American Journal of Emergency Medicine 34 (2016) 7982

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American Journal of Emergency Medicine

journal homepage: www.elsevier.com/locate/ajem

Original Contribution

ECG abnormalities predict neurogenic pulmonary edema in patients with

subarachnoid hemorrhage,
Wei-Lung Chen, MD, MS, PhD a,b,, Chi-Hung Huang, MD b,c, Jiann-Hwa Chen, MD, MPH, PhD a,b,
Henry Chih-Hung Tai, MD a,b, Su-Hen Chang, MD a,b, Yung-Cheng Wang, MD d,e
a
Department of Emergency Medicine, Cathay General Hospital, Taipei 106, Taiwan
b
School of Medicine, Fu-Jen Catholic University, Taipei 242, Taiwan
c
Department of Cardiology, Cathay General Hospital, Taipei 106, Taiwan
d
Department of Radiology, Cathay General Hospital, Taipei 106, Taiwan
e
School of Medicine, Taipei Medical University, Taipei 106, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Objective: The study aims to assess if electrocardiographic (ECG) abnormalities could predict the development of
Received 3 August 2015 neurogenic pulmonary edema (NPE) within 24 hours in cases of spontaneous subarachnoid hemorrhage (SAH).
Received in revised form 12 September 2015 Methods: We studied prospectively a cohort of 269 adult patients with nontraumatic SAH in an emergency de-
Accepted 21 September 2015 partment of a university-afliated medical center. A 12-lead ECG was taken for these patients. The patients
were stratied into NPE and non-NPE based on serially clinical and radiologic ndings. The ECG abnormalities
were compared between these 2 groups of patients.
Results: Compared with the non-NPE (n = 229), the NPE (n = 40) had signicantly 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 signicantly higher in
NPE, in which nonspecic ST- or T-wave changes (NSSTTCs) are signicantly higher. Multiple logistic regression
model identied World Federation of Neurological Surgeons class (95% condence 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.
2015 Elsevier Inc. All rights reserved.

1. Introduction recognition and appropriate management with cardiac monitoring

Neurogenic pulmonary edema (NPE) is a well-recognized phenom-
enon in subarachnoid hemorrhage (SAH), especially in high-grade pa-
tients [13]. 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.
Conict of interest: The authors declare that they have no conict 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: weilung.chen@msa.hinet.net (W.-L. Chen).
and uid 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 [79], 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/ 2015 Elsevier Inc. All rights reserved.
80 W.-L. Chen et al. / American Journal of Emergency Medicine 34 (2016) 7982
neurological outcome [1013]. 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
ndings 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.
2. Materials and methods
2.1. 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.
2.2. Study setting and selection of participants
This study was conducted in a 700-bed university-afliated medical
center with a 40-bed ED staffed with board-certied 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 rst clinical symptoms with nontraumatic SAH
diagnosed by computed tomographic scans of brain, or xanthochromia
of the cerebrospinal uid 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).
2.3. Study protocol
After obtaining the written informed consent, a standard 12-lead ECG
recording was performed immediately after the diagnosis was made. The
patients 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 ratecorrected QT in-
terval (QTc) using the Bazett formula. The morphological abnormalities
were dened 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) nonspecic 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 dened by both serially clinical
and radiologic ndings [4]. A standard chest radiograph (CXR) was
taken after diagnosis made and 24 hours later. The patients 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 inltrates 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 uid.
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 decit; class II, GCS = 13-
14, no motor decit; class III, GCS = 13-14, presence of motor decit;
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 classied as survivors in this
study; otherwise, the patients were referred to as nonsurvivors (in-
hospital mortality).
2.4. 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 signicant. Statistical analyses were
performed using a common statistical package (SPSS 16.0 for Windows;
SPSS Inc, Chicago, IL).
3. 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 nal analysis.
Based on development of NPE, those 269 patients, aged 19 to 77 years,
were stratied 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 signicant differences in age, sex, mean arterial
pressure (MAP), white blood cell, glucose, comedication, and underly-
ing diseases except diabetes mellitus (DM) between these 2 groups of
patients. However, the WFNS class, Hunt-Hess scale, DM, and the occur-
rence of ECG morphological abnormalities were signicantly higher,
whereas the length of hospital stay were signicantly 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-
nicantly higher frequency of NSSTTC than the non-NPE.
 W.-L. Chen et al. / American Journal of Emergency Medicine 34 (2016) 7982 81

