Surgical management of traumatic brain injury: a comparative-effectiveness study of 2 centers

Clinical article

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Object

Mass lesions from traumatic brain injury (TBI) often require surgical evacuation as a life-saving measure and to improve outcomes, but optimal timing and surgical technique, including decompressive craniectomy, have not been fully defined. The authors compared neurosurgical approaches in the treatment of TBI at 2 academic medical centers to document variations in real-world practice and evaluate the efficacies of different approaches on postsurgical course and long-term outcome.

Methods

Patients 18 years of age or older who required neurosurgical lesion evacuation or decompression for TBI were enrolled in the Co-Operative Studies on Brain Injury Depolarizations (COSBID) at King's College Hospital (KCH, n = 27) and Virginia Commonwealth University (VCU, n = 24) from July 2004 to March 2010. Subdural electrode strips were placed at the time of surgery for subsequent electrocorticographic monitoring of spreading depolarizations; injury characteristics, physiological monitoring data, and 6-month outcomes were collected prospectively. CT scans and medical records were reviewed retrospectively to determine lesion characteristics, surgical indications, and procedures performed.

Results

Patients enrolled at KCH were significantly older than those enrolled at VCU (48 vs 34 years, p < 0.01) and falls were more commonly the cause of TBI in the KCH group than in the VCU group. Otherwise, KCH and VCU patients had similar prognoses, lesion types (subdural hematomas: 30%–35%; parenchymal contusions: 48%–52%), signs of mass effect (midline shift ≥ 5 mm: 43%–52%), and preoperative intracranial pressure (ICP). At VCU, however, surgeries were performed earlier (median 0.51 vs 0.83 days posttrauma, p < 0.05), bone flaps were larger (mean 82 vs 53 cm2, p < 0.001), and craniectomies were more common (performed in 75% vs 44% of cases, p < 0.05). Postoperatively, maximum ICP values were lower at VCU (mean 22.5 vs 31.4 mm Hg, p < 0.01). Differences in incidence of spreading depolarizations (KCH: 63%, VCU: 42%, p = 0.13) and poor outcomes (KCH: 54%, VCU: 33%, p = 0.14) were not significant. In a subgroup analysis of only those patients who underwent early (< 24 hours) lesion evacuation (KCH: n = 14; VCU: n = 16), however, VCU patients fared significantly better. In the VCU patients, bone flaps were larger (mean 85 vs 48 cm2 at KCH, p < 0.001), spreading depolarizations were less common (31% vs 86% at KCH, p < 0.01), postoperative ICP values were lower (mean: 20.8 vs 30.2 mm Hg at KCH, p < 0.05), and good outcomes were more common (69% vs 29% at KCH, p < 0.05). Spreading depolarizations were the only significant predictor of outcome in multivariate analysis.

Conclusions

This comparative-effectiveness study provides evidence for major practice variation in surgical management of severe TBI. Although ages differed between the 2 cohorts, the results suggest that a more aggressive approach, including earlier surgery, larger craniotomy, and removal of bone flap, may reduce ICP, prevent cortical spreading depolarizations, and improve outcomes. In particular, patients requiring evacuation of subdural hematomas and contusions may benefit from decompressive craniectomy in conjunction with lesion evacuation, even when elevated ICP is not a factor in the decision to perform surgery.

Abbreviations used in this paper:COSBID = Co-Operative Studies on Brain Injury Depolarizations; CSD = cortical spreading depression; DC = decompressive craniectomy; DECRA = Decompressive Craniectomy (study); ECoG = electrocorticography; ICP = intracranial pressure; ISD = isoelectric spreading depolarization; KCH = King's College Hospital; RESCUEicp = Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intra-Cranial Pressure; TBI = traumatic brain injury; VCU = Virginia Commonwealth University.

Abstract

Object

Mass lesions from traumatic brain injury (TBI) often require surgical evacuation as a life-saving measure and to improve outcomes, but optimal timing and surgical technique, including decompressive craniectomy, have not been fully defined. The authors compared neurosurgical approaches in the treatment of TBI at 2 academic medical centers to document variations in real-world practice and evaluate the efficacies of different approaches on postsurgical course and long-term outcome.

Methods

Patients 18 years of age or older who required neurosurgical lesion evacuation or decompression for TBI were enrolled in the Co-Operative Studies on Brain Injury Depolarizations (COSBID) at King's College Hospital (KCH, n = 27) and Virginia Commonwealth University (VCU, n = 24) from July 2004 to March 2010. Subdural electrode strips were placed at the time of surgery for subsequent electrocorticographic monitoring of spreading depolarizations; injury characteristics, physiological monitoring data, and 6-month outcomes were collected prospectively. CT scans and medical records were reviewed retrospectively to determine lesion characteristics, surgical indications, and procedures performed.

Results

Patients enrolled at KCH were significantly older than those enrolled at VCU (48 vs 34 years, p < 0.01) and falls were more commonly the cause of TBI in the KCH group than in the VCU group. Otherwise, KCH and VCU patients had similar prognoses, lesion types (subdural hematomas: 30%–35%; parenchymal contusions: 48%–52%), signs of mass effect (midline shift ≥ 5 mm: 43%–52%), and preoperative intracranial pressure (ICP). At VCU, however, surgeries were performed earlier (median 0.51 vs 0.83 days posttrauma, p < 0.05), bone flaps were larger (mean 82 vs 53 cm2, p < 0.001), and craniectomies were more common (performed in 75% vs 44% of cases, p < 0.05). Postoperatively, maximum ICP values were lower at VCU (mean 22.5 vs 31.4 mm Hg, p < 0.01). Differences in incidence of spreading depolarizations (KCH: 63%, VCU: 42%, p = 0.13) and poor outcomes (KCH: 54%, VCU: 33%, p = 0.14) were not significant. In a subgroup analysis of only those patients who underwent early (< 24 hours) lesion evacuation (KCH: n = 14; VCU: n = 16), however, VCU patients fared significantly better. In the VCU patients, bone flaps were larger (mean 85 vs 48 cm2 at KCH, p < 0.001), spreading depolarizations were less common (31% vs 86% at KCH, p < 0.01), postoperative ICP values were lower (mean: 20.8 vs 30.2 mm Hg at KCH, p < 0.05), and good outcomes were more common (69% vs 29% at KCH, p < 0.05). Spreading depolarizations were the only significant predictor of outcome in multivariate analysis.

