INTRODUCTION
Subarachnoid haemorrhage (SAH) is one of the devastating conditions, especially aneurysmal
bleed with high mortality as well as morbidity. The estimated incidence of aneurysmal
SAH is approximately 5–20/1 lac population.[1] The mortality and morbidity caused by SAH have been recognised to be caused by both
neurological and systemic causes. The alterations in systemic and other organ damage
could cause death in up to 40% of SAH patients.[2]
[3]
Cardiac, pulmonary, inflammatory and renal effects constitute the major extracranial
organ dysfunction in these patients.[4] This chapter specifically attempts to describe the cardiovascular manifestations
of aneurysmal SAH. The importance for anaesthesiologist lies in the differentiation
of secondary myocardial damage caused by SAH with the primary cardiac disease.
PATHOPHYSIOLOGY
The exact mechanism by which the systemic manifestations occur in SAH is unknown.
However, it has been postulated that acute SAH triggers widespread neuroendocrine
responses, inflammatory and immune-mediated mechanisms that are responsible for its
systemic actions including the myocardium and the blood vessels. Various neural and
humoral mechanisms have been implicated in the cardiac dysfunction in SAH. Immediately
following SAH, there is intense activation in the regions of hypothalamus, insula
and brain stem signifying activation of sympathetic nerve endings causing release
of norepinephrine.[5]
[6]
Blocking of cardiac sympathetic nerves has been found to reduce the cardiac injury
in animal experiments. In addition, it has been found that there are high levels of
circulating catecholamines in the blood of patients with cardiac damage indicating
the stimulation of adrenal medulla and the humoral mechanism of injury.[7]
[8]
The histopathology of myocardial necrosis is called coagulative myocytolysis and is
characterised by an excessive calcium influx and early myocyte calcification.[9]
[10] In addition, an influx of neutrophil granulocytes, lymphocytes and macrophages occurs
into the myocardium of patients who died after SAH. In some, this feature coincided
with myocytolysis and thrombi in intramyocardial arteries. This may pave the way for
a novel therapeutic option in the management like antithrombotic agents.[11]
INFLAMMATORY CASCADE
In addition to the above mechanisms, inflammatory cascade also has been postulated
in the development of cardiac injury caused by activation of the monocytes release
of inflammatory cytokines.
Neuroinflammation is another potential mechanism contributing to the injury to the
brain and heart in both acute and delayed phase of SAH. Various therapeutic modalities
are being tried to reduce the neuroinflammatory response.[12] Immediately following SAH, there is disruption of blood brain barrier and release
of blood in subarachnoid space. The red blood cells disintegrate to haemoglobin, haeme
and haemin. The haemin is considered to release redox-active iron which tilts the
balance between antioxidants (NADPH and glutathione) versus oxidants (superoxide,
liposomal peroxidation products). To remove the haemoglobin from subarachnoid space,
microglia cells are activated which attracts the neutrophils and macrophages from
blood vessels. The neutrophils and macrophages are recruited from the blood into the
subarachnoid space and get trapped in the subarachnoid space. Their activation as
well as death causes release of inflammatory mediators such as cytokines, complement
activation which are thought to be responsible for vasospasm and delayed cerebral
ischaemia (DIC), meningitis, etc. Interleukin 1 (IL-1), IL-6 and tumour necrosis factor
are released into both the serum and cerebrospinal fluid following SAH. The role of
cytokines is yet to be elucidated; the clinical signs such as neutrophilia, pyrexia
and general cerebral oedema are thought to be associated with the cytokine storm.
The magnitude of inflammation affects the outcome of the patients in SAH. In addition
to the local inflammatory reaction, the systemic inflammatory reactions to SAH have
been also thought to be contributing to the clinical features.
Following SAH, there is a decrease in parasympathetic outflow and increased sympathetic
activity caused by ischaemia to hypothalamus, temporal lobe and brain stem. This causes
myocardial and endothelial damage in peripheral blood vessels. The damaged myocardial
and endocardial cells also provoke the systemic inflammatory response, activation
of cytokines, complement system. This activation reaches the brain through blood vessels
and can further damage the brain causing ischaemic damage.
