American Journal of Emergency Medicine (2012) 30, 770-774

Brief Report

Relationship between the hemoglobin level at hospital arrival and post-cardiac arrest neurologic outcome

SOS-KANTO study group?

Received 26 February 2011; revised 30 March 2011; accepted 31 March 2011

Abstract

Background: The hemoglobin level is an essential determinant of oxygen delivery. The restoration of blood perfusion to vital organs and the capacity for oxygen delivery may be associated with ischemia and reperfusion injuries during cardiac arrest and after cardiac arrest. However, whether the Hb level is associated with neurologic outcome in post-cardiac arrest patients remains unclear.

Methods: Emergency medical service information and Clinical demographics were compiled for witnessed out-of-hospital cardiac arrest patients with coma after the restoration of spontaneous circulation. The study end point was defined as a Favorable neurologic outcome at 28 days. We evaluated the relationship between the Hb level at the time of hospital arrival and the neurologic outcome using univariate analyses and a multivariate logistic regression analysis.

Results: There were 137 witnessed cardiac arrest patients: 49 (35.7%) survived and 34 (24.8%) achieved a favorable neurologic outcome. Univariate analyses showed that the favorable outcome group was characterized as having a higher Hb level, a younger age, a higher percentage of male patients, and ventricular fibrillation as the initial cardiac rhythm. In a multivariate analysis adjusting for potential confounding factors, the Hb level at the time of hospital arrival (odds ratio, 1.26; 95% confidence interval, 1.00-1.58) was an independent predictor of a favorable neurologic outcome.

Conclusion: A higher Hb level at the time of hospital arrival was associated with a favorable short-term neurologic outcome among post-cardiac arrest patients with a presumed cardiac etiology.

(C) 2012

Introduction

Post-cardiac arrest syndrome is characterized by brain injury, myocardial dysfunction, and a systemic ischemia/ reperfusion response and is often complicated by the persisting acute pathology that caused or contributed to the cardiac arrest itself [1]. Recently, higher survival rates have been reported for patients treated with therapeutic

* Members listed at end of paper. Correspondence to: Kei Hayashida, MD. The SOS-KANTO Committee,

Department of Emergency and Critical Care Medicine, School of Medicine, Keio University, Shinjyuku-ku, Tokyo, 160-8582, Japan.

Tel.: +81 3 3225 1323; fax: +81 3 3353 2232.

E-mail address: [email protected].

hypothermia after successful resuscitation from cardiac arrest [2,3], confirming that patient outcome is determined not only by the time of circulation recovery but also by the pathophysiologic processes triggered by cardiac arrest. Other treatments, such as early hemodynamic optimization [1], controlled reoxygenation [4], supportive care, and disease-specific interventions guided by the patients’ conditions, have potential benefit for patients with post- cardiac arrest syndrome. One possible benefit of the above treatments is the prevention of an increase in the oxygen debt and a decrease in the systemic and cerebral metabolic rates of oxygen consumption [5].

The restoration of blood perfusion to vital organs and the capacity for oxygen delivery are strongly associated with ischemia and reperfusion injuries during cardiac arrest and

0735-6757/$ - see front matter (C) 2012 doi:10.1016/j.ajem.2011.03.031

after cardiac arrest. The hemoglobin (Hb) level is known to be an essential determinant of oxygen delivery. Although many previous studies have shown that anemia can be harmful to patients with Neurologic dysfunction [6,7],we could not find any studies evaluating the relationship between the Hb level and the neurologic outcome among out-of-hospital cardiac arrest (OHCA) patients. In the present study, we hypothesized that a low Hb level causes a poorer short-term neurologic outcome among OHCA patients.

Methods

The prospective, multicenter, observational database created for the SOS-KANTO study was used to survey OHCA in the Kanto region of Japan between September 1, 2002, and December 31, 2003. In the SOS-KANTO study, data based on the Utstein-style guidelines for reporting OHCA were collected prospectively; the surveyed data included age, sex, medical history, initial cardiac rhythm, several key time intervals, Hb levels, and subsequent specific therapies for post-cardiac arrest syndrome. During the study period, 8 815 OHCA patients between the ages of 15 and 89 years were transported by paramedics to the emergency hospitals participating in the SOS-KANTO study. Among these patients, 5 481 were witnessed cardiac arrest patients with a presumed cardiac etiology; spontaneous circulation was restored in 1 629 of these 5 481 patients. We

Table 1 Baseline characteristics and medical therapies of the patients

subsequently excluded 1 492 of the 1 629 patients (1 127 patients without bystander cardiopulmonary resuscitation, 306 patients with an Hb level less than 7.0 g/dL or greater than 18.0 g/dL, and 32 patients with a Glasgow Coma Scale greater than 8 at intensive care unit admission), and data for the remaining 137 patients were analyzed in this study.

