Accepted Manuscript

The Extra-Cranial Consequences of Sub-Arachnoid Haemorrhage

Allan Hall, Roddy O’Kane

PII: S1878-8750(17)31743-6
DOI: 10.1016/j.wneu.2017.10.016
Reference: WNEU 6669

To appear in: World Neurosurgery

Received Date: 17 July 2017

Revised Date: 2 October 2017
Accepted Date: 4 October 2017

Please cite this article as: Hall A, O’Kane R, The Extra-Cranial Consequences of Sub-Arachnoid
Haemorrhage, World Neurosurgery (2017), doi: 10.1016/j.wneu.2017.10.016.

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 ACCEPTED MANUSCRIPT
The Extra-Cranial Consequences of Sub-Arachnoid Haemorrhage

Allan Hall, Roddy O’Kane

Subarachnoid haemorrhage is managed across the full spectrum of healthcare from clinical
diagnosis to management of the haemorrhage and associated complications. Knowledge of the
pathogenesis and pathophysiology of SAH is widely known however a full understanding of the
underlying molecular, cellular and circulatory dynamics has still to be achieved. Intracranial

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complications including delayed ischaemic neurological deficit (vasospasm), re-bleed and
hydrocephalus form the targets for initial management. However the extra-cranial consequences
including hypertension, hyponatremia and cardio-pulmonary abnormalities can frequently arise

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during the management phase and have shown to directly affect clinical outcome. Therefore regular
monitoring and early recognition of these extra-cranial consequences, including a standard set of

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admission investigations, is important in order to optimise clinical outcome, particularly when
management is out with the specialist tertiary environment. Furthermore the management of any
extra-cranial consequences should be undertaken in parallel with the intra-cranial consequences in

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order to both minimise the systemic effects and the exacerbation of the intra-cranial complications.
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Introduction
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The general incidence of sub-arachnoid haemorrhage (SAH) is 6-7 per 100,000 person-years.(1)(2) This
cohort of patients is managed across the full spectrum of healthcare from primary care through to tertiary
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care. Although the intra-cranial consequences of sub-arachnoid haemorrhage are broadly recognised, the
extra-cranial consequences, particularly outside of the specialist tertiary care environment, are generally less
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well understood. This review will provide an update on the pathophysiology of SAH, including the intra and
extra cranial consequences, with a particular focus on the extra-cranial consequences of SAH which may
help improve the management of these cohort of patients particularly when this management is out with the
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specialist tertiary care environment.

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Pathophysiology of Sub-arachnoid haemorrhage

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The fundamental pathology in SAH is the extravasation of blood within the central nervous system,
specifically the subarachnoid space. The cause of the initial haemorrhage can either be the result of a single
factor or multi-factorial. The main causes of SAH can be split into traumatic and spontaneous, with further
categorisation of spontaneous SAH including idiopathic peri-mesencephalic haemorrhage, berry aneurysm,
arteriovenous malformation and neoplastic-related (table 1).

The pathogenesis of SAH is the result of changes or alterations within three main central nervous system
(CNS) blood circulatory components: blood flow dynamics, blood constituents and blood vessel architecture.
A disruption or alteration in one or more of these components can lead to subarachnoid haemorrhage. All of
the known causes of SAH can be grouped into one or more of these three components. Many of the risk
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factors associated with aneurysmal development and rupture are widely appreciated such as smoking,
hypertension, increasing age and excess alcohol intake,(79) however the role of inflammation both as a
cause of aneurysm development and poorer outcome following rupture is becoming more apparent. Whilst
subarachnoid haemorrhage secondary to vasculitis is rare the implications of inflammation after SAH is
important. It has been shown that soon after SAH occurs inflammatory-modulation cells within the CNS such
as microglia and astrocytes recruit inflammatory cells which subsequently enter the sub-arachnoid space.
These trapped cells of the the peripheral circulation lead to release of inflammatory material which results in
a variety of potentially damaging events including vasoconstriction, meningitis and oedema.(61) Furthermore

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these events of inflammation have shown to be an independent risk factor for vasospasm.(62) Some studies
have looked at using the potential link between inflammation and poor outcome in patients with SAH. For
example, it has been shown that the level of CRP upon admission or shortly after SAH could help predict

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those patients with good grade SAH who are at increased risk of clinical deterioration.(60) There are still
several aspects of the pathophysiology of SAH that remain unclear however from the work undertaken to

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date it is likely that the pathophysiology will consist of different overlapping components, with each having a
varying contribution between patients.

