a b s t r a c t

Objective: The study aims to assess if electrocardiographic abnormalities could predict the development of Neurogenic pulmonary edema (NPE) within 24 hours in cases of spontaneous subarachnoid hemorrhage (SAH). Methods: We studied prospectively a cohort of 269 adult patients with nonTraumatic SAH in an emergency de- partment of a University-affiliated medical center. A 12-lead ECG was taken for these patients. The patients were stratified into NPE and non-NPE based on serially clinical and radiologic findings. The ECG abnormalities were compared between these 2 groups of patients.

Results: Compared with the non-NPE (n = 229), the NPE (n = 40) had significantly higher World Federation of Neurological Surgeons class (P b .001), higher Hunt-Hess scale (P b .001), and higher prevalence of diabetes mellitus (P = .033). In addition, the percentage of ECG morphological abnormality was significantly higher in NPE, in which nonspecific ST- or T-wave changes (NSSTTCs) are significantly higher. Multiple logistic regression model identified World Federation of Neurological Surgeons class (95% confidence interval [CI], 2.6-13.3; P b

.001), abnormal Q or QS wave (95% CI, 1.1-9.1; P = .038), and NSSTTCs (95% CI, 1.2-7.5; P = .016) as the signif- icant variables associated with NPE. Conclusions: electrocardiographic abnormalities, especially abnormal Q or QS wave and NSSTTCs, may predict the development of NPE within 24 hours in adult patients with spontaneous SAH.

(C) 2015

Introduction

Neurogenic pulmonary edema (NPE) is a well-recognized phenom- enon in subarachnoid hemorrhage , especially in high-grade pa- tients [1-3]. Neurogenic pulmonary edema often presents in the emergency department (ED), and the incidence of NPE is approximately 25% [2,4]. Neurogenic pulmonary edema can lead to an acute cardiopul- monary failure with consequent global hypoperfusion and hypoxia. These circumstances might cause severe secondary ischemic brain dam- age, and it has been reported to be associated with a worsened outcome [2,4]. Morbidity and mortality due to NPE might be reduced by early

? Contributors: WLC planned the study. WLC, JHC, HCT, and SHC obtained the data. WLC, CHH, JHC, HCT, SHC, and YCW performed data analysis and interpreted the data. WLC and JHC performed statistical analysis. WLC drafted and submitted the manuscript. All authors have approved the manuscript.

?? Conflict of interest: The authors declare that they have no conflict of interest related to

the current study.

* Corresponding author at: Department of Emergency Medicine, Cathay General Hospi- tal, No. 280, Sec. 4, Jen-Ai Rd, Taipei, Taiwan.

E-mail address: [email protected] (W.-L. Chen).

recognition and appropriate management with cardiac monitoring and fluid balance [1,4,5]; therefore, the awareness of development of NPE is essential for those potentially confronted with patients with SAH in the early stage.

Several mechanisms have been implicated in the pathogenesis of NPE, but the exact interactions remain unclear [2]. Increased permeabil- ity in the pulmonary capillary bed due to a disruption of the endothelial barrier by the transient increase in intravascular pressure seems to be one possible cause because patients who developed NPE have a protein concentration similar to that of plasma [2,4]. In addition, acute stunned myocardium, characterized by metabolic acidosis, cardiogenic shock, pulmonary edema, and electrocardiographic (ECG) abnormalities, due to a massive sympathetic discharge may also play an important role in the development of NPE [6]. Subarachnoid hemorrhage has been re- ported to be the most notorious intracranial event that manifests with ECG abnormalities which most often include morphologic changes and Rhythm disturbances [7-9], and diverse ECG changes have been re- ported to occur in 25% to 90% of patients with SAH [10]. Previous studies have suggested that patients with more severe SAH are more likely to develop Cardiac abnormalities and are further associated with poor

http://dx.doi.org/10.1016/j.ajem.2015.09.032

0735-6757/(C) 2015

80 W.-L. Chen et al. / American Journal of Emergency Medicine 34 (2016) 79-82

neurological outcome [10-13]. Because both occurrence of NPE and presence of ECG abnormalities have been suggested to be associated with poor outcome in these patients and acute stunned myocardium characterized by ECG abnormalities is believed to be a possible patho- genesis factor of NPE, we therefore speculated that ECG abnormalities may indicate the occurrence of NPE in patients with SAH.

