The DECRA trial

Dr. Joe M Das

Introduction

• Among patients who are hospitalized with severe traumatic brain injury, 60% either die or survive with severe disability.

• After severe traumatic brain injury, medical and surgical therapies are performed to minimize secondary brain injury.

• Many patients with severe traumatic brain injury have raised intracranial pressure that is refractory to first-tier therapies.

• In such cases, surgical decompressive craniectomy is performed with increasing frequency to control ICP.

• The multicenter, randomized, controlled trial to test the efficacy of bifrontotemporoparietal decompressive craniectomy in adults under the age of 60 years with traumatic brain injury in whom first-tier intensive care and neurosurgical therapies had not maintained intracranial pressure below accepted targets

• Principal Investigator: D. J. Cooper (The Alfred Hospital & National Trauma Research Institute)

Trial design

• From December 2002 through April 2010, adults with severe traumatic brain injury in the intensive care units (ICUs) of 15 tertiary care hospitals in Australia, New Zealand, and Saudi Arabia were recruited

• The trial protocol was designed by the study’s executive committee and approved by the ethics committee at each study center.

Patients• Inclusion criteria:

– Severe diffuse Traumatic Brain Injury defined as:• GCS < 9 and CT scan with evidence of brain swelling (DII + swelling, DIII

or DIV)• OR• GCS >8 before intubation and DIII or DIV (basal cistern compression ±

midline shift)

– Age 15 – 60 years– First 72 hours from time of injury– ICP monitor in situ. EVD strongly recommended. Parenchymal ICP

catheter (Codman) acceptable when technical difficulties or other factors mean that an EVD is not in place. Some patients will have an EVD occluded by brain swelling. These should then have a Codman type catheter inserted additionally to enable ICP measurements, and appropriate therapies. If an EVD is used it must be inserted and drained before randomisation.

PatientsExclusion criteria:

• Intracranial haemorrhage > 3 cm diameter• Intracranial mixed haemorrhagic contusion >5cm in long axis• Previous craniectomy• EDH/SDH/ or large contusion requiring evacuation• EDH/SDH >0.5 cm thickness• Spinal cord injury• Penetrating brain injury• Arrest at scene• Unreactive pupils >4mm, and GCS=3• Neurosurgery contraindicated (eg: severe coagulopathy)• No chance of survival after consideration of CT and clinical

findings following Neurosurgical consultant assessment (eg hemispheric infarct after carotid dissection).

Study Procedures

• Treated in ICUs with ICP monitors • Patients received treatment for intracranial hypertension

whenever the intracranial pressure was >20 mm Hg.• An early refractory elevation in ICP was defined as a

spontaneous increase in intracranial pressure for >15 minutes (continuously or intermittently) within a 1-hour period, despite optimized first-tier interventions.

• 1st tier interventions included optimized sedation, the normalization of arterial carbon dioxide pressure, and the use of mannitol, hypertonic saline, neuromuscular blockade and EVD.

• Within the first 72 hours after injury, patients were randomly assigned either to undergo decompressive craniectomy plus standard care or to receive standard care alone, using an automated telephone randomisation / allocation system.

Surgical technique – Polin• The operation will comprise bi-frontal decompressive craniectomies

with a single fronto-temporal bone flap extending across the midline.

• The temporalis muscles will be reflected inferiorly. • Burr holes are located either side of the sagittal sinus at the posterior

extent and bilaterally at the keyhole and at the root of the zygoma. This will create a large bifrontal craniectomy defect extending posteriorly to the coronal sutures. Bilateral large sub-temporal decompressions will be performed down to the skull base.

• The final bone cut is made along the supraorbital ridges with an attempt to preserve the frontal sinus. Burr holes will be placed either side of the sagittal sinus inferiorly and the bone will be lifted out.

• The dura will be opened in one of two alternative ways: – 1. The dura is opened with a cruciate incision

bilaterally. – OR – 2. A large L shaped incision with the lower corner

of the L facing laterally. The advantage to this method is that the cerebral veins are not disturbed medially by this incision.

• The dural opening should be covered with a dural or facial patch, so that the brain does not adhere to the scalp. Water tight dural closure is not necessarily aimed for.

• For patients receiving EVD monitoring, an ICP monitor with ventricular catheter (± optional PO2 and temperature monitor) may be placed prior to closure.

