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Internal Medicine Journal 45 (2015)

O R I G I N A L A RT I C L E S

Role of decompressive hemicraniectomy in extensive middle cerebral artery strokes: a meta-analysis of randomised trials L. Back, V. Nagaraja, A. Kapur and G. D. Eslick The Whiteley-Martin Research Centre, Discipline of Surgery, The University of Sydney, Nepean Hospital, Sydney, New South Wales, Australia

Key words surgical decompression, medical management, hemicraniectomy, MCA infarction, meta-analysis, randomised trial. Correspondence Guy D. Eslick, Discipline of Surgery, The University of Sydney, Sydney, NSW 2006, Australia. Email: [email protected] Received 22 December 2014; accepted 2 February 2015. doi:10.1111/imj.12724

Abstract Background: Prognosis for patients with ‘malignant’ or space-occupying oedema post middle cerebral artery infarct remains poor despite maximal medical therapy delivered in the intensive care setting. Aim: We performed a meta-analysis to evaluate the value of surgical decompression versus medical management alone in patients suffering from malignant middle cerebral artery infarct. Methods: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google Scholar, Science Direct and Web of Science. Original data was abstracted from each study and used to calculate a pooled odds ratio (OR) and 95% confidence interval (95% CI). Results: The overall OR for mRS 6 (death) at 6 months for decompressive surgery as compared with standard medical management revealed a statistically significant reduction with OR of 0.19 (95% CI: 0.10–0.37). The frequency of patients with mRS 2, 3 and 5 outcomes was higher in the decompressive surgery cohort; however, these outcomes did not reach statistical significance. On the other hand, the number of patients with a mRS score of 4 was significantly higher in the decompressive surgery cohort with an OR of 3.29 (95% CI: 1.76–6.13). The overall OR for mRS 6 (death) at 12 months for decompressive surgery as compared with standard medical management revealed a statistically significant reduction with OR of 0.17 (95% CI: 0.10–0.29). The frequency of patients with mRS 3 and 5 outcomes was higher in the decompressive surgery cohort; however, these outcomes did not reach statistical significance. On the other hand, the number of patients with a mRS score of 4 was significantly higher in the decompressive surgery cohort with an OR of 4.43 (95% CI: 2.27–8.66). In the long run it was also observed that the number of patients with a mRS score of 2 was significantly higher in the decompressive surgery cohort an OR of 4.51 (95% CI: 1.06–19.24). Conclusions: Our results imply that surgical intervention decreased mortality of patients with fatal middle cerebral artery infarct at the expense of increasing the proportion suffering from substantial disability at the conclusion of follow up.

Introduction Malignant middle cerebral artery (MCA) infarction, defined as development of space-occupying cerebral oedema following disruption of arterial supply to the MCA territory, is a debilitating and potentially fatal condition occurring in 1–10% of all supratentorial infarcts.1–3 Prognosis for patients who develop malignant cerebral

Funding: None. Conflict of interest: None

oedema with mass effect post MCA infarct is poor, despite maximal medical and intensive care treatment. In numerous large intensive care-based prospective studies, fatality rates for patients admitted with malignant MCA infarctions approached 80%, with a significant proportion of those patients surviving experiencing severe neurologic disability.3,4 The management of such patients following massive cerebral infarction is still a controversial issue in neurology and neurosurgery. Traditional conservative management dictates the use of medical intervention, including sedation, hyperventilation, barbiturates and osmotic therapy as the mainstay of protection

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Table 1 The modified ranking scale 0 – No symptoms. 1 – No significant disability. Able to carry out all usual activities, despite some symptoms. 2 – Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. 3 – Moderate disability. Requires some help, but able to walk unassisted. 4 – Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. 5 – Severe disability. Requires constant nursing care and attention, bedridden, incontinent. 6 – Dead.

against severe increases in intracranial pressure. To date, there is insufficient randomised evidence to support these conservative strategies and their effect on patient outcome remains unclear.5–8 Due to the noted limitations of medical therapies alone, decompressive surgery has been proposed as an alternative or adjunct management strategy for patients with space-occupying cerebral oedema. Several recent randomised, controlled trials have added to the evidence in support of hemicraniectomy post-MCA infarction, due to a suggested reduction in disability, as quantified on the modified Rankin Scale (mRS), and death (Table 1).9,10 The pooled analysis of the three European randomised trials, published in 2007, claims to provide evidence for the efficacy of decompressive hemicraniectomy in reducing mortality and lowering disability grading, and has significantly impacted the management of patients with malignant MCA infarction worldwide.11 The objective of this study was to pool the available randomised data on decompressive surgery and reassess its value in the management of malignant MCA infarctions.