Studies have suggested that the ECG abnormalities usually appeared early after brain injury and disappeared within 1 day [14]. Moreover, cardiac dysfunction in the context with NPE, presenting with Pathologic findings in ECG during the Acute stage, seems to be of transient and re- versible nature [5]. Therefore, the aim of this study was to investigate if the ECG abnormalities assessed early in the ED could predict the devel- opment of NPE within 24 hours in patients with spontaneous SAH.

Materials and methods

Study design

This was a prospective cohort study that investigated whether the ECG abnormalities assessed in the ED are independently associated with the development of NPE within 24 hours in adult patients with spontaneous SAH. The study protocol was approved by the Institutional Review Board of the hospital. Written informed consent was obtained from the patients themselves or their next of kin before enrolling in the study.

Study setting and selection of participants

This study was conducted in a 700-bed university-affiliated medical center with a 40-bed ED staffed with board-certified emergency physi- cians that provide care for approximately 55,000 patients per year. From October 2004 to September 2014, adult patients who were admitted within 12 hours of the first clinical symptoms with nontraumatic SAH diagnosed by Computed tomographic scans of brain, or xanthochromia of the cerebrospinal fluid if the computed tomographic scan was nondiagnostic, were eligibly enrolled. The exclusion criteria of this study included (1) tumor bleeding, (2) known arrhythmia (reviewing the past medical record or by the statements of the patients them- selves), (3) cardiac pacing, (4) aged less than 18 years, or (5) referred from other hospital (the ECG abnormalities and NPE of the patient seen in our ED were not in the early stage any more).

Study protocol

After obtaining the written informed consent, a standard 12-lead ECG recording was performed immediately after the diagnosis was made. The patient’s ECG was interpreted by the same cardiologist who was blinded to the outcome of the patient. The following measurements were made for each ECG: heart rate (ventricular rate) and heart rate-corrected QT in- terval (QTc) using the Bazett formula. The morphological abnormalities were defined as the presence of 1 or more of the following 7 variables, which are commonly noted after SAH [8,15,16], in at least 2 leads: (1) ab- normal Q or QS wave (>=30 milliseconds or a pathological R wave in V1 to V2); (2) ST elevation (ST elevation >=0.1 mV); (3) ST depression (ST de- pression >= 0.1 mV, 80 milliseconds post-J point); (4) peaked upright T wave (prominent peaked T wave); (5) T-wave inversions (pathologic T-wave inversion); (6) giant T-wave inversions (T-wave inversions N 10 mV in depth); or (7) nonspecific ST- or T-wave changes (NSSTTCs) (ST- or T-wave abnormalities not meeting the above criteria).

The study period started at the time of diagnosis made and lasted 24 hours thereafter. The patients were divided into 2 groups: NPE and non- NPE. Neurogenic pulmonary edema was defined by both serially clinical and radiologic findings [4]. A standard chest radiograph was taken after diagnosis made and 24 hours later. The patient’s CXR was interpreted by the same radiologist who was blinded to the clinical symptoms and outcome of the patient. A Radiologic diagnosis of NPE

was made if bilateral, symmetric, smooth and diffuse, alveolar edema- like infiltrates were present in the CXR. Clinical criteria for NPE were one of presence of crackles by chest auscultation assessed at the same time of CXR taken by 2 emergency physicians and presence of frothy pink tracheal fluid.

The following demographic data and clinical variables were record- ed at the same time for all patients: age, sex, vital signs, laboratory data, Hunt-Hess scale (class I, asymptomatic or mild headache; class II, mod- erate or Severe headache, Nuchal rigidity, can have oculomotor palsy; class III, confused, drowsiness, or mild focal signs; class IV, stupor or hemiparesis; class V, coma, moribund, and/or extensor posturing) [12], World Federation of Neurological Surgeons (WFNS) class (class I, Glasgow Coma Scale [GCS] = 15, no motor deficit; class II, GCS = 13- 14, no motor deficit; class III, GCS = 13-14, presence of motor deficit; class IV: GCS = 7-12; class V: GCS = 3-6) [17], underlying diseases, and comedication that can affect the heart rate. To avoid misdiagnosis of actual ischemic heart disease, the serial ECGs, cardiac enzymes, and echocardiography were checked after admission in those patients with Ischemic changes of ECG. Following hospital discharge, the inpa- tient medical record was reviewed to complete the data collection: length of hospital stay and outcome (in-hospital mortality). Patients discharged from the hospital in less than 28 days or who remained alive for more than 28 days were classified as “survivors” in this study; otherwise, the patients were referred to as “nonsurvivors” (in- hospital mortality).

