Download Repolarization Abnormalities in Patients with Subarachnoid and

Neuroscience in Anesthesiology and Perioperative Medicine
Section Editor: Gregory J. Crosby
Repolarization Abnormalities in Patients with
Subarachnoid and Intracerebral Hemorrhage:
Predisposing Factors and Association with Outcome
Eija Junttila, MD,* Maarika Vaara, MD,* Juha Koskenkari, MD, PhD,* Pasi Ohtonen, MSc†,
Ari Karttunen, MD, PhD‡, Pekka Raatikainen, MD, PhD§‖; and Tero Ala-Kokko, MD, PhD*
BACKGROUND: Electrocardiographic (ECG) abnormalities are frequent in patients with intracranial insult. In this study, we evaluated the factors predisposing to the repolarization abnormalities, i.e., prolonged corrected QT (QTc) interval, ischemic-like ECG changes and morphologic
end-repolarization abnormalities, and examined the prognostic value of these abnormalities in
patients with subarachnoid and intracerebral hemorrhages requiring intensive care.
METHODS: This was a prospective, observational clinical study in a university-level intensive
care unit. Clinical characteristics, the level of consciousness, and findings in primary head
computed tomography were recorded on admission. The study period was divided into three
2-day sections. In each section, a 12-lead ECG, transthoracic echocardiography, the results
of standard blood electrolytes and cardiac troponin I, as well as the rate of vasoactive and
sedative drug infusions were recorded. Repolarization abnormalities such as prolongation of
the QTc interval (millisecond), ischemic-like ECG changes, and morphologic end-repolarization
abnormalities (present/absent) were evaluated and analyzed. The 1-year functional outcome
was determined using the Glasgow Outcome Score.
RESULTS: During the 2-year study period, 108 patients were included in the study. Different
repolarization abnormalities were frequent in both types of hemorrhage. Prolongation of the
QTc interval was predisposed by female gender (β, 24.5; P = 0.010) and the use of propofol
(β, 30.5; P = 0.001). The predisposing factor for ischemic-like ECG changes were male gender
(odds ratio [OR], 5.9; P = 0.003) and for morphological end-repolarization abnormalities aneurysmatic bleeding (OR, 13.0; P = 0.002). Ischemic-like ECG changes were common, in 87/108
patients during the study period, and were associated with a poorer 1-year functional outcome
(OR, 4.7; lower 95% confidence interval, 1.5; P = 0.010).
CONCLUSIONS: Each repolarization abnormality has characteristic predisposing factors.
Ischemic-like ECG changes are common and are associated with a poorer 1-year functional
outcome. (Anesth Analg 2013;116:190–7)
E
lectrocardiographic (ECG) changes are frequently
seen in patients with intracranial insult.1,2 There are
several reports on ECG abnormalities in patients
with subarachnoid hemorrhage (SAH)3,4 but only a few in
patients with intracerebral hemorrhage (ICH).5–9 Likewise,
data on nontraumatic intracranial hemorrhage (SAH, ICH,
and intraventricular hemorrhage [IVH]),10 as a whole, are
From the *Department of Anesthesiology, Division of Intensive Care, Oulu
University Hospital; †Departments of Anesthesiology and Surgery, Oulu
University Hospital; ‡Department of Radiology, Oulu University Hospital;
§Department of Internal Medicine, Oulu University Hospital, Oulu, Finland;
and ‖Heart Center Co, Tampere University Hospital, Tampere, Finland.
Accepted for publication August 14, 2012
The authors declare no conflicts of interest.
Supported by the Pro Humanitate Foundation, Finland.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions of
this article on the journal’s website (www.anesthesia-analgesia.org).
Reprints will not be available from the authors.
Address correspondence to Eija Junttila, MD, Department of Anesthesiology, Oulu University Hospital, PO Box 21, FIN-90029 OUH, Oulu, Finland.
­Address e-mail to [email protected].