CLINICAL MANIFESTATIONS
The cardiac manifestations of SAH can be varied from asymptomatic to fulminant myocardial
damage, cardiac failure and sudden cardiac arrest. The true incidence of the various
cardiac anomalies in SAH is not known due to lack of appreciation of the cardiac dysfunction
in SAH patients, especially in mild forms, under-reporting, presence of coexisting
cardiac diseases with SAH and specific test used for diagnosing the myocardial damage
in SAH patients. The changes in the heart available in the literature in SAH patients
are described below.
Electrocardiographic changes
Electrocardiographic (ECG) changes are the most widely recognised and studied abnormalities
following SAH. ECG changes are seen in 25%–90% of SAH patients.[13]
[14]
[15] Burch et al. described the repolarization abnormalities seen in stroke and SAH as ‘cerebral T
waves’ as early as 1954.[16]
ECG changes are usually seen in the acute stage of SAH and resolve within 6 weeks.
The ECG changes can be either repolarization abnormalities or ischaemic changes. In
addition, rhythm and conduction disturbances also may occur alone or coexist with
other ECG changes. Majority of the rhythm changes are benign and include sinus bradycardia
or sinus tachycardia. Atrial fibrillation, ventricular ectopics, junctional rhythm
have also been reported to occur in SAH patients.[17] Predisposing factors for arrhythmia occurrence include female gender, QTc prolongation;
myocardial damage caused by excessive sympathetic discharge, coronary vasospasm and
electrolyte disturbances, pre-existing hypertension, etc.
Repolarization abnormalities are the most common ECG alterations described in patients
with SAH. The common abnormalities seen are prolongation of the QT interval, changes
in the ST segment and T wave morphology. The aetiology has been thought to be increased
sympathetic activity and most likely due to right insular injury.[18]
Even though wide variety of ECG ischaemic changes such as ST segment elevation or
inversion, pathological Q waves, T inversion, U waves are seen in SAH patients, the
presence of either inverted T waves or severe QTc segment prolongation on any ECG
change was associated with 100% sensitivity and 81% specificity for left ventricular
(LV) dysfunction determined as regional wall motion abnormalities (RWMAs) in echocardiography.
Borderline creatine kinase-MB elevation (≥2%) was associated with a similar high degree
of sensitivity (100%) and specificity (94%).[19] In another series of SAH patients, Junttila et al. found that heart rate increased, PQ and QRS interval decreased and was associated
with QTc prolongation in 91% SAH patients. Repolarization abnormalities were associated
with female gender and propofol use whereas ischaemic ECG changes were seen in male
gender. Both repolarization and ischaemic changes were associated with aneurysmal
bleeding, increase in cardiac troponin I (cTnI). Ischaemic changes were associated
with global LV dysfunction, whereas in repolarization changes, LV function was in
the normal range. Repolarization abnormalities were not seen in low Glasgow Coma Scale
patients who were intubated and sedated in their series indicating the sympathoadrenal
mechanism of ECG changes. The ischaemic changes were associated with poor outcome
whereas the repolarization abnormalities were not.[20]
In a study of the follow-up of IHAST trial, the admission ECG changes in the pre-operative
period with SAH were analysed for correlation of ECG changes with the outcome. The
analysis found that ECG changes were seen in 80% of SAH patients at admission. The
most common abnormality seen in ECG was non-specific ST/T-wave changes (NSSTTWA),
followed by ST elevation, T-wave inversion and ST depression. ECG abnormalities were
most commonly observed in the anterior leads. There was no correlation between ECG
changes and World ferderation of Neurosurgical Society (WFNS) score as well as Fisher
grade of SAH severity. The study showed that pre-operative bradycardia (heart rate
60 beats/min), relative tachycardia (heart rate 80 beats/min) and NSSTTWA were associated
with increased mortality in patients with SAH treated with surgical aneurysm clipping.