Table 1 Table 3
Demographic and clinical characteristics of the patients with SAH in the ED Statistically independent variables associated with NPE in the multiple logistic regression
models
NPE Non-NPE P value
OR (95% CI) P value
(n = 40) (n = 229)
WFNS class 5.8 (2.6-13.3)a b.001
Age (y), mean SD 57 12 55 11 .470
Abnormal Q or QS wave 3.1 (1.1-9.1) .038
Sex, male/female, n 18/22 93/136 .606
NSSTTC 3.0 (1.2-7.5) .016
Vital signs, mean SD
MAP (mm Hg) 128 10 125 12 .099 CI, condence interval; OR, odds ratio.
a
WFNS class, n (%) b 0.001 The OR for WFNS class represents the OR for each 1-point increase from low-grade
I-III 25 (63) 208 (91) WFNS (I-III) to high-grade WFNS (VI-V).
IV-V 15 (37) 21 (9)
Hunt-Hess scale, n (%) b 0.001
I-III 24 (60) 200 (87) study, presence of abnormal Q or QS wave or NSSTTC in patients with
IV-V 16 (40) 29 (13) SAH was indicative of development of NPE within 24 hours. Abnormal
Laboratory data, mean SD Q or QS wave may have resulted from old myocardial infarction because
WBC (per mm3) 10288 2437 10121 2489 .696
the prevalence of DM was higher especially in NPE. The previous ECGs
Glucose (mg/dL) 109 27 103 34 .272
Comedication, n (%) and history have been completely obtained to compare with patients
-Blocker 3 (8) 8 (3) .214 with abnormal Q or QS wave (n = 24), and we found that there was
Calcium channel blocker 6 (15) 30 (13) .801 no abnormal Q or QS wave in the previous (old) ECGs. In addition,
Diuretics 2 (5) 11 (5) 1.000 there was no acute myocardial infarction found in the patients with ab-
Prior comorbidity, n (%)
Hypertension 6 (15) 42 (18) .823
normal Q or QS wave by serial ECGs, cardiac enzymes, and echocardiog-
DM 8 (20) 19 (8) .040 raphy study. Therefore, the abnormal Q or QS wave did not result from
Heart diseasea 4 (10) 17 (7) .530 either old or new-onset myocardial infarction but was the result of SAH.
COPD/asthma 3 (8) 24 (10) .777 Studies have suggested that the most pronounced ECG changes oc-
ECG MA, n (%) 22 (55) 84 (37) .035
curred during the rst 72 hours after SAH and 90% of patients had ECG
Length of hospital stay, mean SD 15 7 18 5 .007
In-hospital mortality 22(55) 26(11) b.001 abnormalities during the rst 48 hours [18]. In addition, NPE that devel-
oped within minutes to days has been reported to be the predominating
COPD, chronic obstructive pulmonary disease; ECG MA, ECG morphological abnormalities;
WBC, white blood cell count.
feature in patients with SAH at the ED [19]. Although Inamasu et al [20]
a
Prior heart disease was dened as a history of angina, myocardial infarction, heart reported that there was no signicant difference in ECG abnormality be-
failure, or valvular heart disease. tween NPE and non-NPE, our results established the relationship be-
P b .05 between 2 groups. tween ECG abnormalities of transient cardiac injury and NPE of
pulmonary complication in patients with SAH. The lower study number
Multiple logistic regression models with forward selection were and time of ECG recording in the previous study would be the possible
used to analyze the factors of NPE (dependent variable), and the inde- reasons to explain the differences between the previous study and the
pendent variables included in the analysis were MAP, WFNS class, present results.
Hunt-Hess scale, DM, abnormal Q or QS wave, and NSSTTC. The results Studies have further demonstrated that SAH, by causing local cere-
showed that WFNS class, abnormal Q or QS wave, and NSSTTC were bral arteriolar spasm, can give rise to ischemic lesions in the hypothala-
the signicant independent variables associated with development of mus and surrounding area [21], which therefore cause sympathetic
NPE for adult patients with nontraumatic SAH in the ED. The odds stimulation of the heart via elevated plasma catecholamine which in
ratio and P value for these 3 variables are listed in Table 3. The sensitiv- turn is responsible for the ECG abnormalities via 1 of 2 pathways: an in-