• The bone flap is replaced once bone swelling has resolved and the patient has improved and left the intensive care unit (6-12 weeks). The bone flap is stored at - 20 to -70°C until reinsertion or it may be implanted in the subcutaneous tissue of the abdominal wall as an alternative.

The DECRA operation procedure• The procedure does not involve a fish-mouth opening of the

dura and dividing the sagittal sinus.• The craniectomy extends from just above the supra-orbital

ridge inferiorly to the coronal suture superiorly and posteriorly.

• An extension of the craniectomy is performed from the lower edge of the bone cut in the temporal region so that the squamous temporal bone is removed by rongeurs extending inferiorly close to the floor of the middle fossa on each side.

• In order to avoid opening the frontal sinus the bone can be left in place in the inferior cut so that the sinus is not entered.

• There is no mid-line strip of bone left in place.• There is no problem with potential kinking of the sagittal sinus

at the superior bone incision margin.

• The dura is opened on each side and this can be done with a generous cruciate incision centred on the frontal pole on each side or with an 'L' shaped incision with the vertical limb of the 'L' laterally and the horizontal limb pointing inwards toward the sagittal sinus. There is a theoretical advantage in the protection of the bridging veins if this technique is used although the coordinating site has not encountered any problem with cruciate incision.

• A dural patch is placed over the durotomy and this can be temporalis fascia and pericranium or synthetic dura and does not necessarily need to be water-tight. It is there to protect the surface of the brain from adhering to the scalp and to act as a further barrier to infection.

• The excision of bone does not proceed posterior to the coronal suture on either side.

• The bone can be stored in a subcutaneous pouch in the abdominal region or preserved in the refrigerator.

• The ventricular catheter should be passed through a separate burr hole posterior to the superior margin of the bone cut and brought out through a separate incision

• After all swelling and infection had resolved, 2 to 3 months after craniectomy, the bone was replaced.

• Standard care from the time of enrollment followed clinical practice guidelines that were based on those recommended by the Brain Trauma Foundation.

• In the two study groups, second-tier options for refractory elevation of ICP included mild hypothermia (to 35°C), the optimized use of barbiturates, or both.

• For patients receiving standard care, the trial protocol permitted the use of lifesaving decompressive craniectomy after a period of 72 hours had elapsed since admission.

Assessments & Data Collection

• All source data were verified in every patient by monitors. At baseline, demographic and clinical characteristics were recorded from medical files. These data included the initial CT findings, which were scored with the use of the Marshall criteria, and the Injury Severity Score

• The Trauma Score–Injury Severity Score was also calculated.• Hourly ICP and MAP measurements were recorded for 12

hours before randomization and 36 hours after randomization.• Also recorded were first- and second-tier therapeutic

interventions and surgical complications of craniectomy and of subsequent cranioplasty.

Outcome Measures• Outcome measures were evaluated by telephone by three trained

assessors who were unaware of study-group assignments. • The original primary outcome was the proportion of patients with

an unfavorable outcome, a composite of death, a vegetative state, or severe disability, as assessed with the use of a structured, validated telephone questionnaire at 6 months after injury.

• After the interim analysis in January 2007, the primary outcome was revised to be the functional outcome at 6 months after injury on the basis of proportion proportional odds analysis of the Extended GOS.

• Secondary outcomes were ICP measured hourly, the intracranial hypertension index, the proportion of survivors with a score of 2 to 4 on the Extended GOS, the numbers of days in the ICU and in the hospital, and mortality in the hospital and at 6 months.

Study Oversight

• Funding was provided by the National Health and Medical Research Council of Australia; the Transport Accident Commission of Victoria, Australia; the Intensive Care Foundation of the Australian and New Zealand Intensive Care Society; and the Western Australian Institute for Medical Research.

Statistical analysis• The trial was originally designed to identify an increase in the

proportion of favorable outcomes (defined as a score of 5 to 8 on the Extended GOS) from 30% among patients receiving standard care to 50% among patients undergoing craniectomy, with a sample size of 210 patients.

• To allow the trial to be completed within a reasonable time frame, the sample size was decreased to 150, with an additional enrollment of 15 patients permitted if necessary to replace patients lost to follow-up.

• Ordinal logistic regression for univariate between-group comparisons of scores on the Extended Glasgow Outcome Scale and logistic regression for comparisons of unfavorable outcomes

• Stata statistical software

• Of 3478 patients who were assessed for trial eligibility, 155 were enrolled

• The first 5 patients who were enrolled in the trial participated in a pilot study

• The most common reasons for exclusion from the trial were the presence of a cerebral mass lesion and successful control of ICP with the use of first-tier therapies.

