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P. MICHEL
Physicians talking to the next of kin in acute settings have to be very cautious and inform them of the
potent ially severe and sometimes irreversible nature of the disease. The clinical and radiological state
at 24-48 hours is currently much more reliable for prognosticat ion than the early assessment. If
prognosis seems very poor at this point, a discussion about the patients wishes, intensity of
resuscitation, further diagnostic test, and nutritional support should be initialed with the next of kin.
Palliative care consultations may be obtained to help in decision making and to guarantee the patients
comfort.
56.7. Airways, oxygenation, and respiratory function
56.7.1. Overview and pathophysiotogy
A substantial number of patients experience hypoxem ia at some point during the acute phase of
stroke (Sulter et al., 2000). The ischemic penumbra with its decreased blood flow and increased
oxygen extraction is particularly sensitive to hypoxemia; infarct growth is one likely mechanism
worsening the neurological injury in hypoxemic patients.
Causes for hypoxemia are multiple: pre-existing lung and heart disease, decreased ventilatory drive,
generalized epileptic seizures, airway obstruction, card iac failure, and decreased pulmonary gas
exchange due to pneumonia, atelectasis, and pulmonary emboli. Patients with large hemispheric or
bilateral brainstem strokes are at highest risk for early broncho-aspiration (Smithard, 2002). Sleep
apnea and hypopnea is freq uent during the first night after cerebral infarction and is associated with
early neurological worsening (Iranzo et al., 2002; Bassetti et al., 2006).
Small randomized studies have not yet shown a benef it from routine oxygen supplementation
(Ronning and Guldvog, 1999), and trials randomizing patients with hypoxemia would be ethically
difficult to perform. The use of high flow (Nighoghossian et al., 1995) or hyperbar ic oxygen therapy
(Bennett et al., 2005) still lacks evid ence of efficacy in acute ischemic stroke patients.
56.7.2. Monitoring
Continuous monitoring with pulse oxymetry in the acute and sibacute stage of stroke will detect
hypoxem ia. Blood gas analysis or an expiratory pCO2 meas urement should be performed in patients
with signs of impaired respiratory functions or with severe stroke. In experimental settings,
intracerebral oxygen utilization may be measured by PET or estimated by MRI (Geisler et aL, 2006).
56.7.3. Management
Maintaining oxygen saturation above 92% is recomm ended (Adams Jr et al., 2003; Toni et al., 2004)
and can often be achieved by administration of 24 litres of 02/min via a nasal tube. In patients with
noct urnal oxygen desaturation due to obstructive sleep apnea, non-invasive continuous positive
airway press ure via a nasal or face mask might be used (Iranzo et al., 2002). Situations where
intubation may be cons idered are the patients inability to maintain suffic ient tissue oxygenation, the
need for sedation during intra-arterial procedures, the risk of bronchoa spiration, the preoperative
management of mass effect, and experimental hypothermia treatment. The prognosis of patients who
need endotracheal intubat ion is rather poor (Grotta et al., 1995; Steiner et a!., 1997). Therefore, rapid
assessment of the chances for recovery from respiratory compromise and stroke, and of the patients
will should be performed before intubation.
56.8. Temperature management, hyperthermia, and hypothermia
56.8.1. Overview and pathophysiology
Body temperature is increased in up to 50% of patients in the acute phase of stroke (Corbett and
Thornhill, 2000). The main causes may be the stroke itself, espec ially if it is severe (Boysen and
Christensen, 2001) and infections occurring before (Grau et al., 1995) or after stroke onset (Grau et
al., 1999). Stroke is rarely the cause of persistent fever however.
Fligh body temperature may favor stroke progression (Castillo, 1999) and a body temperature above
37.5 decreases the odds for a good outcome (Reith et al., 1996; Hajat et al., 2000). Experiments have
shown that fever increases infarct size (Fukuda et al., 1999), presumably due to decreased survival of
penumbral parenchyma.
56.8.2. Monitoring
Frequent measures of temperature with external devices is recommended, especially in the acute
phase. In cases of fever, a thorough search for frequent causes of infect ions (pneumonia, urinary
tract infections, phlebitis, sinusitis) and rarer causes (endocarditis, sepsis, abdomi nal or
retroperitoneal abscess, bed sores, prostatitis) should be undertaken. If hypothermia is induced
experim entally, continuous semi-invasive (esophageal, rectal) measurements should be used.
with dysphagia (see below), and occurs even if patients are not fed. Urinary tract infections are
also frequent in immobilized patients with indwelling catheters. Pressure sores, sinusitis from
nasogastric tubes, endocarditis, and sepsis from peripheral or central lines are other causes of
infect ions in stroke patients. Infections or post-infectious vasculopathy may be found in relation
to varicellaz oster virus, H1V infections, tuberculous and aspergili ns meningitis, and
neurosyphilis.
