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Cardiac and central vascular functional alterations in the
acute phase of Aneurysmal Subarachnoid Hemorrhage
John Papanikolaou1, Demosthenes Makris1, Dimitrios Karakitsos2, Theodosios
Saranteas3,
Andreas
Karabinis4,
Georgia
Kostopanagiotou3,
Epaminondas
Zakynthinos1
1
Department of Critical Care, School of Medicine, University of Thessaly, University
Hospital of Larissa, Thessaly, Greece
2
Department of Critical Care, General State Hospital of Athens, Athens, Greece
3
2nd Department of Anaesthesiology, School of Medicine, University of Athens, University
Hospital of Athens ‘Attikon’, Athens, Greece
4
Onassis Cardiac Surgery Centre, Athens, Greece
2
Materials and Methods
Outcomes
Neurological functional outcome was evaluated according to the Glasgow
Outcome Scale (GOS) at discharge from ICU (E1); GOS 1-3 (death or severe
dependence) was considered as poor neurological outcome (PNO) and GOS 4-5
(independence) as good outcome (E2).
Cardiovascular assessment – Ultrasound studies
Cardiac and vascular ultrasound examinations were performed by specialized
doctors (JP, MD, Cardiologist-Intensivist- University Hospital of Thessaly, Greece,
official
national
qualification,
six-year
experience
in
transthoracic
and
transesophageal echocardiography) and TS (MD, PhD, Anaesthesiologist-Intensivist,
anesthetic consultant, General State Hospital of Athens, Greece, accredited by the
European Society of Echocardiography). Ultrasound examinations were performed by
same investigators at each centre.Echocardiography was performed from the apical 4chamber view with an ultrasound device (Philips, XD11 XE, Andover, MA, U.S.A),
equipped with the tissue Doppler imaging program and a phased array multifrequency
transducer (E3). Echocardiographic studies were performed while patients were
sedated and mechanically ventilated (tidal volume 8ml/kg) on supine position.
Patients were euvolemic during examination based on clinical criteria and pulse
pressure
variation
(ΔPP)
monitoring,
as
previously
described
(E4-E5).
Transesophageael echocardiography (TEE) including transgastric views was used in
patients who were not applicable for transthoracic echocardiography (TTE) (mainly
due to poor acoustic window).
Two dimensional (2-D) images and Doppler echocardiographic signals were
recorded along with the electrocardiogram and respiratory cycle waveform at a sweep
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speed of 100 mm/s and were stored digitally in the hardware for later analysis. Offline echocardiographic analysis was carried out by an experienced cardiologist (EZ,
MD, PhD Cardiologist-Intensivist, professor of Critical Care Medicine of University
Hospital of Thessaly, accredited and awarded by the British Society of
Echocardiography) blinded to patients’ identity. Doppler echocardiographic variables
were measured at end-expiratory phase, and the average of 3 end-expiratory cycles
was used (E6).
LV 2-D analysis
The LV ejection fraction (LVEF) was measured using the Simpson’s biplane
method of disks (E3) and a LVEF≤50% was considered abnormal (E7). The American
Society of Echocardiography 16-segment model and regional wall motion score index
(WMSI) (E3) were used for the analysis of regional wall motion abnormalities
(RWMA). Each LV segment was graded as normal (score = 1), hypokinetic (score =
2), or akinetic/dyskinetic (score = 3), and WMSI was calculated by averaging the sum
of the 16 segments.
Doppler echocardiographic LV function assessment
Mitral inflow curves were recorded from the apical 4-chamber view, as
previously described [E3].The peak Doppler velocities of early (E) and late diastolic
flow (A), the E-wave deceleration time (DTE) and the E/A ratio were measured.
Several mitral inflow velocity variables (short DTE, increased E/A ratios) have been
reported to correlate well with advanced LV diastolic dysfunction and increased LV
filling pressures; this association has been outlined in patients with impaired LV
systolic function. However, in patients with normal LV systolic function mitral
variables are poorly associated with central hemodynamics (E6).