Conclusions

This comparative-effectiveness study provides evidence for major practice variation in surgical management of severe TBI. Although ages differed between the 2 cohorts, the results suggest that a more aggressive approach, including earlier surgery, larger craniotomy, and removal of bone flap, may reduce ICP, prevent cortical spreading depolarizations, and improve outcomes. In particular, patients requiring evacuation of subdural hematomas and contusions may benefit from decompressive craniectomy in conjunction with lesion evacuation, even when elevated ICP is not a factor in the decision to perform surgery.

The failure of many randomized controlled drug treatment trials to show clinical benefit in treating traumatic brain injury (TBI) is leading to a reexamination of the research approach to improve TBI outcomes. Despite failure of therapeutic trials, gradual improvements in outcome have been gained as a result of observational studies, meta-analyses of individual patient data, and guideline development.27,34,43 However, the level of evidence to support most guidelines is low, and many uncertainties regarding best clinical practice remain. Thus, substantial variance in clinical management between centers can confound results of clinical trials.13,41 On the other hand, observational and comparative-effectiveness studies can take advantage of this variance to identify best management practice and drive guideline development. The goal of comparative-effectiveness research is to measure differences in outcome and relate them to differences in disease management in ordinary settings and broad populations.

Here we have adopted this comparative-effectiveness approach to compare practices of surgical management of TBI and their efficacy in an observational study of two academic, university-affiliated centers in Europe and the United States. Since the 1970s there has been ongoing controversy regarding the procedure of decompressive craniectomy (DC),4,8,12,16,48 which is primarily used in two types of patients. The first consists of patients with sustained elevated intracranial hypertension that is refractory to medical management.51 The DECRA (Decompressive Craniectomy) trial showed no efficacy of DC in such cases with diffuse swelling,15 although the RESCUEicp trial (Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intra-Cranial Pressure), which involves a broader patient mix, is ongoing.38 The second group consists of patients who undergo DC in conjunction with evacuation of intracranial lesions such as contusions or subdural hematomas. In these cases, craniectomy with removal of the bone flap is performed with the auxiliary purpose of prophylactic decompression to preempt a possible rise in intracranial pressure (ICP) later in the patient's course. There has recently been a resurgence in the use of DC in conjunction with mass lesion evacuation,14 and early DC has become a standard of care for treatment of severe TBI in the military setting when other treatment options are limited.5 Several recent retrospective, single-center studies have examined the effectiveness of DC as a primary intervention with differing results.1,17,18,36,46,52,54

The uses of DC as either a primary preemptive procedure or as a secondary procedure for patients with refractory intracranial hypertension are thus controversial and there is insufficient evidence to support guidelines for DC use in either scenario. The Brain Trauma Foundation Guidelines merely suggest that DC may be an appropriate choice in patients with posttraumatic edema, hemispheric swelling, or diffuse injury.9,10 Furthermore, dichotomization between primary preemptive and secondary DC is a simplification of the indications for and use of DC in everyday clinical practice. A majority of patients with mass lesions may fall between these extremes and undergo lesion evacuation with a craniotomy or craniectomy of variable size only after a “wait-and-see” approach, with evidence of neurological decline or ICP elevation with or without failure of medical management.

In this study we examined different surgical methods and the use of DC to treat TBI in real-world scenarios by comparing injury characteristics, surgical methods, and outcomes between one neurosurgical center in the United Kingdom and a similar service in the United States. The Co-Operative Studies on Brain Injury Depolarizations (COSBID) uses electrocorticography with subdural electrode strips to monitor the pathologic entity of cortical spreading depolarizations, which arise spontaneously in 50%–60% of patients with severe TBI and are associated with worse outcomes.25,29–31 As a prerequisite to placement of electrode strips, only patients who undergo neurological surgery for lesion evacuation or decompression are enrolled. This allows the opportunity to compare surgical management approaches and their efficacy in an observational study of different centers. Comparison of these two centers suggests that earlier surgical intervention and craniectomy procedures with a large area of bone removal are associated with lower incidence of spreading depolarizations, reduced intracranial pressures, and better outcomes.

Methods

We compared all TBI patients enrolled in the Co-Operative Studies on Brain Injury Depolarizations (COSBID) at King's College Hospital (KCH, London, UK) and Virginia Commonwealth University (VCU, Richmond, Virginia). COSBID uses subdural electrocorticography (ECoG) to monitor spreading depolarizations in patients with acute brain injury who require neurosurgical intervention with dural opening. Thus, the same broad inclusion criteria were used at both centers: clinical decision for craniotomy/craniectomy for lesion evacuation, decompression, or both, and age 18 years or older. Patients with fixed, dilated pupils were excluded. Because ECoG is a primary endpoint of the COSBID studies, 4 of a total of 55 patients were excluded due to poor technical quality of ECoG recordings. Research protocols were approved by the VCU Institutional Review Board and the Cambridgeshire 4 Research Ethics Committee, and surrogate informed consent was obtained for all patients. Research was conducted in accordance with the Declaration of Helsinki.

Procedures

Seven variables based on patient characteristics at hospital admission were collected prospectively, as defined by the IMPACT study,37,45 to measure injury severity and prognostic risk. These were age, Glasgow Coma Scale motor score, pupillary reactivity, Marshall category of admission CT, and the presence of hypotension, hypoxia, and traumatic subarachnoid hemorrhage. Motor and pupillary responses most reflective of the post-resuscitation condition were used. Hypotension and hypoxia were determined based on the period preceding and at hospital admission. Patients were considered hypotensive if there was a recorded systolic blood pressure less than 90 mm Hg and hypoxic if there was a recorded PaO2 < 60 mm Hg or SaO2 < 90%.

To assess prognostic risk based on these admission variables in a summary prognostic score, we used the linear predictor from the published 7-variable model.37 For instance, prognostic scores of −2.2, 0.0, and 2.2 correspond to 10%, 50%, and 90% probabilities of poor outcome (dead, vegetative state, or severe disability). In effect, we used the large sample of cases analyzed by Hukkelhoven and colleagues to give an appropriate weighting of these 7 conventional variables. A few covariate values (4 [1.1%] of 357) were missing and were imputed using their expected values conditional on the recorded covariates and the outcomes for the relevant patients, using modeling from a larger patient series.29

Presurgical CT scans were evaluated by a central neuroradiologist (A.V.) at a different institution who was blinded to all other study data. Scans were scored for lesion type and size, degree of traumatic subarachnoid hemorrhage, swelling, and evidence of mass effect. Operative notes were reviewed to determine the primary indications for surgery (initial CT, expanding lesion, clinical deterioration, and/or refractory elevated ICP) and the surgical procedures performed, including decompression and lesion evacuation. Postsurgical CT scans were scored for craniotomy or craniectomy type, size, and method of bone flap fixation (see below). If patients required more than one craniotomy or craniectomy, only the first procedure was evaluated; subsequent procedures were considered unexpected complications.