56.9.2. Monitoring
Measuring temperature, a full blood cell count, C-reactive protein, and occasionally the
sedimentation rate on admission identifies patients with early inflamm atory states. These tests
should be repeated if fever or fluctuation of the neurological status is observed. Appropriate
tests in search of sources of infections should be performed. If no infectious source for a systemic
inflammation is found, tests for systemic vasculitis (such as giant cell arteritis, systemic lupus
erythematosus, Takayasus arteritis or Cogans synd rome) and endocarditis should be
performed.
56.9.3. Management
If no cause for persistent fever and inflammation is found after a thorough seareh, recurrent
bronchoaspirat ion, pulmonary emboli, and systemic vasculitis may be suspected and treated. The
choice of antibiotic depends on the sitewhether the infections were acquired at home or in
hospitaland on possible local resistance pattern and side-effects. A randomized trial of routine
use of antibiotics during the first days after stroke has not shown a benefit (Chamorro et a!.,
2005). There is no convincing evidence to date for a clinical effect of anti- inflammatory dnigs
such as high-dose aspirin (Dutch hA Trial Study Group, 1991) or statins (Montaner et al., 2004) in
acute stroke patients.
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P. MICHEL
mechanisms for this observation are not well understood, several factors may be involved such as
activation of neuro-endocrine systems (coiticotrophic, sympathetic, reninangiotensin), increase in
cardiac output, high blood pressure secondary to increased intracranial pressure (Cushing reflex),
pain, and uiinary retention (Carlberg et aL, 1991). Cardiac baroieceptor sensitivity is impaired after
acute stroke and may explain increased blood press ure variability (Robinson et al., 1997). It also
appears that persistent cerebral arterial occlusion contributes to persistent elevation of blood pressure
in acute stroke patients (Mattle et al., 2005).
Cerebral blood flow (CBF) autoregulation is freq uently defective in an area of evolving
infarction (Eames et al., 2002). This leads to a direct dependency on the mean arterial pressure
(MAP) of blood flow in the isehemic tissue. Maintenance of CBF above the infarction threshold
is facilitated by high blood press ure. A drop of blood pressure and therefore of flow below
critical thresholds in the penumbra zone may explain the relationship between low blood
pressure at hospital admission and stroke progression (Dvalos et al., 1990; Powers, 1993;
Jorgensen et al., 1994) and bad outcome (Ahmed et al., 2000; Leonardi-Bee et al., 2002a;
Wilimot et al., 2004). In addition to poor autoregulation of blood flow in ischemic areas, many
stroke patients are chronically hypertensive and their brain autoregulatory curve is shifted to the
right. Therefore hypertensive stroke patients may bett er tolerate higher blood pressure levels.
Blood press ure decreases spontaneously and gradually in most hypertensive stroke patients
after the first hours and days (Britton et al., 1986; Broderick et al., 1993), which may partially
be explained by (spontaneous) recanalization (Mattle et al., 2005).
The relationship between blood pressure during the acute phase and prognosis is a U-shaped
curve (Leonardi-Bee et al., 2002a; Bath, 2004; Willmot et al., 2004). High blood pressure in
ischemic stroke appears to be associated with early recurrence and cereb ral edema (Hatashita et
al., 1986; Leonardi-Bee et al., 2002a). It remains controversial whether hemorrhagic
transformation of the infarct is also facilitated by persist ent hypertension in non-thrombolyzed
patients (Bowes et al., 1996; Leonardi-Bee et al., 2002a). In spontaneous intracerebral
hemorrhage, however, it is more evident that elevated blood pressure promotes hematoma
growth (Aralcawa et al., 1998).
