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, 0.09- 2.73) 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.

(C) 2015

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 un- known [3,4]. Severe acidemia, defined as arterial pH less than 7.2 [5,6], at the time of initiation of targeted temperature management in shockable post-cardiac arrest patients is associated with poor neuro- logic outcomes [7]. Lower arterial pH in post-cardiac arrest patients upon intensive care unit admission is associated with poor neuro- logic 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).

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 pre- dictive factor for neurologic outcomes in post-cardiac arrest patients treated with TTM.

Methods

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 cardi- ac 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,

http://dx.doi.org/10.1016/j.ajem.2015.11.030

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Laboratory measurements“>426 K. Tetsuhara et al. / American Journal of Emergency Medicine 34 (2016) 425-428

Table 1b

CPC 3-5

n = 7

pH ? 7.2 on arrival n = 14

Patients treated with TTM

n = 32

Cardiac arrest patients n = 826

CPC 1,2

n = 6

pH < 7.2 on arrival n = 18

Baseline characteristics (n = 31)

Good outcome (n = 13)

Poor outcome P

(n = 18)

Cardiogenic n = 24 Non-cardiogenic n = 4 Unknown n = 4

initial cardiac rhythm = shockable 10 (76.9) 10 (55.6) .275 Values are expressed as number (percentage).

CPC 3-5

n = 12

CPC 1,2

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 II score, and cerebral performance catego- ries (CPC) on discharge from the hospital. Cerebral performance catego- ries 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 mea- sured on discharge from the hospital. Causes of cardiac arrest were de- termined 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.

Targeted temperature management

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.

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).

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 sum- marized 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 contin- uous 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].

Table 1a Baseline characteristics (n = 32)
	Good outcome (n = 13)	Poor outcome (n = 19)	P
Age (y)	53 (49.0-64.0)	66 (48.0-76.5)		.134
Sex (male)	10 (76.9)	11 (57.9)		.450
Witness of faint	10 (76.9)	11 (57.9)		.450
Performed bystander CPR	5 (38.5)	6 (31.6)		.721
ROSC at prehospital pH on arrival	10 (76.9) 7.22 (6.87-7.32)	10 (52.6) 7.12 (6.92-7.30)		.267 .759

PaCO2 on arrival (mm Hg)	49.3 (39.9-67.3)	44.6 (31.1-67.6)	.578	3. Results
Base excess on arrival (mmol/L)	-10.6	-12.5	.527

Lactate on arrival (mmol/L)	(-15.8 to -7.8) 6.6 (4.9-9.9)	(-19.3 to -9.9) 5.9 (3.5-8.9)	.388
pH on ICU admission	7.40 (7.32-7.43)	7.36 (7.26-7.40)	.399
GCS after ROSC	3 (3.0-5.0)	3 (3.0-4.5)	.768
Existence of light reflex	13 (100.0)	7 (36.8)	b.001
within 24 h from ROSC Tympanic temperature (?C)	35.4 (34.7-35.7)	35.3 (34.8-36.0)	.848
APACHE II	20.0 (18.0-23.0)	22.0 (19.0-24.5)	.441
PCPS	3 (23.1)	3 (15.8)	.666

Values are expressed as number (percentage) and median (interquartile range), as appropriate.

Abbreviations: CPR, cardiopulmonary resuscitation; PCPS, percutaneous cardiopulmonary support device.

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) 425-428 427

Table 1c

Baseline characteristics (n = 28)

Good outcome (n = 11)

Poor outcome (n = 17)

Table 3 Association of arterial pH and neurologic outcome in all causes after matched pair on age, sex, and existence of light reflex

P

CPC 1-2 CPC 3-5

Cause of cardiac arrest, cardiogenic 11 (100) 13 (76.5) .132 Values are expressed as number (percentage).

pH b7.2 6 9 15

pH >= 7.2 7 4 11

13 13 26

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 signif-		CPC 1-2	CPC 3-5
icantly between the case and control groups. The arterial pH on arrival	pH b7.2	5	7	12
was significantly lower than that at ICU admission (P b .001). The causes	pH >= 7.2	6	4	10
of cardiac arrest were as follows: cardiogenic (n = 24), noncardiogenic		11	11	22
(n = 4), and unknown (n = 4).

Table 4 Association of arterial pH and neurologic outcome in cardiogenic causes after matched pair on age, sex, and existence of light reflex

Primary end point

Patient group with all causes of cardiac arrest

Arterial pH on arrival was not significantly associated with neurolog- ic outcomes in the 32 patients with cardiogenic, noncardiogenic, or un- known 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).

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).

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 shock- able patients and lower pH at ICU admission were associated with poor neurologic outcomes [7,8]. Delays in blood sampling may influence Lab- oratory results because intensive care may have started before sam- pling. 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 analy- sis 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 car- diac arrest, including hyperkalemia/hypokalemia and severe acidosis, but is not useful for predicting neurologic outcomes. These results sug- gest 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

CPC 1-2 CPC 3-5

pH b7.2 6 12 18

pH >= 7.2 7 7 14

13 19 32

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.

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.

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