Clinical review: Therapy for refractory intracranial hypertension in ischaemic stroke

cc6087 CCJ Review Clinical review: Therapy for refractory intracranial hypertension in ischaemic stroke Jüttler Eric eric.juettler@med.uni-heidelberg.de Schellinger D Peter Peter.Schellinger@neuro.imed.uni-erlangen.de Aschoff Alfred alfred_aschoff@med.uni-heidelberg.de Zweckberger Klaus klaus.zweckberger@med.uni-heidelberg.de Unterberg Andreas andreas.unterberg@med.uni-heidelberg.de Hacke Werner werner.hacke@med.uni-heidelberg.de

Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany

Department of Neurology, University of Erlangen, Schwabachanlage 6, D-91054 Erlangen, Germany

Department of Neurosurgery, University of Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany

Critical Care 1364-8535 2007 11 5 231 http://ccforum.com/content/11/5/231 1800149110.1186/cc6087 25 10 2007 2007 BioMed Central Ltd

Abstract

The treatment of patients with large hemispheric ischaemic stroke accompanied by massive space-occupying oedema represents one of the major unsolved problems in neurocritical care medicine. Despite maximum intensive care, the prognosis of these patients is poor, with case fatality rates as high as 80%. Therefore, the term 'malignant brain infarction' was coined. Because conservative treatment strategies to limit brain tissue shift almost consistently fail, these massive infarctions often are regarded as an untreatable disease. The introduction of decompressive surgery (hemicraniectomy) has completely changed this point of view, suggesting that mortality rates may be reduced to approximately 20%. However, critics have always argued that the reduction in mortality may be outweighed by an accompanying increase in severe disability. Due to the lack of conclusive evidence of efficacy from randomised trials, controversy over the benefit of these treatment strategies remained, leading to large regional differences in the application of this procedure. Meanwhile, data from randomised trials confirm the results of former observational studies, demonstrating that hemicraniectomy not only significantly reduces mortality but also significantly improves clinical outcome without increasing the number of completely dependent patients. Hypothermia is another promising treatment option but still needs evidence of efficacy from randomised controlled trials before it may be recommended for clinical routine use. This review gives the reader an integrated view of the current status of treatment options in massive hemispheric brain infarction, based on the available data of clinical trials, including the most recent data from randomised trials published in 2007.

Stroke David Menon

Introduction

Subtotal or complete middle cerebral artery (MCA) territory infarctions, including the basal ganglia, occasionally with additional infarction of the anterior cerebral artery (ACA) or the posterior cerebral artery (PCA) or both, are found in 1% to 10% of patients with supratentorial infarcts 123. They are commonly associated with serious brain swelling, which usually manifests itself between the second and the fifth day after stroke onset 12345678. Space-occupying cerebral infarction is a life-threatening event. Mass effect leads to the destruction of formerly healthy brain tissue and, in severe cases, to extensive brain tissue shifts resulting in transtentorial or uncal herniation and brain death 369. These complications are responsible for the rapid neurologic deterioration seen in such patients 1. In intensive care-based prospective series, the case fatality rate of these patients was approximately 78% despite maximum medical therapy 31011. For these catastrophic cerebral infarcts, the term 'malignant infarction' was coined by Hacke and colleagues 3 in 1996.

Clinically, these patients present with dense hemiplegia, head and eye deviation, and multimodal hemineglect; global aphasia coexists when the dominant hemisphere is involved 23. The National Institutes of Health Stroke Scale score is typically greater than 20 when the dominant hemisphere is involved and greater than 15 when the nondominant hemisphere is involved 1213. They show a rapidly progressive deterioration of consciousness over the first 24 to 48 hours and frequently a reduced ventilatory drive 3. Neuroimaging typically shows definite infarction of at least two thirds of the MCA territory, including the basal ganglia, with or without additional infarction of the ipsilateral ACA or the PCA territories, or an infarct volume of greater than 145 cm³using diffusion-weighted imaging 1415161718. Because of an increasing number of young patients suffering from brain infarction (a group of patients at particular danger of malignant infarction), finding an optimal treatment solution has made this a most urgent topic in neurointensive care medicine during the last decade.

Treatment options

1. Conservative treatment

1.1. General stroke treatment

As far as blood pressure, blood glucose level, body core temperature control, fluid and nutrition management, and prophylaxis of deep venous thrombosis are concerned, patients with malignant MCA infarctions are treated according to the current guidelines of general ischaemic stroke treatment 192021. There are some modifications:

Induced hypertension may be useful in case of haemo-dynamic relevant vessel stenoses or to maintain critical perfusion in the presence of radiologically confirmed penumbra 22. However, there are no controlled trials to confirm this, and available data are contradictory 2324. In a prospective trial in patients with malignant MCA infarction, induced hypertension increased cerebral perfusion pressure (CPP) without a relevant increase of intracranial pressure (ICP) 25. An exception is made in patients receiving decompressive surgery. In these cases, systolic blood pressure during the postoperative phase of the first 8 hours after surgery is kept at 140 to 160 mm Hg to avoid severe bleeding 26.

Previous recommendations of elevation of the head of 30° in patients with malignant MCA infarction should not generally be followed. The idea is that head elevation may improve venous drainage. Furthermore, an upright body positioning reduces the risk of nosocomial infections 272829. In fact, although elevation of the head may decrease ICP, the effect on CPP is less predictable. In several studies, head elevation increased CPP 303132, decreased CPP 3334, or left CPP unaltered 353637. Most of these studies investigated patients with traumatic brain injury or subarachnoid haemorrhage. However, in large ischaemic stroke, different pathophysio-logical aspects such as the possibility of salvaging tissue in the ischaemic penumbra must be taken into consideration. Only one study has investigated the effect of body positioning in patients with large hemispheric ischaemic stroke 34. According to the results, a plane positioning of the head is recommended. Only in case of considerable increases in ICP or in patients at high risk of nosocomial infections, a moderate elevation of the head of 15° to 30° is recommended, always depending on the CPP 34. Any form of compression of the jugular veins should be avoided.

As soon as ventilatory drive is depressed, airway protection becomes paramount, necessitating intubation, ventilation, and sedation. Patients should be intubated at a Glasgow Coma Scale (GCS) score of lower than 8, or if there are any signs of respiratory insufficiency (partial pressure of oxygen [pO₂] of less than 60 mm Hg or partial pressure of carbon dioxide [pCO₂] of greater than 48 mm Hg) or signs of ineffective swallowing or cough reflexes, or if the airway is compromised 38. Deep sedation is recommended to avoid uncontrolled increases of ICP 2728. The following parameters should be targeted: PaO₂(arterial partial pressure of oxygen) above 75 mm Hg and arterial partial pressure of carbon dioxide (PaCO₂) of 36 to 44 mm Hg. In case of raised ICP, the ventilation mode should be changed: Minute ventilation should be adjusted to maintain PaCO2 levels between 35 and 40 mm Hg and pO₂above 100 mm Hg. A minimum of 5 cm H2O of positive end-expiratory pressure and a minimum FiO2 (fraction of inspired oxygen) to maintain SaO2 (saturation of oxygen [arterial blood]) above 90% are advocated 26273940.

All patients with malignant MCA infarction should be treated at an experienced neurointensive care unit 262728. The treatment options listed below can be effective only with detailed haemodynamic, neuroimaging, and invasive multimodal monitoring tools (at least ICP and CPP, measurement in the ipsilateral side), the possibility of rapid interventions, and an experienced neurosurgical department in house. CPP measurement and repeated neuroimaging are strongly recommended. ICP alone is not a good parameter for neurologic deterioration and does not monitor brain displacement 6.

1.2. Anti-oedema therapy

The use of osmotic agents is based on the idea of creating an osmotic pressure gradient over the semipermeable membrane of the blood-brain barrier and thereby drawing interstitial and intracellular water from the swollen brain into intravascular spaces. For the treatment of brain oedema after stroke, mannitol, glycerol, hydroxyethyl starch, and hypertonic saline are currently the most widely used 41. According to the current guidelines, osmotherapy should be started in the case of increases of ICP 192021. The use of mannitol (100 ml of 20% solution or 0.5 to 1.0 g/kg every 4 to 6 hours; maximum daily dose, 2.5 g/kg), glycerol (250 ml of 10% solution, four times per day), or hydroxyethyl starch (6% hetastarch in 0.9% NaCl injection, 100 to 250 ml every 8 hours; maximum daily dose, 750 ml) is recommended. Onset of action of these substances is within minutes, and the duration is as long as 4 to 8 hours 27284142. In repeated use, dosage depends on serum osmolality, which should be targeted at 315 to 320 mOsmol. Hyperosmolar saline solutions (10% NaCl, 75 ml, repeated doses) may be used as an alternative. The advantage of hyperosmolar saline is that it is actively excluded from an intact blood-brain barrier 43. Another advantage is that it can be combined with mannitol because it counteracts mannitol-induced hyponatremia, which develops in almost every patient treated by repeated doses of mannitol 4445.