Methods Study protocol We followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses PRISMA guidelines where possible in performing our systematic review.12 We performed a systematic search through MEDLINE (from 1950), PubMed (from 1946), EMBASE (from 1949), Current Contents Connect (from 1998), Cochrane library, Google scholar, Science Direct and Web of Science to December 2014. The search terms included ‘middle cerebral artery infarctions’ AND ‘decompressive surgery’, ‘hemicraniectomy for middle cerebral artery infarctions’ and ‘surgical decompression for cerebral oedema in acute stroke’, which were searched as text word and as

expanded medical subject headings where possible. No language restrictions were used in either the search or study selection. The reference lists of relevant articles were also searched for appropriate studies. A search for unpublished literature was not performed.

Study selection We included studies that met the following inclusion criteria: – Studies identifying the population of patients with clinically and radiologically confirmed middle cerebral artery infarcts complicated by malignant, spaceoccupying cerebral oedema. – Randomised, controlled trials comparing surgical decompression alone or as an adjunct to conservative, medical management only.

Quality of the studies Two independent reviewers screened the studies for inclusion, extracted data and evaluated quality. Quality assessment of randomised controlled trials was performed by two reviewers according to the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 based on the following aspects: random sequence generation, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias. Three bias levels including low risk, high risk and unclear were assigned to every study aspect. Studies with more ‘low risk’ bias assignations were recognised as superior. Disagreements were resolved by consensus. This has been summarised in Tables 2 and 3.

Data extraction We performed the data extraction using a standardised data extraction form, collecting information on the publication year, study design, number of cases, total sample size, population type, country, continent, mean age and clinical data. The event rate and confidence intervals were calculated.

Statistical analysis Pooled event rate and 95% confidence intervals were determined using a random effects model (DerSimonian and Laird).17 We tested heterogeneity with Cochran’s Q statistic, with P < 0.10 indicated heterogeneity, and quantified the degree of heterogeneity using the I2 statistic, which represents the percentage of the total variable across studies which is due to heterogeneity. I2 values of © 2015 Royal Australasian College of Physicians

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Table 2 Characteristics of the studies included in the systematic review and meta-analysis Trial

Year

Country

DESTINY 2 Juttler et al.9 HEADDFIRST Frank et al.10 Zhao et al.13

2014

Germany

2014

U.S.A

2012

China

HAMLET Hofmeujer et al.14 DECIMAL Vahedi et al.15 DESTINY Juttler et al.16

2009

Netherlands

2007

France

2007

Germany

25%, 50% and 75% corresponded to low, moderate and high degrees of heterogeneity respectively.18 The quantified publication bias using the Egger’s regression model,19 with the effect of bias assessed using the fail–safe number method. The fail–safe number was the number of studies that we would need to have missed for our observed result to be nullified to statistical non-significant at the P < 0.05 level. Publication bias is generally regarded as a concern if the fail–safe number is less than 5n + 10, with n being the number of studies included in the meta-analysis.20 All analyses were performed with Comprehensive Metaanalysis (version 2.0; Biostat, Englewood, NJ, USA).