Copyright © 2012 International Anesthesia Research Society
DOI: 10.1213/ANE.0b013e318270034a
190
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scarce, and data considering the effect of repolarization
abnormalities on the long-term outcome of these patients
are contradictory.4,11–13
Repolarization abnormalities such as a prolongation
of the QT interval and changes in the ST segment and T
wave morphology are the most common ECG alterations
in patients with SAH11 and ICH.9 The mechanisms of these
abnormalities are not completely understood, but they
are thought to be related to the sympathetic overactivity
induced by the intracranial hemorrhage. Injury in the rightsided insular area has particularly been noted to be associated with ECG alterations.2,3,14,15 In addition, female gender
and hypokalemia (potentially manifested by the hyperadrenergic state)16 have been reported to be independent
risk factors for QT prolongation in patients with SAH.17
An association between QT prolongation and ischemic-like
ECG changes with prior coronary artery disease has been
reported in patients with ICH.1 On the other hand, there are
reports of ECG abnormalities in patients with ICH in the
absence of prior heart disease. It is thought that the same
mechanisms that act in SAH are also prevalent in these
patients.7,8 There are, however, insufficient data concerning
January 2013 • Volume 116 • Number 1
the type and the incidence of ECG changes and the predisposing factors for ECG alterations in different type of
intracranial hemorrhages, nor an association with outcome.
The aim of this study was to evaluate the factors predisposing to repolarization abnormalities, i.e., prolonged
corrected QT (QTc) interval, ischemic-like ECG changes,
and morphologic end-repolarization abnormalities, and to
examine the prognostic value of these abnormalities in SAH
and ICH patients requiring intensive care.
METHODS
Patients
This prospective, single-center study was approved by the
Ethics Committee of the Oulu University Hospital, and
written informed consent was obtained from the patient
or a legal surrogate in all cases. This was an observational
study of patients admitted to the tertiary level intensive
care unit (ICU) over a 2-year period, from December 2007 to
December 2009. All patients admitted to the ICU with nontraumatic intracranial hemorrhage during the study period
were screened. Exclusion criteria included an intracranial
hemorrhage resulting from tumor, arteriovenous malformation, or recent head/neck operation, age <18 years, and an
ICU admission delay from hospital admission >48 hours.
Patient characteristics, including age, sex, and medical
history, were recorded. The level of consciousness on
hospital admission or before sedation was assessed using
the Glasgow Coma Score.18 Data considering ICU scores
were retrieved from a prospectively collected electronic
patient database (Critical Care Information Management
System [CCIMS], Clinisoft, GE, Helsinki, Finland), in which
the Acute Physiology And Chronic Health Evaluation II
score19 is recorded on admission, as is the daily Sequential
Organ Failure Assessment score.20
Head computed tomography (CT) scan was performed
on admission, and the diagnosis of intracranial hemorrhage
was established. SAH and IVH were classified according to
the Hijdra SAH CT score,21 and the ICH volume (in milliliters) was calculated (d1 × d2 × d3 [3 perpendicular diameters, d]). Diffuse cerebral edema, acute hydrocephalus, and
midline shift were dichotomized as present or absent. The
etiology of the hemorrhage was recorded based on the data
from head CT scans, CT angiographies, digital subtraction
angiographies, and operation and autopsy reports. On the
basis of these findings, patients were divided into 2 groups:
the SAH/IVHa group included patients with aneurysmatic
SAH or IVH and perimesencephalic SAH, whereas the
ICH/IVHo group was composed of patients with primary
and secondary ICH or IVH.
Clinical Management
During the ICU stay, all patients were treated according
to our normal clinical practice, consistent with the latest
guidelines.22–24 Patients with aneurysmatic hemorrhage
were treated by an endovascular or surgical method in the
early phase. IV nimodipine was used, and normovolemia
was maintained to minimize the risk for the development
of vasospasm. The mean arterial blood pressure was individually targeted from 60 to 80 mm Hg. When intracranial
pressure was monitored, the calculated cerebral perfusion
January 2013 • Volume 116 • Number 1
pressure (cerebral perfusion pressure = mean arterial blood
pressure – intracranial pressure) was generally targeted
to be >60 mm Hg. The calibration of the intracranial and
arterial pressure transducers was performed at the level of
patient’s eye angle, as in our clinical practice. Vasoactive
drugs and fluid administration were guided by the patients’
hemodynamics. The blood hematocrit level was maintained
>0.30, the blood glucose level was 6.0 to 8.0 mmol/L, and
electrolytes were within the normal range. A normothermic
body temperature was targeted.
