial pH on arrival was not significantly associated with neurologic outcomes on the Mantel-Haenszel test (P = .45; OR, 0.4; 95% CI, 0.08-2.06) (Table 3). 3.2.2. Patient group with cardiogenic cardiac arrest. In 24 patients with cardiac arrest from cardiogenic causes, arterial pH on arrival was not significantly associated with neurologic outcomes on the Mantel-Haenszel test (P = .68; OR, 0.5; 95% CI, 0.09-2.73) after matched-pair analysis on age, sex, and existence of light reflex (Table 4). 4. Discussion Severe acidemia on arrival at the ED is not a significant predictive factor for neurologic outcomes in post–cardiac arrest patients treated with TTM, particularly in those with cardiogenic cardiac arrest. Previous studies reported that severe acidemia at the initiation of TTM in shockable patients and lower pH at ICU admission were associated with poor neurologic outcomes [7,8]. Delays in blood sampling may influence laboratory results because intensive care may have started before sampling. In our study, the arterial pH on arrival was significantly lower than that at ICU admission. Consistent with our results, another study reported that arterial pH on arrival at the ED was not associated with neurologic outcomes [9]. However, that study used multivariate analysis of various laboratory measurements; unlike our study, the primary end point was not the association between arterial pH and neurologic outcomes. Arterial pH is useful for determining treatable causes of cardiac arrest, including hyperkalemia/hypokalemia and severe acidosis, but is not useful for predicting neurologic outcomes. These results suggest that even if post–cardiac arrest patients have severe acidemia, treatment should not be withheld. Numerous predictive factors for poor neurologic outcomes in post– cardiac arrest patients have been reported, including absent pupillary light reflexes, absent corneal reflexes, absent motor response [2], Table 2 Association of arterial pH and neurologic outcome in all causes
pH b7.2 pH ≥7.2
CPC 1-2
CPC 3-5
6 7 13
12 7 19
427
18 14 32
pH b7.2 pH ≥7.2
CPC 1-2
CPC 3-5
6 7 13
9 4 13
15 11 26
Table 4 Association of arterial pH and neurologic outcome in cardiogenic causes after matched pair on age, sex, and existence of light reflex
pH b7.2 pH ≥7.2
CPC 1-2
CPC 3-5
5 6 11
7 4 11
12 10 22
nonwitnessed cardiac arrest, cardiogenic causes, advanced age, initial nonshockable rhythm [12], lower GCS after ROSC [13], and lower body temperature [14]. In our study, only absent pupillary light reflex was significantly associated with poor neurologic outcomes. This difference in results may arise from the sample size in our study, which may be too small to detect significant differences. Our study has several limitations. First, this study was a retrospective single-center study with a small cohort. Only 4 patients had noncardiogenic causes of cardiac arrest. Second, confounding factors and selection bias may influence our results. To avoid these problems, we used stratification and matched-pair analysis. Third, the protocol for TTM depended on the discretion of emergency physicians. A prospective, multicenter study is needed to evaluate the predictive value of pH at the time of arrival at the ED for neurologic outcomes. 5. Conclusions Severe acidemia on arrival at the ED is not a significant predictive factor for neurologic outcomes in post–cardiac arrest patients treated with TTM, particularly in patients with cardiogenic causes of cardiac arrest. These findings suggest that treatment should not be withheld from post–cardiac arrest patients with severe acidemia. A prospective, multicenter study is needed to evaluate the predictive value of pH at the time of arrival at the ED for neurologic outcomes. References [1] Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Böttiger BW, et al. Post–cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 2008;118:2452–83. [2] Soar J, Callaway CW, Aibiki M, Böttiger BW, Brooks SC, Deakin CD, et al. Part 4: advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2015;132:S84–S145. [3] Makino J, Uchino S, Morimatsu H, Bellomo R. A quantitative analysis of the acidosis of cardiac arrest: a prospective observational study. Crit Care 2005;9:R357–62. [4] Prause G, Ratzenhofer-Comenda B, Smolle-Jüttner F, Heydar-Fadai J, Wildner G, et al. Comparison of lactate or BE during out-of-hospital cardiac arrest to determine metabolic acidosis. Resuscitation 2001;51:297–300. [5] Kraut JA, Kurtz I. Use of base in the treatment of acute severe organic acidosis by nephrologists and critical care physicians: results of an online survey. Clin Exp Nephrol 2006;10:111–7. [6] Kraut JA, Madias NE. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 2010;6:274–85. [7] Ganga HV, Kallur KR, Patel NB, Sawyer KN, Gowd PB, Nair SU, et al. The impact of severe acidemia on neurologic outcome of cardiac arrest survivors undergoing therapeutic hypothermia. Resuscitation 2013;84:1723–7.