Tissue Doppler Imaging (TDI) myocardial velocities were obtained from the
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apical 4-chamber view, as suggested [E3, E6]. A 1.5-mm sample volume was placed
at the lateral corner of mitral annulus and peak systolic (Sm), early diastolic (Em) and
late diastolic (Am) velocities were recorded. Analysis was also performed for Em/Am
as well as for E/Em ratios. TDI variables also reflect LV diastolic function.
Accordingly, decreased Em velocities and Em/Am ratios are also associated with LV
diastolic dysfunction.
An increased E/Em ratio, which is a combined mitral inflow and TDI Doppler
index, has been reported to be a strong indicator of elevated LV filling pressures [E6],
even in mechanically ventilated patients (E8-E9). However, the clinical utility of TDI
signals (E/Em and Em/Am) in predicting LV diastolic dysfunction may be hampered
by several factors, such as young age, mitral regurgitation, mitral annular
calcification, structural myocardial or pericardial disease. Nevertheless, TDI variables
correlate better with LV filling pressures and invasive indices of LV stiffness than
mitral inflow variables (E-wave DT, E/A velocity ratio), as the latter are associated
poorly with central hemodynamics in patients with normal LV systolic function. [E6].
Peak systolic velocity (Sm) has been reported to correlate well and to be a
surrogate of LVEF (E10), especially in those patients with poor image quality, where
quantitative assessment of LVEF is technically difficult; it is also significantly
decreased in subendocardial ischemia as well as in diastolic heart failure even in
patients with normal LV ejection fraction (E11-E12).
Assessment of aortic stiffness
Aortic stiffness was assessed by determining the carotid-femoral PWV by
using transcutaneous Doppler flow recordings and the foot-to-foot method, as
previously described (E13). An Acuson Aspen (Siemens, Mountainview, CA, USA)
with a 7 to 10 MHz linear transducer was used for this purpose and the pulse wave
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sample gate was positioned at 1 to 2cm proximally to the bifurcation of the right
common carotid and the right femoral artery. Electrocardiogram (ECG) and Doppler
signals were recorded simultaneously at a sweep speed of 100mm/s. The R-wave on
ECG was used as a timing reference to determine the time intervals to the upstroke
(foot) of the Doppler waveforms. The time intervals were averaged over five cardiac
cycles for both carotid and femoral signals. The "carotid-femoral pulse transit time
(T)" was calculated by the subtraction of carotid from the femoral mean time interval.
The distance between the sternal notch and femoral artery scanning site was measured
by a tape measure and was used as the path length (D) travelled by the flow wave in
this above mentioned time interval T. PWV was calculated from D and T (PWV=
D/T) (E13). Echocardiography and vascular ultrasound were performed during the
same examination session for each individual subject.
PWV/LVEF ratio
PWV/LVEF ratio is a combined sonographic index we introduced to
incorporate both aortic stiffness and LV systolic dysfunction in the same parameter
(e.g. a patient with PWV=10m/sec and LVEF=0.5 has a PWV/LVEF ratio of
20m/sec).
Inter-observer reproducibility in ultrasound measurements
Reproducibility of measurements was evaluated in 10 randomly selected ICU
patients at each centre in a preliminary phase. We compared evaluations of different
echocardiographic items by two independent observers or by the same observer by
using both Bland-Altman analyses [%difference vs. average] and Pearson bivariate
two-tailed correlations. Interobserver variability [bias of agreement (95% limits of
agreement)] between two pairs of observers (EZ/TS and EZ/JP) in the two centers
were: for LV ejection fraction (LVEF), 0.35 (-19.4,20), r=0.94, P<0.001 and -0.43
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(-14.7,13.8), r=0.94, P<0.001, respectively; for pulsed-Doppler mitral inflow
velocities, -1.28 (-25,23), r=0.83, P<0.001 and 0.97 (-17.8,19.8), r=0.85, P<0.001; for
tissue Doppler Imaging (TDI) velocities at the lateral mitral annulus -4.7 (-26,17),
r=0.95, P<0.001 and -2.7 (-30,24.5), r=0.91, P<0.001, respectively. Interobserver
variability for aortic pulse wave velocity was 1.32 (-8.1, 10.7), r=0.94, P<0.001;
Intraobserver variability was overall -1.39 (-13.2,10.4), r=0.98, P< 0.001.