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Intra-cranial consequences

The intra-cranial consequences of SAH are broadly recognised amongst clinicians which include seizures,
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hydrocephalus, vasospasm and re-bleed. Since the focus of this review is on the extra-cranial consequences
of SAH the intra-cranial consequences will only briefly be covered.
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Seizures
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Seizures are a well recognised consequence after sub-arachnoid haemorrhage. Seizures occur in up to 26%
of patients with subarachnoid haemorrhage, most of which occur within the first 24 hours.(3)(4)(5) The fact
that SAH-related seizures influence outcome makes the efficient management and prevention of these
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seizures important.(6)(7)(8)

Although it has been shown that the prophylactic use of some anti-epileptic drugs for SAH-related seizures
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improves the incidence (4-8%) of SAH-related seizures (4)(7), other anti-epileptic drugs have shown to
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worsen cognitive outcome at 3 months.(9) Furthermore a recent systematic review of case series and
randomised control trials found that routine use of anti-epileptic drugs did not appear to prevent seizures
after SAH.(13)

Therefore in order to address the controversy surrounding the use of prophylactic anti-convulsive medication
in patients with aneurysmal SAH work has been undertaken to identify those patients who are at increased
risk of seizure activity with the aim of improving the decision making process and thus improve the risk/
benefit ratio for patients. For example, it has been shown that a greater sub-arachnoid clot burden and larger
sub-dural haemotoma is associated with seizure occurrence following aneurysmal SAH.(10) Furthermore,
other factors such as a pro-inflammatory state (11) and cocaine use (12) have been associated with
increased risk of seizure activity.
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Given the conflicting evidence surrounding the benefits of the prophylactic use of anti-epileptic drugs in
patients with SAH-related seizures, it is not surprising that the use of such medications across different
institutions is varied. Further work is therefore needed in order to clarify the effectiveness of their use with
different studies producing more homogenous results.

Vasospasm / Delayed Ischaemic Neurological Deficit (DIND)

Vasospasm is one of the most devastating intracranial consequences of SAH. Vasospasm, although a
simplistic term to describe the complex underlying pathophysiology, is the result of macro and microvascular

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spasms within the intracranial cavity which normally occur between 5 and 14 days post haemorrhage. The
angiographic incidence of vasospasm between this period is reported to be between 70- 90%. (14)(15). The

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main complication of vasospasm is delayed cerebral ischaemia however vasospasm itself is not a necessary
condition for this to occur. (16)

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There are a number of theories for the underlying pathophysiology of vasospasm and the resulting delayed
cerebral ischaemia however one of the more promising theories is the reduction in expression of vasodilators
or the increase in expression of vasoconstrictors such as endothelin-1 and the associated stimulation of

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calcium. This along with imbalance of other factors such as cerebral blood flow and intracranial pressure
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contributes to the disturbance in cerebral auto-regulation and thus the onset of cerebral ischaemia (Figure
1). The potent vasoconstrictor property of calcium is currently used as a therapeutic target through the use of
the calcium antagonist nimodipine. Furthermore, increases in intracranial pressure along with decreases in
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cerebral blood flow, which are exacerbated by alterations in cerebral auto-regulation, are thought to lower
the threshold for vasospasm to occur. The main stay of treatment is fluid resuscitation which has shown to
increase CBF to areas of cerebral tissue most vulnerable to ischaemia. (76) This is then followed by more
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aggressive measures such as vasopressors. Given the underlying pathophysiology of vasospasm and
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subsequent delayed cerebral ischaemia remains ambiguous research into delineating the cellular and
molecular mediators involved is warranted in order to identify potential therapeutic targets
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Hydrocephalus

The development of hydrocephalus in patients with SAH is usually a direct result of the impairment of the
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cerebrospinal circulatory pathway and the resulting disturbance in the CSF circulatory dynamics. Patients
with acute hydrocephalus normally exhibit several signs and symptoms including a gradual reduction in
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conscious level following a period of alertness. However these signs and symptoms are not exclusive and
CT scanning should be used to diagnose hydrocephalus when clinically relevant. The treatment options can
be broadly categorised into a period of observation (24 hours), lumbar puncture and external drainage from a
catheter placed via a burr hole. The decision on which management option to take depends on several
factors including the stability of the patient and the underlying pathology (with the presence of a space-
occupying haematoma being a contraindication to lumbar puncture)(17).

Re-bleed
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Re-bleeding of a SAH has a direct effect on patient outcome with 80% of patients dying or remaining
disabled following a re-bleed.(18) Therefore preventing re-bleeding is of high priority in the management of
patients with SAH. As a result of randomised trials such as the International Subarachnoid Aneurysm Trial
(ISAT) endovascular coiling has shown benefit over surgical clipping, traditionally the gold standard(19).
However there is still uncertainty over some aspects of coiling including the length of time which patients
need to be followed up after coiling and whether a second procedure is needed for aneurysm necks that
have re-canalised by impaction of the coils.

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One of the highest risk factors for re-bleed is hypertension with a systolic blood pressure of >160 mmHg
associated with an increase of re-bleeding.(52) However the specific ranges of blood pressure management
in SAH patients remains unclear.