Steroids are widely used to reduce oedema in brain tumours. However, they have not shown any benefit for brain oedema treatment in ischaemic stroke, although there are no trials investigating the use of steroids in space-occupying ischaemic stroke 46474849. In addition, the rate of infections and complications in patients with diabetes mellitus is significantly increased with steroids.

1.3. Intracranial pressure-lowering therapies

Barbiturates have been administered in a variety of clinical conditions to control elevated ICP, especially in head trauma. Barbiturates may be helpful in acute ICP crisis in those patients awaiting more definitive treatment. Their routine use, however, is discouraged 272850.

Buffer solutions may be used as an option when other interventions have failed. Trishydroxy-methyl-aminomethane (THAM) (Tris buffer) is given by continuous intravenous infusion via a central venous catheter (1 mmol/kg as bolus infusion over 45 minutes followed by 0.25 mmol/kg-hour, aiming for a target arterial pH of 7.5 to 7.55) 28. THAM can be used to raise blood pH independently from respiratory function. The mode of action is probably related to neutralization of an acidosis-related vasodilatation and thus a decrease of ICP 2851. ICP should fall by 10 to 15 mm Hg within 15 minutes after bolus infusion; otherwise, treatment is not effective 2728.

Hyperventilation is not recommended unless intracranial hypertension cannot be controlled by any other therapy and the patient is considered a candidate for more definitive treatment such as decompressive surgery 2728. The patient's respiratory mode is adjusted for PaCO₂(target 30 to 35 mm Hg) and venous oxygenation with jugular bulb oxymetry (>50%), which is best achieved by raising the ventilation rate at a constant tidal volume. After pCO₂target is reached, it may take up to 30 minutes until ICP is reduced by 25% to 30%. Prolonged hyperventilation is discouraged because the effect wears off within 3 to 4 hours 2728.

So far, none of these therapeutic strategies is supported by adequate evidence of efficacy from experimental studies or randomised clinical trials. To understand why medical treatment alone often fails to prevent clinical deterioration, the following points have to be remembered: (a) Clinical deterioration usually is not due to increases of global ICP but to massive local swelling and tissue shifts. Increase of ICP is a secondary late-stage result and represents a terminal and, most likely, an irreversible event that occurs when mass expansion exceeds intracranial compliance. (b) Many agents can work only at an intact blood-brain barrier, which is usually severely compromised in massive cerebral ischaemia. (c) CPP and midline shift are the major surrogate markers of treatment in massive infarction. ICP values are not associated with the extent of midline shift nor do they predict fatal outcomes, and reduction of ICP is not necessarily associated with an increase in CPP 52.

Therefore, from a pathophysiological point of view, all of the above-mentioned therapeutic strategies may be effective only for a short period of time, if at all, but are doomed to fail in the long term 4453. Several reports suggest that they are not only ineffective but even detrimental 3934414445505455565758596061:

Osmotic therapy with hyperosmolar agents aimed at lowering ICP and reducing brain oedema by drawing water from infarcted tissue may be detrimental by primarily dehydrating intact brain, contracting healthy brain tissue volume, thereby aggravating pressure differentials, and causing devastating shifts of brain tissue 642445862.

In malignant infarctions, there are large areas where the blood-brain barrier is significantly disrupted. Hyperosmolar agents have been demonstrated to accumulate in infarcted brain tissue, aggravating brain oedema and space occupation instead of reducing them and thereby (especially in the case of repeated use) worsening brain tissue shifts 5559. In addition, after discontinuing hyperosmolar therapy, rebound effects may occur 60636465.

Prolonged hyperventilation-induced hypocarbia and considerable decreases in cerebral blood flow by cerebral vaso-constriction both aggravate ischaemic brain injury 54666768. Profound hyperventilation may also jeopardise oxygen delivery to the brain tissue at risk. The underlying physiological mechanism is the Bohr effect: In the presence of carbon dioxide, the dissociation of oxygen from haemoglobin increases. A decrease in blood carbon dioxide by hyper-ventilation increases the affinity of oxygen to haemoglobin. This leads to a reduction in brain tissue pO2 and, as a result, to increased ischaemic damage indicated by increases in extracellular glutamate, pyruvate, and lactate 6970.

In some patients with poor cerebral compliance, strict hyperventilation may cause paradoxical ICP elevation by increasing thoracic venous and cerebrospinal fluid pressure. Other side effects include barotrauma and hypokalemia. As with osmotherapy, adverse rebound effects may occur if normoventilation is resumed too rapidly 262854.

Barbiturates often do not lead to sustained control of ICP but may reduce CPP 507172737475. In addition, treatment may cause severe side effects such as hypotension, decreased cardiac performance, or severe infections. Cardiovascular side effects may be aggravated by concomitant dehydration advocated by osmotherapy and reduced cardiac filling pressures 2850.

As a result, none of the conservative treatment options has shown a beneficial effect on outcome in clinical trials, except for glycerol, for which a few clinical trials demonstrate an effect on short-time survival. However, glycerol also failed to demonstrate a long-term benefit 466176. This failure of conservative treatment is reflected by our clinical experience: In larger case series of maximum conservative treatment in malignant MCA infarction, case fatality rates are 53% to 78% 3117778.

2. Mild to moderate hypothermia

Induced hypothermia is defined as physical or pharmacological lowering of the physiological body core temperature to 36.0°C to 36.5°C (minimal hypothermia), 33.0°C to 35.9°C (mild hypothermia), 28.0°C to 32.9°C (moderate hypothermia), or 10.0°C to 27.9°C (deep hypothermia) 79. It is well known in ischaemic stroke that body temperature on admission and during the first 24 hours is associated with the extent of ischaemic damage and is an independent predictor of mortality and outcome 808182.

Although the neuroprotective effect of hypothermia has been known since the 1950s, the earliest experimental findings in ischaemic stroke were reported in the late 1980s 8384. There are numerous animal experiments demonstrating promising results, but only a few of them on massive cerebral infarctions 85868788. The beneficial effect was pronounced when hypothermia was started early and continued for more than 24 hours 899091.

Only one randomised trial has investigated mild-moderate hypothermia in severe, but not necessarily malignant, stroke (cooling for acute ischaemic brain damage, or COOL-AID). Patients were randomly assigned to either hypothermia or standard medical treatment. Target temperature in the pilot trial was 32°C maintained for 12 to 72 hours. In the subsequent phase I trial, a target temperature of 33°C was maintained for 24 hours. Due to the small sample sizes, the studies did not show statistically significant differences in mortality or functional outcome 9293. There are no published controlled, randomised, or prospective comparative clinical studies of hypothermia in malignant MCA infarction. Available clinical studies in malignant cerebral infarction are listed in Table 1.

Table 1

Studies on hypothermia in malignant hemispheric infarction

Authors

Number

Target temperature

Time to induction of hypothermia (hours)

Duration of hypothermia (hours)

Schwab et al., 1998 [95]

33°C (external cooling)

4–24, mean 14 ± 7

48–72

Schwab et al., 2001 [134]

32°C–33°C (external cooling)

4–75, mean 22 ± 9

24–72

Georgiadis et al., 2001 [99]

33°C (endovascular cooling)

12–58, mean 28 ± 17

48–78

Georgiadis et al., 2002 [124]

33°C (n = 8 endovascular cooling; n = 11 external cooling)

18–24, mean 24

24–116

Milhaud et al., 2005 [94]

32°C–33°C (external cooling)

4–24, mean 11 ± 7

120–504

These report mortality rates of between 17% and 48% (Table 2). Data on functional outcome are summarized in Table 3. Only one study has evaluated functional outcome after 6 months in patients with malignant MCA infarction treated by hypothermia, and only 10 patients were involved 94. Data on long-term outcome are completely lacking (Table 3).