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[8] Uribarri A, Bueno H, Pérez-Castellanos A, Loughlin G, Sousa I, Viana-Tejedor A, et al. Impact of time to cooling initiation and time to target temperature in patients treated with hypothermia after cardiac arrest. Eur Heart J Acute Cardiovasc Care 2015;4:365–72. [9] Cho YM, Lim YS, Yang HJ, Park WB, Cho JS, Kim JJ, et al. Blood ammonia is a predictive biomarker of neurologic outcome in cardiac arrest patients treated with therapeutic hypothermia. Am J Emerg Med 2012;30:1395–401. [10] Cummins RO, Chamberlain DA, Abramson NS, Allen M, Baskett PJ, Becker L, et al. Recommended guidelines for uniform reporting of data from out-of-hospital cardiac arrest: the Utstein Style. A statement for health professionals from a task force of the American Heart Association, the European Resuscitation Council, the Heart and Stroke Foundation of Canada, and the Australian Resuscitation Council. Circulation 1991;84:960–75.
[11] Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013;48:452–8. [12] Goto Y, Maeda T, Nakatsu-Goto Y. Neurological outcomes in patients transported to hospital without a prehospital return of spontaneous circulation after cardiac arrest. Crit Care 2013;17:R274. [13] Grossestreuer AV, Abella BS, Leary M, Perman SM, Fuchs BD, Kolansky DM, et al. Time to awakening and neurologic outcome in therapeutic hypothermia–treated cardiac arrest patients. Resuscitation 2013;84:1741–6. [14] den Hartog AW, de Pont AC, Robillard LB, Binnekade JM, Schultz MJ, Horn J. Spontaneous hypothermia on intensive care unit admission is a predictor of unfavorable neurological outcome in patients after resuscitation: an observational cohort study. Crit Care 2010;14: R121.
Contents lists available at ScienceDirect
American Journal of Emergency Medicine journal homepage: www.elsevier.com/locate/ajem
Original Contribution
Severe acidemia on arrival not predictive of neurologic outcomes in post–cardiac arrest patients☆,☆☆ Kenichi Tetsuhara, MD ⁎, Hiroshi Kato, MD, Takashi Kanemura, MD, Ichiro Okada, MD, Nobuaki Kiriu, MD Department of Critical Care Medicine and Trauma, National Disaster Medical Center, 3256 Tachikawa City, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 31 October 2015 Accepted 14 November 2015
a b s t r a c t Purpose: This study aimed to determine whether severe acidemia (pH b 7.2) on arrival at the emergency department (ED) is a predictive factor for neurologic outcomes of post–cardiac arrest patients treated with targeted temperature management (TTM). Materials and methods: Data in the National Disaster Medical Center, a tertiary care hospital, were used to perform a case-control study on post–cardiac arrest patients treated with TTM from January 2013 to April 2015. The case group comprised patients with good neurologic outcomes (cerebral performance categories 1 and 2), whereas the control group comprised patients with poor neurologic outcomes (cerebral performance categories 3-5). Exposure was defined as arterial pH less than 7.2 on arrival at the ED. Results: We identified 32 patients matching our criteria, of which 13 had good outcomes and 19 poor outcomes. Arterial pH on arrival was not significantly associated with neurologic outcomes (P = .47; odds ratio, 0.5; 95% confidence interval, 0.09-2.61). In 24 patients with cardiogenic causes of cardiac arrest, pH on arrival was not significantly associated with neurologic outcomes (P = .68; odds ratio, 0.5; 95% confidence interval, 0.092.73) after matched-pair analysis by age, sex, and presence of light reflex. Conclusion: Severe acidemia on arrival at the ED is not a significant predictive factor for neurologic outcomes in post–cardiac arrest patients treated with TTM, particularly in patients with cardiogenic causes of cardiac arrest. These results suggest that treatment should not be withheld in post–cardiac arrest patients with severe acidemia. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Post–cardiac arrest patients suffer damage to multiple organs, including the brain [1]. Various prognostic factors for poor neurologic outcomes have been reported, including the absence of pupillary light reflexes, corneal reflexes, and motor response [2]. Although severe acidemia frequently occurs in patients during and after cardiac arrest, the prognostic value of severe acidemia for neurologic outcomes is unknown [3,4]. Severe acidemia, defined as arterial pH less than 7.2 [5,6], at the time of initiation of targeted temperature management (TTM) in shockable post–cardiac arrest patients is associated with poor neurologic outcomes [7]. Lower arterial pH in post–cardiac arrest patients upon intensive care unit (ICU) admission is associated with poor neurologic outcomes [8]. The association between arterial pH at the time of arrival at the emergency department (ED) and neurologic outcomes has seldom been reported [9]. ☆ Conflicts of interest: All authors declare no conflict of interest. ☆☆ Source of support: All authors declare no source of support. ⁎ Corresponding author at: Critical Care Medicine and Trauma, National Disaster Medical Center, 3256 Midori-cho, Tachikawa City, Tokyo, Japan. Tel.: +81 42 526 5511; fax: +81 42 526 5729. E-mail addresses: [email protected] (K. Tetsuhara), [email protected] (H. Kato), [email protected] (T. Kanemura), [email protected] (I. Okada), [email protected] (N. Kiriu). http://dx.doi.org/10.1016/j.ajem.2015.11.030 0735-6757/© 2015 Elsevier Inc. All rights reserved.
Targeted temperature management is the recommended treatment for comatose post–cardiac arrest patients [2]. This case-control study aims to determine whether severe acidemia on arrival at the ED is a predictive factor for neurologic outcomes in post–cardiac arrest patients treated with TTM.
2. Methods 2.1. Study population We used a prospective database of all patients admitted to the ICU of the National Disaster Medical Center, a tertiary care hospital in Tokyo, Japan. This database included data on age, sex, date of admission, diagnosis, and management. From the database, we chose patients who were treated with TTM after a nontraumatic, out-of-hospital cardiac arrest between January 2013 and April 2015. We excluded patients who did not complete TTM. For all patients, we extracted data regarding arterial blood gas analysis (pH, pCO2, and base excess) on arrival at the ED and on admission to the ICU, whether cardiac arrest was witnessed, bystander cardiopulmonary resuscitation, shockable or nonshockable rhythm on initial cardiac electrogram, return of spontaneous circulation (ROSC) before or after arrival at the hospital, cause of cardiac arrest, Glasgow Coma Scale (GCS) between ROSC and initiation of TTM,
426
K. Tetsuhara et al. / American Journal of Emergency Medicine 34 (2016) 425–428 Table 1b Baseline characteristics (n = 31)
Cardiac arrest patients n = 826
Patients treated with TTM n = 32
Cardiogenic
n = 24
Non-cardiogenic
n=4
Unknown
n=4
Initial cardiac rhythm = shockable
Good outcome (n = 13)
Poor outcome (n = 18)
P
10 (76.9)
10 (55.6)
.275
Values are expressed as number (percentage).