The researchers have suggested compared to pre-operative clinical status; ECG changes
may have more prognostication value in 1-year outcome of SAH patients. In addition,
they found that pre-operative NSSTTWA, relative tachycardia and a prolonged QTc interval
identified patients who would have haemodynamic instability, need for vasopressors
during their hospital stay.[21] In addition to the effects of ECG on cardiac function, abnormal Q or QS wave and
NSSTTWA were independently associated with neurogenic pulmonary oedema (NPE). Their
finding shows that NPE may be the result of myocardial injury caused by excessive
sympathetic stimulation.[22] Majority of ECG changes occurred within 24 h, especially ischaemic changes representing
the myocardial injury. The QTc prolongation can be delayed up to 48 h.[21]
In a study trying to correlate ECG changes with DIC, no association was found between
ECG changes and the incidence of DCI.[23] However, a recent study from the CONSCIOUS-1 trial has shown that QTc prolongation
and sinus tachycardia were associated with increased incidence of vasospasm.[24]
Echocardiographic changes
Echocardiography is a major diagnostic tool in patients with aneurysmal SAH in assessing
the cardiac function and has been studied more elaborately. Changes in cardiac function
due to SAH using echocardiography have been well recognised. Echocardiography may
show features of global or regional systolic dysfunction, diastolic dysfunction. There
can be fallen in stroke volume and cardiac output. The incidence of impaired LV function
in the form of either RWMAs or globally impaired contractility by echocardiography
ranged from 8% to 50%.[25]
[26]
In a small series of SAH patients, ECG changes were seen in 48% of patients whereas
echo evidence of RWMA was found in 9%. All the patients with echo abnormality had
ECG changes of ischaemia. The echo changes correlated with the SAH severity grade
whereas no such correlation was found with respect to ECG changes. Moreover, the researchers
have found that echo changes were seen predominantly in anterior circulation aneurysms
whereas ECG changes were seen more in posterior circulation aneurysms.[27]
RWMA was seen to occur within 1–2 days of SAH and gradually improves over time. Majority
of patients with RWMA following SAH have normal coronaries. Pre-operative comorbidities
such as hypertension, old age, diabetes mellitus and hyperlipidaemia were not associated
with risk of RWMA whereas poor Hunt-Hess classification, elevated cTnI >1.0 μg/L,
has been found to be a strong predictor of RWMA.[28]
RWMA has been found to occur at either admission or later during hospitalization.
Abnormal findings on admission ECG (sinus tachycardia, ST-segment elevation or ST-segment
depression) and positive troponin T are risk factors for early RWMA, and a myocardial
infarction (MI) pattern on the admission ECG and positive troponin T also predicts
late RWMA.[29] Studies have shown that the RWMA is seen in the apical segments whereas the basal
segments were hyperkinetic. Most of the RWMA also occurs in the anterior or anteroseptal
area. However, some studies have shown that RWMA does not correspond to a particular
coronary artery territory. RWMA has been associated with poor outcome including DIC
and death. Patients with apical RWMAs had more risk of DCI, whereas mid-ventricular
WMAs were associated with death. This finding might be explained by an impaired cardiac
output in combination with disturbed cerebral autoregulation after aneurysmal SAH.[30] In another study, the same group has found that patient with LV dysfunction had
lower cerebral blood flow compared to those without LV dysfunction.[31]
In addition to the global and regional systolic function, the right ventricular function
may be impaired in SAH patients. Diastolic function is also affected. Impaired diastolic
function was seen in 71% of SAH patients and was associated with the development of
pulmonary oedema and elevated troponin T levels. Diastolic dysfunction can impair
the fluid management in these patients.[32]
Neurogenic stunned myocardium and stress-induced (Takotsubo) cardiomyopathy Besides
the ECG changes and RWMA, extensive myocardial injury following SAH can present as
severely depressed global cardiac, especially LV function. The condition is described
as neurogenic stunned myocardium (NSM). The condition is considered as fully reversible,
occurring within 24 h of SAH and gradual recovery as early as 48 h to 7 days. Recent
terminology for NSM is ‘stress-related cardiomyopathy syndromes’.[33]
In addition, the patient may present as stress-induced cardiomyopathy or takotsubo
cardiomyopathy (TC). The proposed diagnostic criteria for NSM are as follows:[34]
-
Acute structural or functional brain disorder
-
New onset of systolic and/or diastolic LV dysfunction. Systolic dysfunction can include
RWMA and/or global wall-motion abnormality. RWMAs should be extending beyond a single
epicardial vascular distribution
-
Partial or complete resolution of LV dysfunction in 4 weeks
-
At least one of the following:
-
No history of congestive heart failure, LV dysfunction or coronary artery disease
-
No evidence of myocardial ischaemia on myocardial perfusion scan
-
Absence of angiographic evidence of obstructive coronary disease or of acute plaque
rupture.