Table 2

Mortality data on patients with malignant middle cerebral artery infarction treated with hypothermia

Authors

Number

Mean age (years)

Mortality in hospital

Mortality up to 3 months

Mortality up to 6 months

Mortality up to 12 months

Schwab et al., 1998 [95]

44%

48%

Schwab et al., 2001 [134]

38%

Georgiadis et al., 2001 [99]^a

17%

Milhaud et al., 2005 [94]^b

50%

^aTarget temperature in one patient 34.5°C. ^bTwo patients were excluded in this analysis because they received hemicraniectomy in addition to hypothermia due to worsening of cerebral oedema on day 1 and day 7, respectively; both survived. NA, not available.

Table 3

Functional outcome data on patients with malignant middle cerebral artery infarction treated with hypothermia

Authors

Number

Mean age (years)

Dominant/nondominant hemisphere

+ ACA and/or PCA

Mean time to hypothermia (hours)

Mean time to follow-up (months)

Independent

Mild to moderate disability

Severe disability

Death

Schwab et al., 1998 [95]

68%/32%

20%

Median Barthel Index 70

48%

Schwab et al., 2001 [134]

10%

38%

Georgiadis et al., 2001 [99]

83%/17%

17%

Milhaud et al., 2005 [94]

50%/50%

10%

30%

10%

50%

Functional outcome was classified according to Gupta and colleagues [123] as (1) independent outcome (modified Rankin Scale [mRS] 0 to 1, Glasgow Outcome Scale [GOS] 5, Barthel Index [BI] greater than or equal to 90), (2) mild to moderate disability (mRS 2 to 3, GOS 4, BI 60 to 85), (3) severe disability (mRS 4 to 5, GOS 2 to 3, BI less than 60), and (4) death. In the case of patients in whom more than one outcome scale was given, we classified outcome according to the following priority: mRS – GOS – BI. NA indicates data not given or values of the BI, GOS, or mRS given as means [135,136]. ACA, anterior cerebral artery; PCA, posterior cerebral artery.

Hypothermia in these studies was associated with a high rate of complications, the most frequent being pneumonia, severe bradycardia and heart failure with severe hypotension, and severe thrombocytopenia and coagulopathy. Especially in the rewarming phase, a high percentage of patients developed severe increases in ICP. Increased ICP and herniation were the most common reasons for early mortality 95. Most studies on hypothermia in ischaemic stroke used body temperature for monitoring. It has to be kept in mind, however, that brain temperature is 0.5°C ± 0.3°C above rectal temperature, that temperature within the brain may vary up to 1°C, and that initial temperature in the ischaemic hemisphere is 0.8°C higher than in the healthy hemisphere 84969798.

As long as there is no sufficient evidence of benefit, hypothermia should be used only in the setting of clinical trials. Hypothermia is an invasive procedure that needs treatment in an experienced ICU, including ventilation, relaxation, and measurement of ICP. External cooling is complicated, especially in adipose patients because of the comparatively long time for cooling with increased use of muscle relaxants and anaesthetics. If available, endovascular cooling should be used because the target temperature can be obtained comparatively quickly (approximately 3.5 hours) 929399. Instead of passive rewarming, controlled rewarming and long rewarming periods (+0.1°C to 0.2°C per 2 to 4 hours) should be used to avoid increases in ICP or decreases in CPP 100. Cooling of the head alone seems to be insufficient 96, although further clinical evaluation is required and devices are still being developed 101102.

3. Decompressive surgery

Decompressive surgery in large ischaemic strokes dates back to as early as 1935 103. It is the only available treatment that primarily addresses mass effect, based on simple mechanical reasoning. The rationale is to remove a part of the neurocranium in order to create space to accommodate the swollen brain, to avoid ventricular compression, to reverse brain tissue shifts, and to prevent secondary mechanical tissue damage. Normalisation of ICP and tissue oxygenation is more a secondary effect 9104105106107108.

Two different techniques are used: external decompression (removal of the cranial vault and duraplasty) or internal decompression (removal of nonviable, infarcted tissue [that is, in the case of malignant MCA infarction, temporal lobectomy]). The two can be combined 109110. In theory, resection of the temporal lobe may reduce the risk of uncal herniation. However, this has never been proven consistently by clinical studies, which show similar results as series using external decompression 111112. Resection of infarcted tissue is more complicated, and it is difficult to distinguish between already infarcted and potentially salvageable tissue. Therefore, in most institutions, external decompressive surgery (consisting of a large hemicraniectomy and dura-plasty) is performed: In short, a large (reversed) question mark-shaped skin incision based at the ear is made. A bone flap with a diameter of at least 12 cm (including the frontal, parietal, temporal, and parts of the occipital squama) is removed. Additional temporal bone is removed so that the floor of the middle cerebral fossa can be explored. Then the dura is opened and an augmented dural patch, consisting of homologous periost and/or temporal fascia, is inserted (usually, a patch of 15 to 20 cm in length and 2.5 to 3.5 cm in width is used). The dura is fixed at the margin of the craniotomy to prevent epidural bleeding. The temporal muscle and the skin flap are then reapproximated and secured. In surviving patients, cranioplasty usually is performed after 6 to 12 weeks, using the stored bone flap or an artificial bone flap (Figures 1 and 2). Complications occur rarely and include postoperative epidural and subdural haemorrhage and hygromas or wound and bone flap infections 77109. These can be recognized easily and usually do not contribute to perioperative mortality. A more common and far more serious problem is a hemicraniectomy that is too small. Because the proportion of brain tissue to be allowed to shift outside the skull is closely related to the diameter of the bone flap (which is removed), small hemicraniectomies not only are insufficient but may lead to herniation through the craniectomy defect 113. Ventriculostomy is not recommended; although it may help to decrease ICP by allowing drainage of cerebrospinal fluid, it promotes brain tissue shifts at the same time and therefore may be detrimental.

Figure 1

Hemicraniectomy: external decompressive surgery technique

Hemicraniectomy: external decompressive surgery technique. I. Fronto-temporo-parietal hemicraniectomy: (a) schematic drawing of the hemicraniectomy defect, (b) incision, (c) craniectomy borders (to the skull base), (d) tense dura mater with swollen brain underneath. II. Dura mater is removed for duraplasty: (a) preparation, (b) dura stretched on aluminium foil. III. Dura incisions: (a) schematic drawing of incisions, (b) preparation. IV. Insertion of the dura (duraplasty). V. Bone flap is stored at -80°C. Cranioplasty is performed after 6 to 12 weeks.

Figure 2

Left hemispheric malignant middle cerebral artery infarction after hemicraniectomy (magnetic resonance imaging)

Left hemispheric malignant middle cerebral artery infarction after hemicraniectomy (magnetic resonance imaging). The swollen brain is allowed to expand outside.

Between 1935 and 2007, more than 80 case reports and series of patients with malignant brain infarctions including more than 1,700 patients have been published. Larger case series were not published until 1995 77. Only a few prospective trials have compared decompressive surgery with conservative treatment. Some of them used historical control groups, and most control groups consisted of patients with a higher age, more comorbidity, and (more frequently) lesions of the dominant hemisphere 377104109111114115116117118119120121122. These studies report mortality rates of 0% to 33% in surgically treated patients compared with 60% to 100% in conservatively treated patients. In a review by Gupta and colleagues 123 analysing all available individual patient data from 138 patients, the overall mortality rate after hemicraniectomy after a period of 7 to 21 months was 24%. Only one study compared decompressive surgery with hypothermia 124, and one study compared mild hypothermia plus hemicraniectomy with hemicraniectomy alone 125 (Tables 4 and 5).