Treatment of extremely high blood pressure is indic ated because this puts not only the brain but
also the heart and kidneys at risk. Nonetheless, if blood pressure is lowered in unselected
hypertensive patients in the acute phase, early neurological deterioration, increased infarct
volume, and poorer outcome at 3 months have
been described, especially if systolic blood pressure reduction is more than 20 mmHg (Castillo et
aL, 2004). Rapid fall of blood pressure induced by niniodipine explained the bad outcome in the
Intravenous Nimodip ine West European Stroke Trial (Ahmed et al., 2000). A randomized
controlled study using oral candesartan during the first 7 days after ischemic stroke has shown
good tolerability and a decrease of cardiovascular events over the following 12 months (Schrader
et al., 2003). The mechanisms of this observation was questioned, because no significant lowering
of peripheral blood pressure was observed, effects on the outcome of the stroke were not described,
and an effect produced weeks and months after the treatment on other organs seems unlikely
(Michel and Bogousslavsky, 2003).
More aggressive blood pressure treatment is indic ated in patients undergoing thrombolysis or
having particular concomitant medical conditions. Because of the above-mentioned risk of early
rebleeding, blood pressure should also be treated more aggressively in hypertensive patients
with spontaneous intracerebral hemorrhage and subarachnoid hemorrhage.
56.10.2. Monitoring
Blood pressure can usually be measured with suffic ient precision with an arm cuff adapted to the
patients arm circumference. It should be compared between both arias at least once in the acute
phase; a difference may suggest stenosis of subclavian or axilary arteries in relation to dissections
of aortic aneurysms, with severe atherosclerosis, or rarely arteritis. Intra-arterial blood pressure
monitoring may occasionally be required in patients with very high blood pressure resisting initial
treatment, with requirements for aggressive intravenous blood pressure-lowering, and with
concomitant acute medical conditions.
If measured non-invasively, the frequency of blood pressure measurements should initially be every
35 minutes. if the patient and the blood pressure remain stable, the frequency can be decreased to
every 1530 nun. Specific recommendations are available for blood pressure-monitoring during
thrombolysis (Brott et al, 1998; Adams Jr et al., 2003).
The ideal target blood pressure may be quite variable from one acute stroke patient to the other.
Continuous monitoring of cerebral tissue perfusion at the bedside could potentially help in finding
the best blood pressure and cardiac output for an individual situation. Tissue harmonic imaging by
transcranial Doppler (Seidel et al., 2004) or repeat perfusion imag ing by MRI or perfusion-CT may
become useful for this in the future.
doses of 550 mg/hour (Toni et al., 2004) seems to be suitable as it increases cardiac output without
substantially affecting heart rate or blood pressure. Dopamine may be particularly useful in patients with
hypotension or renal insufficiency. Positioning of the body in a horizontal or even in a head down
(Trendel enburg) position may increase regional cerebral blood flow iii vasoactively impaired tissue
(Novak et al., 2003; Diserens et al., 2006) and may be useful during periods of hypotension.
Drug-induced hypertension in patients with acute stroke may be of particular value in the very acute
phase where the proportion of penumbra tissue is highe st, and in patients with clinical worsening due to
pers istent arterial occlusion or locally low flow. It may however increase the risk of brain edema,
hemorrhagic transfonnation, cardiac ischemia or arrhythmias. The intervention also requires quite
intensive close monit oring. Drugs that have been used for this purpose include intravenous
phenylephrine, epinephrine, norep inephrme, and oral midodrine (Rordorf et al., 2001; Hillis et al.,
2003; Marzan et al., 2004). These trials have shown that this intervention is feasible and safe
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P. MICHEL
as long as hypertension remains moderate. In a random ized pilot study, Hillis et al. (2003) found that druginduced hypertension can improve blood flow in ischemic tissue and lessen the neurological conseq uences of
stroke. Before data from several larger, randomized trials are available, drug treatment of patients with low
blood pressure in the acute stroke phase has to be individualized.
56.11.2. Monitoring
In most patients, fluid balance does not need to be measured, but hydration status can be estimated clinic ally
from vital signs, cardiorespiratory examination, dryness of mucosae, and an estimation of urinary outp ut. In
patients who have manifest volume deficiency or overload or who are at risk for it (see above), measuring input
and output using a urinary catheter, and measuring central venous pressure may be necess aiy. The latter should
be maintained at approximately 810 cm H20. Monitoring of electrolytes should be adapted to initial
abnormalities, stroke severity, and concomitant medical conditions. When major correct ions of fluids and
electrolytes are required, continuous clinical and ECG monitoring must be available.
56.11.3. Management
Peripheral venous access is sufficient for initial fluid management in most patients. There is no consensus of
whether the access should preferably be on the paretic or on the other side. A central venous catheter is indicated
in case of infusion of larger volumes of fluids, high osmolality solutions or irritant substances, or in unstable
patients. It also allows measures of central venous press ure (Toni et a!., 2004). In a euvolemic patient with no
other specific conditions, initial intravenous isotonic sali ne or Ringers solution should be given at
approximately 25 ml per kg per 24 hours. Reasons to increase or decrease this rate are mentioned in the above
paragraph.