2.2. Targeted temperature management
pH < 7.2 on arrival n = 18
CPC 1,2 n=6
CPC 3-5 n = 12
pH ≥ 7.2 on arrival n = 14
CPC 1,2 n=7
CPC 3-5 n=7
Figure. Flow chart of patients.
tympanic temperature on arrival, existence of light reflex within 24 hours after ROSC, lactate on arrival, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and cerebral performance categories (CPC) on discharge from the hospital. Cerebral performance categories are defined as follows: CPC1, good cerebral performance, conscious, alert, and able to work and lead a normal life; CPC 2, moderate cerebral disability, conscious with sufficient cerebral function for part-time work in a sheltered environment or independent activities of daily life; CPC 3, severe cerebral disability, conscious but dependent on others for daily support because of impaired brain function; CPC 4, comatose, vegetative state; and CPC 5, death [10]. The primary end point was the CPC measured on discharge from the hospital. Causes of cardiac arrest were determined by emergency physicians and cardiologists to be cardiogenic, noncardiogenic, or unknown based on medical history and findings of laboratory data and coronary arteriography. When we could not determine whether the cause of arrest was cardiogenic, it was categorized as “unknown.” This study was approved by the institutional review board of the National Disaster Medical Center.
Table 1a Baseline characteristics (n = 32)
Age (y) Sex (male) Witness of faint Performed bystander CPR ROSC at prehospital pH on arrival PaCO2 on arrival (mm Hg) Base excess on arrival (mmol/L) Lactate on arrival (mmol/L) pH on ICU admission GCS after ROSC Existence of light reflex within 24 h from ROSC Tympanic temperature (°C) APACHE II PCPS
Good outcome (n = 13)
Poor outcome (n = 19)
P
53 (49.0-64.0) 10 (76.9) 10 (76.9) 5 (38.5) 10 (76.9) 7.22 (6.87-7.32) 49.3 (39.9-67.3) −10.6 (−15.8 to −7.8) 6.6 (4.9-9.9) 7.40 (7.32-7.43) 3 (3.0-5.0) 13 (100.0)
66 (48.0-76.5) 11 (57.9) 11 (57.9) 6 (31.6) 10 (52.6) 7.12 (6.92-7.30) 44.6 (31.1-67.6) −12.5 (−19.3 to −9.9) 5.9 (3.5-8.9) 7.36 (7.26-7.40) 3 (3.0-4.5) 7 (36.8)
.388 .399 .768 b.001
35.4 (34.7-35.7) 20.0 (18.0-23.0) 3 (23.1)
35.3 (34.8-36.0) 22.0 (19.0-24.5) 3 (15.8)
.848 .441 .666
.134 .450 .450 .721 .267 .759 .578 .527
Values are expressed as number (percentage) and median (interquartile range), as appropriate. Abbreviations: CPR, cardiopulmonary resuscitation; PCPS, percutaneous cardiopulmonary support device.