Statistical analyses

?² test or Fisher exact test when appropriate was used for the statis- tical analysis of categorical variables. Continuous variables were pre- sented as mean (SD) and compared using the independent-samples t test. For statistical purposes, the Clinical scores used in this study were dichotomized into good and poor groups (WFNS 1-3 vs WFNS 4-5, Hunt-Hess 1-3 vs Hunt-Hess 4-5). The clinical variables and ECG abnor- malities with univariate comparison P b .2 between 2 groups were eligi- ble for inclusion in a forward selection multiple logistic regression model to identify the variables assessed early in the ED that were inde- pendently associated with NPE of the patients with spontaneous SAH. A P b .05 was considered statistically significant. Statistical analyses were performed using a common statistical package (SPSS 16.0 for Windows; SPSS Inc, Chicago, IL).

Results

During the 10-year study period, a total of 319 nontraumatic adult SAH patients were treated in the ED. Of them, 50 patients who did not meet the inclusion criteria were not included in the present study: 13 patients were tumor bleeding, 10 patients had known arrhythmia, 3 pa- tients had cardiac pacing, 22 patients were already diagnosed with SAH at another hospital, and 2 patients died soon before CXR or ECG was taken. In all, 269 of 319 patients were included in the final analysis. Based on development of NPE, those 269 patients, aged 19 to 77 years, were stratified into NPE (n = 40) or non-NPE (n = 229).

The basic characteristics of both groups of patients are shown in Table 1. There were no significant differences in age, sex, mean arterial pressure (MAP), white blood cell, glucose, comedication, and underly- ing diseases except diabetes mellitus between these 2 groups of patients. However, the WFNS class, Hunt-Hess scale, DM, and the occur- rence of ECG morphological abnormalities were significantly higher, whereas the length of hospital stay were significantly lower, in the NPE as compared with those in the non-NPE. In addition, the frequency of ECG morphological abnormalities for all enrolled patients was noted to be 39% (106/269).

Table 2 demonstrates the heart rate, QTc, and ECG morphological ab- normalities for both groups of patients. We found that the NPE had sig- nificantly higher frequency of NSSTTC than the non-NPE.

W.-L. Chen et al. / American Journal of Emergency Medicine 34 (2016) 79-82 81

Table 1

Demographic and clinical characteristics of the patients with SAH in the ED

	NPE		Non-NPE	P value
	(n = 40)		(n = 229)
Age (y), mean +- SD	57 +- 12		55 +- 11	.470
Sex, male/female, n	18/22		93/136	.606
Vital signs, mean +- SD
MAP (mm Hg)	128 +- 10	125 +- 12		.099
WFNS class, n (%)	b 0.001?
I-III	25 (63)	208 (91)
IV-V	15 (37)	21 (9)
Hunt-Hess scale, n (%) I-III	b 0.001? 24 (60)	200 (87)
IV-V	16 (40)	29 (13)
Laboratory data, mean +- SD
WBC (per mm3)	10288 +- 2437	10121 +- 2489		.696
Glucose (mg/dL)	109 +- 27	103 +- 34		.272
Comedication, n (%)
?-Blocker	3 (8)	8 (3)		.214
Calcium channel blocker	6 (15)	30 (13)		.801
Diuretics	2 (5)	11 (5)		1.000
Prior comorbidity, n (%)
Hypertension	6 (15)	42 (18)		.823
DM	8 (20)	19 (8)		.040?
Heart diseasea	4 (10)	17 (7)		.530
COPD/asthma	3 (8)	24 (10)		.777
ECG MA, n (%)	22 (55)	84 (37)		.035?
Length of hospital stay, mean +- SD	15 +- 7	18 +- 5		.007?
In-hospital mortality	22(55)	26(11)		b.001?

COPD, chronic obstructive pulmonary disease; ECG MA, ECG morphological abnormalities; WBC, white blood cell count.

^a Prior heart disease was defined as a history of angina, myocardial infarction, heart failure, or valvular heart disease.

* P b .05 between 2 groups.