The usual cause for hypovolemia with hyperosmolali ty is insufficient hydration of a patient with increased
demands, often pneumonia and fever. The free water deficit can be calculated in this situation, and the patient
may transiently receive glucose-free hypotonic solut ion to correct it. Normo-osmolar hypovolemia due to
insufficient hydration or sepsis should be treated with a high rate infusion or repeat boluses of isotonic fluids.
Hyperosmolar hypovolemia may be related to dehyd ration. If cerebral salt wasting syndrome is the cause of
hypovolemia (which is usually hypo-osmolar), increases in input volume and sodium loading are required.
Hypervolemia from cardiac failure requires salt and fluid restriction. Diuretics given as boluses or continuous
The pathogenesis of hyperglycemia in patients without diabetes is incompletely understood. Based on the
correlation between the severity of stroke, glyc emic serum levels (Candelise et al., 1985; Jorgensen et al., 1994)
and the elevation of hormones such as cortisol (Mitchell and Kirckpatrick, 1997), a stress response is likely. The
latter may be further enhanced by concomitant cardiac disease, aspiration pneumonia, or other infections. Most
often these patients do actua lly have some degree of insulin resistance and impaired in,sulin secretion, which
explains why they are not able to maintain nonnoglycemia during the stress response. Moreover, it can be seen
as a prediab etic stage with an increased risk of overt diabetes in the future. This risk can however be reduced
effic iently by medical and lifestyle interventions. Hypog lycemia may be caused by advanced liver disease,
insulin secretagogues, long-acting insulin preparations, malnutrition, and more rarely by endocrine
diseases like adrenal insufficiency or insulinoma.
Hypoglycemia can rarely mimic an acute ischemic infarction (Huff, 2002). Alterations in behavior,
wors ening neurological deficits, and decreased levels of consciousness may indicate hypoglycemia
and is usually rapidly detected and corrected in a monitored stroke unit. Prolonged and profound
hypoglycemia may lead to irreversible brain damage in patients without stroke. The influence of
hypoglycemia on acutely ischemic tissue is unknown in humans.
Stroke severity of diabetic and non-diabetic patients is similar in most studies (Toni et al., 1992;
Jorgensen et al., 1994; Karapanayiotides et al., 2004). Hiperglikemia in non-diabetics during the acute
phase of ischemic stroke is an independent prognostik faktor for a poor outcome, regardless of age,
severity of stroke, or type of stroke (Candelise et a!., 1985; Weir et al., 1997; Bruno et al., 1999;
Capes et al., 2001; Muir et al., 2007). A negative influence on prognosis is less clear for hemorrhagic
stroke (Capes et al., 2001). In diabetic patients, most studies show that initial hyperglycemia and its
severity do not influence prognosis independently of other factors (Murros et al., 1992; Capes et al.,
2001; Karapanayiotides et al., 2004). Still, in a few studies, early mortality was higher in diabetic
patients (Toni et al., 1992; Jorgensen et al., 1994) and recovery was slower (Jorgensen et al., 1994).
Differences in patient populat ion, functional outcome scales used, and follow-up duration may
account for the contradictory results.
Several reasons why hyperglycemia leads to poorer outcome in non-diabetics are cited: increasing
tissue acidosis secondary to anerobic glycolysis, increased bloodbrain barrier permeability (Adams
Jr et a!., 2003), and decreased fibrinolysis. These and possibly other mechansinis (protein catabolism,
oxidative stress, endothelial dysfunction) lead to less penumbra survival (Parsons et al., 2002) and to
larger stroke volumes (Candelise et al., 1985; Toni et al., 1994). Furthermore, hyperglycemia
decreases the efficacy and increases the hemorrhage rate of thrombolysis (Bruno et a!., 1999; Kase et
a!., 2001).
Which level of hyperglycemia is harmful and the degree to which blood sugar should be lowered
remains unknown. The meta-analysis by Capes et al. (2001) has shown a correlation between even
mildly elevated glucose levels of 6.17 mmolIl on admission and an increased risk of 30-day
mortality and poor functional recovery.
Data on the effect of treatment of acute hyperglycem ia are scarce. A pilot study on patients with mild
to moderate hyperglycemia randomized to saline or a