The blood Hb concentration at the time of hospital arrival and the 28-day neurologic outcome data according to the Glasgow-Pittsburgh cerebral-performance category (CPC) were obtained and analyzed in the present study. CPC-1 (good recovery) and CPC-2 (moderate disability) were defined as the favorable outcome group; CPC-3 (severe disability), CPC-4 (vegetative state), and CPC-5 (death) were defined as the poor outcome group.

In the univariate analyses, the ?2 test for categorical variables and the Mann-Whitney U test for continuous variables were used. To determine the impact of the blood Hb level on neurologic outcome, a logistic regression model was used as a multivariate model. The P value in the present study was .05. We performed all the analyses using SPSS 17.0J (SPSS Inc, Chicago, IL).

Results

Of the 137 patients analyzed, 88 deaths were observed, and the remaining 49 patients were alive at 28 days after

OHCA, leading to a 28-day survival rate of 36%. Of the

49 surviving patients, 34 patients had a favorable outcome (favorable outcome group: 24 patients with CPC-1 and 10 patients with CPC-2). Among the remaining patients, 5 were diagnosed as CPC-3, and 10 were diagnosed as CPC-4. These 15 patients with CPC-3 and CPC-4 and the 88 deaths (CPC-5) were assigned to the unfavorable outcome group, which consisted of a total of 103 patients.

Univariate analyses showed that the favorable outcome group was characterized as having a higher Hb level, a younger age, a higher percentage of male patients, a higher percentage of ventricular fibrillation as the initial cardiac rhythm, a short time interval between the emergency medical service call and arrival at the patient’s side, and a higher percentage of cases in which postarrest therapies were used (Table 1). In a multivariate logistic regression analysis using the backward elimination method, the Hb level was chosen as an independent predictor for a favorable neurologic outcome after 28 days of OHCA (Table 2). Furthermore, the percentage of patients with a

Variable Favorable Unfavorable P a outcome outcome (n = 34) (n = 103)

Hb (g/dL), median (IQR) 14.4 (1.6) 12.8 (4.0) .001 Male, n (%) 29 (85.3) 65 (63.1) .01 Age (y), median (IQR) 55 (15) 65 (22) .003 Arrest witnessed at 20 (58.8) 48 (46.6) .21 home, n (%) VF as initial cardiac 28 (82.4) 41 (39.8) b.001 rhythm, n (%) Medical history, n (%) Coronary heart disease 8 (23.5) 19 (18.4) .51 Hypertension 4 (11.8) 20 (19.4) .30 Diabetes 5 (14.7) 12 (11.7) .63 Cerebrovascular disease 1 (2.2) 3 (2.9) .99 Key time interval (min), median (IQR) From EMS call to arrival 7 (2) 8 (3) .03 at patient’s side From arrival at patient’s 17 (7) 18 (7) .62 side to departure from scene Transport interval from 6 (11) 9 (6) .30 scene to hospital Postarrest therapies, n (%) Therapeutic Mild hypothermia 9 (26.5) 11 (10.7) .02 PCI after ROSC 14 (41.2) 9 (8.7) b.001

Hb indicates hemoglobin level at the time of hospital arrival; n, number; VF, ventricular fibrillation; ROSC, restoration of spontaneous circula- tion; IQR, interquartile range. EMS, emergency medical service. a P value refers to comparisons between each group using Mann- Whitney U tests for continuous variables and ?2 tests for categorical variables.

100%

90%

Proportion of the neurological outcome

at 28 days (%)

80%

70%

60%

50%

40%

30%

20%

10% *

0%

CPC=5 CPC=3/4 CPC=1/2

*

*

Our results are in accordance with those of previous reports studying the relationships between the Hb level and critically ill patients including patients with subarachnoid hemorrhage [6], traumatic brain injury [7], coronary heart disease [8], cardiopulmonary bypass surgery [9], and heart failure [10]. Moreover, acute hemodilutional anemia accen- tuated cerebral tissue hypoxia after fluid percussion injury, experimentally [11]. Thus, a low Hb level may be associated with a detrimental neurologic outcome among patients with brain damage, including post-cardiac arrest patients.

The improvement in the impaired oxygen debt arising during the cardiac arrest and post-cardiac arrest periods may

7.1 - 12.3 12.4 - 14.4 14.5 - 17.6

Fig. 1 Association between the tertiles of Hb levels and the 28- day neurologic outcome. *An increased incidence of favorable neurologic outcome (CPC = 1 and 2) was associated with increasing tertiles of Hb concentration at the time of hospital arrival (10.6%, 26.7%, and 37.8%, respectively; ?² test, P = .01).

favorable outcome increased in parallel with an increase in the Hb levels (Fig. 1).