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Extra-cranial consequences

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The extra-cranial consequences of SAH range from derangements in sodium homeostasis to cardiac
abnormalities. Given the potential serious consequences of these extra-cranial or systemic events
recognition and appropriate management is of vital importance. Furthermore the fact that extra-cranial

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complications occur in more than half of patients with SAH and are an important contributor to poor outcome
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(20)(21) (grading scales which use extra-cranial complications provide a more accurate indication of
outcome following SAH then those which use neurological characteristics alone.) (22) the early recognition
and management of these complications is crucial in achieving the best outcome for patients. This includes
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knowledge of when each complication is most likely to arise during the post-hemorrhagic period. (Figure 2)

Fever
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Fever is closely related to increased mortality in patients with SAH and the presence of intra-ventricular
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haemorrhage along with older age proving to be independent predictors of fever developing in these patients
(23)(24). Other factors such as extravasated blood and hydrocephalus have shown no relation to fever. (31)
Current guidelines advise active temperature management however this is more from expert opinion rather
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than high grade evidence (25)(26). The use of parental diclofenac to decrease the fever burden on SAH
patients has been supported by a small randomised trial (27). Although good fever control was achieved
there was a decrease in blood pressure among most patients which subsequently led to a decline in cerebral
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tissue oxygenation which in turn had a worse outcome.

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However in order to optimise temperature control in patients with brain injury, and therefore reduce pyrexia-
induced secondary brain injury, an understanding of the thermoregulatory process is important. For example
one of the centres of thermoregulation, the medial pre-optic anterior hypothalamus, is influenced by several
mechanisms including multiple thermoreceptors, feed forward reflex pathways and feedback mechanisms,

as well as dendritic input from the third ventricle and endogenous signals from the cerebrospinal fluid. (28)
(29)
Other methods of temperature control in SAH patients with refractory pyrexia such as local cooling with neck
pads has shown encouraging results however despite reducing the temperature the effects were only
transient with patient’s temperature increasing again after 5 hours.
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The use of prophylactic fever control in patients with SAH, both through endovascular cooling devices and
normal interventions such as NSAIDs and cooling blankets, has been investigated. Whilst endovascular
cooling devices showed a reduction in fever burden, there was no significant difference in the long term, 6
month, follow up.(34) One factor which may have influenced this result was the infectious complications
experienced in the device group which highlights the potential risks of infection associated with such
strategies.(35)

The importance of fever control in patients with SAH is evident both in terms of the association with delayed

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cerebral ischaemia as well as the generally poor outcome (30)(32), therefore normothermia has been found
to be a reasonable therapeutic strategy following SAH.(33)

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Anaemia

Patients who are anaemic following SAH require careful consideration of their management since better

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outcome is associated with the absence of blood transfusion.(36) However the development of anaemia,
which is a common finding in patients following SAH, can exacerbate delayed cerebral ischaemia due to the
reduction in cerebral oxygen delivery. Therefore it is unsurprising that lower haemoglobin is associated with

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poorer outcome including a higher rate of cerebral infarction. (37)(38).
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However if clinicians are able to predict which patients are more likely to develop anaemia then quicker
interventions can be undertaken in order to improve outcome. For example, it has been shown that female
gender, lower baseline haematocrit level (<36%, haemoglobin under 12g/dl), poor clinical status and greater
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systemic inflammatory response are admission criteria which most likely predicts anaemia.(39) Since red
blood cell transfusion has been associated with poorer outcome and an increased risk of vasospasm any
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decision to transfuse SAH patients who are anaemic should not be undertaken lightly(40). Whilst transfusion
can be associated with improving brain tissue oxygenation there is no clear effect on cerebral metabolism.
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(41)(43) However further studies have demonstrated the potential benefit of transfusion in a certain sub-
group of SAH patient who are at increased risk of delayed cerebral ischaemia (42).
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One potential alternative to blood transfusion is the use of erythropoietin (EPO) however given the time of
onset of EPO its use would be limited unless it was given soon after admission to patients identified as
suitable candidates.
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It is clear from studies to date that transfusion in patients with subarachnoid haemorrhage may be beneficial
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in a certain sub-group of patients however these benefits must be weighed against the potential risks
including the possibility of an increased viscosity and impaired cerebral blood flow, as a result of the
increased haemoglobin, in the setting of vasospasm.

Hypertension

Hypertension following sub-arachnoid haemorrhage can be due to the initial treatment or as a direct result of
the SAH. Hypertension, along with hypervolaemia and haemodilution (triple-H therapy) is a widely used
medical therapy for combating vasospasm in patients with SAH. However when first line measures such as
fluid management do not work, vasopressors are often used to maintain adequate mean arterial pressure
and therefore minimise the occurrence of vasospasm, or help reverse it. Therefore patients developing
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hypertension is not necessarily seen as a negative consequence of the initial treatment of SAH since it is
often used as part of the triple-H therapeutic strategy for minimising vasospasm.

However induced hypertension does pose certain potential risks including re-bleed from the initial site,
rupture of a distant co-existing unsecured aneurysm, as well as detrimental physiological effects on cerebral
tissue itself during a time when certain cerebral auto-regulatory mechanisms may be impaired.