Results
There were no statistically significant differences between the two centres in
terms of baseline clinical data according to age (42.6±2.9 vs. 42.8±3.3, P=0.97),
female sex (57% vs. 69%, P=0.49), APACHE II score (20.5±0.9 vs. 20±1, P=0.72),
SOFA score (6.9±0.4 vs. 6.3±0.3, P=0.35) , aneurysm’s location (P=0.73-0.96), HuntHess grades>III(62% vs. 63%, P=1.0), Fisher CT grades>II (52% vs. 75%, P=0.19).
There were also no differences either in risk factors for ASAH, such as hypertension
(24% vs. 19%, P=0.72), smoking (52% vs. 31%, P=0.21) and alcohol abuse (10% vs.
19%, P=0.43), or in interventional therapies performed, such as surgical clipping
(33% vs. 50%, P=0.32), endovascular coiling (24% vs. 13%, P=0.4) and
decompressive craniectomy (67% vs. 63%, P=0.8). In addition, there were no
significant differences between the two centres according to ASAH outcomes, such as
intra-ICU death (29% vs. 25%, P=0.82), severe dependence (GOS 2-3) (30% vs. 50%,
P=0.19), and delayed cerebral infarctions (25% vs. 44%, P=0.25) at ICU discharge.
ECHO indices assessed in this study were similar between the two centers
(P=0.79), either measured during the acute ASAH (P level between 0.15-0.99) or at
stable state (P level between 0.17-0.91); the only exception was the measurements of
E-wave DT at stable stage, P=0.04.
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Cardiovascular ultrasonography and serum biomarkers in the acute phase of
ASAH
i) LV function
Among patients with LVEF≤50%, a) two patients (2/12, 17%) demonstrated
the classic phenotypic form of Tako Tsubo Cardiomyopathy (apical ballooning
syndrome) (E14), b) seven patients (7/12, 58%) manifested the apex-sparing pattern
of LV systolic dysfunction (where RWMAs were predominately observed at the basal
and mid-ventricular LV walls) (E7, E15), and c) three patients (3/12, 25%) showed
extensive LV circumferential dyskinesia-akinesia with a hyperkinetic apex and severe
mitral regurgitation (inverted Tako Tsubo Cardiomyopathy) (E16); these three
patients demonstrated severe hemodynamic compromise (fatal in one case, in which
post-mortem analysis revealed normal coronary arteries and no evidence of
myocarditis).
Left ventricular systolic function was found significantly impaired in ASAH
patients with more severe initial bleeding. LVEF and TDI-derived peak systolic
velocity (Sm) at the lateral border of the mitral annulus were significantly decreased
in patients with Hunt and Hess grading>III (53.1±2.92 vs. 63.57±2.67%, P=0.02 and
7.78±0.47 vs. 11.52±0.71cm/sec, P<0.001, respectively), as well as in patients with
Fisher grade>II (51.9±2.8 vs. 65.5±2.2%, P=0.002 and 8.19±0.6 vs. 10.84±0.7cm/sec,
P=0.008, respectively) compared to the remainders (Hunt and Hess grading≤ III,
Fisher grade≤ II, respectively). In addition, statistically significant differences
between the distribution of ruptured aneurysms in terms of baseline LVEF values
were found (ANOVA, P= 0.001); notably, ruptured aneurysms of the ACoA were
characterized by lower LVEFs comparing to patients with MCA (-14.2±4, P= 0.008)
or ACA (-24.1±7.3, P= 0.007) aneurysms (Bonferoni post hoc test). Finally, patients
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presenting impaired LV wall motion (WMSI>1) demonstrated higher SOFA scores
upon admission (7.64±0.5 vs. 6±0.27, P=0.003).