Table 4

Mortality data in patients with malignant middle cerebral artery infarction: studies with comparative data on conservative treatment versus decompressive surgery

Authors

Patients treated with conservative treatment

Patients treated with decompressive surgery

Mean age (years)

Mortality in hospital

Mortality up to 3 months

Mortality up to 6 months

Mortality up to 12 months

Delashaw et al., 1990 [118]^a

NA vs. 57

100% vs. 0%

100% vs. 11%

100% vs. NA

Steiger 1991 [119]^b

100% vs. 25%

Rieke et al., 1995 [77], Hacke et al., 1996 [3], Wirtz et al., 1997 [104], Schwab et al., 1998 [109]^c

56 vs. 50

78% vs. 25%

NA vs. 25%

Holtkamp et al., 2001 [114]^d

73 vs. 65

83% vs. 17%

83% vs. 25%

83% vs. 33%

Mori et al., 2001 [120]

72 vs. 63

60% vs. 11%

67% vs. 16%

Mori et al., 2004 [111]^e

72 vs. 65

62% vs. 12%

71% vs. 24%

Kuroki et al., 2001 [121]^f

80 vs. 72

86% vs. 13%

Cho et al., 2003 [115]^g

64 vs. 63

80% vs. 29%

Maramattom et al., 2004 [116]^h

63 vs. 55

60% vs. 0%

Yang et al., 2005 [122]ⁱ

66 vs. 59

64% vs. 10%

Wang et al., 2006 [117]^j

67 vs. 62

22% vs. 29%

Authors

Patients treated with hypothermia

Patients treated with decompressive surgery

Mean age (years)

Mortality in hospital

Mortality up to 3 months

Mortality up to 6 months

Mortality up to 12 months

Georgiadis et al., 2002 [124]

56 vs. 52

47% vs. 12%

Authors

Patients treated with decompressive surgery + hypothermia

Patients treated with decompressive surgery

Mean age (years)

Mortality in hospital

Mortality up to 3 months

Mortality up to 6 months

Mortality up to 12 months

Els et al., 2006 [125]^k

49 vs. 49

8% vs. 15%

^aNot randomised. All four patients in the nonintervention group had a dominant MCA infarction, and all nine patients in the intervention group had a nondominant MCA infarction.

^bNot randomised. All patients were younger than 60 years. There is a selection bias because conservatively treated patients were not regarded as being suitable for surgery.

^cNot randomised. These studies represent the largest case series in the literature using the case series of Hacke and colleagues (1996) [3] as historical control group. Mortality rates of early versus delayed surgery were 16% versus 34%.

^dNot randomised. There is a selection bias by advanced age and more comorbidity in conservatively treated patients. All patients were older than 55 and younger than 75 years.

^eNot randomised. There is a selection bias because treatment decision was based primarily on the consent by the patient's relatives. Some patients received internal decompression. Mortality rates of early versus late surgery were 19% versus 28%. The case series of 2004 included the patients of the case series of 2001.

^fNot randomised. The study used historical controls.

^gNot randomised. Mortality rates of ultra-early (<6 hours) versus delayed surgery were 8% versus 37%.

^hNot randomised. Hemicraniectomy was performed only in patients, who deteriorated clinically.

ⁱNot randomised.

^jNot randomised. There was no difference between late and early hemicraniectomies.

^kRandomised. Twelve patients received mild hypothermia (35°C) in addition to hemicraniectomy. In the group treated by hemicraniectomy alone more patients had a right-sided infarction and additional infarction of the ACA or PCA.

ACA, anterior cerebral artery; NA, not available; PCA, posterior cerebral artery.

Table 5

Mortality data in patients with malignant middle cerebral artery infarction: studies with reviews on conservative treatment versus decompressive surgery

Authors

Patients treated with conservative treatment

Patients treated with decompressive surgery

Mean age (years)

Mortality

Gupta et al., 2004 [123]

138

Overall mortality 24% (follow-up 7–21 months)

Morley et al., 2002 [137]

Gives an overview on available data.

No trial fulfills the criteria of a randomised controlled study design to be included in a meta-analysis.

Various trials suggest that decompressive surgery not only reduces mortality but also increases the number of patients with independent functional outcome without increasing the number of severely disabled patients 109111115118126. Other studies doubt these results, especially in patients with increased age and with additional infarction of the ACA or PCA 116117122127128. Among other predictors that have been proposed to predict unfavourable outcome are preoperative midline shift, low preoperative GCS, presence of anisocoria, early clinical deterioration, and internal carotid artery occlusion 129130. In the review by Gupta and colleagues 123, age was the only prognostic factor for poor outcome, whereas time to surgery, the presence of brainstem signs prior to surgery, and additional infarction of the ACA or PCA territory were not associated with outcome. Data from comparative studies and reviews are summarized in Tables 6 and 7.

Table 6

Functional outcome data in patients with malignant middle cerebral artery infarction: studies with comparative data on conservative treatment versus decompressive surgery

Authors

Patients treated with conservative treatment

Patients treated with decompression

Mean age (years)

Dominant/nondominant hemisphere

+ ACA and/or PCA

Mean time to surgery (hours)

Mean time to follow-up (months)

Independent outcome

Mild to moderate disability

Severe disability

Death

Delashaw et al., 1990 [118]

100%/0%

100%

0%/100%

56%

22%

44%

11%

Steiger 1991 [119]

100%

75%

25%

Rieke et al., 1995 [77]

62%/38%

22%

78%

Hacke et al., 1996 [3]

17%/83%

35%

40%

33%

25%

Wirtz et al., 1997 [104]

Schwab et al., 1998 [109]

Mori et al., 2001 [120]

52%/48%

33%

24%

71%

Mori et al., 2004 [111]

26%/74%

36%

10%

56%

24%

Kuroki et al., 2001 [121]

14%

86%

87%

13%

Holtkamp et al., 2001 [114]

83%/17%

67%

17%

83%

25%/75%

42%

67%

33%

Cho et al., 2003 [115]

60%/40%

50%

20%

80%

52%/48%

38%

71%

29%

Maramattom et al., 2004 [116]

40%/60%

10%

30%

60%

22%/78%

71%

38%

63%

Yang et al., 2005 [122]

43%/57%

57%

36%

64%

30%/70%

60%

10%

30%

50%

10%

Wang et al., 2006 [117]

56%/44%

25%

54%

22%

38%/62%

14%

57%

29%

Authors

Patients treated with hypothermia

Patients treated with decompression

Mean age (years)

Dominant/nondominant hemisphere

+ ACA and/or PCA

Mean time to surgery (hours)

Mean time to follow-up (months)

Independent outcome

Mild to moderate disability

Severe disability

Death

Georgiadis et al., 2002 [124]

100%/0%

26%

47%

0%/100%

24%

12%

Authors

Patients treated with decompression + hypothermia

Patients treated with decompression

Mean Age (years)

Dominant/nondominant hemisphere

+ ACA and/or PCA

Mean time to surgery (hours)

Mean time to follow-up (months)

Independent outcome

Mild to moderate disability

Severe disability

Death

Els et al., 2006 [125]

92% (median mRS 2)

88% (median mRS 3)

12%

Functional outcome was classified as described in Table 2. ACA, anterior cerebral artery; NA, not available; PCA, posterior cerebral artery.

Table 7

Functional outcome data in patients with malignant middle cerebral artery infarction: studies with reviews on conservative treatment versus decompressive surgery

Authors

Patients treated with conservative treatment

Patients treated with decompression

Mean age (years)

Dominant/nondominant hemisphere

+ ACA and/or PCA

Mean time to surgery (hours)

Mean time to follow-up (months)

Independent outcome

Mild to moderate disability

Severe disability

Death

Gupta et al., 2004 [123]

138

20%/80%

32%

59.3

7–21

35%

34%

24%

Morley et al., 2002 [137]

Gives an overview on available data.

No trial fulfills the criteria of a randomised controlled study design to be included in a meta-analysis.

Functional outcome was classified as described in Table 2. ACA, anterior cerebral artery; PCA, posterior cerebral artery.

These controversial results lead to constant discussion among experts about the benefit of decompressive surgery in malignant MCA infarction and to large regional differences in the application of the procedure. This dilemma could be resolved only by randomised trials. Since 2000, five randomised trials have been conducted: the American HeADDFIRST (Hemicraniecomy And Durotomy Upon Deterioration From Infarction Related Swelling Trial), the French DECIMAL (DEcompressive Craniectomy In MALignant middle cerebral artery infarcts) trial, the Dutch HAMLET (Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial), the Philippine HeMMI (Hemicraniectomy For Malignant Middle Cerebral Artery Infarcts) trial, and the German DESTINY (DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY) trial 161718131132.