Study Protocol
The study period started on the day of ICU admission (day
0) and lasted 5 days thereafter (days 1–5), unless the patient
died or was transferred to another hospital. It was divided
into three 2-day sections: T1: days 0 to 1; T2: days 2 to 3;
and T3: days 4 to 5. Twelve-lead ECGs and blood samples
were taken, and transthoracic echocardiography (TTE) was
performed at least once in each section. According to the
study protocol and our clinical practice, blood samples
(such as cardiac troponin I [cTnI]), magnesium, and glomerulus filtration rate were taken once a day at 7:00 am, and
ECGs were usually recorded between 7:00 and 9:00 am. In
addition, arterial blood gas analyses and basic electrolytes
(sodium, potassium and ionized calcium) were taken every
6 hours. Levels for potassium <3.5 mmol/L, ionized calcium
<0.9 mmol/L, and magnesium <0.70 mmol/L were defined
as being decreased. The glomerulus filtration rate was estimated using the Cockcroft–Gault formula (1.15 × [140 Age]
× Weight [kg] / P-Krea [μmol/L], × 0.85 in female patients),25
and <60 mL/min was defined as being decreased. cTnI was
measured using an immunofluorometric method (Innotrac
Aio!™, Innotrac Diagnostics OY, Turku, Finland), and a
result >0.06 μg/L was defined as being elevated. The use
and the rate of vasoactive (norepinephrine, dobutamine,
and nimodipine) and sedative (propofol) drug infusions at
the time of the ECG were recorded.
The prospectively collected ECGs were retrospectively
manually analyzed by 2 observers (EJ and MV) for rhythm,
heart rate, PQ interval duration, QRS interval duration and
morphology, QT interval duration, ST segment changes,
and T and U wave abnormalities. The Sokolow–Lyon criteria were used to identify left ventricular (LV) hypertrophy.
The QT interval was measured using the tangent method
and corrected (QTc) for heart rate by the Bazett formula.
Repolarization abnormalities were defined and analyzed
in 3 categories according to the following criteria: (1) prolonged QTc: the maximal QTc >440 ms in male patients and
>470 ms in female patients; (2) ischemic-like ECG changes:
ST segment elevation and depression ≥0.1 mV in limb leads
and ≥0.2 mV in chest leads, inverted (negative) T wave in
any lead apart from aVR and V1; and (3) morphologic endrepolarization abnormalities: biphasic, 2-peaked or tailed T
wave or separated U wave ≥0.1 mV.
TTE was performed by 1 of the authors (EJ), and the
global LV function was determined by measuring the ejection fraction (EF) of the LV. It was categorized in 3 classes:
(1) EF ≥ 50%; (2) EF 40% to 49%; and (3) EF < 40%.26 An EF
< 50% was defined as global LV dysfunction.
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Repolarization in Subarachnoid and Intracerebral Hemorrhage
The 1-year functional outcome was assessed using the
Glasgow Outcome Score (GOS).27 Data were collected by
telephone interview with the patient or a surrogate by 2 of
the authors (EJ and MV) and dichotomized as good (GOS
4–5: no to moderate disability) or poor (GOS 1–3: severe disability, vegetative state, death). Data considering the cause
of death were received from the official national database
(Statistics Finland, Helsinki, Finland). On the basis of the
data, the causes of death were categorized as cardiac and
noncardiac. Patients with the decision to withdraw life support (neurologically hopeless prognosis) were recorded.
Statistical Analysis
The SPSS (version 15.0, SPSS Inc., Chicago, IL) and SAS
(version 9.2, SAS Institute Inc., Cary, NC) software were
used for statistical analysis. Summary measurements were
expressed as a mean with SD or as a median with 25th to
75th percentile, unless otherwise stated.
Continuous variables were analyzed using the Student
t-test or the Mann–Whitney U test. The χ² test or the Fisher
exact test were used for categorical variables.
The analyses of repeatedly measured data were
performed to test the possible differences in repolarization
abnormalities between the SAH/IVHa and ICH/IVHo
groups during the study period. Repeatedly measured
variables were analyzed by a linear random coefficients
model (continuous variables) or by a generalized linear
random effects model with Gaussian quadrature for integral
approximation (dichotomous variables). In both mixed
models, the unstructured covariance pattern was specified
for random effects, and the following P-values are reported:
Pt (Ptime), the overall change over measurement points; Pg
(Pgroup), the average difference between groups; and Pg+t
(Pgroup × time), group–time interaction, that is, the difference
between groups over time. Residual versus predicted
value plots were performed to assess the normality of
the residuals, and they were reasonably close to normally
distributed.