ii) Aortic stiffness
PWV values on admission were 8.1±0.37 m/sec. Twenty three patients (62%)
were found to present supra-normal PWV value compared to normal expected value
(E17). PWV was significantly associated with both Fisher and Hunt and Hess severity
grading. Patients with severe ASAH (Hunt-Hess grade>III or Fisher grade of >II)
presented higher PWV (8.76±0.44 vs. 7.14±0.57m/sec, P=0.03 and 8.7±0.43 vs.
7.23±0.61m/sec, P=0.05, respectively). PWV values were significantly different in
respect of the site of the ruptured aneurysm (ANOVA, P=0.017); patients with
anterior communicating artery aneurysms presented with depressed aortic elasticity
and significantly higher PWV (compared to patients with middle cerebral artery
aneurysms (2.1±0.72, P= 0.018, Bonferoni post hoc test). Finally, patients who
presented increased PWV values (N=23) demonstrated higher SOFA scores upon
admission (7.1±0.36 vs. 5.86±0.4, P=0.033).
Comments
BNP
In our cohort, BNP levels on admission correlated with LV systolic
dysfunction indices (LVEF, TDI-derived Sm and WMSI) and aortic stiffness (PWV
values) but not either with diastolic function surrogates (E/Em ratio) or the severity of
ASAH (Fisher scale). This might indicate that BNP at this stage is primarily of
cardiac than cerebral origin (E18). Another hypothesis may be that the trigger for
BNP cardiac production in acute ASAH is increased LV systolic wall stress (LV
afterload) due to acute aortic stiffening rather than elevated LV end-diastolic pressure
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(E19). BNP levels on admission were found to be related with ASAH outcome in our
series (E2, E20-21) (see Figure 4 on main text). Despite that BNP has been reported
to lack specificity in ICU, as it may be influenced by several clinical conditions,
particularly sepsis (E22), BNP>164pg/mL early after ASAH manifested a specificity
of 92% and a positive predicting value of 95% for predicting poor neurological
outcome.
PWV/LVEF index
In addition to established echocardiographic markers of ASAH outcome (such
as LVEF and WMSI) (E2, E23-24), our study introduces novel early ultrasound
indicators (PWV, Sm, Em/Am), which may possibly have a role in the prediction of
DCI or poor neurological functional status (Table 5). Furthermore, PWV/LVEF ratio
(a combined sonographic index we introduced in order to incorporate in the same
parameter both aortic stiffness and LV systolic dysfunction)>16.3m/sec manifested
the greatest diagnostic performance in predicting DCI (AUC=0.9) and positive
predictive value of 100% in predicting death or severe dependency.
Cardiovascular alterations and acute brain injury early in ASAH
There is increasing evidence that acute brain injury following aneurysm
rupture may significantly contribute to patient outcomes, by causing acute
development of cerebral edema, oxidative stress, inflammation, apoptosis, and
infarction (E25). Acute cardiovascular alterations and BNP over-secretion may reduce
cardiac output and plasma volume, impairing cerebral blood flow; however, whether
these changes are associated with DCI and neurological outcomes through the
pathway of the development of ASAH-induced acute brain injury or not remains to be
elucidated in the future.
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Supplemental Figure 1. Changes in left ventricular ejection fraction (LVEF) and
aortic pulse wave velocity (PWV) between acute ASAH and stable condition. In
order to view the Supplemental Figure 1, follow this link (Supplemental Digital
Content 2, http://links.lww.com/CCM/A318).