DESTINY and DECIMAL were stopped early in 2006, and the results were published recently 1617. In both trials, decompressive surgery significantly reduced mortality, but the primary endpoint in both trials, dichotomization of the modified Rankin scale (mRS) score of less than or equal to 3, failed to show statistically significant results. Nevertheless, both trials were stopped not only because of ethical considerations to continue randomisation, but also because of expectations of a prospectively planned pooled analysis of the three European trials (DECIMAL, DESTINY, and HAMLET). This pooled analysis is the first in the field of stroke in which individual patient data from three different randomised trials were pooled while these trials were still ongoing. Of the 93 patients who were included, 51 were randomly assigned to decompressive surgery and 42 to conservative treatment. Results demonstrate that decompressive surgery (a) significantly reduces mortality (71% versus 22%, p < 0.0001, absolute risk reduction [ARR] 50%), (b) significantly increases the chance to survive with an mRS score of less than or equal to 4 (that is, not being bedridden and completely dependent) (24% versus 75%, p < 0.0001, ARR 51%), and (c) also significantly increases the chance to survive with an mRS score of less than or equal to 3 (that is, being able to walk and being independent in at least some activities of daily living) (21% versus 43%, p < 0.014, ARR 23%) (Figures 3 and 4) 133. There is no statistically significant heterogeneity between the three trials, and the treatment effects remain essentially the same for all analyses if baseline differences between the treatment groups are taken into account. The resulting numbers needed to treat are 2 for survival, 2 for the prevention of an mRS score of 5 or death, and 4 for the prevention of an mRS score of 4 or 5 or death. Decompressive surgery was beneficial in all predefined subgroups, including age (dichotomized at 50 years), presence of aphasia, and time to randomisation (dichotomized at 21.5 hours), as measured by an mRS score of less than or equal to 4 at 12 months.

Figure 3

Mortality and functional outcome after conservative treatment in patients with malignant middle cerebral artery infarction

Mortality and functional outcome after conservative treatment in patients with malignant middle cerebral artery infarction. Results from randomised controlled trials. The pooled analysis includes 93 patients (all patients from DECIMAL and DESTINY and 23 patients from HAMLET). DECIMAL, DEcompressive Craniectomy In MALignant middle cerebral artery infarcts; DESTINY, DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY; HAMLET, Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial; mRS, modified Rankin scale.

Figure 4

Mortality and functional outcome after hemicraniectomy in patients with malignant middle cerebral artery infarction

Mortality and functional outcome after hemicraniectomy in patients with malignant middle cerebral artery infarction. Results from randomised controlled trials. The pooled analysis includes 93 patients (all patients from DECIMAL and DESTINY and 23 patients from HAMLET). DECIMAL, DEcompressive Craniectomy In MALignant middle cerebral artery infarcts; DESTINY, DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY; HAMLET, Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial; mRS, modified Rankin scale.

Summary

For many years, there has been no agreement among experts concerning the question of which treatment is beneficial in patients with malignant MCA infarctions. In comparison with the usually unsuccessful conservative treatment strategies, hypothermia and decompressive surgery seem to be much more promising therapies 95395. Although hypothermia has been demonstrated to be feasible in patients with large hemispheric infarctions, data on safety and efficacy are currently insufficient to recommend hypothermia in patients with malignant infarctions outside clinical trials 99134.

Because of promising results from numerous case reports, retrospective case series, and a small number of prospective studies, decompressive surgery has already been increasingly incorporated into routine intensive care protocols 77109123. In 2007, the results from nonrandomised studies were confirmed by a pooled analysis of three randomised controlled trials, supporting the widespread opinion among experts that hemicraniectomy in malignant MCA infarction not only reduces mortality but also leads to an improved outcome of the survivors without increasing the number of completely dependent patients 133. So far, early hemicraniectomy is the only effective treatment in malignant ischaemic stroke.

Abbreviations

ACA = anterior cerebral artery; ARR = absolute risk reduction; CPP = cerebral perfusion pressure; DECIMAL = DEcompressive Craniectomy In MALignant middle cerebral artery infarcts; DESTINY = DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY; GCS = Glasgow Coma Scale; HAMLET = Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial; ICP =intracranial pressure; MCA = middle cerebral artery; mRS = modified Rankin scale; PaCO₂= arterial partial pressure of carbon dioxide; PCA = posterior cerebral artery; pCO₂= partial pressure of carbon dioxide; pO₂= partial pressure of oxygen; THAM = Tris-hydroxy-methyl-aminomethane.

Competing interests

The authors declare that they have no competing interests.

Note

This article is part of a review series on Stroke, edited by David Menon.

Other articles in the series can be found online at http://ccforum.com/articles/theme-series.asp?series=CC_Stroke