Therefore certain aspects of induced hypertension such as vasopressor induced hypertension in patients
who have coexisting un-ruptured and unprotected aneurysms warrants careful consideration. Despite the

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obvious risk of hypertension induced rupture of an unsecured aneurysm, it has been shown that any rupture
from small unprotected aneurysms is rare and that vasopressor induced hypertension therapy should not be

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withheld from these patients.(44)(45) Furthermore since hypertension leads to improvements in cerebral
blood flow and brain tissue oxygenation, as opposed to hypervolemia or haemodilution which have shown to
have detrimental effects on brain tissue oxygenation, it is understandable why withholding such therapy in

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the context of no consistent evidence is not recommended. (46)(47)

However, in patients with delayed cerebral ischaemia, some studies have found that hypertension has no

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significant effect on cerebral blood flow compared with control groups. (48)
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One of the more difficult aspects of managing patients with SAH is knowing the acceptable upper limits of
hypertension and the threshold for implementing blood pressure lowering treatments. Animal studies have
shown that AVP Va1 receptor inhibitors to reduce post-hemorrhagic systolic blood pressure results in the
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reduction of brain oedema, a subsequent reduction in mortality from 50% to 20%, and a better functional
outcome. (49) More recent human studies have shown that induced hypertension worsens neuro-
behaviourial outcome and that larger studies are required to determine what the optimum blood pressure
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management is, with focus on the thresholds required to achieve the best neurological outcome.(50)
Although the general consensus of preventing hypotension in patients with SAH is clear, expert opinion still
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varies as to how beneficial induced hypertension is on both intracranial circulatory dynamics and in turn
cerebral tissue itself. Further studies are required to investigate what the best ranges are for circulatory
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dynamics including systolic blood pressure which will optimise patient neurological outcome and provide
clinicians with a better guide which is evidence based.
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Hypotension
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The main complication of hypotension in patients with SAH is vasospasm. Therefore whilst there is no
current consensus on the range or thresholds for hypertension, the prevention of hypotension in these
patients is widely acknowledged with a cerebral perfusion pressure <70mmHg associated with metabolic
crisis and brain tissue hypoxia.(86)

Hypotension in patients with SAH can be caused by several factors including lack of fluid resuscitation,
disturbance of the hypothalamic-pituitary axis, and medication-induced. For example, the use of calcium
antagonist medication such as nimodipine, which forms a critical part of the initial therapy, can cause
hypotension, with intravenous route posing a greater risk than the oral route.(51) Therefore the oral route is
preferred, when possible, for this reason.
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Careful monitoring of patient’s blood pressure whilst on such medication is vitally important particularly
during the initial period and when vasospasm is most likely (day 5 - 14).
Patients with SAH who develop hypotension as a result of a calcium antagonist i.e. nimodipine are usually
managed by altering the dosage and frequency of the drug and ensuring adequate fluid resuscitation. For
example, the routine prescription of nimodipine for SAH patients can be altered from 60mg every four hours
to 30mg every two hours.

However although adequate fluid resuscitation and management is important, clinicians must recognise

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when fluid management alone is not adequate to manage hypotension and begin to consider adjunctive
measures such as vasopressors. Furthermore, due to the sodium and pulmonary oedema complications
which can arise in patients with SAH, continuing to use fluid resuscitation as the only management will likely

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exacerbate these conditions.

Finally, in addition to the intra-cranial consequences of hypotension such as vasospasm, the other important

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systemic effects of hypotension on other organs such as kidneys, liver and heart must also be acknowledge
since any such effects will have a cumulative effect on the neurological outcome of these patients and their
management.

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Hyperglycaemia

Hyperglycaemia is a common problem in patients with SAH occurring in 70-90% of patients. (53)
It has shown to both increase the risk of vasospasm (53) as well as poor outcome,(54) with aggressive
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glucose management associated with better neurological outcome. (55)

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Hyperglycaemia was initially thought to be due to insulin resistance, however it has been shown that
transient pancreatic beta cell dysfunction, particularly during the first week, also plays a role and that the
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resulting abnormalities in glucose metabolism are most likely due to a combination of the two. (57)
Furthermore hyperglycaemia in SAH patients, which can be a result of the stress response, has shown to
predict certain complications in these patients including the insertion of extra-ventricular drainage devices,
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but not ventriculo-peritoneal shunt placement. (56).

It has been shown that blood glucose levels on hospital admission are frequently high in patients following a
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SAH, however whether there is causality between elevated blood sugars on admission and poor clinical
outcome remains unclear.(58)
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Hyponatremia & Hypernatremia

Hyponatremia

Derangements in sodium levels is one of the main complications of subarachnoid haemorrhage with
hyponatremia the most common electrolyte abnormality to occur following SAH (59). The causes of
hyponatremia in SAH patients can be, in principle, divided in to syndrome of inappropriate antidiuretic
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hormone secretion (SIADH), cerebral salt wasting (CSW), acute ACTH/glucocorticoid deficiency, excess IV
fluids and diuretic therapy.

Recognition of SIADH and CSW, and the difference between them, is important since the management of
each is diametrically opposed, with fluid replacement required for CSW and fluid restriction required for
SIADH.
In order to differentiate these two syndromes, four investigations and/or measurements must be performed:
serum sodium and osmolality, urine sodium and osmolality, haematocrit/urea levels and urinary output. The

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results must be accurately interpreted as the difference in results can often be subtle. (table 2). In addition,
patient daily weights help to differentiate the two syndromes, with weight gain in SIADH and weight loss in
CSW.