Multivariate linear and logistic regression models were
built to identify the predisposing factors for repolarization
abnormalities (the length of QTc interval, ischemic-like ECG
changes, and morphologic end-repolarization abnormalities) and association with a poorer outcome (GOS 1–3). The
variables tested were entered into the model one at a time,
and the variables in the final models were chosen based on
the P-value (P < 0.05), or the variables affecting the value
of coefficient of determination (r²) in the linear regression
model (>10% change) and –2x log likelihood functions
between 2 subsequent models in logistic regression models
(P < 0.05 according to χ2 test for the difference, with degrees
of freedom = 1). Age and gender were used as adjusting factors, and they were left in the model if they were statistically
significant. The interaction terms between the variables at
the final regression models were created, and each of the
interaction terms was found nonsignificant (all P > 0.15).
The linearity assumption of the continuous variable age in
the logistic regression model was evaluated by adding polynomial terms of (centered) age into the model. The variables
tested in the regression models for the evaluation of predisposing factors for each repolarization abnormality were
demographics, the type and the aneurysmatic etiology of
192 www.anesthesia-analgesia.org
bleeding and the level of consciousness on admission, cTnI
elevation and LV dysfunction at the time or before the ECG
recording, and electrolyte concentrations and the use of
infused drugs (norepinephrine, dobutamine, nimodipine,
and propofol) at the time of ECG recording.
Two-tailed P-values were reported. Due to several
dependent analyses performed, the significance level was
set to ≤ 0.01 (i.e., P ≤ 0.01).
RESULTS
During the 2-year study period, 191 patients with nontraumatic intracranial hemorrhage were treated in our ICU,
and 108 of these patients were included in the analyses.
The flow chart of the study is shown in Figure 1. Sixty-six
(61%) patients had an SAH/IVHa type of hemorrhage, and
59 (89%) of the patients were aneurysmatic. An ICH/IVHo
type of hemorrhage was diagnosed in 42 (39%) patients, of
which 4 had aneurysmatic bleeding without an SAH component, as observed in the primary head CT scan.
Clinical characteristics, data concerning the ICU stay,
and neurosurgical interventions are presented in Table 1
and online supplemental Tables S1 and S2, (Supplemental
Digital Content 1, http://links.lww.com/AA/A473).
Except for better level of consciousness on admission in
SAH/IVHa patients, there were no differences in clinical
characteristics between the groups.
Figure 1. Flow chart of the study. ICU = intensive care unit;
AVM = arteriovenous malformation.
ANESTHESIA & ANALGESIA
Table 1. Clinical Characteristics According to the Type of Hemorrhage
Age (y), mean (SD)
Gender, male, n (%)
Comorbidities, n (%)
Hypertension, n (%)
Heart disease, n (%)
Chronic renal failure, n (%)
Prior medications, n (%)
β-blockers, n (%)
Calcium channel blockers, n (%)
Digitalis, n (%)
The level of consciousness on admission, n (%)
GCS 15
GCS 13–14
GCS 7–12
GCS 3–6
APACHE II mean (SD)
SAH/IVHa
n = 66
57.3 (11.6)
34 (52)
40 (61)
26 (39)
8 (12)
1 (2)
29 (44)
12 (18)
7 (11)
1 (2)
ICH/IVHo
n = 42
57.5 (12.2)
22 (52)
26 (62)
15 (36)
7 (17)
2 (5)
19 (45)
9 (21)
0
2 (5)
19 (29)
21 (32)
8 (12)
18 (27)
19.5 (6.6)
2 (5)
10 (24)
13 (31)
17 (41)
20.9 (6.2)
P
>0.9
>0.9
0.9
0.7
0.5
0.6
0.9
0.7
0.041
0.6
0.003
0.3
SAH = subarachnoidal hemorrhage; IVH = intraventricular hemorrhage; ICH = intracerebral hemorrhage; GCS = Glasgow Coma Score; APACHE = Acute
Physiology And Chronic Health Evaluation.
ECG findings during the study period are presented in
Table 2. ECGs were available for review as follows: all 3 in
82 patients, 2 in 23 patients, and 1 in 3 patients. Ninety-eight
patients (91%) had normal sinus rhythm in all analyzed
ECGs. The heart rate increased, and the duration of the PQ
and QRS intervals decreased during the follow-up. The QTc
interval was prolonged in at least 1 ECG during the study
period in 60 (91%) patients with SAH/IVHa and in 41 (98%)
patients with ICH/IVHo (P = 0.2). The frequency and the
progression of different repolarization abnormalities were
equal between the groups.