Early mortality following stroke: a prospective review Silver FL Norris JW Lewis AJ Hachinski VC Stroke 1984 15 492 496 6729878 Brain edema after stroke. Clinical syndrome and intracranial pressure Ropper AH Shafran B Arch Neurol 1984 41 26 29 6606414 'Malignant' middle cerebral artery infarction. Clinical course and prognostic signs Hacke W Schwab S Horn M Spranger M DeGeorgia M von Kummer R Arch Neurol 1996 53 309 315 8929152 Swelling of the brain following ischemic infarction with arterial occlusion Shaw CM Alvord EC Jr Berry RG Arch Neurol 1959 1 161 177 14445627 Massive cerebral infarction with severe brain swelling: a clinicopathological study Ng LK Nimmannitya J Stroke 1970 1 158 163 5522913 Large hemispheric infarction, deterioration, and intracranial pressure Frank JI Neurology 1995 45 1286 1290 7617183 Outcome after external decompression for massive cerebral infarction Sakai K Iwahashi K Terada K Gohda Y Sakurai M Matsumoto Y Neurol Med Chir (Tokyo) 1998 38 131 135 9597855 Large infarcts in the middle cerebral artery territory. Etiology and outcome patterns Heinsius T Bogousslavsky J Van Melle G Neurology 1998 50 341 350 9484351 Hemicraniectomy in space-occupying hemispheric infarction: useful early intervention or desperate activism? Schwab S Rieke K Aschoff A Albert F von Kummer R Hacke W Cerebrovasc Dis 1996 6 325 329 10.1159/000108046 Middle cerebral artery territory infarction and early brain swelling: progression and effect of age on outcome Wijdicks EF Diringer MN Mayo Clin Proc 1998 73 829 836 9737218 Mortality of space-occupying (malignant) middle cerebral artery infarction under conservative intensive care Berrouschot J Sterker M Bettin S Koster J Schneider D Intensive Care Med 1998 24 620 623 10.1007/s001340050625 9681786 Early clinical and radiological predictors of fatal brain swelling in ischemic stroke Krieger DW Demchuk AM Kasner SE Kauss M Hantson L Stroke 1999 30 287 292 9933261 Measurements of acute cerebral infarction: a clinical examination scale Brott T Adams HP Olinger CP Marler JR Barsan WG Biller J Spilker J Holleran R Hertzberg V Rorick M Stroke 1989 20 864 870 2749846 Computed tomographic parameters predicting fatal outcome in large middle cerebral artery infarction Barber PA Demchuk AM Zhang J Kasner SE Hill MD Berrouschot J Schmutzhard E Harms L Verro P Krieger D Cerebrovasc Dis 2003 16 230 235 10.1159/000071121 12865610 Prediction of malignant middle cerebral artery infarction by diffusion-weighted imaging Oppenheim C Samson Y Manaï R Lalam T Vandamme X Crozier S Srour A Cornu P Dormont D Rancurel G Stroke 2000 31 2175 2181 10978048 Sequential-design, multicenter, randomized, controlled trial of early decompressive craniectomy in malignant middle cerebral artery infarction (DECIMAL Trial) Vahedi K Vicaut E Mateo J Kurtz A Orabi M Guichard JP Boutron C Couvreur G Rouanet F Touze E Stroke 2007 38 2506 2517 10.1161/STROKEAHA.107.485235 17690311 Decompressive Surgery for the Treatment of Malignant Infarction of the Middle Cerebral Artery (DESTINY): a randomized, controlled trial Juttler E Schwab S Schmiedek P Unterberg A Hennerici M Woitzik J Witte S Jenetzky E Hacke W Stroke 2007 38 2518 2525 10.1161/STROKEAHA.107.485649 17690310 Hemicraniectomy after middle cerebral artery infarction with life-threatening edema trial (HAMLET). Protocol for a randomised controlled trial of decompressive surgery in space-occupying hemispheric infarction Hofmeijer J Amelink GJ Algra A van Gijn J Macleod MR Kappelle LJ van der Worp HB the HAMLET investigators Trials 2006 7 29 1570365 16965617 10.1186/1745-6215-7-29 Guidelines for the management of patients with acute ischemic stroke: A statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association Adams HP Brott TG Crowell RM Furlan AJ Gomez CR Grotta J Helgason CM Marler JR Woolson RF Zivin JA Stroke 1994 25 1901 1914 8073477 Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association Adams H Adams RJ DelZoppo G Goldstein LB Stroke 2005 36 916 923 10.1161/01.STR.0000163257.66207.2d 15800252 European Stroke Initiative Recommendations for Stroke Management – Update 2003 The European Stroke Initiative Executive Committee and the EUSI Writing Committee Cerebrovasc Dis 2003 16 311 337 10.1159/000072554 14584488 Induced hypertension improves cerebral blood flow in acute ischemic stroke Chalela JA Dunn B Todd JW Warach S Neurology 2005 64 1979 10.1212/01.WNL.0000156360.70336.18 15955961 High initial blood pressure after acute stroke is associated with poor functional outcome Ahmed N Wahlgren G J Intern Med 2001 249 467 473 10.1046/j.1365-2796.2001.00831.x 11350571 Progression of stroke after arrival at hospital Britton M Roeden A Stroke 1985 16 629 632 2411028 Effects of induced hypertension on intracranial pressure flow velocities of the middle cerebral arteries in patients with large hemispheric stroke Schwarz S Georgiadis D Aschoff A Schwab S Stroke 2002 33 998 1004 10.1161/01.STR.0000014584.17714.2E 11935051 Critical care of stroke Hacke W Steiner T Schwab S Cerebrovascular Disorders London, UK: Butterworth Batjer HH, Caplan LR 1997 523 534 Mass effect with cerebral infarction Demchuk AM Krieger DW Curr Treat Options Neurol 1999 1 189 199 10.1007/s11940-999-0003-y 11096709 Treatment options for large hemispheric stroke Steiner T Ringleb P Hacke W Neurology 2001 57 61 68 Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial Drakulovic MB Torres A Bauer TT Nicolas JM Nogue S Ferrer M Lancet 1999 354 1851 1858 10.1016/S0140-6736(98)12251-1 10584721 Raising the head-of-bed by 30 degrees reduces ICP and improves CPP without compromising cardiac output in euvolemic patients with traumatic brain injury and subarachnoid haemorrhage: a practice audit Schulz-Stubner S Thiex R Eur J Anaesthesiol 2006 23 177 180 10.1017/S0265021505232118 16426476 Influence of body position on tissue-pO2, cerebral perfusion pressure and intracranial pressure in patients with acute brain injury Meixensberger J Baunach S Amschler J Dings J Rossen K Neurol Res 1997 19 249 253 9192375 Effects of head posture on cerebral hemodynamics: its influences on intracranial pressure, cerebral perfusion pressure, and cerebral oxygenation Ng I Lim J Wong HB Neurosurgery 2004 54 593 597 10.1227/01.NEU.0000108639.16783.39 15028132 Cerebral perfusion pressure, intracranial pressure, and head elevation Rosner MJ Coley IB J Neurosurg 1986 65 636 641 3772451 Effects of body position on intracranial pressure and cerebral perfusion in patients with large hemispheric stroke Schwarz S Georgiadis D Aschoff A Schwab S Stroke 2002 33 497 501 10.1161/hs0202.102376 11823659 Effects of head elevation on intracranial pressure, cerebral perfusion pressure, and cerebral blood flow in head-injured patients Feldman Z Kanter MJ Robertson CS Contant CF Hayes C Sheinberg MA Villareal CA Narayan RK Grossman RG J Neurosurg 1992 76 207 211 1730949 Influence of body position on jugular venous oxygen saturation, intracranial pressure, and cerebral perfusion pressure Schneider GH von Helden GH Franke R Lanksch WR Unterberg A Acta Neurochir Suppl (Wien) 1993 59 107 112 8310857 Is cerebral perfusion pressure a major determinant of cerebral blood flow during head elevation in comatose patients with severe intracranial lesions? Moraine JJ Berre J Melot C J Neurosurg 2000 92 606 614 10761649 Prognosis of stroke patients requiring mechanical ventilation in a neurological critical care unit Steiner T Mendoza G De Georgia M Schellinger P Holle R Hacke W Stroke 1997 28 711 715 9099184 Influence of inspiration:expiration ratio on intracranial and cerebral perfusion pressure in acute stroke patients Georgiadis D Schwarz S Kollmar R Baumgartner RW Schwab S Intensive Care Med 2002 28 1089 1093 10.1007/s00134-002-1351-1 12185430 Influence of positive end-expiratory pressure on intracranial pressure and cerebral perfusion pressure in patients with acute stroke Georgiadis D Schwarz S Baumgartner RW Veltkamp R Schwab S Stroke 2001 32 2088 2092 10.1161/hs0901.095406 11546901 Treatment of space-occupying cerebral infarction Hofmeijer J van der Worp HB Kappelle LJ Crit Care Med 2003 31 617 625 10.1097/01.CCM.0000050446.16158.80 12576974 The effects of mannitol on cerebral edema after large hemispheric cerebral infarct Manno EM Adams RE Derdeyn CP Powers WJ Diringer MN Neurology 1999 52 583 587 10025792 Hypertonic saline as a safe and efficacious treatment of intracranial hypertension Zornow MH J Neurosurg Anesthesiol 1996 8 175 177 8829566 Effects of hypertonic saline, hydroxyethyl starch solution, and mannitol in patients with increased intracranial pressure after stroke Schwarz S Schwab S Bertram M Aschoff A Hacke W Stroke 1998 29 1550 1555 9707191 Effects of hypertonic (10%) saline in patients with raised intracranial pressure after stroke Schwarz S Georgiadis D Aschoff A Schwab S Stroke 2002 33 136 140 