Jüttler E, Unterberg A, Woitzik J, Bösel J, Amiri H, Sakowitz OW, et al. Hemicraniectomy in Older Patients with Extensive Middle-Cerebral-Artery Stroke. N Engl J Med. 2014 Mar 20;370(12):1091–100.
Introduction
Massive hemispheric involvement occurs in up to 10% of patients with supratentorial infarcts (1). Life-threatening cerebral edema often follows, referred to as malignant middle-cerebral-artery syndrome (2), with a mortality of 70-80% (3). The onset of clinical deterioration usually occurs between 3–5 days of stroke onset, characterized by increasing drowsiness, leading to coma. Therapeutic modalities commonly employed include sedation, mechanical ventilation with maintenance of hypocapnia, corticosteroids, and osmotherapy. However, there is no evidence to support the efficacy of these measures (4,5); some reports suggest that they may indeed be harmful (6). Beginning from the 1950s, surgical decompression with hemicraniectomy and duraplasty was proposed as a rescue measure in this situation (7).
Nearly five decades ago, Ivamoto et al. published a detailed case report of a 49-year-old housewife who presented with flaccid hemiplegia, homonymous hemianopia, and Babinsky’s sign following extensive infarction involving the right middle-cerebral-artery territory (8). Her condition deteriorated gradually; by the third day of her illness, she lay in a stuporous state, with irregular respirations, and progressive bradycardia. Her right pupil was blown and hardly reacting to light, suggesting impending herniation. A bolus dose of 20% mannitol led to transient improvement; however, death appeared imminent. Her surgeon decided to perform decompressive surgery as a last resort to save her life. She underwent a large craniotomy and subtemporal craniectomy with an anterior dural incision. Her intracranial pressure, measured using a fiberoptic device, reduced dramatically following the procedure; by early next morning, she was alert and orientated, with normal pupils and respiration. She was discharged home 3 weeks later; her left hemiparesis had marginally improved by that time. The authors reviewed an additional 17 cases of decompressive craniectomy performed for ischemic stroke reported in literature. They concluded that large cerebral infarcts may lead to significant edema and cause a life-threatening rise in intracranial pressure. These effects may be alleviated by a life-saving decompressive craniectomy; however, they proposed controlled trials to evaluate the true clinical efficacy of this procedure.
Hemicraniectomy enables the creation of space to accommodate the swollen brain and ameliorate raised intracranial pressure, thereby preventing fatal brain herniation. The turn of the millennium witnessed the commencement of three randomized controlled trials (RCT) – DESTINY, DECIMAL, and HAMLET – to evaluate the efficacy of decompressive craniectomy compared with conservative management among patients with malignant middle-cerebral-artery syndrome (9–11). A pooled analysis of these trials revealed improved 1-year survival with early hemicraniectomy compared with conservative management (78% vs. 29%) (12). Furthermore, functional outcomes were superior following hemicraniectomy, with 43% experiencing relatively good outcomes with mild or moderate disability compared to 21% in the control group.
Enrolment was limited to patients who were 60 years old or less in all three RCTs. Hence, the possible efficacy of hemicraniectomy among older patients with ischemic stroke was unclear. A systematic review of 19 studies found higher mortality with decompressive craniectomy following malignant middle-cerebral-artery stroke among those >60 years old compared to younger patients. Besides, clinical outcomes among survivors were less favorable in this age group (13). A database analysis evaluated outcomes following decompressive craniectomy among patients with infarction involving the middle-cerebral-artery. On multivariate analysis, age >50 years was a predictor of unfavorable outcomes (14). Death or significant disability was also found to be more common among patients >50 years of age who underwent decompressive craniectomy following large hemispheric infarcts (15). Considering the lack of robust evidence and conflicting results from observational trials, a compelling need arose for an RCT to evaluate the possible benefit of decompressive craniectomy in extensive middle-cerebral-artery stroke among older patients.
The DESTINY II investigators sought to evaluate outcomes following early hemicraniectomy compared with conservative management among patients >60 years old with malignant middle-cerebral-artery infarction (16).