Post–cardiac arrest patients with GCS 8 or less were treated with TTM based on the discretion of emergency physicians. We terminated TTM in cases involving shock requiring large amounts of inotropes, a bleeding tendency, a clotting disorder, excess hypothermia on arrival, and underlying conditions in which bleeding may lead to death. In our TTM protocol, the target temperature of 34°C ± 0.5°C is reached within 6 hours after ROSC using internal and external cooling. The core temperature is monitored using bladder probes. Internal cooling is performed using intravenous cold extracellular fluid. External cooling is performed using a cooling blanket and MEDI-THERM III (Gaymar, Orchard Park, NY). The target temperature is maintained for 24 hours. Patients are rewarmed to 36°C at 0.5°C per hour using the cooling blanket and MEDI-THERM III. 2.3. Laboratory measurements Blood samples for analysis of arterial blood gas and lactate were obtained as soon as possible after arrival at the ED. Arterial blood gas analysis was evaluated using RAPID POINT 500 (Siemens K.K., Tokyo, Japan). Lactate was evaluated using LACTATE PRO 2 LT-1730 (Arkray, Kyoto, Japan). 2.4. Statistical analysis In this case-control study, the case group comprised patients with good neurologic outcomes (CPC 1 and 2), whereas the control group comprised patients with poor neurologic outcomes (CPC 3-5). Exposure was arterial pH less than 7.2. Continuous variables that were not normally distributed were summarized by median and interquartile range. Categorical variables were summarized by counts and percentages. Fisher exact test was used for categorical variables, and the Mann-Whitney U test was used for continuous variables that were not normally distributed. The Mantel-Haenszel test was used for comparisons between the case and control groups. Wilcoxon signed rank test was used for comparisons between arterial pH on arrival and at ICU admission, as these variables were not normally distributed. P b .05 was considered statistically significant. We used EZR version 1.27 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) for data analysis. EZR is a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) [11]. 3. Results 3.1. Baseline characteristics The patient flow chart is shown in the Figure. Of 826 cardiac arrest patients, 37 patients who survived had started TTM on admission. Targeted temperature management was discontinued in 5 of these patients for the following reasons: shock requiring large amounts of inotrope (n = 1), bleeding tendency (n = 1), clotting disorder (n = 1), excess hypothermia (n = 1), and aortic dissection (n = 1). Targeted temperature management was completed in 32 patients. Of 18 patients with arterial pH less than 7.2 on arrival, at the time of hospital discharge, 6 were CPC 1 or 2, whereas 12 were CPC 3 to 5. Of 14 patients with pH
K. Tetsuhara et al. / American Journal of Emergency Medicine 34 (2016) 425–428 Table 1c Baseline characteristics (n = 28)
Cause of cardiac arrest, cardiogenic
Table 3 Association of arterial pH and neurologic outcome in all causes after matched pair on age, sex, and existence of light reflex
Good outcome (n = 11)
Poor outcome (n = 17)
P
11 (100)
13 (76.5)
.132
Values are expressed as number (percentage).
greater than or equal to 7.2 on arrival, 7 were CPC 1 or 2, and 7 were CPC 3 to 5 at the time of hospital discharge. Baseline characteristics of the patients are shown in Tables 1a, 1b, and 1c. Arterial pH on arrival did not differ significantly between the case and control groups. The presence of the light reflex differed significantly between the case and control groups. The arterial pH on arrival was significantly lower than that at ICU admission (P b .001). The causes of cardiac arrest were as follows: cardiogenic (n = 24), noncardiogenic (n = 4), and unknown (n = 4). 3.2. Primary end point 3.2.1. Patient group with all causes of cardiac arrest Arterial pH on arrival was not significantly associated with neurologic outcomes in the 32 patients with cardiogenic, noncardiogenic, or unknown causes on Fisher exact test (P = .47; odds ratio [OR], 0.5; 95% confidence interval [CI], 0.09-2.61) (Table 2). After matched-pair analysis on age, sex, and presence of light reflex, arterial pH on arrival was not significantly associated with neurologic outcomes on the Mantel-Haenszel test (P = .45; OR, 0.4; 95% CI, 0.08-2.06) (Table 3). 3.2.2. Patient group with cardiogenic cardiac arrest. In 24 patients with cardiac arrest from cardiogenic causes, arterial pH on arrival was not significantly associated with neurologic outcomes on the Mantel-Haenszel test (P = .68; OR, 0.5; 95% CI, 0.09-2.73) after matched-pair analysis on age, sex, and existence of light reflex (Table 4). 