Multiple logistic regression models with forward selection were used to analyze the factors of NPE (dependent variable), and the inde- pendent variables included in the analysis were MAP, WFNS class, Hunt-Hess scale, DM, abnormal Q or QS wave, and NSSTTC. The results showed that WFNS class, abnormal Q or QS wave, and NSSTTC were the significant independent variables associated with development of NPE for adult patients with nontraumatic SAH in the ED. The odds ratio and P value for these 3 variables are listed in Table 3. The sensitiv- ity, specificity, positive predictive value, and negative predictive value of abnormal Q or QS wave were 0.18, 0.93, 0.29, and 0.87, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of NSSTTC were 0.28, 0.90, 0.32, and 0.88, respectively.

Discussion

The main findings of this study are that the ECG abnormalities, espe- cially abnormal Q or QS wave and NSSTTC, assessed early in the ED were independently associated with NPE in patients with spontaneous SAH. With good specificity and negative predictive value noted in the present

Table 2

electrocardiographic findings of the patients

	NPE		Non-NPE	P value
	(n = 40)		(n = 229)
Heart rate (beat/min), mean +- SD	82 +- 21		82 +- 17	.919
QTc (ms), mean +- SD Morphology changes, n (%)	463 +- 48		462 +- 44	.890
Abnormal Q or QS wave	7 (18)	17 (7)		.064
ST elevation	1 (3)	9 (4)		1.000
ST depression	3 (8)	23 (10)		.777
Peaked upright T wave	2 (5)	3 (1)		.161
T-wave inversion	2 (5)	12 (5)		1.000
Giant T-wave inversions	1 (3)	7 (3)		1.000
NSSTTC	11 (28)	23 (10)		.007?
* P b .05 between 2 groups.

Table 3

Statistically independent variables associated with NPE in the multiple logistic regression models

OR (95% CI) P value

WFNS class 5.8 (2.6-13.3)^a b.001

Abnormal Q or QS wave 3.1 (1.1-9.1) .038

NSSTTC 3.0 (1.2-7.5) .016

CI, confidence interval; OR, odds ratio.

^a The OR for WFNS class represents the OR for each 1-point increase from low-grade WFNS (I-III) to high-grade WFNS (VI-V).

study, presence of abnormal Q or QS wave or NSSTTC in patients with SAH was indicative of development of NPE within 24 hours. Abnormal Q or QS wave may have resulted from old myocardial infarction because the prevalence of DM was higher especially in NPE. The previous ECGs and history have been completely obtained to compare with patients with abnormal Q or QS wave (n = 24), and we found that there was no abnormal Q or QS wave in the previous (old) ECGs. In addition, there was no acute myocardial infarction found in the patients with ab- normal Q or QS wave by serial ECGs, cardiac enzymes, and echocardiog- raphy study. Therefore, the abnormal Q or QS wave did not result from either old or new-onset myocardial infarction but was the result of SAH. Studies have suggested that the most pronounced ECG changes oc- curred during the first 72 hours after SAH and 90% of patients had ECG abnormalities during the first 48 hours [18]. In addition, NPE that devel- oped within minutes to days has been reported to be the predominating feature in patients with SAH at the ED [19]. Although Inamasu et al [20] reported that there was no significant difference in ECG abnormality be- tween NPE and non-NPE, our results established the relationship be- tween ECG abnormalities of transient cardiac injury and NPE of pulmonary complication in patients with SAH. The lower study number and time of ECG recording in the previous study would be the possible reasons to explain the differences between the previous study and the present results.

Studies have further demonstrated that SAH, by causing local cere- bral arteriolar spasm, can give rise to ischemic lesions in the hypothala- mus and surrounding area [21], which therefore cause sympathetic stimulation of the heart via elevated plasma catecholamine which in turn is responsible for the ECG abnormalities via 1 of 2 pathways: an in- direct effect via humoral mediators such as epinephrine and norepi- nephrine, and a direct effect via afferent and efferent connections with the sympathetic and vagal nervous systems [22,23]. In addition, hypox- ia, electrolyte imbalance, and sudden increase in intracranial pressure are also reported to be factors that may influence the development of arrhythmias in these patients [21]. Cardiac injury due to elevated myo- cardial wall stress associated with arrhythmias has been suggested as a causative factor. Yuki et al [24] proposed that Coronary vasospasm and reversible postischemic “stunned myocardium” may influence the de- velopment of ECG morphological changes, and the coronary arteries were found to be normal at autopsy in patients with SAH. It suggested that the ECG abnormalities were due to the central nervous system event and not related to myocardial damage or coronary artery occlu- sion. Therefore, the abnormal Q or QS wave, a classic ECG abnormality of acute myocardial infarction, could be caused by focal ischemia from transient vasoconstriction of the myocardial microcirculation or by di- rect toxic effect from catecholamine in patients with SAH [24], but not actual myocardial infarction. Because the clinical syndrome of severe acute stunned myocardium is characterized by ECG abnormalities and pulmonary edema [6], it may suggest why occurrences of ECG abnor- malities are associated with development of NPE in patients with SAH. Though the investigations about the mechanisms of NPE are still ongo- ing, the present reports may further explain the possible pathophysio- logic mechanisms of NPE.