At the conclusion of surgery, an electrode strip was placed on the surface of the cortex for subsequent electrocorticography to monitor for spreading depolarizations.24,53 The strip was placed near the injury focus on viable but often edematous or contused cortex with a low load of subarachnoid blood. After surgery, patients were transferred to the intensive care unit where continuous electrocorticography was initiated. Neurocritical care practices were consistent with guidelines for management of severe TBI7 and were similar at the two sites, except as noted here. Preferred sedatives and analgesics were propofol, benzodiazepines, and fentanyl at both sites; these medications have minimal influence on depolarizations.33 Phenytoin was used for seizure prophylaxis, but continuous electroencephalography was not standard at either site. Nimodipine was never used. Target values for cerebral perfusion pressure and ICP were > 60 mm Hg and < 20 mm Hg, respectively. ICP control was achieved by head elevation, analgosedation, temperature control, mannitol or hypertonic saline, and barbiturate coma as a late salvage therapy. VCU also made aggressive, early use of CSF drainage by ventriculostomy and hypothermia (33°C–34°C) as a late salvage therapy, in contrast to KCH. Hyperventilation to PaCO2 < 35 mm Hg was not used. ICP values recorded in nursing charts were used for analysis. ECoG recordings were terminated, and electrode strips were removed at the bedside by gentle traction when invasive neuromonitoring was no longer clinically required or after a maximum of 7 days. No hemorrhagic or infectious complications were associated with the electrode strip. Neurological outcome was assessed at 6 months according to the extended Glasgow Outcome Scale by a telephone interview or clinic visit and dichotomized to good (moderate disability or good recovery; 5–8) or poor (dead, vegetative state, or severe disability; 1–4).

Electocorticography

Electrocorticographic recordings were made from a linear subdural strip, which consisted of 6 electrodes with 10-mm spacing between contacts (Wyler, Ad-Tech Medical). Electrodes were connected in a sequential bipolar fashion to AC-coupled amplifiers (Dual Bioamp or Octal amplifiers, ADInstruments; GT205, Guger Technologies) with 0.02- or 0.01-Hz high-pass cutoff. Data were recorded and reviewed with 200-Hz sampling by a Powerlab 16/SP and LabChart software, version 7.2 (ADInstruments).

Recordings were analyzed offline for spreading depolarizations by central COSBID reviewers (M.F. and J.A.H.) according to methods previously established.24,29 Briefly, the signature of spreading depolarization is a slow-potential change of 1- to 5-mV peak-to-peak amplitude in the near-DC (< 0.1 Hz) frequency band, reflecting in part the intracellular flux of cations during mass tissue depolarization.32 When spontaneous brain electrical activity is present (0.5–100 Hz), the depolarization also causes suppression of this activity (that is, spreading depression), which spreads between electrodes at 1–6 mm/min along with the slow potential. Thus, we identified depolarizations by spreading slow-potential changes and classified them either as isoelectric spreading depolarization (ISD), when no spontaneous activity was present, or as cortical spreading depression (CSD), when depolarization caused depression of spontaneous electrocorticographic activity. ISDs represent a more severe form of spreading depolarization, as they are analogous to peri-infarct depolarizations, which cause lesion expansion in ischemic stroke.3,11,35 The distinction between ISD and CSD has been made in previous clinical studies of TBI,29,31 ischemic stroke,19 and aneurysmal subarachnoid hemorrhage.23

Scoring of CT Scans

Postsurgical CT scans were evaluated to quantify craniotomy/craniectomy size by a central neurosurgeon (C.Z.) who was located at a different institution and blinded to other clinical data. Since the shape of a typical craniotomy most closely resembles an ellipse, bone flap areas were approximated using the formula for an ellipse: ABπ/4, where A is the major axis and B the minor axis. The major axis was defined as the greatest anterior-posterior length as determined on the axial CT cuts. The number of axial cuts containing the craniotomy was multiplied by the slice thickness to determine the minor axis. Because cranial sizes vary, we also calculated the proportion of skull removed by dividing the craniotomy area by the entire area of the intact skull. To estimate the intact skull area, we again used the formula for an ellipse as a loose approximation for the area of the hemicranium, determining the major and minor axes as described above. This value was multiplied by 2. For patients with bilateral craniotomies, sizes of each craniotomy were calculated separately and the larger of the two was used for analysis.

Results

All Surgical Patients

We studied 27 KCH and 24 VCU patients who required neurosurgical treatment for TBI between July 2004 and March 2010. Table 1 shows the injury characteristics and surgical indications for the two groups. Causes of injury were mostly blunt closed-head trauma, and falls were more common at KCH, occurring in 70% of patients compared with only 25% at VCU (p = 0.001). KCH patients were also significantly older (48 ± 18 vs 34 ± 18 [SD] years, p < 0.01), although prognostic scores based on 7 admission variables including age did not significantly differ between the centers. Maximal ICP values were also similar between patients who received ICP monitoring prior to surgery. Patients at both centers were predominantly male (KCH: 20 [74%] of 27; VCU: 19 [79%] of 24).

TABLE 1:

Summary of preoperative clinical characteristics for all patients*

VariableKCH (n = 27)VCU (n = 24)p Value
baseline indicators
cause of trauma
 fall1960.001
 MVA16
 assault31
 GSW04
 motorcycle03
 bicycle03
 ped-MVA11
 unknown30
mean prognostic score−0.15 ± 0.990.22 ± 1.090.22
mean max preop ICP (mm Hg)44.4 ± 14.348.3 ± 26.60.67
indication for surgery
 initial CT15 (56%)14 (58%)
 expanding lesion5 (19%)8 (33%)
 clinical deterioration10 (37%)12 (50%)
 refractory ICP8 (30%)12 (50%)
preop CT measures
primary lesion
 SDH7 (30%)8 (35%)
  mean thickness (mm)12.8 (3.8)13.6 (4.8)0.74
 contusion11 (48%)12 (52%)
  mean vol (cm3)§51 ± 1276 ± 470.21
 EDH4 (17%)0
 SAH02 (9%)
 ICH1 (4%)0
 depressed skull fx01 (4%)
basal cisterns compressed/absent11 (48%)17 (74%)0.07
midline shift ≥ 5 mm12 (52%)10 (43%)0.56

Values indicate numbers of patients (%) unless otherwise indicated; mean values are given with SDs. EDH = epidural hematoma; fx = fracture; GSW = gunshot wound; ICH = intracerebral hemorrhage; MVA = motor vehicle accident; ped-MVA = pedestrian struck by motor vehicle; SAH = subarachnoid hemorrhage; SDH = subdural hematoma.