10.1161/hs0102.100877 11779902 Therapy against brain swelling in stroke patients. A retrospective clinical study on 227 patients Candelise L Colombo A Spinnler H Stroke 1975 6 353 356 1098232 High dose steroid treatment in cerebral infarction Norris JW Hachinski VC Br Med J (Clin Res Ed) 1986 292 21 23 1338973 3080050 Efficacious experimental stroke treatment with high-dose methylprednisolone de Courten-Myers GM Kleinholz M Wagner KR Xi G Myers RE Stroke 1994 25 487 493 8303761 Corticosteroids for acute ischaemic stroke Qizilbash N Lewington SL Lopez-Arrieta JM Cochrane Database Syst Rev 2000 CD000064 10796290 Barbiturate coma in severe hemispheric stroke: useful or obsolete? Schwab S Spranger M Schwarz S Hacke W Neurology 1997 48 1608 1613 9191775 Cerebral blood flow, cerebral blood volume, and cerebrovascluar reactivity after severe head injury Bouma GJ Muizelaar JP J Neurotrauma 1992 9 Suppl 1 S333 S348 1588625 The value of intracranial pressure monitoring in acute hemispheric stroke Schwab S Aschoff A Spranger M Albert F Hacke W Neurology 1996 47 393 398 8757010 Surgical decompression of patients with large middle cerebral artery infarcts is effective Schwab S Hacke W Stroke 2003 34 2304 2305 10.1161/01.STR.0000089295.37380.A4 12947161 Adverse effects of prolonged hyperventilation in patients with severe head injury: a randomized clinical trial Muizelaar JP Marmarou A Ward JD Kontos HA Choi SC Becker DP Gruemer H Young HF J Neurosurg 1991 75 731 739 1919695 Aggravation of vasogenic cerebral edema by multiple-dose mannitol Kaufmann AM Cardoso ER J Neurosurg 1992 77 584 589 1527619 Complications of acute ischaemic stroke Van der Worp HB Kappelle LJ Cerebrovasc Dis 1998 8 124 132 10.1159/000015830 9548012 Management of massive hemispheric cerebral infarct: is there a ray of hope? Wijdicks EFM Mayo Clin Proc 2000 75 945 952 10994830 Mannitol bolus preferentially shrinks non-infarcted brain in patients with ischemic stroke Videen TO Zazulia AR Manno EM Derdeyen CP Adams RE Diringer MN Powers WJ Neurology 2001 57 2120 2122 11739839 Hypertonic saline worsens infarct volume after transient focal ischemia in rats Bahrdwaj A Harukuni I Murphy SJ Alakayed NJ Crain BJ Koehler RC Hurn PD Traystman RJ Stroke 2000 31 1694 1701 10884475 Mannitol for acute stroke Bereczki D Liu M do Prado GF Fekete I Cochrane Database Syst Rev 2001 CD001153 11279707 Glycerol for acute stroke Righetti E Celani MG Cantisani T Sterzi R Boysen G Ricci S Cochrane Database Syst Rev 2000 CD000096 11034673 Multiple-dose mannitol reduces brain water content in a rat model of cortical infarction Paczynski RP He YY Diringer MN Hsu CY Stroke 1997 28 1437 1443 9227697 Effect of mannitol on intracranial pressure in focal cerebral ischemia: an experimental study in rats Kotwica Z Persson L Mater Med Pol 1991 23 280 284 1842234 Temporary reversal of serum to cerebrospinal fluid glycerol concentration gradient after intravenous infusion of glycerol Nau R Prins FJ Kolenda H Prange HW Eur J Clin Pharmacol 1992 42 181 185 10.1007/BF00278481 1618250 Slow elimination of mannitol from human cerebrospinal fluid Nau R Desel H Lassek C Thiel A Schinschke S Rossing R Kolenda H Pranke HW Eur J Clin Pharmacol 1997 53 271 274 10.1007/s002280050375 9476044 Pial arteriolar vessel diameter and CO2 reactivity during prolonged hyperventilation in the rabbit Muizelaar JP van der Poel HG Li ZC Kontos HA Levasseur JE J Neurosurg 1988 69 923 927 3142972 The use of hyperventilation and its impact on cerebral ischemia in the treatment of traumatic brain injury Yundt KD Diringer MN Crit Care Clin 1997 13 163 184 10.1016/S0749-0704(05)70300-6 9012580 Hyperventilation-induced cerebral ischemia in patients with acute brain lesions: demonstration by xenon-enhanced CT Stringer WA Hasso AN Thompson JR Hinshaw DB Jordan KG AJNR Am J Neuroradiol 1993 14 475 484 8456732 CO2 reactivity and brain oxygen pressure monitoring in severe head injury Carmona Suazo JA Maas AI van den Brink WA van Santbrink H Steyerberg EW Avezaat CJ Crit Care Med 2000 28 3268 3274 10.1097/00003246-200009000-00024 11008991 Effect of hyperventilation on extracellular concentrations of glutamate, lactate, pyruvate, and local cerebral blood flow in patients with severe traumatic brain injury Marion DW Puccio A Wisniewski SR Kochanek P Dixon CE Bullian L Carlier P Crit Care Med 2002 30 2619 2625 10.1097/00003246-200212000-00001 12483048 Pentobarbital protection from cerebral infarction without suppression of edema Hoff JT Nishimura M Newfield P Stroke 1982 13 623 628 7123594 Barbiturate-induced coma to protect against cerebral ischemia and increased intracranial pressure Pappas TN Mironovich RO Am J Hosp Pharm 1981 38 494 498 7025614 Barbiturates in brain ischaemia Shapiro HM Br J Anaesth 1985 57 82 95 10.1093/bja/57.1.82 3881116 High dose barbiturates in non-traumatic brain swelling: ICP reduction and effect on outcome Woodcock J Ropper AH Kennedy SK Stroke 1982 13 785 787 7147292 High-dose barbiturate therapy in humans: a clinical review of 60 patients Rockoff MA Marshall LF Shapiro HM Ann Neurol 1979 6 194 199 10.1002/ana.410060303 534417 Is there a real treatment for stroke? Clinical and statistical comparison of different treatments in 300 patients Santambrogio S Martinotti R Sardella F Porro F Randazzo A Stroke 1978 9 130 132 417428 Decompressive surgery in space-occupying hemispheric infarction: Results of an open, prospective trial Rieke K Schwab S Krieger D von Kummer R Aschoff A Schuchardt V Hacke W Crit Care Med 1995 23 1576 1587 10.1097/00003246-199509000-00019 7664561 Predictors of fatal brain edema in massive hemispheric ischemic stroke Kasner SE Demchuk AM Berrouschot J Schmutzhard E Harms L Verro P Chalela JA Abbur R McGrade H Christou I Stroke 2001 32 2117 2123 10.1161/hs0901.095719 11546905 Induced hypothermia in critical care medicine: a review Bernard SA Buist M Crit Care Med 2003 31 2041 2051 10.1097/01.CCM.0000069731.18472.61 12847402 Timing for fever-related brain damage in acute ischemic stroke Castillo J Davalos A Marrugat J Noya M Stroke 1998 29 2455 2460 9836750 Influence of admission body temperature on stroke mortality Wang Y Lim LL Levi C Heller RF Fisher J Stroke 2000 31 404 409 10657413 Body temperature in acute stroke: relation to stroke severity, infarct size, mortality, and outcome Reith J Jorgensen HS Pedersen PM Nakayama H Raaschou HO Jeppesen LL Olsen TS Lancet 1996 347 422 425 10.1016/S0140-6736(96)90008-2 8618482 Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury Busto R Dietrich WD Globus MY Valdes I Scheinberg P Ginsberg MD J Cereb Blood Flow Metab 1987 7 729 738 3693428 The importance of brain temperature in cerebral ischemic injury Busto R Dietrich WD Globus MYT Ginsberg MD Stroke 1989 20 1113 1114 2756546 The significance of brain temperature in focal cerebral ischemia: histopathological consequences of middle cerebral artery occlusion in the rat Morikawa E Ginsberg MD Dietrich WD Duncan RC Kraydieh S Globus MY Busto R J Cereb Blood Flow Metab 1992 12 380 389 1569134 Prolonged mild hypothermia therapy protects the brain against permanent focal ischemia Yanamoto H Nagata I Niitsu Y Zhang Z Xue JH Sakai N Kikuchi H Stroke 2001 32 232 239 11136942 Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model Colbourne F Corbett D Zhao Z Yang J Buchan AM J Cereb Blood Flow Metab 2000 20 1702 1708 10.1097/00004647-200012000-00009 11129786 Neuroprotective effect of delayed moderate hypothermia after focal cerebral ischemis: an MRI study Kollmar R Schabitz WR Heiland S Georgiadis D Schellinger PD Bardutzky J Schwab S Stroke 2002 33 1899 1904 10.1161/01.STR.0000019603.29818.9C 12105372 Temperature modulation (hypothermic and hyperthermic conditions) and its influence on histological and behavioural outcomes following cerebral ischemia Corbett D Thornhill J Brain Pathol 2000 10 145 152 10668904 Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation Maier CM Ahern K Cheng ML Lee JE Yenari MA Steinberg GK Stroke 1998 29 2171 2180 9756600 Combination of decompressive craniectomy and mild hypothermia ameliorates infarction volume after permanent focal ischemia in rats Doerfler A Schwab S Hoffmann TT Engelhorn T Forsting M Stroke 2001 32 2675 2681 10.1161/hs1101.098369 11692033 Cooling for acute ischemic brain damage (COOL-AID): an open pilot study of induced hypothermia in acute ischemic stroke Krieger DW De Georgia MA Abou-Chebl A Andrefsky JC Sila CA Katzan IL Mayberg MR Furlan AJ Stroke 2001 32 1847 1854 11486115 Cooling for acute ischemic brain damage (COOL-AID): a feasibility trial of endovascular cooling De Georgia MA Krieger DW Abou-Chebl A Devlin TG Jauss M Davis SM Koroshetz WJ Rordorf G Warach S Neurology 2004 63 312 317 15277626 Prolonged moderate hypothermia in massive hemispheric infarction: clinical experience Milhaud D Thouvenot E Heroum C Escuret E J Neurosurg