The risk factors for NSM development include Hess and Hunt SAH grade of >3, old age,
history of smoking. Other factors were not found to be significant in the development
of NSM. Variations in NSM can also occur in SAH which consists of:[33]
-
Apical and mid-ventricular LV dysfunction (TC)
-
Isolated mid-ventricular and basal LV dysfunction/isolated mid-ventricular LV dysfunction
(apical-sparing TC)
-
Isolated basal LV dysfunction
-
Global LV hypokinesia
-
Other non-coronary distribution wall motion abnormalities.
TC or broken heart syndrome is a severe form of myocardial injury following SAH. It
is described in post-menopausal women and with a variety of stress such as surgery,
SAH, head injury and emotional stress. The clinical presentation resembles that of
acute coronary syndrome (ACS) like chest pain, ischaemic changes in ECG and elevation
of cardiac enzymes. The characteristic echo findings are apical ballooning with RWMA
of apical and mid-segments, hyper contracting basal regions.
Mayo Clinic has proposed diagnostic criteria for TC in 2004, which have been modified
recently:[35] (1) transient hypokinesis, akinesis or dyskinesis in the LV mid-segments with or
without apical involvement; RWMAs that extend beyond a single epicardial vascular
distribution; and frequently, but not always, a stressful trigger; (2) the absence
of obstructive coronary disease or angiographic evidence of acute plaque rupture;
(3) new ECG abnormalities (ST-segment elevation and/or T-wave inversion) or modest
elevation in cTn; and (4) the absence of pheochromocytoma and myocarditis.
Takotsubo cardiomyopathy must be differentiated from ACS. Elevation of cTnI levels
in TC are not as high as ACS and there is relative sparing of basal regions and angiographically
normal coronary arteries compared to ACS. TC needs to be differentiated from NSM.
TC presents with features of chest pain, ECG shows ST elevation whereas NSM presents
with heart failure, T wave inversion and no ST changes are seen in ECG. Most TC patients
present with the typical apical ballooning due to mid-ventricular and apical a/dyskinesia
with hypercontractile basal segments while NS patients showed hypo/akinesia affecting
predominantly the basal and mid-ventricular segments. Cardiac enzyme levels were elevated
similarly. However, TC represents transmural ischaemia and is more severe than NSM
which causes subendocardial ischaemia.[36]
Cardiac enzymes elevation
Approximately 30%–50% of SAH patients who reach the hospital alive die and another
10%–20% remain dependent on help for daily activities. It is of paramount importance
to differentiate the myocardial dysfunction from NSM following SAH. Bulsara et al. retrospectively analysed the SAH patients admitted to their hospital from 1995 to
2000 using ECG, echocardiography, creatine phosphokinase (CPK)-MB and cTn. They found
that the NSM occurred in more severe grades of SAH. The CPK-MB and ECG did not correlate
with NSM. The cTnI increased within 12 h, peaked within 48 h and returned to normal
in 7–10 days. cTnI is a regulatory protein which is highly specific for cardiac muscle.
It is considered to be a reliable marker of myocardial injury leading to LV dysfunction.