• The patients were randomly assigned to one of the two treatment groups: 73 to undergo early decompressive craniectomy and 82 to receive standard care.

• The median age was 23.7 years in the craniectomy group and 24.6 in the standard-care group.

• The median ICP during the 12 hours before randomization was 20 mm Hg.

• The median time from randomization to surgery in the craniectomy group was 2.3 hours

• Fifteen patients (18%) in the standard-care group underwent delayed decompressive craniectomy as a lifesaving intervention, according to the protocol.

• In four patients (5%) in the standard-care group, craniectomy was performed less than 72 hours after admission, contrary to the protocol.

Outcomes

• Of patients, 70% in the craniectomy group had an unfavourable outcome versus 51% in the standard care group.

• Among adults with severe diffuse TBI and refractory intracranial hypertension in the ICU, decompressive craniectomy decreased ICP, the duration of mechanical ventilation, and the time in the ICU, as compared with standard care.

• In the craniectomy group, the duration of the hospital stay was unchanged, and the rate of surgical complications was low.

• However, patients in the craniectomy group had a lower median score on the Extended Glasgow Outcome Scale and a higher risk of an unfavorable outcome (as assessed on that scale) than patients receiving standard care.

• Craniectomy or cranioplasty may also have had other harmful complications, including hydrocephalus.

• The rates of most complications were similar in the two study groups.

Limitations• The medical and surgical teams were obviously aware of

study-group assignments, although the assessors were not. • One center recruited more than one third of trial participants.• There were imbalances in some baseline characteristics of the

patients, particularly the proportion of patients without pupil reactivity at hospital admission.

• The primary outcome measure was revised during the course of the trial, though with preservation of blinded study-group assignments. Such a change in protocol is not optimal from the standpoint of trial design, although ultimately, the same results were observed for both the original primary outcome measure and the final primary outcome measure.

• It is unlikely that the findings were due to an increased rate of survival of severely injured patients in a vegetative state , because even though the number of such patients increased after craniectomy, the rates of death were similar in the two study groups.

• Decompressive craniectomy instead shifted survivors from a favorable outcome to an unfavorable outcome

• One possible explanation is that craniectomy allowed expansion of the swollen brain outside the skull and caused axonal stretch. Alterations in cerebral blood flow and metabolism may also be relevant.

• Some surgeons prefer a unilateral procedure, with studies suggesting that the bilateral approach may have more complications. Some surgeons divide the sagittal sinus and falx cerebri, which is a component of the original Polin procedure, but others do not. Complications are possible with both alternatives.

• The results of this trial can be said to apply only to the specific craniectomy procedure that was performed; they may not necessarily apply to other approaches or in other types of brain injury.

Criticisms• The median ICP in the hours prior to randomization was 20 mm Hg, which raises the

important question of whether the patients in the study truly had intracranial hypertension and whether the patients should have ever been considered for surgery.

• 27% of the patients randomized to surgery had bilateral nonreactive pupils, compared to only 12% of the patients in the medical group. This key discrepancy was statistically significant, and when accounting for this between-group difference, there was no difference in outcomes between patients in the decompressive craniectomy and medical management groups.

• Performing their analysis via an “intention-to-treat” design, despite an 18% crossover rate to surgery in the patient group initially randomized to medical management.

• Managing ICPs for 15 minutes prior to randomization, changing the study design at the midpoint analysis instead of stopping the trial for futility, and enrolling in the study only 4% of screened patients over 7 years.

• The DECRA trial contains no data or valuable information to inform modern management of TBI and thus should be ignored by practitioners evaluating treatment options for severe TBI.

Conclusion

In patients with severe diffuse traumatic brain injury and increased intracranial pressure that was refractory to first-tier therapies, the use of craniectomy, as compared with standard care, decreased the mean intracranial pressure and the duration of both ventilatory support and the ICU stay but was associated with a significantly worse outcome at 6 months, as measured by the score on the Extended GlasgowOutcome Scale.

• Intracranial hypertension index – the number of end-hourly measures of ICP of > 20 mm Hg divided by the total number of measurements, multiplied by 100

MARSHALL CT BRAIN GRADING SCORE

Extended Glasgow Outcome Score