Mean preoperative ICP values are based on 11 patients in the KCH cohort and 12 in the VCU cohort.

Analysis of CT measures (other than for contusion volume) is based on 23 patients in each cohort due to missing CT scans.

Mean contusion volume is based on those patients in whom contusions could be quantified and the volume was > 25 cm3: 8 patients in the KCH cohort and 7 in the VCU cohort.

The clinical indications for surgery were similar between groups, with initial CT scan as a principal factor in 56% of KCH and 58% of VCU patients. Scoring of presurgical CT scans also indicated a similar distribution of pathoanatomical factors between the groups: subdural hematomas and contusions were the primary lesion types in 30%–35% and 48%–52% of patients, respectively. There were no significant differences in subdural hematoma thicknesses or contusion volumes. Epidural hematomas, which carry a more positive prognosis among lesion types,42 occurred only in KCH patients (17%). There was no significant difference in midline shift between the centers, although basal cisterns were compressed or absent in 74% of VCU patients compared with only 48% of KCH patients (p = 0.07).

Despite these similarities in baseline injury severity, KCH patients had more intracranial pathology following surgery (Table 2). Maximum postoperative ICP values were significantly higher at KCH, and spreading depolarizations occurred in 17 (63%) of 27 KCH patients, compared with only 10 (42%) of 24 patients at VCU. Furthermore, the more pathological form of spreading depolarization, ISD, was observed in 5 KCH patients, but no VCU patients (Table 2). KCH patients had a total of 322 depolarizations in 1357 recording hours (0.24/hour), including 144 ISDs; MCV patients had only 166 depolarizations in 2216 recording hours (0.07/hour) and no ISDs. Figure 1 shows the timing and type of spreading depolarizations observed relative to the period of ECoG monitoring for each patient. Pooling patients from both centers, we found that patients with ISDs had significantly higher maximal ICPs (43.4 ± 14.5 mm Hg) than those with no spreading depolarizations (24.3 ± 7.3 mm Hg) or those with only the CSD type (25.6 ± 7.4 mm Hg; ANOVA with Tukey's test, p < 0.02). There were no statistically significant associations between lesion types or sizes with occurrence of depolarizations (p > 0.05 for all).

TABLE 2:

Summary of surgical data and postoperative course for all patients*

VariableKCH (n = 27)VCU (n = 24)p Value
postop course
mean max postop ICP (mm Hg)31.4 ± 11.422.5 ± 6.10.003
ECoG depolarizations
 none10 (37%)14 (58%)0.13
 CSD1210
 ISD50
mean ECoG duration (hrs)50 ± 2392 ± 34<0.001
hospital discharge
 home310.005
 rehab center717
 long-term care facility02
 another hospital100
 death63
complications
 return to OR43
 hydrocephalus10
 ventriculitis00
 wound infection12
mortality at 6 mos7 (27%)4 (17%)0.50§
outcome at 6 mos
 good12 (46%)16 (67%)0.144
 poor14 (54%)8 (33%)
surgical procedures
location
 lateralized2221
 bilateral32
 bifrontal21
craniotomy/craniectomy dimensions**
 mean major axis length (cm)8.3 ± 2.611.1 ± 2.4<0.001
 mean area (cm2)52.9 ± 28.482.4 ± 22.9<0.001
 mean % skull††18.0 ± 9.127.8 ± 7.2<0.001
purpose of surgery‡‡
 evacuation25 (93%)21 (88%)0.54
 decompression14 (52%)18 (75%)0.09
type of surgery
 craniotomy15 (56%)6 (25%)0.03
 craniectomy12 (44%)18 (75%)
time to surgery
 median no. of days (IQR)0.83 (0.35–1.86)0.51 (0.13–0.74)0.04§§
 <24 hrs14 (52%)20 (83%)0.02

Values represent numbers of patients (%) unless otherwise indicated. Mean values are given with SDs. CSD = cortical spreading depression; EDH = epidural hematoma; IQR = interquartile range; ISD = isoelectric spreading depolarizations; OR = operating room; rehab = rehabilitation; SDH = subdural hematoma.

Based on measurements in 22 patients in the KCH cohort and 21 in the VCU cohort.

Based on 26 patients in KCH cohort; 1 patient was lost to follow-up.

Fisher's exact test.

There were no posterior fossa craniotomies.

In cases of lateralized craniotomy in both hemispheres, only the larger of two sides was used. For bifrontal craniotomies, the whole area was used.

Based on 24 patients in the KCH cohort and 23 in the VCU cohort.

Evacuation and decompression purposes were not mutually exclusive.

Gehan-Breslow-Wilcoxon test.

Fig. 1.
Fig. 1.

Timing, incidence, and type of spreading depolarizations. Raster plots show the time of occurrence of each spreading depolarization as a vertical tick mark through the first 10 days posttrauma for all study patients. CSDs and ISDs are shown as black and red ticks, respectively. Each row represents 1 patient and horizontal gray bars indicate periods of valid ECoG recordings for the patient. Patients are ordered vertically in ascending order of the total number of depolarizations observed. One KCH patient who had 24 CSDs on Days 12–14 is not shown.

At 6 months after injury, 14 (54%) of 26 KCH patients had poor outcomes, defined as death, vegetative state, or severe disability, compared with 8 (33%) of 24 patients treated at VCU (p = 0.14). Outcomes at KCH were worse than predicted based on prognostic scores (42% predicted poor outcome), but at VCU they were better than predicted (48% predicted poor outcome).37 Patients treated at VCU were more frequently discharged to home or a rehabilitation center.