ity, specicity, positive predictive value, and negative predictive value of direct effect via humoral mediators such as epinephrine and norepi-
abnormal Q or QS wave were 0.18, 0.93, 0.29, and 0.87, respectively. The nephrine, and a direct effect via afferent and efferent connections with
sensitivity, specicity, positive predictive value, and negative predictive the sympathetic and vagal nervous systems [22,23]. In addition, hypox-
value of NSSTTC were 0.28, 0.90, 0.32, and 0.88, respectively. ia, electrolyte imbalance, and sudden increase in intracranial pressure
are also reported to be factors that may inuence the development of
4. Discussion arrhythmias in these patients [21]. Cardiac injury due to elevated myo-
cardial wall stress associated with arrhythmias has been suggested as a
The main ndings of this study are that the ECG abnormalities, espe- causative factor. Yuki et al [24] proposed that coronary vasospasm and
cially abnormal Q or QS wave and NSSTTC, assessed early in the ED were reversible postischemic stunned myocardium may inuence the de-
independently associated with NPE in patients with spontaneous SAH. velopment of ECG morphological changes, and the coronary arteries
With good specicity and negative predictive value noted in the present 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-
Table 2
sion. Therefore, the abnormal Q or QS wave, a classic ECG abnormality
Electrocardiographic ndings of the patients
of acute myocardial infarction, could be caused by focal ischemia from
NPE Non-NPE P value transient vasoconstriction of the myocardial microcirculation or by di-
(n = 40) (n = 229) rect toxic effect from catecholamine in patients with SAH [24], but not
actual myocardial infarction. Because the clinical syndrome of severe
Heart rate (beat/min), mean SD 82 21 82 17 .919
QTc (ms), mean SD 463 48 462 44 .890 acute stunned myocardium is characterized by ECG abnormalities and
Morphology changes, n (%) pulmonary edema [6], it may suggest why occurrences of ECG abnor-
Abnormal Q or QS wave 7 (18) 17 (7) .064 malities are associated with development of NPE in patients with SAH.
ST elevation 1 (3) 9 (4) 1.000
Though the investigations about the mechanisms of NPE are still ongo-
ST depression 3 (8) 23 (10) .777
Peaked upright T wave 2 (5) 3 (1) .161 ing, the present reports may further explain the possible pathophysio-
T-wave inversion 2 (5) 12 (5) 1.000 logic mechanisms of NPE.
Giant T-wave inversions 1 (3) 7 (3) 1.000 Kawasaki et al [15] have reported that ECG abnormalities can be pre-
NSSTTC 11 (28) 23 (10) .007 dictors of mortality after SAH in a retrospective study. By assessing the
P b .05 between 2 groups. preoperative 12-lead ECG in a substudy of aneurysm surgery trial,
82 W.-L. Chen et al. / American Journal of Emergency Medicine 34 (2016) 7982
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 [2426]. In addition, the development of NPE in pa-
tients with SAH has been reported to be associated with a worsened
clinical outcome [2426], 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 failureinduced 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 uid management adequately, an early
cardiac monitor is required to achieve specic 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
nal 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 signicant
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 patients 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 ndings, the patients CXR has been reviewed by
the same investigator (radiologist) who was blinded to the clinical nd-
ings and outcome of the patient. In addition, crackles on chest ausculta-
tion were proved by 2 emergency physicians to minimize the
interpreted bias.
5. 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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