Discussion

This study revealed that the Hb concentration at the time of hospital arrival was an independent predictor of the 28- day favorable neurologic outcome among witnessed OHCA patients with a presumed cardiac etiology who regained spontaneous circulation. To the best of our knowledge, this is the first report to evaluate the relationship between the Hb concentration at the time of hospital arrival and the short- term neurologic outcome among the aforementioned OHCA patients. This study showed that the Hb level was an independent predictor of a favorable neurologic outcome according to the age- and sex-adjusted odds ratio in the multivariate model (Table 2), and the progressive increase of patients with a favorable neurologic outcome was observed using stratified Hb levels (Fig. 1). Our results suggest that a low Hb level is poorly tolerated in post- cardiac arrest patients.

Table 2 Multivariable analysis for factors associated with favorable neurologic outcome ^a

Predictor Odds ratio (95% CI)

Hb level 1.26 (1.00-1.58) PCI 6.31 (2.09-19.00) VF as initial cardiac rhythm 4.49 (1.43-12.80) Time from EMS call to arrival 0.79 (0.65-0.97) at the patient’s side

a Multivariable logistic regression using the backward elimination method was performed. The Hosmer-Lemeshow test was used to assess the goodness of fit of these models (P = .39).

depend on the blood Hb level because the Hb level is a major determinant of the oxygen-carrying capacity. Previous studies have demonstrated that anemia induces tissue hypoxia in the most vulnerable regions affected by ischemia [9,12,13]. In tissue that is ischemic during the post-cardiac arrest period, the impaired tissue and mitochondrial function require an increase in oxygen delivery. The increased delivery of oxygen could theoretically result in an equivalent increase in Oxygen metabolism. Therefore, the Hb level, as a major determinant of oxygen delivery, may determine the tissue metabolism, at least in part, in ischemic tissue.

A reduced Hb level results in the up-regulation of nitric oxide production-induced cerebral vasodilatation [14]. Other biochemical mediators, such as the vascular endothe- lial growth factor hypoxia inducible factor 1?, are also up- regulated in the brain in response to anemia [14]. Moreover, previous animal studies have revealed that the penumbral brain appears to be much more vulnerable than the normal brain, with the O₂ delivery and cerebral metabolic rate progressively declining as the Hb concentration decreases [15,16]. All these mechanisms appear to be physiologic neuroprotective mechanisms against ischemia caused by low Hb levels or anemia. That a low Hb level was associated with an unfavorable outcome in our study suggests that physiologic protective mechanisms for brain damage may be impaired in the presence of a reduction in Hb in patients with postcardiac brain injury.

In the present study, Primary percutaneous coronary intervention was recognized as an effective interven- tion for post-cardiac arrest therapy, whereas hypothermia therapy was eliminated and did not remain in the multivariate model. These results suggest that effective Circulatory support and intervention are indispensable for stabilizing the pathophysiologic state of post-cardiac arrest patients. Previous studies [17,18] have reported that coronary Reperfusion strategies, such as Primary PCI, provided a much better outcome in OHCA patients, regardless of therapeutic hypothermia, compared with the outcomes of patients who did not receive PCI strategies.

This study should be interpreted with due consideration of the following limitations. First, this study was performed in a retrospective observational manner. Second, we could not obtain clinical data regarding the causes of anemia or low Hb levels. The causes of anemia, such as malignancy or chronic

kidney disease, may have affected the prognosis of the patients. Third, the blood erythropoietin level, which has been considered to exhibit tissue-protective properties in both heart disease and Hypoxic-ischemic encephalopathy, was not measured. Finally, the Hb level was only measured at the time of hospital arrival in this study. The relationship between the Hb level over time and the clinical course remains unknown. Therefore, the clinical role of red blood cell transfusion on the outcome has not yet been determined.

Conclusion

The blood Hb level at the time of hospital arrival was associated with the neurologic outcome of OHCA patients with a presumed cardiac etiology regardless of the use of therapeutic hypothermia. Further prospective, randomized, blinded, clinical trials are clearly needed to assess the neurologic outcomes at different Hb levels among patients with post-cardiac arrest syndrome.

Conflict of Interest

There are no conflicts of interest to declare.

Contributors

Kei Hayashida, Masaru Suzuki, Akiko Shiroshita- Takeshita, Shingo Hori, Ken Nagao

SOS-KANTO study group

Nihon University Surugadai Hospital (Ken Nagao, Kimio Kikushima); Teikyo University Hospital (Tetsuya Saka- moto); Kawaguchi Municipal Medical Center (Kazuhide Koseki); Toho University Oomori Hospital (Masaki Igara- shi); St Luke’s International Hospital (Shinichi Ishimatsu); Saitama Medical School Hospital (Akira Sato); Keio University Hospital (Shingo Hori); Showa University Fugigaoka Hospital (Shigeru Kanesaka); Tokyo Metropol- itan Bokutoh Hospital (Yuichi Hamabe); National Defense Medical College (Daizo Saito); and Kimitsu Chuo Hospital (Shinya Kitamura).