Kawasaki et al [15] have reported that ECG abnormalities can be pre- dictors of mortality after SAH in a retrospective study. By assessing the preoperative 12-lead ECG in a substudy of aneurysm surgery trial,

82 W.-L. Chen et al. / American Journal of Emergency Medicine 34 (2016) 79-82

Coghlan et al [16] further reported that NSSTTCs were strongly and in- dependently associated with 3-month mortality in a substudy of the in- traoperative hypothermia aneurysm trial in patients with mild to moderate SAH. Moreover, previous studies have suggested that patients with more severe SAH are more likely to develop cardiac abnormalities [10,11,13] and NPE [24-26]. In addition, the development of NPE in pa- tients with SAH has been reported to be associated with a worsened clinical outcome [24-26], which is compatible with the present report (in-hospital mortality, 55% vs 11%). Therefore, it suggests that occur- rence of ECG abnormalities and development of NPE may share the same pathogenesis in patients with SAH.

Management of NPE after SAH is centered on the traditional treat- ment strategies for cardiac failure-induced pulmonary edema, such as a reduction in preload and afterload by administration of diuretics and the use of inotropics to avoid hypervolemia. However, Hoff et al [27] have suggested that SAH patients developing NPE may have a lower blood volume than do those without NPE and are hypovolemic, and hy- povolemia is further associated with delayed cerebral ischemia and with poor outcome. To guide fluid management adequately, an early cardiac monitor is required to achieve specific hemodynamic goals in these patients. An early 12-lead ECG interpretation may provide clini- cians practical information about patients with SAH at high risk of de- velopment of NPE.

Our study did have some limitations. Firstly, a relatively small sam- ple size was enrolled in this study. Further study with a large sample size is needed in the future. Secondly, it is problematic to identify if the ECG abnormalities assessed in the present study were acute changes for those patients (n = 14) who had no history of arrhythmias or ECG morphological abnormalities because the history could not be obtained or no previous 12-lead ECG could be obtained to compare with. There could be potential biases when those patients were included in the final analysis. Thirdly, the abnormal Q or QS wave noted in this study was assumed as new onset; however, it still might have resulted from the probable myocardial infarction attack between the time of the pre- vious ECG recording and this episode of SAH, although the probability was low. Fourthly, the serial ECGs and cardiac enzymes have been checked and even echocardiography has been performed after admis- sion in those patients with ischemic changes in initial ECG to avoid mis- diagnosis of acute myocardial infarction, and there was no significant myocardial infarction found. However, cardiac angiography was not performed routinely to make sure if there was actual coronary artery disease, so the intracranial insult could be not the only predisposing fac- tor of ECG abnormally. Fifthly, the interpretation of ECG morphological abnormalities, especially for NSSTTCs, might be subjective. To minimize the bias, the patient’s ECG has been interpreted by the same investigator (cardiologist) who was blinded to the outcome of the patient. Lastly, the diagnosis of NPE might be subjective. To minimize the bias of interpre- tation of radiological findings, the patient’s CXR has been reviewed by the same investigator (radiologist) who was blinded to the clinical find- ings and outcome of the patient. In addition, crackles on chest ausculta- tion were proved by 2 emergency physicians to minimize the interpreted bias.

Conclusions

The study demonstrated that abnormal Q or QS wave, from neither old nor new-onset myocardial infarction, and NSSTTCs assessed early in ED are indicative of development of NPE within 24 hours in adult pa-

tients with spontaneous SAH. Stunned myocardium, represented by ECG abnormalities, may explain the Pathophysiologic mechanisms of NPE.

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