The predisposing factors for the repolarization abnormalities are presented in Table 3. Prolongation of the QTc
interval was predisposed by female gender (β, 24.5; lower
95% confidence interval [CI], 6.0; P = 0.010) and the use of
propofol (β, 30.5; lower 95% CI, 12.2; P = 0.001). The predisposing factor for ischemic-like ECG changes was male
gender (odds ratio [OR], 5.9; lower 95% CI, 1.8; P = 0.003),
and for morphologic end-repolarization abnormalities, it
was aneurysmatic bleeding (OR, 13.0; lower 95% CI, 2.7; P =
0.002). In addition, cTnI elevation may have been a predisposing factor for QTc prolongation and ischemic-like ECG
changes, as well as aneurysmatic bleeding for QTc prolongation, but the sample size was too small to determine these
findings. There was also an inverse association between
nimodipine use and ischemic-like ECG changes, as well
as unconsciousness and morphologic end-repolarization
abnormalities.
TTE was performed in all patients at time point T1, in
which the frequency of global LV dysfunction was the highest: EF ≥50%, 85 (79%), EF 40% to 49%, 17 (16%) and EF <
40%, 6 (6%). Ischemic-like ECG changes were more frequent
in patients with global LV dysfunction (18/22 [82%] vs
49/83 [59%]; P = 0.048). The other repolarization abnormalities were not associated with global LV dysfunction (data
not shown).
The 1-year GOS is presented in Table 4. The mortality
rate was 18% (12/66) in the SAH/IVHa group and 29%
(12/42) in the ICH/IVHo group. Of 17 patients, life support
was withdrawn in 16 because of poor neurologic prognosis
Table 2. Electrocardiographic Findings During the Study Period According to the Type of Hemorrhage
Heart rate, bpm, mean (SD)
Sinus rhythm, n (%)
PQ interval, mean (SD)
QRS duration, mean (SD)
Normal QRS morphology, n (%)
QTc max, ms, med (25th–75th)
Ischemic-like ECG changes, n (%)
MERA, n (%)
Type
SAH/IVHa
ICH/IVHo
SAH/IVHa
ICH/IVHo
SAH/IVHa
ICH/IVHo
SAH/IVHa
ICH/IVHo
SAH/IVHa
ICH/IVHo
SAH/IVHa
ICH/IVHo
SAH/IVHa
ICH/IVHo
SAH/IVHa
ICH/IVHo
T1
69 (13)
71 (16)
61 (95)
38 (93)
148 (29)
153 (36)
97 (15)
92 (13)
62 (97)
36 (89)
493 (465–536)
492 (465–528)
40 (63)
27 (66)
44 (69)
22 (54)
T2
72 (14)
74 (14)
57 (93)
33 (89)
140 (26)
146 (33)
94 (15)
91 (11)
59 (97)
34 (92)
470 (434–526)
478 (443 (496)
39 (64)
27 (73)
54 (89)
24 (65)
T3
78 (19)
77 (16)
56 (95)
30 (91)
138 (22)
144 (31)
92 (12)
88 (11)
58 (98)
31 (94)
459 (429–487)
452 (436–479)
37 (63)
24 (73)
49 (83)
17 (52)
Pgroup
0.37
Ptime
0.003
Pgroup+time
0.59
0.69
>0.9
>0.9
0.48
<0.001
>0.9
0.15
<0.001
0.68
0.83
0.60
0.054
>0.9
<0.001
>0.9
0.73
0.64
0.46
0.086
0.064
0.16
T1, days 0–1, ECG n = 105: SAH/IVHa n = 64, ICH/IVHo n = 41; T2, days 2–3, ECG n = 98: SAH/IVHa n = 61, ICH/IVHo n = 37; T3, days 4–5, ECG n = 92:
SAH/IVHa n = 59, ICH/IVHo n = 33.
ECG = electrocardiography; SAH = subarachnoidal hemorrhage; IVH = intraventricular hemorrhage; ICH = intracerebral hemorrhage; QTc =QT interval corrected
by Bazett formula; MERA = Morphological End-repolarization Abnormalities.