Differences in surgical approaches were examined as a potential explanation for the divergent postoperative courses of the 2 groups (Table 2). Almost all surgical procedures at both centers were lateralized in a single hemisphere (81% at KCH; 88% VCU); the remainder were bifrontal decompressions or lateralized procedures in both hemispheres. However, the sizes of bone flaps removed were significantly larger at VCU (Fig. 2 and Table 2). The average area of 82.4 cm2, for instance, is 56% greater than the average bone flap area at KCH. This difference partly reflects greater use of DC at VCU. At VCU, decompression was an intended surgical objective in 75% of cases, and in these patients, craniectomies were performed with removal of the bone flap. At KCH, by contrast, decompression was intended in 52% of cases and DC was performed in 44% (p = 0.03, vs VCU). In the remaining 56% of KCH patients who underwent craniotomy, bone flaps were either fixed to intact skull (n = 4), hinged (n = 8), or left floating (n = 3). Finally, VCU patients were taken to surgery significantly earlier, with 83% of patients undergoing surgery within 24 hours of injury, compared with 52% at KCH (Fig. 2).

Fig. 2.
Fig. 2.

Timing of surgery and bone flap sizes of all patients. Upper: Distribution of bone flap sizes, as a percentage of the total area of cranium, for 24 KCH and 23 VCU patients. Lower: Cumulative distribution plots of the percentage of patients undergoing surgery as a function of time after trauma.

Patients With Emergency Lesion Evacuation

Based on these analyses, we hypothesized that differences in postsurgical course between the centers were attributable in part to differential use of prophylactic DC in patients with CT indications for immediate lesion evacuation. To examine this, we separately analyzed those cases in which patients had lesions evacuated within 24 hours, with or without additional neurological, CT, or ICP indications for surgery. Thus, patients who underwent delayed surgery after clinical deterioration or ICP elevation, and those undergoing decompression only, were excluded. Table 3 shows the characteristics of these subgroups, which had similar indications for surgery, baseline prognostic scores, preoperative ICPs, and pathoanatomical findings at the two centers. The majority of patients at both centers had subdural hematomas and contusions. As previously, there were indications of more severe injury at VCU, such as 80% of patients with compressed or absent basal cisterns, but these differences did not reach statistical significance. Age was again an exceptional difference, with the KCH subgroup being considerably older (57 ± 16 years vs 34 ± 21 years, p < 0.01).

TABLE 3:

Summary of preoperative characteristics for patients with early lesion evacuation*

VariableKCH (n = 14)VCU (n = 16)p Value
baseline indicators
indication for surgery
 initial CT13 (93%)12 (75%)
 expanding lesion2 (14%)4 (25%)
 clinical deterioration3 (21%)9 (56%)
 refractory ICP1 (7%)5 (31%)
mean prognostic score0.07 ± 1.150.42 ± 1.080.41
mean max preop ICP (mm Hg)44.7 ± 22.060.8 ± 37.20.48
preop CT measures§
primary lesion
 SDH6 (46%)8 (53%)
 contusion4 (31%)5 (33%)
 EDH3 (23%)0
 SAH02 (13%)
basal cisterns compressed/absent6 (46%)12 (80%)0.06
midline shift ≥ 5 mm8 (61%)9 (60%)0.93

Values represent numbers of patients (%) unless otherwise indicated. Mean values are given with SDs.

Based on 14 patients in the KCH cohort and 15 in the VCU cohort.

Based on 3 patients in the KCH cohort and 5 in the VCU cohort.

Based on 13 patients in the KCH cohort and 15 in the VCU cohort, due to missing CT scans.

Table 4 summarizes the surgical procedures and postsurgical outcomes. Most patients (85%–88%) at both centers underwent evacuation of subdural hematomas, but the craniotomy techniques used and postsurgical courses differed considerably. Craniectomy with removal of bone flap was performed in 75% of cases at VCU, compared with only 43% at KCH (p = 0.07). Bone flaps were significantly larger at VCU: the mean area of 85.4 cm2 is 78% greater than the mean area (48.0 cm2) of bone flaps at KCH (p < 0.001). When comparing only those patients patients who underwent decompression, craniectomies were still significantly larger at VCU (90 ± 17 cm2 vs 54 ± 27 cm2, p = 0.01). Postoperatively, VCU patients had significantly lower maximum ICP values and significantly lower incidence of spreading depolarizations. There were 257 depolarizations in 687 recording hours (0.37/hour) at KCH compared with 57 in 1407 hours (0.04/hour) at VCU. At 6 months after injury, only 31% of VCU patients had poor outcomes, compared with 71% at KCH (p = 0.03, chi-square). Figure 3 illustrates representative cases involving patients with large subdural hematomas at the two centers.

TABLE 4:

Summary of surgical data and postoperative course for patients with early lesion evacuation

VariableKCH (n = 14)VCU (n = 16)p Value
surgical procedures
location
 lateralized1316
 bilateral10
procedures performed
 SDH evacuation12 (85%)14 (88%)
 EDH evacuation4 (29%)4 (25%)
 contusion evacuation5 (36%)1 (6%)
 decompression7 (50%)12 (75%)
type of surgery
 craniotomy8 (57%)4 (25%)0.07
 craniectomy6 (43%)12 (75%)
craniotomy/craniectomy dimensions*
 mean major axis length (cm)8.1 ± 2.211.6 ± 1.5<0.001
 mean area (cm2)48.0 ± 22.785.4 ± 17.3<0.001
 mean % skull16.1 ± 7.929.1 ± 5.3<0.001
mean time to surgery in days0.46 ± 0.330.38 ± 0.300.47
postop course
mean max ICP after surgery (mm Hg)30.2 ± 11.620.8 ± 5.90.02
mean ECoG duration (hrs)49 ± 2688 ± 300.001
ECoG depolarizations
 none2 (14%)11 (69%)0.003
 CSD85
 ISD40
mortality at 6 mos5 (36%)2 (13%)0.20
outcome at 6 mos
 good4 (29%)11 (69%)0.03
 poor10 (71%)5 (31%)

Based on 13 patients in the KCH cohort and 16 in the VCU cohort.

Based on 13 patients in the KCH cohort and 14 in the VCU cohort.

Fisher's exact test.