Participating investigators

Akiko Nonaka, Atsushi Katsumi, Atsushi Sakurai, Hiroaki Suzuki, Hiroshi Imai, Hiroshi Miyauchi, Hiroyasu Suga, Jozi Tomioka, Kazutaka Imai, Kazuya Kiyota, Ken Arima, Kitoji Takuhiro, Kiyoshi Matsuda, Kohei Takahashi, Masafumi Naito, Masaharu Yagi, Masato Honma, Masaru Sasaki, Masaru Suzuki, Minoru Nakano, Naohiko Fugiyoshi, Naoki Kozima, Naoshige Harada, Noriyoshi Ohashi, Noriyuki Suzuki, Ryutaro Moriwaki, Ryoji Takahashi, Satoru Kikuchi, Seichi Noda, Shigeto Oda, Shohei Imaki, Tadashi Fugikawa, Takaaki Kikuno, Takashi Kamohara, Takayuki Suda, Tatsuo Ishii, Tokuzi Irabu, Tomohito Sadahiro, Toshiaki Ikeda, Toshiharu Tanaka, Toshihiko Obayashi, Toshiro Ogawa, Yasuyuki Miyahara, Yoshihide Nakagawa, Yoshiki Tokuyasu, Yoshio Tawara, Yoshiyuki

Haga, Yoshiyuki Minowa, Yukio Tanaka, Zyunichi Sasaki, and Zyunmei Fudouzi.

References

1. Neumar RW, Nolan JP, Adrie C, 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 Cardiopul- monary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 2008;118(23): 2452-83.
2. THE HYPOTHERMIA AFTER CARDIAC ARREST STUDY

GROUP. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346(8):549-56.

1. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346(8):557-63.
2. Balan IS, Fiskum G, Hazelton J, et al. Oximetry-guided reoxygenation improves neurological outcome after Experimental cardiac arrest. Stroke 2006;37(12):3008-13.
3. Gaieski DF, Band RA, Abella BS, et al. Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest. Resuscitation 2009;80(4):418-24.
4. Wartenberg KE, Schmidt JM, Claassen J, et al. Impact of Medical complications on outcome after subarachnoid hemorrhage. Crit Care Med 2006;34(3):617-23 [quiz 24].
5. Van Beek JG, Mushkudiani NA, Steyerberg EW, et al. Prognostic value of admission laboratory parameters in traumatic brain injury: results from the IMPACT study. J Neurotrauma 2007;24(2): 315-28.
6. Al Falluji N, Lawrence-Nelson J, Kostis JB, et al. Effect of anemia on 1-year mortality in patients with acute myocardial infarction. Am Heart J 2002;144(4):636-41.
7. Karkouti K, Djaiani G, Borger MA, et al. Low hematocrit during cardiopulmonary bypass is associated with increased risk of perioperative stroke in cardiac surgery. Ann Thorac Surg 2005;80(4):1381-7.
8. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation 2003;107(2):223-5.
9. Hare GM, Mazer CD, Hutchison JS, et al. Severe hemodilutional anemia increases cerebral tissue injury following acute neurotrauma. J Appl Physiol 2007;103(3):1021-9.
10. Habib RH, Zacharias A, Schwann TA, et al. Adverse effects of low hematocrit during cardiopulmonary bypass in the adult: should current practice be changed? J Thorac Cardiovasc Surg 2003;125(6): 1438-50.
11. Kramer AH, Zygun DA. Anemia and red blood cell transfusion in Neurocritical care. Crit Care 2009;13(3):R89.
12. Hare GM, Tsui AK, McLaren AT, et al. Anemia and cerebral outcomes: many questions, fewer answers. Anesth Analg 2008;107(4):1356-70.
13. Korosue K, Heros RC. Mechanism of cerebral blood flow augmentation by hemodilution in rabbits. Stroke 1992;23(10): 1487-92 [discussion 92-3].
14. Todd MM, Wu B, Maktabi M, et al. Cerebral blood flow and oxygen delivery during hypoxemia and hemodilution: role of arterial oxygen content. Am J Physiol 1994;267(5 Pt 2):H2025-31.
15. Wolfrum S, Pierau C, Radke PW, et al. Mild therapeutic hypothermia in patients after out-of-hospital cardiac arrest due to Acute ST-segment elevation myocardial infarction undergoing

immediate percutaneous coronary intervention. Crit Care Med 2008;36(6):1780-6.

1. Lettieri C, Savonitto S, De Servi S, et al. Emergency percutaneous coronary intervention in patients with ST-elevation myocardial infarction complicated by out-of-hospital cardiac arrest: early and medium-term outcome. Am Heart J 2009;157(3):569-75.