January 2013 • Volume 116 • Number 1
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Repolarization in Subarachnoid and Intracerebral Hemorrhage
Table 3. Predisposing Factors for Repolarization Abnormalities in Multivariable Linear and Logistic
Regression Models Using QTc Interval as a Linear Variable and Ischemic-like ECG Changes and Morphologic
End-Repolarization Abnormalities as Binary Variables
Variable
Gender, female
Aneurysmatic bleeding
Cardiac troponin I >0.06 μg/L
Use of propofol
Gender, male
Cardiac troponin I >0.06 μg/L
Use of nimodipine
Aneurysmatic bleeding
GCS 13–15d
GCS 7–12d
GCS 3–6d
QTc interval, msa
Ischemic-like electocardiograph changes, n = 87 (81%)b
MERA, n = 92 (85%)c
β/odds ratio (95%
confidence interval)
24.5 (6.0–43.0)
19.6 (0.92–38.2)
19.9 (0.72–39.0)
30.5 (12.2–48.8)
5.9 (1.8–18.7)
3.6 (1.0–12.9)
0.32 (0.11–0.95)
13.0 (2.7–63.1)
1.0
0.31 (0.06–1.6)
0.21 (0.05–0.95)
P
0.010
0.040
0.042
0.001
0.003
0.049
0.041
0.002
0.16
0.043
QTc = QT interval corrected by Bazett formula; ECG = electrocardiographic; MERA = Morphological End-repolarization Abnormalities; GCS = Glasgow Coma
Score.
a 2
R 0.24.
b
–2 Log likelihood 89.08.
c
–2 Log likelihood 68.76
d
The level of consciousness on admission, compared with those with GCS 13–15.
during the hospitalization. All these patients died. There
was 1 cardiac-caused death in a patient with prior severe
coronary artery disease, whose life support was withdrawn
because of poor prognosis caused by the severe heart disease, age, and neurologic deficit. Data regarding functional
outcome were received from all 84 of the patients surviving
the first year after the insult, and it was poorer in patients in
the ICH/IVHo group. Ischemic-like ECG changes were common in 87 of 108 patients during the study period. These
changes were associated with a poorer 1-year functional
outcome in the entire study group (OR, 4.7; lower 95% CI,
1.5; P = 0.010) as well as in the nonwithdrawn patients (OR,
8.5; lower 95% CI, 1.7; P = 0.010; Table 5).
DISCUSSION
The main findings of this study were given as follows: (1)
there were no differences in the frequency, the type, or
the progression of different repolarization abnormalities
between the SAH/IVHa and the ICH/IVHo groups; (2) each
Table 4. 1-Year Functional Outcome Defined by
Glasgow Outcome Score, Categorization of Death
in Nonsurviving Patients and Withdrawn Decisions
According to the Type of Hemorrhage
Outcome
Good
5 (good recovery)
4 (moderate disability)
Poor
3 (severe disability)
2 (vegetative state)
1 (dead)
Cardiac
Noncardiac
Withdrawna
SAH/IVHa
n = 66
39 (59)
27
12
27 (41)
14
1
12
0
12
6
ICH/IVHo
n = 42
13 (31)
6
7
29 (69)
17
0
12
1
11
11
GOS = Glasgow Outcome Score; SAH = subarachnoidal hemorrhage; IVH =
intraventricular hemorrhage; ICH = intracerebral hemorrhage.
a
All withdrawn patients died.
194 www.anesthesia-analgesia.org
repolarization abnormality had characteristic predisposing
factors; and (3) ischemic-like ECG changes were common
and associated with a poorer 1-year functional outcome.
Repolarization abnormalities were equally frequent in
the SAH/IVHa and the ICH/IVHo groups in our study.
This supports the argument that they are related to the location and extent of the brain lesion rather than to the exact
mechanism of the cerebrovascular insult.28 On the other
hand, there has been a trend from the first reports showing
that these abnormalities are more frequent in patients with
SAH.29 One explanation could be the probability of a more
severe global brain injury, which was observed in our study
with a higher frequency of diffuse brain edema in the SAH/
IVHa group. Nevertheless, in our study, the only difference
between the SAH/IVHa and ICH/IVHo groups was in the
frequencies of morphologic end-repolarization abnormalities, which were slightly more frequent in the SAH/IVHa
group and predisposed to by aneurysmatic bleeding. The
rupture of an aneurysm probably has a specific disruptive
effect on the balance of the autonomic nervous system, but
comparative studies in patients with different types and etiologies of hemorrhage are lacking.
In this study, the prolongation of the QTc interval reached
a maximum within 2 days of the insult and shortened
thereafter in both groups. This has been demonstrated
in patients with SAH.13,30 In contrast, morphologic endrepolarization abnormalities were delayed, being most
frequent and prominent 2 to 3 days after the insult. This
unique finding indicates that these abnormalities are
obviously triggered by the hemorrhage, although the exact
mechanism of the progression is unclear.