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Once the cause of hyponatremia has been identified and if fluid replacement is required caution regarding
the rate of sodium replacement must be taken as increasing hyponatremia too quickly (> 1-2 mmol/L per

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hour or >12 within a 24 hour period) can cause central pontine myelinloysis. If fluid restriction is required to
correct the hyponatremia then caution must be taken to ensure the patient does not become hypovolemic
since this is associated with cerebral ischaemia and worse outcome.(63) Therefore, in general, every attempt

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should be made to keep patients at least euvolemic at all times.(64)
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Furthermore, as hyponatremia can often be transient expectant management should be considered,
particularly when the hyponatremia is mild and the patient is asymptomatic.
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Hypernatremia
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Hypernatremia is usually the result of excessive sodium replacement or fluid loss / dehydration. Patients with
SAH can develop diabetes insipidus for example from vasospasm-induced ischaemia of the hypothalamus
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from anterior communicating aneurysms. This results in excessive volumes of dilute urine. Diagnosis is
made using similar investigations and measurements undertaken to diagnosis SIADH and CSW which
usually shows increased serum osmolality and sodium, decreased urinary osmolality and increased urinary
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volumes. If diabetes insipidus is diagnosed then treatment is usually with half strength saline (0.45%), or 5%
dextrose if the hypernatremia is severe. Vasopressin analogue, DDAVP, can also be used in cases where
large volumes of dilute urine are produced with worsening hypernatremia. Care must be taken with the rate
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of correction of the hypernatremia in order to avoid complications such as seizures and cerebral oedema.
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Finally, although sodium abnormalities are common in patients with SAH a comprehensive assessment of
other potential causes (including a full history, clinical examination and medication review) should not be
overlooked which could exacerbate the derangements of sodium levels including thyroid, gastrointestinal and
renal causes.

Cardiac abnormalities

Patients with SAH can suffer from certain cardiac abnormalities including ECG changes, ranging from
arrhythmia to ST depression and elevation, and echocardiograph changes including wall motion
abnormalities. It has been shown that only wall motion abnormalities (WMA) are independent risk factors for
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clinical outcome(65) however ECG changes, troponin rises and sinus tachycardia are in turn independent
predictors of early WMA.(66)

Cardiac arrhythmias can develop in patients with subarachnoid haemorrhage which is thought to be due to
involvement of the autonomic cardiovascular centres.(67) Of these arrhythmias sinus tachycardia is the most
common and usually develop within 48 hours, with patients with pre-existing cardiac problems at increased
risk (68). Other ECG changes include QT prolongation and the associated severe ventricular arrhythmias
which can develop (69). Furthermore, prolonged elevation of heart rate (>95 beats per min for >12 hours) is

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associated with major adverse cardiopulmonary events and poor outcome in patients following SAH.(70)
Although ECG abnormalities have been linked to poorer outcome in patients with SAH, it is changes within
the cardiac muscle itself in the form of wall motion abnormalities that has shown to be an independent risk

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factor for clinical outcome.

Rises in Troponin can be a sign of underlying cardiac ischaemia in patients with SAH, however this must be

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interpreted as part of the overall clinical picture. Furthermore abnormal troponin levels have shown to be a
powerful predictor of cardiac and pulmonary complications, however were found to be of no additional
prognostic value for clinical outcome.(73)

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Finally, neurogenic stunned myocardium represents a triad of left ventricular dysfunction, ECG changes and
elevation in cardiac enzymes which is believed to be due to excess catecholamines resulting in cardiac
dysfunction.(71) This condition can mimic a myocardial infarction and poses significant therapeutic
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challenges particularly in the presence of vasospasm. However the prognosis of neurogenic stunned
myocardium is good provided it is recognised early with timely intervention.
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Cardiac complications of SAH are relatively common, particularly in those patients with pre-existing cardiac
problems. If early recognition and prompt management isn’t undertaken then these patients have the
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potential to deteriorate quickly with associated affects on intracranial circulation and thus neurological
outcome.
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Pulmonary oedema

Pulmonary oedema in patients with SAH can be split into two categories: neurogenic and cardiogenic.
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Neurogenic pulmonary oedema occurs in patients with SAH during the delayed phase with excessive realise
of catecholamines thought to be the principle cause, with nor-adrenaline thought to play a more active role
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than adrenaline. (72)(74) However overactivity of the sympathetic nerves which supply the lungs are also
thought to contribute to neurogenic pulmonary oedema.(77)

Pulmonary oedema (and pulmonary complications in general) play an important part in the neurological
outcome of patients with SAH since it predisposes patients to a higher incidence of symptomatic vasospasm.
(75) However the incidence of neurogenic pulmonary oedema is low with one study reporting only five out of
three hundred and five patients developing the complication.(78)

Cardiogenic pulmonary oedema usually occurs during the early phase and typically arises in patents with
pre-existing cardiac disease. However in addition to the usual causes of precipitated cardiac failure (fluid
overload, ischaemia, increasing age) neurogenic pulmonary odema can in turn cause cardiac failure due to
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the increase in the afterload generated. Therefore although each form of pulmonary oedema is described
here as having separate pathogenesis, overlap between the two can occur.

Furthermore cardiogenic pulmonary oedema becomes increasingly more likely in patients with vasospasm
who subsequently undergo hypertensive/hypervolemic therapy.