Anesthesiol 2005 17 49 53 15632543 Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction Schwab S Schwarz S Spranger M Keller E Bertram M Hacke W Stroke 1998 29 2461 2466 9836751 Brain temperature monitoring and modulation in patients with severe MCA infarction Schwab S Spranger M Aschoff A Steiner T Hacke W Neurology 1997 48 762 767 9065562 Moderate hypothermia and brain temperature in patients with severe middle cerebral artery infarction Schwab S Schwarz S Aschoff A Keller E Hacke W Acta Neurochir Suppl 1998 71 131 134 9779165 Direct intraoperative measurement of human brain temperature Stone JG Goodman RR Baker KZ Baker CJ Solomon RA Neurosurgery 1997 41 20 24 10.1097/00006123-199707000-00007 9218291 Endovascular cooling for moderate hypothermia in patients with acute stroke: first results of a novel approach Georgiadis D Schwarz S Kollmar R Schwab S Stroke 2001 32 2550 2553 10.1161/hs1101.097382 11692015 Effect and feasibility of controlled rewarming after moderate hypothermia in stroke patients with malignant infarction of the middle cerebral artery Steiner T Friede T Aschoff A Schellinger PD Schwab S Hacke W Stroke 2001 32 2833 2835 10.1161/hs1201.99511 11739982 Rapid and selective cerebral hypothermia achieved using a cooling helmet Wang H Olivero W Lanzino G Elkins W Rose J Honings D Rodde M Burnham J Wang D J Neurosurg 2004 100 272 277 15086235 A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology Gulumna KZ Hemmen TM Olsen SE Rapp KS Lyden PD Acad Emerg Med 2006 13 820 827 10.1197/j.aem.2006.03.559 16766740 Post-traumatic thrombosis of the carotid artery [in Italian] Greco T Arch Ital Chir 1935 39 757 784 Hemicraniectomy with dural augmentation in medically uncontrollable hemispheric infarction Wirtz CR Steiner T Aschoff A Schwab S Schnippering H Steiner HH Hacke W Kunze S Neurosurgery Focus 1997 2 E3 Decompressive craniectomy for cerebral infarction: an experimental study in rats Forsting M Reith W Schaebitz WR Heiland S von Kummer R Hacke W Sartor K Stroke 1995 26 259 264 7831699 Decompressive craniectomy, reperfusion, or a combination for early treatment of acute 'malignant' cerebral hemispheric stroke in rats: potential mechanisms studied by MRI Engelhorn T Doerfler A Kastrup A Beaulieu C de Crespigny A Forsting M Moseley ME Faraci FM Stroke 1999 30 1456 1463 10390323 Delayed decompressive surgery increases apparent diffusion coefficient and improves peri-infarct perfusion in rats with space-occupying cerebral infarction Hofmeijer J Schepers J Veldhuis WB Nicolay K Kappelle LJ Bar PR van der Worp HB Stroke 2004 35 1476 1481 10.1161/01.STR.0000128415.31274.3a 15131314 Improvement of brain tissue oxygen and intracranial pressure during and after surgical decompression for diffuse brain oedema and space occupying infarction Jaeger M Soehle M Meixensberger J Acta Neurochir Suppl 2005 95 117 118 16463833 Early hemicranectomy in patients with complete middle cerebral artery infarction Schwab S Steiner T Aschoff A Schwarz S Steiner HH Jansen O Hacke W Stroke 1998 29 1888 1893 9731614 Unco-parahippocampectomy for direct surgical treatment of downward transtentorial herniation Mori K Ishimaru S Maeda M Acta Neurochir (Wien) 1998 140 1239 1244 10.1007/s007010050244 9932123 Early external decompressive craniectomy with duroplasty improves functional recovery in patients with massive hemispheric embolic infarction: timing and indication of decompressive surgery for malignant cerebral infarction Mori K Nakao Y Yamamoto T Maeda M Surg Neurol 2004 62 420 429 15518850 Clinical course and surgical management of massive cerebral infarction Robertson SC Lennarson P Hasan DM Traynelis VC Neurosurgery 2004 55 55 62 10.1227/01.NEU.0000126875.02630.36 15214973 Suboptimum hemicraniectomy as a cause of additional cerebral lesions in patients with malignant infarction of the middle cerebral artery Wagner S Schnippering H Aschoff A Koziol JA Schwab S Steiner T J Neurosurg 2001 94 693 696 11354398 Hemicraniectomy in elderly patients with space occupying media infarction: improved survival but poor functional outcome Holtkamp M Buchheim K Unterberg A Hoffmann O Schielke E Weber JR Masuhr F J Neurol Neurosurg Psychiatry 2001 70 226 228 11160473 10.1136/jnnp.70.2.226 Ultra-early decompressive craniectomy for malignant middle cerebral artery infarction Cho DY Chen TC Lee HC Surg Neurol 2003 60 227 232 10.1016/S0090-3019(03)00266-0 12922040 Which patient fares worse after early deterioration due to swelling from hemispheric stroke? Maramattom BV Bahn MM Wijdicks EMF Neurology 2004 63 2142 2145 15596765 Factors predictive of fatality in massive middle cerebral artery territory infarction and clinical experience of decompressive hemicraniectomy Wang KW Chang WN Ho JT Chang HW Lui CC Cheng MH Hung KS Wang HC Tsai NW Sun TK Eur J Neurol 2006 13 765 771 10.1111/j.1468-1331.2006.01365.x 16834708 Treatment of right hemispheric cerebral infarction by hemicraniectomy Delashaw JB Broaddus WC Kassell NF Haley EC Pendleton GA Vollmer DG Maggio WW Grady MS Stroke 1990 21 874 881 2349590 Outcome of acute supratentorial cerebral infarction in patients under 60. Development of a prognostic grading system Steiger HJ Acta Neurochir (Wien) 1991 111 73 79 10.1007/BF01400491 1950691 Aggressive decompressive surgery in patients with massive hemispheric embolic cerebral infarction associated with severe brain swelling Mori K Aoki A Yamamoto T Horinaka N Maeda M Acta Neurochir (Wien) 2001 143 483 492 10.1007/s007010170078 11482699 Decompressive craniectomy for massive infarction of middle cerebral artery territory [abstract] Kuroki K Taguchi H Sumida M Yukawa O Marukami T Onda J Eguchi K No Shinkei Geka 2001 29 831 835 11596466 Is decompressive craniectomy for malignant middle cerebral artery infarction of any worth? Yang X Yao Y Hu W Li G Xu J Zhao X Liu W J Zheijang Univ Sci B 2005 6B 644 649 10.1631/jzus.2005.B0644 Hemicraniectomy for massive middle cerebral artery territory infarction. A systematic review Gupta R Connolly ES Mayer S Elkind MS Stroke 2004 35 539 543 10.1161/01.STR.0000109772.64650.18 14707232 Hemicraniectomy and moderate hypothermia in patients with severe ischemic stroke Georgiadis D Schwarz S Aschoff A Schwab S Stroke 2002 33 1584 1588 10.1161/01.STR.0000016970.51004.D9 12052995 Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke Els T Oehm E Voigt S Klisch J Hetzel A Kassubek J Cerebrovasc Dis 2006 21 79 85 10.1159/000090007 16330868 Recovery from aphasia after hemicraniectomy for infarction of the speech-dominant hemisphere Kastrau F Wolter M Huber W Block F Stroke 2005 36 825 829 10.1161/01.STR.0000157595.93115.70 15705934 Outcome and prognostic factors of hemicraniectomy for space occupying cerebral infarction Uhl E Kreth FW Elias B Goldammer A Hempelmann RG Liefner M Nowak G Oertel M Schmieder K Schneider HH J Neurol Neurosurg Psychiatry 2004 75 270 274 14742603 Outcome after decompressive craniectomy in patients with severe ischemic stroke Harscher S Reichart R Terborg C Hagemann G Kalff R Witte OW Acta Neurochir (Wien) 2006 148 31 37 10.1007/s00701-005-0617-0 16172833 Factors affecting the outcome of decompressive craniectomy for large hemispheric infarctions: a prospective cohort study Kilincer C Asil T Utku U Hamamcioglu MK Turgut N Hicdonmez T Simsek O Ekuklu G Cobanoglu S Acta Neurochir (Wien) 2005 147 587 594 10.1007/s00701-005-0493-7 15739038 Factors predicting prognosis after decompressive hemicraniectomy for hemispheric infarction Rabinstein AA Mueller-Kronast N Maramottom BV Zazulia AR Bamlet WR Diringer MN Wijdicks EFM Neurology 2006 67 891 893 16966561 10.1212/01.wnl.0000233895.03152.66 Hemicraniectomy and durotomy upon deterioration from massive hemispheric infarction: a proposed multicenter, prospective, randomized study Frank JI Krieger D Chyatte D Cancian S Stroke 1999 30 243 Major ongoing stroke trials [No authors listed] Stroke 2006 37 e18 26 16432243 Early decompressive surgery in malignant middle cerebral artery infarction: a pooled analysis of three randomised controlled trials Vahedi K Hofmeijer J Juettler E Vicaut E George B Algra A Amelink GJ Schmiedek P Schwab S Rothwell PM for the DECIMAL, DESTINY, and HAMLET investigators Lancet Neurology 2007 6 215 222 10.1016/S1474-4422(07)70036-4 17303527 Feasibility and safety of moderate hypothermia after massive hemispheric infarction Schwab S Georgiadis D Berrouschot J Schellinger PD Graffagnino C Mayer SA Stroke 2001 32 2033 2035 10.1161/hs0901.095394 11546893 Cerebral vascular accidents in people over the age of 60: II. Prognosis Rankin J Scott Med J 1957 2 200 215 13432835 Functional evaluation. The Barthel Index Mahoney GI Barthel DW MD State Med J 1965 14 61 65 14258950 Surgical decompression for cerebral oedema in acute ischaemic stroke Morley NC Berge E Cruz-Flores S Whittle IR Cochrane Database Syst Rev 2002 CD003435 12137695