The lengthening of the QTc interval was predisposed by
female gender and the use of propofol. Female gender is
associated with prolonged QT intervals in healthy subjects31
and in patients with SAH,17 but a novel finding in our study
was that propofol lengthened QTc intervals. This could
explain the sensitivity of this patient population, with an
already prolonged QT interval, to malignant ventricular
arrhythmias—1 symptom described in propofol infusion
ANESTHESIA & ANALGESIA
Table 5. Risk Factors for Poor 1-Year Functional Outcome in All Patients (n = 108) and in Nonwithdrawn
Patients (n = 91) in Logistic Regression Models Using the Glasgow Outcome Score as a Binary Variable
Variable
Age, y
ICH/IVHo type of hemorrhage
GCS 3–6 on admission
Ischemic-like ECG changes
All patients
OR (95% CI)
1.08 (1.03–1.12)
3.5 (1.4–8.7)
3.6 (1.3–9.9)
4.7 (1.5–15.3)
P
0.001
0.008
0.013
0.010
Withdrawn patients excluded
OR (95% CI)
P
1.06 (1.01–1.11)
0.044
3.1 (1.1–8.4)
0.028
2.9 (0.9–8.6)
0.062
8.5 (1.7–46.9)
0.010
–2 Log likelihood 119.86, for all patients; –2 Log likelihood 102.38, for nonwithdrawn patients; Glasgow Outcome Score (poor outcome, scores 1–3: dead,
vegetative state, severe disability).
ICH = intracerebral hemorrhage; IVH = intraventricular hemorrhage; GCS = Glasgow Coma Score; ECG =, electrocardiographic; OR = odds ratio; CI = confidence interval.
syndrome.32 We did not, however, find any correlation
between the duration of the QTc interval and the rate of
propofol infusion (data not shown). Although the association
between QTc prolongation and ventricular arrhythmias
were not noted in patients with SAH,33 propofol should be
used cautiously with moderate infusion rates. In addition,
the QT interval should be monitored frequently in patients
with intracranial hemorrhage and prolonged QTc interval
based on data regarding patients with long QT syndrome,34
case reports in patients with propofol-related infusion
syndrome,32 and the present results.
The frequency of the ischemic-like ECG changes did not
depend on the type of hemorrhage. In our study, ischemiclike ECG changes were associated with an elevation in
cTnI levels in a logistic regression model. In addition, an
association with global LV dysfunction was noted. These
findings indicate that ischemic-like ECG changes may be
caused by myocardial injury. Our findings are supported
by the recent findings by Hasegawa et al.6 in patients with
ICH. In their study, ECGs were only analyzed on arrival,
which may have caused an underestimation of these abnormalities, as seen in the lower rates of these abnormalities
compared with ours. It was also notable that the intracranial insult was more severe (lower Glasgow Coma Scores
on admission and larger ICH volumes) in the patients in
our study.
Myocardial injury after intracranial insult is supposed to
be multifactorial caused by the direct cardiac toxity of norepinephrine released from intracardiac nerve endings, systemic hyperadrenergic state, and coronary vasospasm. The
histopathology of myocardial necrosis is called coagulative
myocytolysis and is characterized by an excessive calcium
influx and early myocyte calcification.2,35,36 Interestingly
in this study, we noted that nimodipine use was inversely
associated with ischemic-like ECG changes. Theoretically,
this could be explained by the vasodilating effects of
nimodipine on coronaries as well as on the cerebral arteries and/or by the inhibition of excessive calcium influx into
the myocytes.37 This, however, needs further evaluation for
confirmation.