Population and design
The DESTINY II trial recruited patients between August 2009 and May 2013 across 13 centers in Germany. Patients ≥61 years old, with malignant middle-cerebral artery infarction, were randomized in a 1:1 ratio to conservative treatment or hemicraniectomy. The eligibility criteria included an NIHSS (National Institutes of Health Stroke Scale) score >14 in a nondominant hemisphere and >19 in a dominant hemisphere stroke, with impaired consciousness. Besides, the infarct had to involve at least two-thirds of the middle-cerebral-artery territory, including the basal ganglia.
Excluded
Patients with a premorbid score of >1 on the modified Rankin scale were excluded (patients included in the trial had no significant disability and were able to carry out all usual activities at baseline). Patients with a pre-existing score of <95 on the Barthel index were also excluded (patients included in the trial were almost totally independent with activities of daily living at baseline). Also excluded were patients with absent pupillary reflexes, a score of <6 on the Glasgow Coma Scale (GCS), intracranial hemorrhage, contraindications for surgery, and a life expectancy of <3 years. Randomization was carried out within 48 hours of symptom onset. Treatment was commenced in both groups within 48 hours of symptom onset and not later than 6 hours after randomization.
The conservative treatment group
In the conservative arm, treatment was based on a consensus protocol. Osmotherapy included mannitol, hypertonic hydroxyethyl starch, or glycerol; invasive mechanical ventilation with hypocapnia to 28–32 mm Hg was resorted to as appropriate.
The hemicraniectomy group
A large hemicraniectomy with duraplasty was performed with a bone flap of at least 12 cm, including the frontal, parietal, temporal, and part of the occipital squamae. Among survivors, cranioplasty was carried out at 6 weeks to 8 months using the stored bone flap or an artificial flap. In the postoperative period, the systolic blood pressure was maintained between 140–160 mm Hg for the first 8 hours to prevent intracranial bleeding.
Common management
The appropriate use of sedatives and measurement of intracranial pressure were left to clinician judgment. Normothermia was aimed for, and the blood glucose level was maintained between 80–110 mg/dl, with an upper level not to exceed 140 mg/dl. The hemoglobin level was maintained above 10 g/dl; low molecular weight heparin was recommended as prophylaxis against deep vein thrombosis.
Sample size
The primary endpoint was a score of 0–4 on the modified Rankin scale at 6 months (Table 1). The authors used a sequential methodology with pre-planned stoppage of the trial at any stage when efficacy, harm, futility was evident on interim analysis. They calculated the sample size assuming a success rate of 31% for the primary endpoint in the hemicraniectomy group and 8.6% in the control group, thus providing the study with 90% power.
Table 1. The modified Rankin Scale
| SCORE | DESCRIPTION |
| 0 | No symptoms |
| 1 | Some symptoms, but able to perform all routine activities |
| 2 | Mild disability, unable to perform all previous activities; able to look after own affairs unassisted |
| 3 | Moderate disability, requires some help. Able to walk without assistance |
| 4 | Moderately severe disability. Unable to walk without assistance; unable to attend to bodily needs without assistance |
| 5 | Severe disability; bedridden, incontinent and requires nursing care |
| 6 | Death |
Results
Based on pre-specified stopping rules, the study was terminated after the recruitment of 112 patients – 49 in the hemicraniectomy group and 63 in the control group. The median age was 70 years, and the modified Rankin score was similar at baseline in both groups. The median NIHSS score was 20 in the hemicraniectomy group and 21 in the control group among those who were assessable. The median GCS was 12 in the hemicraniectomy group and 10 in the control group.
The primary endpoint
At 6 months, a score of 0–4 on the modified Rankin scale (from no symptoms to moderately severe disability – inability to walk and attend to bodily needs without assistance), considered a favorable outcome, was significantly higher in the hemicraniectomy group (20/49 vs. 10 of 63). The bias-corrected estimated of survival without severe disability was significantly greater with hemicraniectomy (38% vs. 18%, odds ratio, 2.91; 95% CI, 1.06–7.49, p = 0.04). Analysis based on a sequential proportional-odds model confirmed the beneficial impact of hemicraniectomy. However, hemicraniectomy did not reveal a significant benefit when scores were dichotomized to 0–3 (able to walk unassisted) vs. 4–6 (unable to walk unassisted, moderate to severe disability, or death).