Venous thromboembolism (PE/DVT)

Venous thromboembolism (VTE) is a well reported finding in patients with SAH. Therefore ensuring patients

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are adequately protected against VTE without significantly increasing the risk of intra-cerebral bleeding is
important. Knowledge of the risk factors for VTE in patients with SAH will allow better tailoring of VTE
prophylaxis. DVT formation most commonly occurs during the first two weeks following sub- arachnoid

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haemorrhage, with peak incidence between day 5 and 9. (87) Given prophylactic agents such as

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low molecular weight heparin can increase the risk of intra-cerebral haemorrhage careful consideration of the
risks and benefits is important.(80)
Studies have shown that smoking, race (black race), sex (male), length of stay, co-agulopathy, neurological

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disorders, fluid and electrolyte disorders and congestive heart failure are significant risk factors for VTE. (81)
(82). Interestingly, one study showed that smokers who abruptly quit smoking were at an increased risk of
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developing DVT. (81)

Furthermore, in neurosurgical patients it has been shown that pharmacological prophylaxis within 24 - 48
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hours post surgery, reduces the occurrence of VTE without an increased risk of intracerebral haemorrhage.
(83)(84).
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From the studies undertaken to date it is clear that some form of VTE prophylaxis in patients with SAH
should be used. Whether this is mechanical, pharmacological or both will depend on the associated risk
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factors and clinical circumstances. Further, larger studies are required for risk stratification as well as
determining the optimum dosage of pharmacological prophylaxis in order to minimise the risk of VTE and
intra-cerebral haemorrhage as much as possible.
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Gastric Ulceration
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Patients with sub-arachnoid haemorrhage, and other acute intracranial conditions, are at increased risk of
developing gastric ulceration and subsequent haemorrhage due to an increase in acid secretion which is
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stimulated by stress-triggered vagal stimulation of the stomach, in addition to impairment of mucous

protection. (88) Furthermore a rise in ICP, which commonly occurs in SAH patients, is a well known
contributing factor to stress-ulceration. (89) This risk is potentiated by certain risk factors including co-
agulopathy, hypotension and mechanical ventilation. Despite the increased risk of gastric ulceration in these
cohort of patients there is currently a lack of high quality randomised controlled trials to adequately inform
clinical practice including whether the benefits of ulcer prophylaxis out ways the risks of complications such
as nosocomial pneumonia. (90) Therefore currently the use of ulcer prophylaxis should be based on several
factors including past medial history (previous ulceration, lung disease, infections, etc), severity of clinical
condition and medication.
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Nosocomial infections

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Nosocomial infections in SAH patients is a common complication and can directly affect functional outcome
and mortality. The most common nosocomial infections in subarachnoid patients are pneumonia, urinary

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tract infections, blood stream infections and meningitis, with pneumonia and blood stream infections
independently predicting poor outcome. (91)(92) Furthermore, in comparison with other neurosurgical
conditions the rates of nosocomial infections are most prevalent in SAH patients. (93)

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Pneumonia
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Pneumonia occurs in around 20% of patients following subarachnoid haemorrhage with an associated
increase risk in mortality. (94) The most common cause is bacteria in origin which is already a recognised
complication of aneurysmal subarachnoid haemorrhage. (95)(96) However aSAH-induced immuno-
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depression is thought to increase the risk of pneumonia particularly in high WFNS grade SAH in which
immuno-depression has shown to persist beyond day 3 post-haemorrhage. (97) This relatively new concept
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is thought to play a role in the development of pneumonia in patients following sub-arachnoid haemorrhage
in addition to the already established risk factors including ventilator-assisted breathing and dysphagia/
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aspiration.

Independent risk factors for developing pneumonia in aSAH include, age greater than 65 years, male sex,
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severity of SAH, pulmonary hypertension and cardiogenic pulmonary oedema. (98)

Pneumonia is a relatively common complication of SAH however optimum management can be achieved if
those patients at risk are identified as early as possible, including adequate infection control particularly
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during the first few days post-haemorrhage when immuno-depression is prevalent.

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Urinary Tract Infections

Urinary tract infections in SAH patients cause increased morbidity and mortality particularly in the elderly
population. In particular, patients with poor grade SAH in the intensive care setting are at higher risk of
catheter associated urinary tract infections. (99) Furthermore, UTIs have been found to be the most common
noscomial infection in patients with aSAH, with older age and female gender being the most potent
predictors of developing a UTI. (100). Thus interventions aimed at reducing the incidence of UTIs include
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early discontinuation of catheter, intermittent catheterisation, type of catheter material and immobilisation of
catheter tubing. (101)(102)(103) However care must be taken not to avoid using catheters when they are
required, particularly in sub-arachnoid haemorrhage patients where accurate fluid balance is important in
order to optimise patient neurological outcome. Therefore in SAH patients where accurate fluid balance is
important, particularly accurate measurements of fluid output, then optimisation of infection control including
sterile catheter technique and close monitoring for infection, including regular sampling of urine, appear
sensible measures to take in order to prevent UTIs from developing.