Morphologic end-repolarization abnormalities were
observed less frequently among patients who were unconscious on admission. This could be explained by the need
for sedation, intubation, and mechanical ventilation in these
patients, which may have protected the heart by depressing the hemorrhage-induced sympathetic storm.38 This
supports previous findings demonstrating that sympathomimetic stimulation especially causes detectable changes in
the ECG during end-repolarization.39
January 2013 • Volume 116 • Number 1
We demonstrated that ischemic-like ECG changes were
associated with a poorer 1-year functional outcome, which
supports the findings by Coghlan et al.,12 although the
patients studied had aneurysmatic SAHs with a shorter
follow-up time of 3 months. The results in the meta-analysis
performed by van der Bilt et al.4 from the same patient population also agree with ours. In some studies, cTnI elevation
has been reported to be associated with a poor outcome.4,40
In our study, cTnI was not related to a poor outcome; instead,
cTnI elevation was associated with ischemic-like ECG
changes. In summary, according to our study results with
only 1 cardiac-caused death, the myocardial injury and dysfunction after intracranial bleeding, presenting as ischemiclike ECG changes, are rarely fatal. Instead, as demonstrated
in our study, ischemic-like ECG changes are associated with
impaired functional outcome. Therefore, early detection
of these manifestations and evaluation of the need for supportive therapy are essential. The cardioprotective effects of
β-blockers have been demonstrated in SAH patients,41 which
is also theoretically reasonable for the catecholamine-induced
nature of cardiac manifestations. In practice, however, these
patients often need exogenous vasopressors for hypotension
or even inotropic drugs for cardiac failure,42 and the use of
β-blockers is questionable in these situations.
The main limitation of the present study was that only
patients with severe ICH requiring neurosurgical interventions or support of vital functions (e.g., mechanical
ventilation and hemodynamic support) were included in
the study. According to previous studies in patients with
SAH,30,43 these patients often have the most severe cardiovascular disorders, but one needs to be cautious when
extrapolating the results to a population with a less severe
ICH. Second, patients with impaired renal function were
included in the study, which may have affected the results
regarding cTnI elevation. The effects of the ECG findings
are, however, supposed to be minor, and troponin elevation
has been noted to be valuable in predicting cardiac events,
even in patients with renal failure.44 Third, the categorization of hemorrhages into 2 classes (SAH/IVHa and ICH/
IVHo) did not consider the effect of IVH on the outcome. It
was, however, tested in the logistic regression models as an
isolated dichotomous variable and did not achieve statistical significance. In addition, the sample size of this study
was quite small, and the categorization of patients into >2
groups was not reasonable. Last, there were some missing
data in this study, caused mainly by practical and logistical
reasons (4 patients died, 3 patients were withdrawn, and 7
patients were transferred to another hospital during days 0
to 5 after ICU admission).
www.anesthesia-analgesia.org 195
Repolarization in Subarachnoid and Intracerebral Hemorrhage
In conclusion, different repolarization abnormalities
were frequent in both the SAH/IVHa and ICH/IVHo groups,
without differences in the type and progression of these
abnormalities. The predisposing factors for QTc prolongation were female gender and the use of propofol, whereas
male gender predisposed ischemic-like ECG changes.
Morphologic end-repolarization abnormalities were predisposed by aneurysm rupture. In different repolarization
abnormalities, only ischemic-like ECG changes were associated with a poorer 1-year functional outcome. E
DISCLOSURES
Name: Eija Junttila, MD.
Contribution: This author helped design and conduct the
study, analyze the data, and write the manuscript.
Attestation: Eija Junttila has seen the original study data,
reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
Name: Maarika Vaara, MD.
Contribution: This author helped conduct the study and write
the manuscript.
Attestation: Maarika Vaara has seen the original study data,
reviewed the analysis of the data, and approved the final
manuscript.
Name: Juha Koskenkari, MD, PhD.
Contribution: This author helped design and conduct the
study, and write the manuscript.
Attestation: Juha Koskenkari has seen the original study data,
reviewed the analysis of the data, and approved the final
manuscript.
Name: Pasi Ohtonen, MSc.
Contribution: This author helped design the study, analyze the
data, and write the manuscript.
Attestation: Pasi Ohtonen has seen the original study data,
reviewed the analysis of the data, and approved the final
manuscript.
Name: Ari Karttunen, MD, PhD.
Contribution: This author helped analyze the data.
Attestation: Ari Karttunen has seen the original study data and
approved the final manuscript.
Name: Pekka Raatikainen, MD, PhD.
Contribution: This author helped design and conduct the
study, and write the manuscript.
Attestation: Pekka Raatikainen has seen the original study
data, reviewed the analysis of the data, and approved the final
manuscript.
Name: Tero Ala-Kokko, MD, PhD.
Contribution: This author helped design the study, conduct the
study, and write the manuscript.
Attestation: Tero Ala-Kokko has seen the original study data,
reviewed the analysis of the data, and approved the final manuscript.
This manuscript was handled by: Gregory J. Crosby, MD.
ACKNOWLEDGMENTS
The expert help of study nurse Sinikka Sälkiö in the collection
of data and Michael Spalding, MD, PhD, in language issues
was much appreciated.
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