Binary logistic regression was performed to assess directly the impact of variables on dichotomized outcomes in the pooled subgroups from both centers (n = 30). In univariate analysis, the presence of spreading depolarizations (OR 6.1, 95% CI 1.2–31.2, p = 0.03, R2 = 0.22), craniotomy less than 25% of skull (OR 5.0, 95% CI 1.0–24.1, p = 0.05, R2 = 0.18), KCH center (OR 4.0, 95% CI 0.9–18.1, p = 0.08, R2 = 0.14), and greater age (OR 1.03, 95% CI 1.0–1.1, p = 0.08, R2 = 0.14) were significantly associated with poor outcomes at p < 0.10. Prognostic score, maximum ICP value, and time-to-surgery were not significant. In multivariate analysis of significant factors, only spreading depolarizations were significant (OR 5.7, 95% CI 0.8–43.7, p = 0.08). Age was not significantly different between patients with and without depolarizations (49 ± 22 vs 39 ± 21, p = 0.22), and smaller craniotomies (< 25% of skull) were weakly associated with greater incidence of depolarizations (71% vs 40%, chi-square, p = 0.09).

Discussion

Refractory elevated ICP is a common complication following traditional craniotomy to evacuate lesions after severe TBI. The alternate approach of DC in conjunction with lesion evacuation has the potential to circumvent this complication and, furthermore, to prevent pathophysiological dysfunction associated with ICP elevation, such as reduced cerebral blood flow, reduced pressure reactivity, and increased cerebrovascular resistance.6,56 These factors augment the ischemic burden and contribute to secondary lesion growth in perilesional tissue. Despite the potential benefits, however, DC carries its own risks, such as subdural hygroma, infection, new hemorrhage, and lesion expansion.26,55 Thus, there is no consensus as to whether or when DC should be used in patients with mass lesions. In this study we used, for the first time, a comparative-effectiveness approach to examine the variance in neurosurgical treatment of TBI, including use of DC, between two centers in different Western countries. There were no study guidelines for which patients should undergo neurosurgery or which techniques should be used, which allowed for comparison of the surgical approaches and their effectiveness in a “real-world” scenario. We found not only considerable variation in practice between the two centers, but also, consistent with previous single-center studies, evidence for the effectiveness of an aggressive surgical approach to mitigate intracranial hypertension and secondary injury to perilesional tissue.

The two study populations were statistically similar in lesion types and sizes, signs of swelling and mass effect, baseline prognostic scores, and indications for surgery. Nearly all patients had mass lesions, and there were no patients with diffuse swelling only. Despite these similarities, we found significant differences in surgical approaches to treatment, postsurgical intracranial pathophysiology, and long-term outcomes. First, craniectomy with removal of bone flap was performed more frequently at VCU, the area of skull removed was significantly greater, and surgeries were performed sooner after the time of injury. Postoperatively, VCU patients had lower ICP, trended toward less spreading depolarizations, and had better outcomes at 6 months. These differences, other than timing of surgery, were even further accentuated in patients who underwent lesion evacuation within 24 hours of injury. VCU patients, whose bone flaps were 78% larger, had significantly lower ICP values, fewer spreading depolarizations (occurring in 31% vs 86% of cases), and better outcomes (good outcome in 69% vs 29% of cases).

These results provide evidence for major variation in surgical techniques used to manage severe TBI and suggest the superior efficacy of a more aggressive approach, including earlier surgery, larger craniotomy, and removal of bone flap. In particular, our results indicate that patients requiring evacuation of subdural hematomas and other lesions may benefit from DC in conjunction with lesion evacuation, even if elevated ICP was not a factor in the operative decision. In the subgroup of patients with early lesion evacuation, DC was performed in 75% of VCU patients, but only 31% had refractory ICP. The numbers were somewhat lower at KCH, where 50% were described as undergoing decompression; however, the craniectomies were considerably smaller and did not include decompression of the temporal pole (Fig. 3). Thus, the worse outcomes of these patients compared with those treated at VCU suggest a role for craniectomy, of adequate size for decompression, to improve outcomes.

Fig. 3.
Fig. 3.

Representative cases. CT images obtained prior to surgery are shown in comparison with postoperative images obtained on the following day for 2 cases of large subdural hematomas at both KCH and VCU. The operations performed in KCH Case 1 (KCH1) and VCU Case 1 (VCU1) were craniotomies, while those performed in KCH Case 2 (KCH2) and VCU Case 2 (VCU2) were craniectomies. In both cases, KCH bone flaps, in contrast to VCU bone flaps, were smaller and did not extend inferior to include decompression of the anterior temporal pole. Both KCH patients showed worsening on postoperative images with blossoming of contusions and hemorrhagic transformation. SDH = subdural hematoma.

It is important to note several factors that confound these results and interpretation of the role of surgery. Most importantly, the KCH cohort was significantly older, particularly in the subgroup with early lesion evacuation (mean age 57 years). Elderly patients do particularly poorly after DC,18,47 and this fact may have biased our data toward the results obtained by contributing to worse KCH patient outcomes and encouraging less aggressive surgical treatment. Second, falls were significantly more common as causes of trauma at KCH, which may suggest that undocumented differences in comorbidities or drug and alcohol use also contributed to outcome differences. Third, KCH patients were more often returned to their original hospitals instead of rehabilitation centers. Fourth, ICP management was more aggressive at VCU, including preferred use of ventriculostomy and early CSF drainage over parenchymal ICP monitoring, although specific data were not collected on study patients. Other undocumented differences in care, such as pre-hospital care and transport, may also exist. In univariate analysis, KCH center (capturing undocumented differences), greater age, and smaller bone flap size were all significantly associated with worse outcomes, but none were significant in multivariate analysis. Since these factors each co-vary with each other, it is not possible to determine definitively their relative impact.

Nonetheless, given the similarities in lesions types and CT indications of injury severity, the marked differences in postoperative ICP values and incidence of spreading depolarizations suggest that differences in surgical interventions documented here played some substantial role in postsurgical outcomes. In this regard, age in particular is not likely to be a confounding variable, since age decreases susceptibility to spreading depolarizations28,44 and elderly patients have greater intracranial compliance. Furthermore, KCH and VCU patients had similar prognostic scores and predicted outcomes, which take age into account.