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Blood Stream Infections / Sepsis (including CVC infection)

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Blood stream infection / sepsis in SAH patients has shown to independently predict poor outcome. (92)
Sepsis in these cohort of patients can come from a variety of sources including, chest, urinary tract, heart (in

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the form of endocarditis, which can in turn cause mycotic aneurysms) as well as directly from CVC insertion.
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As with urinary tract infections, CVC infections have shown to be reduced by using sterile technique, choice
of catheter material and length of time in-situ.
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Severe sepsis caries a mortality rate of up to 50% and therefore all measures to minimise the development
of sepsis or urgently treat it should be implemented if at all possible. These range from early investigations at
the first signs of sepsis (from general blood cultures to specific investigations to in order to establish the
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underlying cause such as echocardiogram for endocarditis) to strict infection control. As with all cases of
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sepsis, however particularly in SAH patients where maintaining euvolemia is important, treatment should
involved early goal directed therapy with circulatory optimisation. This involves the initial use of fluid
resuscitation (20 ml/kg) followed by vasopressors for refractory hypotension and/or a rising lactate (> 4
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mmol/L). Therapy in these cases should be guided by haemodynamic factors including CVP and central
mixed venous oxygenation (aiming for >70%) as well as biochemical factors such as lactate and renal
function, with intervention at the earliest stages having significant short-term and long-term benefits. (104)
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Iatrogenic Complications

In addition to the extra cranial complications caused by the subarachnoid haemorrhage, complications can
also be caused by the therapeutic strategies used to manage the initial haemorrhage. Whilst this has already
been covered to some extent e.g. hypertension due to HHH therapy, the following other complications must
be appreciated.
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Vasopressors

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Vasopressors form part of the HHH therapy and are used in patients with sub-arachnoid haemorrhage who
develop vasospasm-induced delayed cerebral ischaemia despite optimal fluid therapy. Common

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vasopressors used in SAH patients include nor-adrenaline, dopamine, metaraminol and phenylephrine.
Since vasopressors cause vasoconstriction they in turn increase the systemic vascular resistance. However
despite the obvious effect of hypertension, and the benefit this has on hypotensive SAH patients, the use of

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vasopressors is not without risk or complication. For example, nor-epinephrine has shown, in certain cases,
to have the potential to worsen neurological function when used as part of the HHH therapy.(105) However
this should be balanced against the fact that nor-epinephrine along with dopamine and phenylephrine-
induced hypertension have resulted in

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clinician improvement in neurological deficit in 70%
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patients.(106)(107)(108). Furthermore, the potential harmful effects of vasopressor-induced hypertension on
co-existing unruptured, unprotected aneurysms has been investigated and found to be safe. (109)
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Finally, other potential complications including myocardial ischaemia and renal failure must be monitored for
whilst SAH patients are on vasopressors. This is usually managed by careful titration of the dosage as well
as careful selection of the type of vasopressor taking account of clinical condition and past medical history.
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One of the increasing areas of research is the use of inotropes in combination with vasodilators to try and
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overcome this potentially serious complication of the use of vasoconstrictors in isolation.

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Haemodilution-Induced Co-agulopathy
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One of the more serious iatrogenic complications in patients following SAH is haemodilution-induction
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coagulopathy. Since haemodilution is part of the HHH therapy the potential for co-agulopathy particularly in
patients with unprotected aneurysms must be appreciated since haemodilution strongly affects the dynamic
interactions of eyrthrocytes, platelets and clotting factors. (110-113) Furthermore it has been demonstrated
that the co-agulation system as well as the fibrinolytic system occurs early in the course of SAH. (114)

It is clear haemodilution has the potential to affect co-agulation therefore a full co-agulation screen should be
undertaken upon admission in SAH patients in order to detect any co-agulopathy as early as possible and
instigate correction. Therefore once HHH therapy is instigated, it would be prudent to undertake a
coagulation screen in the early stages of therapy, and certainly if there are any concerns based on clinical
assessment or from past medical history, since the potential complications for patients with unprotected
aneurysm could be serious.
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Conclusion

Although the intra-cranial complications of sub-arachnoid haemorrhage can take priority in the initial

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management (which should be guided by certain therapeutic recommendations, table 3) , the extra-cranial
complications should be monitored for and recognised as early as possible since these complications can
develop at varying times throughout the course of the condition. Therefore a variety of investigations should

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be undertaken upon admission to maximise early recognition of any of the extra-cranial consequences
(Figure 3). This will allow a baseline to be established from which subsequent measurements can be

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compared too in order to detect any deterioration quickly.

Furthermore, since the extra-cranial complications have a direct effect on clinical outcome and can lead to
and exacerbate the intra-cranial complications, monitoring, recognising and managing these complications in

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parallel with the intra-cranial complications is important and would allow optimisation of the patients
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management and thus help improve their overall outcome.
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Figure 1. The imbalance in cerebral dynamics.

Several factors which contribute to adequate cerebral circulatory dynamics and tissue metabolism and
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oxygenation are often unbalanced after subarachnoid haemorrhage which include the proportion of
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vasoconstrictor molecules against vasodilator molecules, cerebral blood flow and intracranial pressure. This
imbalance essentially results in a reduction in physiological reserve and poorer cerebral tissue oxygenation
and thus delayed ischaemic neurological deficit (DIND). Note, although vasospasm can lead to DIND it is not
necessary in order for DIND to occur (illustrated by the dotted red line).