A raised cTnI concentration is a marker of poor prognosis in patients with unstable
cardiac ischaemia and in patients with septic shock. To differentiate MI from SM following
SAH, the authors suggested the following criteria; based on our findings, we propose
the following criteria to differentiate acute MI from reversible SM associated with
aneurysmal SAH: (1) No history of cardiac problems; (2) new onset of abnormal cardiac
function (ejection fraction [EF] - 40%); (3) cardiac wall motion abnormalities on
echocardiogram that do not correlate with the coronary vascular distribution noted
on ECGs; and (4) cTn values <2.8 ng/ml in patients with an EF <40% (>2.8 ng/ml strongly
suggestive of MI).[37]
Studies have shown that in 30%–40% of patients with SAH, increased concentrations
of cTnI were seen on admission. Increased cTnI proved to be a highly sensitive and
specific marker for cardiac dysfunction in patients with SAH too.[38] Studies assessing the level of cTnI on the prognostication have shown variable levels.
This is due to the fact the cut-off level of the enzyme used for the assessment.[39] However, Schuiling et al. have found a cut-off level of cTnI of. 0.3 μg/L found to be significant for cardiac
dysfunction in SAH. The elevated enzyme level correlated with pulmonary oedema, disturbances
of pulmonary gas exchange, rhythm disturbances and an inadequate cardiac performance.
Patients with elevated enzymes also had a poor outcome. Moreover, the severity of
increase correlated with the severity of SAH.[40]
In a similar study, Tanabe et al. showed that cTnI levels of >1.3 ng/ml were associated RWMAs with a sensitivity of
76% and specificity of 91%. The anterior and anteroseptal areas were showing RWMA
and last for a week from the onset of SAH. This correlated with the decrease in the
level of cTnI. Moreover, the researchers have found that 79% of patients with levels
>0.1 ng/ml were associated with pulmonary congestion, diastolic dysfunction and elevated
LV filling pressures. A highly positive cTnI was associated with severity of neurologic
damage and longer intensive care unit stay, as well as evidence of global and regional
LV systolic dysfunction, although degrees of EF depression and wall motion abnormalities
were typically modest and transient. Mild increases in cTnI were associated with diastolic
dysfunction, and importantly, the occurrence of pulmonary congestion increased with
cTnI.[41]
Serum plasma B-type natriuretic peptide (BNP) is a global indicator of left cardiac
dysfunction. Stretch of cardiac myocytes is a potent stimulus for BNP secretion. BNP
levels have been shown to increase in conditions such as diastolic dysfunction and
acute heart failure. Serum BNP levels also have been shown to increase following SAH,
especially in NPE and myocardial dysfunction. The elevated levels are seen within
48 h of aneurysm rupture and last for 2–3 weeks. The average increase in serum levels
of the enzyme appears to be 2–3 times normal values. In a series of SAH patients,
80% of patients develop a BNP levels of >100 ng/L during the first 3 days (peak on
day 2) and lasted for 1 week.[42] The levels of BNP did not correlate with severity of SAH grade or can be used as
a prognostic of the mortality or DIC. The time course of change in the levels of BNP
along with cTnI gives a useful guide in the recovery of myocardial function. A cTnI
>89 ng/L on day 1 after onset of symptoms, a proBNP >2615 ng/L on day 2 after onset
of symptoms and a proBNP >1830 ng/L on day 3 after onset of symptoms had best values
for detection of myocardial injury following SAH, respectively, with a sensitivity
of 100% and specificity of 83%–91%.[43]
CLINICAL RELEVANCE FOR ANAESTHESIOLOGIST
Recognition of the presence of myocardial dysfunction is very important in the perioperative
and critical care management of aneurysmal SAH patients as it influences the outcome.
In addition, it is important to assess the severity of myocardial dysfunction which
helps in modifying treatment. This is usually accomplished with ECG, echocardiography
and cardiac enzymes monitoring. Since the dysfunction is reversible, early recognition
will help differentiate from ACS and prevent unnecessary further tests or coronary
bypass. In addition, it helps in timing for either intervention or surgery as the
NSM usually resolves in 10 days. In the presence of diastolic dysfunction or systolic
dysfunction or pulmonary oedema, it will be important to use intravenous fluids and
inotropes judiciously. There are limited studies or guidelines in the management of
these patients, and the management needs to be titrated individually.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