There were no patients in either group with a score of 0–2 (ability to take care of own affairs without support). In the hemicraniectomy group, 7% of patients had a score of 3 compared with 3% in the control group; a score of 4 occurred in 32% in the hemicraniectomy compared with 15% in the control group.
Secondary endpoints
The 12-month survival was significantly higher in the hemicraniectomy group (57% vs. 24%). Other secondary endpoints included the score on the modified Rankin scale, the NIHSS score, the Barthel index score (the level of activities of daily living), the HDRS score (level of depression), the SF-36 score (quality of life), and the EQ-5D score (self-report) at 12 months. All the above endpoints were more favorable in the hemicraniectomy group.
Safety outcomes
The incidence of adverse events was similar between groups. Infective complications were more common in the hemicraniectomy group. Twenty-three complications were directly related to either the initial hemicraniectomy or reimplantation of the bone flap. In the control group, the most common adverse events were cerebral edema and herniation.
Strengths
Strokes are generally more common among the elderly, and carry worse outcomes than younger subjects. Hence, the DESTINY II investigators addressed an important clinical question regarding the efficacy of hemicraniectomy for malignant middle-cerebral-artery infarction among patients older than 60 years of age. The multicentric design adds to the external validity of the trial. The conclusions were robust and revealed significantly improved survival following hemicraniectomy among older patients with extensive hemispheric stroke, although most survivors required continued assistance with bodily needs.
Weakness
The outcome benefit was largely due to improved survival among patients who underwent hemicraniectomy. However, the level of disability among survivors was similar in both groups. At 1-year follow-up, nearly 50% of survivors in both groups were unable to walk or attend to bodily needs without assistance; one-third of patients in both groups were bedridden, incontinent, or required constant bedside care. Hence, although surgical intervention saved lives, the level of disability remained comparable. The trial was ceased early based on pre-defined stoppage rules, as the efficacy of hemicraniectomy appeared evident. However, early stoppage resulted in a reduced sample size that could have affected the results. A score of 3 on the modified Rankin scale, with the ability to walk unsupported may be considered a preferred endpoint compared with a score of 2, with the inability to attend to bodily needs and walk unsupported. The study was not powered to evaluate the efficacy of hemicraniectomy for this more favorable endpoint.
Summary
Internal carotid or middle-cerebral-artery occlusion leads to massive hemispheric infarction in approximately 10% of ischemic strokes. Three RCTs were published between 2007–2009 that evaluated the efficacy of hemicraniectomy in malignant ischemic stroke within 48 hours of symptom onset. The results from these studies revealed improved survival with favorable neurological outcomes among patients aged 18–60 years. However, ischemic strokes become more common with advancing age, leading to poorer clinical outcomes. The DESTINY II trial addressed the question whether the favorable effects of hemicraniectomy in massive ischemic stroke may be applicable among older patients aged 61 years and above. The median age of patients included was 70 years. The study was stopped early as improved outcomes became evident in the hemicraniectomy group. A score of 0–4 on the modified Rankin scale, considered a favorable outcome, occurred in significantly more patients in the hemicraniectomy group. The outcome benefit was driven mainly by improved survival among patients who underwent hemicraniectomy; the level of disability among survivors remained similar in both groups. Indeed, there were no patients in either group who survived to a level of minor or no disability. Nearly all post-operative survivors were severely disabled. The study established improved survival with hemicraniectomy in patients >60 years old with malignant middle-cerebral-artery infarction. However, most survivors continued to require assistance with bodily needs.
Outcomes from malignant middle-cerebral-artery infarction remain poor with a high mortality of close to 80% among the older population. The DESTINY II trial established improved survival with hemicraniectomy in this population. Most survivors experienced a high level of disability, being unable to walk unsupported, and requiring assistance for bodily needs. It is important to understand the perspective of patients and families regarding what they may consider to be a reasonable outcome. When faced with the prospect of imminent death, many may consider life-saving measures as appropriate while remaining hopeful of reasonable long-term outcomes.
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