4. Discussion Severe acidemia on arrival at the ED is not a significant predictive factor for neurologic outcomes in post–cardiac arrest patients treated with TTM, particularly in those with cardiogenic cardiac arrest. Previous studies reported that severe acidemia at the initiation of TTM in shockable patients and lower pH at ICU admission were associated with poor neurologic outcomes [7,8]. Delays in blood sampling may influence laboratory results because intensive care may have started before sampling. In our study, the arterial pH on arrival was significantly lower than that at ICU admission. Consistent with our results, another study reported that arterial pH on arrival at the ED was not associated with neurologic outcomes [9]. However, that study used multivariate analysis of various laboratory measurements; unlike our study, the primary end point was not the association between arterial pH and neurologic outcomes. Arterial pH is useful for determining treatable causes of cardiac arrest, including hyperkalemia/hypokalemia and severe acidosis, but is not useful for predicting neurologic outcomes. These results suggest that even if post–cardiac arrest patients have severe acidemia, treatment should not be withheld. Numerous predictive factors for poor neurologic outcomes in post– cardiac arrest patients have been reported, including absent pupillary light reflexes, absent corneal reflexes, absent motor response [2], Table 2 Association of arterial pH and neurologic outcome in all causes
pH b7.2 pH ≥7.2
CPC 1-2
CPC 3-5
6 7 13
12 7 19
427
18 14 32
pH b7.2 pH ≥7.2
CPC 1-2
CPC 3-5
6 7 13
9 4 13
15 11 26
Table 4 Association of arterial pH and neurologic outcome in cardiogenic causes after matched pair on age, sex, and existence of light reflex
pH b7.2 pH ≥7.2
CPC 1-2
CPC 3-5
5 6 11
7 4 11
12 10 22
nonwitnessed cardiac arrest, cardiogenic causes, advanced age, initial nonshockable rhythm [12], lower GCS after ROSC [13], and lower body temperature [14]. In our study, only absent pupillary light reflex was significantly associated with poor neurologic outcomes. This difference in results may arise from the sample size in our study, which may be too small to detect significant differences. Our study has several limitations. First, this study was a retrospective single-center study with a small cohort. Only 4 patients had noncardiogenic causes of cardiac arrest. Second, confounding factors and selection bias may influence our results. To avoid these problems, we used stratification and matched-pair analysis. Third, the protocol for TTM depended on the discretion of emergency physicians. A prospective, multicenter study is needed to evaluate the predictive value of pH at the time of arrival at the ED for neurologic outcomes. 5. Conclusions Severe acidemia on arrival at the ED is not a significant predictive factor for neurologic outcomes in post–cardiac arrest patients treated with TTM, particularly in patients with cardiogenic causes of cardiac arrest. These findings suggest that treatment should not be withheld from post–cardiac arrest patients with severe acidemia. A prospective, multicenter study is needed to evaluate the predictive value of pH at the time of arrival at the ED for neurologic outcomes. References [1] Neumar RW, Nolan JP, Adrie C, Aibiki M, Berg RA, Böttiger BW, et al. Post–cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A consensus statement from the International Liaison Committee on Resuscitation (American Heart Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscitation Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 2008;118:2452–83. [2] Soar J, Callaway CW, Aibiki M, Böttiger BW, Brooks SC, Deakin CD, et al. Part 4: advanced life support: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 2015;132:S84–S145. [3] Makino J, Uchino S, Morimatsu H, Bellomo R. A quantitative analysis of the acidosis of cardiac arrest: a prospective observational study. Crit Care 2005;9:R357–62. [4] Prause G, Ratzenhofer-Comenda B, Smolle-Jüttner F, Heydar-Fadai J, Wildner G, et al. Comparison of lactate or BE during out-of-hospital cardiac arrest to determine metabolic acidosis. Resuscitation 2001;51:297–300. [5] Kraut JA, Kurtz I. Use of base in the treatment of acute severe organic acidosis by nephrologists and critical care physicians: results of an online survey. Clin Exp Nephrol 2006;10:111–7. [6] Kraut JA, Madias NE. Metabolic acidosis: pathophysiology, diagnosis and management. Nat Rev Nephrol 2010;6:274–85. [7] Ganga HV, Kallur KR, Patel NB, Sawyer KN, Gowd PB, Nair SU, et al. The impact of severe acidemia on neurologic outcome of cardiac arrest survivors undergoing therapeutic hypothermia. Resuscitation 2013;84:1723–7.
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