Figure 2. Timing of when subarachnoid haemorrhage complications are most likely to occur.
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A knowledge of when the different complications are most likely to occur following sub-arachnoid
haemorrhage is extremely useful and important in order to monitor and detect these complications as early
as possible. However it is important to note that occasionally complications can arise out with the most likely
period, therefore careful monitoring should be adopted from the post-haemorrhage to discharge period. (X-
axis represents number of days post haemorrhage with the SAH occurring on day 0). Note, greater intensity
of colour represents higher likelihood of complication occurring at the corresponding time period.

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Figure 3. Recommendation of admission investigations in order to optimise monitoring of extra-
cranial complications.

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Certain investigations should be undertaken in all sub-arachnoid patients upon admission. By undertaking all
of these basic, non-invasive, investigations upon admission the complications associated with subarachnoid
haemorrhage, particularly the extra-cranial complications, will be detected earlier. Furthermore it will allow

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the clinician to establish a trend early on and therefore allow earlier recognition of any complications should
they develop at a later stage, which will allow earlier intervention and increase the chances of optimum
patient outcome

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Table 1. Causes of spontaneous sub-arachnoid haemorrhage
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Table 2. The important differentiation between SIADH and CSW.

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The biochemical differences between SIADH and CSW are often subtle and can lead to mis-management
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which is very important as the management of each is diametrically opposed. The main parameters for
diagnosis are sodium (both serum and urinary), osmolality (both serum and urinary), urinary output,
haematocrit and/or urea and daily weights.
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Table 3. Therapeutic recommendations in the management of aSAH

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An appreciation of the important factors in the management of patients with aSAH must be achieved in order
to maximise patient outcome. It is important to note that these recommendations are a guide and can be
altered depending on the clinical status of the patient, past medical history and medication at the time of
assessment.
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Spontaneous sub-arachnoid haemorrhage (SAH) Incidence
causes

Aneurysm 85%

Non-aneurysmal peri-mesencephalic haemorrhage 10%

Neoplasm
Angioma
Cortical thrombosis
Infection (meningitis, encephalitis) / mycotic aneurysm 5%
Vasculitis

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Moyamoya Syndrome
Fibromuscular dysplasia

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SIADH CSW

Serum sodium Decreased Decreased

Serum osmolality Decreased Increased

Urinary sodium Increased Increased

Urinary osmolality Increased Increased

Urinary output Normal or decreased Increased

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Haematocrit and/or Urea Decreased Increased

Patient daily weight Increased Decreased

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CVP 10 - 12 mmHg

SBP (no vasospasm , clinically intact) >120mmHg

SBP (vasospasm, clinical deficit) 120 - 150 mmHg for unclipped aneurysm
160 - 200 mmHg for clipped aneurysm

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Maintaining euvolemia - total daily input minus total daily output = 0 - 500 ml
- Urea 2-8 mmol/L

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- haematocrit 30 - 50%
- baseline of 0.9% sodium chloride, 125 mls per hour (NaCl strength and rate

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adjusted according to sodium level, daily input/output and haemodynamic
parameters)
Intubation Unprotected airway, GCS < 8

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Hunt & Hess Scale 4,5 (including some select scale 3 cases)

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Oxygen level 11 - 13 kPa (avoid levels >13 kPa)

Carbon dioxide level 4.5 - 5.0 kPa

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ICP < /= 25mmHg (> 25 mmHg for more than 30 minutes requires intervention)

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The Extra-Cranial Consequences of Sub-arachnoid Haemorrhage

Allan Hall, Roddy O’Kane

Highlights

• The timing of onset and how best to manage the extra-cranial consequences of SAH often
provides issues for clinicians particularly when out with the specialist tertiary care environment.

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• The extra-cranial complications of SAH can arise from immediately after the SAH to more than
one month post-haemorrhage.
• Knowledge of the timing of onset of each complication and how best to manage these is
extremely important since these complications can directly affect patient outcome.

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• A set of basic, non-invasive investigations, as described by this article, should be undertake for
every SAH patient upon admission in order to detect the extra-cranial complications as early as
possible and help establish a trend in order to optimize management and therefore patient outcome.

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Abbreviations

ACTH: Adrenocorticotropic hormone

aSAH: aneurysmal Sub-arachnoid haemorrhage

CNS: Central nervous system

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CRP: C-reactive protein

CSW: Cerebral salt wasting

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DDAVP: Desmopressin

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DIND: Delayed ischaemic neurological deficit

DVT: Deep venous thrombosis

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EPO: Erythropoietin
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ISAT: International sub-arachnoid aneurysm Trial

NSAID: Non-steroidal anti-inflammatory drug

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PE: Pulmonary embolism

SAH: Sub-arachnoid haemorrhage

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SIADH: Syndrome of inappropriate anti-diuretic hormone

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VTE: Venous thrombo-embolism

WMA: Wall (cardiac) motion abnormalities

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