Spreading Depolarizations as Mechanism and Marker of Perilesional Injury

Spreading depolarizations are a relatively new subject in the clinical study of acute brain injury and are used here for the first time as a surrogate outcome measure. As characterized in animal studies, spreading depolarizations describes the phenomena of propagating (1–5 mm/min) mass breakdown of neuronal/astrocytic electrochemical membrane gradients that precede and coincide with cortical lesion development. During depolarization, neurons cease firing, cytotoxic edema develops as water enters cells to maintain osmotic balance,49,50 and cells enter a twilight state of near-death.21 If metabolism is preserved, function can be restored within minutes without permanent damage to affected tissue. If not, spreading depolarizations will be prolonged and eventually persistent, with intracellular Ca2+ accumulation, leading to neuronal death.2

Clinical studies suggest that these principles translate to human disease as well.21,22,40 In severe brain trauma, the occurrence of spreading depolarizations is a strong independent predictor of poor outcome: patients with ISDs have a 7.5-fold increased risk of unfavorable outcome compared with patients with no depolarizations.29 Although we previously found that ICP values are generally higher in patients who exhibit depolarizations than in those who do not,30 here we found more specifically that postoperative ICP values were higher (43.4 ± 14.5 mm Hg) in patients with the isoelectric form of spreading depolarization (ISD), while there was no significant difference between patients with no depolarizations (24.3 ± 7.3 mm Hg) and those with only the CSD type (25.6 ± 7.4 mm Hg). This result suggests a likely interaction between elevated ICP and depolarization: either 1) reduced cerebral blood flow as a consequence of edema could worsen the effect of depolarizations by limiting metabolic substrates for recovery or causing spreading ischemia,20 or 2) persistent cytotoxic edema induced by depolarizations could contribute to ICP elevation, or 3) both mechanisms could be at play. The more prolonged duration of depolarizations associated with isoelectricity suggests the former.31 In either case, repetitive depolarizations leading to isoelectricity in combination with intracranial hypertension appears to be a strong indicator of poor outcome.40

In univariate analysis of outcome in the subgroup of patients undergoing lesion evacuation within 24 hours, we found that only age, center, bone flap size, and spreading depolarizations had significant associations. When combined in a multivariate model, only spreading depolarizations were significant. This finding suggests that spreading depolarizations are a final common pathway reflecting the cumulative effect of prognostic risk factors, therapies, and secondary insults on injury evolution—an interpretation consistent with measurement of a pathologic process occurring on the cellular level and widely affecting vulnerable, perilesional tissue.

Need for Randomized Trial of Preemptive DC

Our results are in agreement with results from several recent studies on the effectiveness of preemptive DC performed in conjunction with lesion evacuation. Most relevant are two studies in which ICP measures and failure of first- and/or second-tier therapies for control of intracranial hypertension were not required prior to craniectomy. The first was a single-center retrospective review of DC versus traditional craniotomy as a primary procedure for patients with hemorrhagic contusions > 20 cm3 with CT signs of mass effect.36 For craniectomies, the authors removed a 12 × 13–cm area of the frontotemporoparietal cranium extending inferior to the floor of the middle cranial fossa at the origin of the zygomatic arch, whereas craniotomies were 7 × 8 cm. Despite similar injury severities between the groups, the authors found that outcomes were better and reoperation rates were lower following craniectomy. In the second study, Jiang et al.39 conducted a large (486 patients) prospective randomized controlled trial comparing the use of smaller temporoparietal craniectomy bone flaps (6 × 8 cm) with large frontotemporoparietal craniectomies (12 × 15 cm) for treatment of unilateral contusions with imaging or clinical evidence of mass effect. In the group undergoing large craniectomies, they found that postoperative ICP values were lower through 7 days, and 6-month outcomes were significantly improved. Other studies are more equivocal and difficult to interpret since, due to their retrospective nature and lack of randomization, comparison groups had differing injury severities.1,46,54

Together these studies suggest that at worst, for patients with hemorrhagic contusions and clinical or imaging evidence of mass effect, DC is a safe alternative to traditional craniotomy as a primary surgical intervention. Given the evidence presented here and from the only prospective randomized trial conducted thus far,39 we suggest the need for a further prospective randomized trial comparing the use of DC (12 × 15 cm) and duraplasty with traditional craniotomy for patients with unilateral contusions or subdural hematoma meeting the Brain Trauma Foundation guidelines for surgical intervention, who exhibit signs of mass effect (compressed basal cisterns, midline shift > 5 mm, or neurological deterioration). Randomization should occur irrespective of ICP monitoring, and surgery should be initiated as a primary intervention as soon as indicated by imaging, without requirement of failure of first-tier therapies to control ICP. This proposed trial design differs considerably from the recently published DECRA (Decompressive Craniectomy) study, which included only patients with diffuse swelling and excluded those with contusions or hematomas, employed only bifrontal craniectomies with limited dural opening, and required only brief ICP increase as an inclusion criterion.15 Such patients represent only a small minority of neurotrauma patients considered for surgical intervention. More germane to the present issue and to neurotrauma in general is the ongoing RESCUEicp (Randomised Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intra-Cranial Pressure) trial, which includes intracranial lesions and unilateral decompression. However, like DECRA, RESCUEicp is a trial of DC for treatment of intractable intracranial hypertension, requiring ICP > 25 mm Hg for at least 1 hour after trial of at least first-tier measures, and will not address the effectiveness of preemptive DC in conjunction with lesion evacuation.

Conclusions

We assessed practice variations in surgical management of TBI and compared their effectiveness at 2 centers in United Kingdom (KCH) and the United States (VCU). We found that patients treated at VCU underwent surgery earlier, had larger bone flaps, and more frequently underwent craniectomy than craniotomy. These differences were particularly accentuated in patients undergoing early lesion evacuation and corresponded to significantly lower postoperative ICP values, less spreading depolarizations, and better outcomes. Together with one previous prospective randomized trial, these results suggest the effectiveness of early preemptive DC as a primary surgical intervention. The variation in both practice and outcomes between these two advanced neurosurgical practices in Western nations, together with previous studies, suggests the need for a multicenter prospective trial of DC in this specific clinical scenario.

Acknowledgment

We thank Adam Wilson, Ph.D., for assistance in figure preparation.

Disclosure

This work was funded in part by the US Army CDMRP PH/TBI Research Program, Contract No. W81XWH-08-2-0016. Dr. Strong acknowledges support from HeadFirst; Dr. Pahl from King's College Hospital Foundation Trust's Research and Development Fund; and Dr. Fabricius from the Novo Nordisk Foundation. Funding sources had no role in study design or in the collection, analysis, interpretation, or reporting of data.