Results The original search strategy revealed 484 studies (Fig. 1). The abstracts were reviewed, and after applying the inclusion and exclusion criteria, articles were selected for full-text evaluation. Of the articles selected, only six studies met full criteria for analysis, and are summarised in Table 2.9,10,13–16 The years of publication ranged from 2007 to 2014. A total of 317 patients from these six studies met criteria for meta-analysis. Patients from the six selected studies were identified as having MCA stroke with evi-

Age, median (years)

Male (%)

70 70 52.3 57.9 63.5 64 50 47.4 43.5 43.3 43.2 46.1

51 49 21 60 75 69.6 63 56 45 50 47 47

Surgical (n = 49) Medical (n = 63) Surgical (n = 14) Medical (n = 10) Surgical (n = 24) Medical (n = 23) Surgical (n = 32) Medical (n = 32) Surgical (n = 20) Medical (n = 18) Surgical (n = 17) Medical (n = 15)

dence of cerebral oedema, and randomly assigned to surgical decompression and/or medical therapy, and medical therapy alone. Patients were assessed at 6 and 12 months (where available) to determine their outcome and level of disability following stroke. Death or disability in all studies was measured using the mRS.

At six months The overall odds ratio (OR) for mRS 6 (death) at 6 months for decompressive surgery as compared with standard medical management revealed a statistically significant reduction with OR of 0.19 (95% CI: 0.10–0.37). The frequency of patients with mRS 2, 3 and 5 outcomes was higher in the decompressive surgery cohort; however, these outcomes did not reach statistical significance. On the other hand, the number of patients with a mRS score of 4 was significantly higher in the decompressive surgery cohort with an OR of 3.29 (95% CI: 1.76–6.13).

At 12 months The overall OR for mRS 6 (death) at 12 months for decompressive surgery as compared with standard

Table 3 Quality assessment Author

Random sequence generation Allocation concealment Blinding of participants and personnel Blind of outcome assessment Incomplete outcome data Selective reporting

DESTINY 2 Juttler et al.9

HEADDFIRST Frank et al.10

Zhao et al.13

HAMLET Hofmeujer et al.14

DECIMAL Vahedi et al.15

DESTINY Juttler et al.16

Low Low Unclear Unclear Low Low

Low Low Unclear Unclear Low Low

Low Low Unclear Unclear Low Low

Low Low Unclear Unclear Low Low

Low Low Unclear Unclear Low Low

Low Low Unclear Unclear Low Low

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Figure 1 Flow of included studies. Records identified through database searching (n = 484)

Additional records identified through other sources (n = 0)

Records after duplicates removed (n = 0)

Records screened (n = 484)

Studies excluded, letters editorials, reviews (n = 478)

Full-text articles assessed for eligibility (n = 6)

Full-text articles excluded, with reasons (n = 0)

Studies included in qualitative synthesis (n = 6)

Studies included in quantitative synthesis (metaanalysis) (n = 6)

medical management revealed a statistically significant reduction with OR of 0.17 (95% CI: 0.10–0.29). The frequency of patients with mRS three and five outcomes was higher in the decompressive surgery cohort; however, these outcomes did not reach statistical significance. On the other hand, the number of patients with a mRS score of 4 was significantly higher in the decompressive surgery cohort with an OR of 4.43 (95% CI: 2.27–8.66). In the long run, it was also observed that the number of patients with an mRS score of 2 was significantly higher in the decompressive surgery cohort of an OR of 4.51 (95% CI: 1.06–19.24).

Heterogeneity and publication bias The heterogeneity of outcomes has been summarised in Table 4. No publication bias was detected using the Egger’s regression model.

Discussion The pooled analysis of randomised trials to date confirms suggestions from the available randomised data that

decompressive surgery undertaken within the acute setting post-MCA infarction significantly reduces patient mortality, and increases the number of patients with a variable functional outcome at 6 and 12 months. A previous Cochrane review performed in 2012 pooling data

Table 4 Overall odds ratio and 95% CI Odds ratio

95% confidence interval

P value

I2

P value

At 6 months mRS 2 mRS 3 mRS 4 mRS 5 mRS 6

2.44 1.87 3.29 1.47 0.19

0.53–11.16 0.78–4.48 1.76–6.13 0.65–3.34 0.10–0.37

0.25 0.16

Role of decompressive hemicraniectomy in extensive middle cerebral artery strokes: a meta-analysis of randomised trials.

Prognosis for patients with 'malignant' or space-occupying oedema post middle cerebral artery infarct remains poor despite maximal medical therapy del...
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