Author contributions to the study and manuscript preparation include the following. Conception and design: Hartings, Strong, Bullock. Acquisition of data: Hartings, Vidgeon, Strong, Ridder, Stanger, Mathern, Pahl, Tolias, Bullock. Analysis and interpretation of data: Hartings, Vidgeon, Strong, Zacko, Vagal, Andaluz, Ridder, Stanger, Fabricius, Bullock. Drafting the article: Hartings. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Hartings. Statistical analysis: Hartings. Administrative/technical/material support: Hartings. Study supervision: Hartings, Strong.

Portions of this work were presented in abstract form and orally at the 30th Annual National Neurotrauma Symposium, Phoenix, Arizona, July 25, 2012.

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Article Information

Address correspondence to: Jed A. Hartings, Ph.D., Department of Neurosurgery, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0517. email: jed.hartings@uc.edu.

Please include this information when citing this paper: published online November 1, 2013; DOI: 10.3171/2013.9.JNS13581.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Timing, incidence, and type of spreading depolarizations. Raster plots show the time of occurrence of each spreading depolarization as a vertical tick mark through the first 10 days posttrauma for all study patients. CSDs and ISDs are shown as black and red ticks, respectively. Each row represents 1 patient and horizontal gray bars indicate periods of valid ECoG recordings for the patient. Patients are ordered vertically in ascending order of the total number of depolarizations observed. One KCH patient who had 24 CSDs on Days 12–14 is not shown.

  • View in gallery

    Timing of surgery and bone flap sizes of all patients. Upper: Distribution of bone flap sizes, as a percentage of the total area of cranium, for 24 KCH and 23 VCU patients. Lower: Cumulative distribution plots of the percentage of patients undergoing surgery as a function of time after trauma.

  • View in gallery

    Representative cases. CT images obtained prior to surgery are shown in comparison with postoperative images obtained on the following day for 2 cases of large subdural hematomas at both KCH and VCU. The operations performed in KCH Case 1 (KCH1) and VCU Case 1 (VCU1) were craniotomies, while those performed in KCH Case 2 (KCH2) and VCU Case 2 (VCU2) were craniectomies. In both cases, KCH bone flaps, in contrast to VCU bone flaps, were smaller and did not extend inferior to include decompression of the anterior temporal pole. Both KCH patients showed worsening on postoperative images with blossoming of contusions and hemorrhagic transformation. SDH = subdural hematoma.

References

1

Aarabi BHesdorffer DCSimard JMAhn ESAresco CEisenberg HM: Comparative study of decompressive craniectomy after mass lesion evacuation in severe head injury. Neurosurgery 64:9279402009

2

Aiba IShuttleworth CW: Sustained NMDA receptor activation by spreading depolarizations can initiate excitotoxic injury in metabolically compromised neurons. J Physiol 590:587758932012

3

Back TGinsberg MDDietrich WDWatson BD: Induction of spreading depression in the ischemic hemisphere following experimental middle cerebral artery occlusion: effect on infarct morphology. J Cereb Blood Flow Metab 16:2022131996

4

Becker DPMiller JDWard JDGreenberg RPYoung HFSakalas R: The outcome from severe head injury with early diagnosis and intensive management. J Neurosurg 47:4915021977

5

Bell RSMossop CMDirks MSStephens FLMulligan LEcker R: Early decompressive craniectomy for severe penetrating and closed head injury during wartime. Neurosurg Focus 28:5E12010

6

Bor-Seng-Shu EFigueiredo EGAmorim RLTeixeira MJValbuza JSde Oliveira MM: Decompressive craniectomy: a meta-analysis of influences on intracranial pressure and cerebral perfusion pressure in the treatment of traumatic brain injury. A review. J Neurosurg 117:5895962012

7

Brain Trauma Foundation American Association of Neurological Surgeons Congress of Neurological Surgeons AANS/CNS Joint Section on Neurotrauma andCritical Care: Guidelines for the management of severe traumatic brain injury. ed 3J Neurotrauma 24:Suppl 1S1S1062007. (Erratum in J Neurotrauma 25:276–278 2008)

8

Britt RHHamilton RD: Large decompressive craniotomy in the treatment of acute subdural hematoma. Neurosurgery 2:1952001978

9

Bullock MRChesnut RGhajar JGordon DHartl RNewell DW: Surgical management of acute subdural hematomas. Neurosurgery 58:3 SupplS16S242006

10

Bullock MRChesnut RGhajar JGordon DHartl RNewell DW: Surgical management of traumatic parenchymal lesions. Neurosurgery 58:3 SupplS25S462006

11

Busch EGyngell MLEis MHoehn-Berlage MHossmann KA: Potassium-induced cortical spreading depressions during focal cerebral ischemia in rats: contribution to lesion growth assessed by diffusion-weighted NMR and biochemical imaging. J Cereb Blood Flow Metab 16:109010991996

12

Clark KNash TMHutchison GC: The failure of circumferential craniotomy in acute traumatic cerebral swelling. J Neurosurg 29:3673711968

13

Clifton GLChoi SCMiller ERLevin HSSmith KR JrMuizelaar JP: Intercenter variance in clinical trials of head trauma—experience of the National Acute Brain Injury Study: hypothermia. J Neurosurg 95:7517552001

14

Compagnone CMurray GDTeasdale GMMaas AIEsposito DPrinci P: The management of patients with intradural post-traumatic mass lesions: a multicenter survey of current approaches to surgical management in 729 patients coordinated by the European Brain Injury Consortium. Neurosurgery 57:118311922005

15

Cooper DJRosenfeld JVMurray LArabi YMDavies ARD'Urso P: Decompressive craniectomy in diffuse traumatic brain injury. N Engl J Med 364:149315022011

16

Cooper PRRovit RLRansohoff J: Hemicraniectomy in the treatment of acute subdural hematoma: a re-appraisal. Surg Neurol 5:25281976

17

Coplin WMCullen NKPolicherla PNVinas FCWilseck JMZafonte RD: Safety and feasibility of craniectomy with duraplasty as the initial surgical intervention for severe traumatic brain injury. J Trauma 50:105010592001

18

De Bonis PPompucci AMangiola APaternoster GFesta RNucci CG: Decompressive craniectomy for elderly patients with traumatic brain injury: it's probably not worth the while. J Neurotrauma 28:204320482011

19

Dohmen CSakowitz OWFabricius MBosche BReithmeier TErnestus RI: Spreading depolarizations occur in human ischemic stroke with high incidence. Ann Neurol 63:7207282008

20

Dreier JP: The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med 17:4394472011

21

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