Early versus delayed cranioplasty after decompressive craniectomy in traumatic brain injury: a multicenter observational study within CENTER-TBI and Net-QuRe.

OBJECTIVE: The aim of this study was to compare the outcomes of early (≤ 90 days) and delayed (> 90 days) cranioplasty following decompressive craniectomy (DC) in patients with traumatic brain injury (TBI). METHODS: The authors analyzed participants enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) and the Neurotraumatology Quality Registry (Net-QuRe) studies who were diagnosed with TBI and underwent DC and subsequent cranioplasty. These prospective, multicenter, observational cohort studies included 5091 patients enrolled from 2014 to 2020. The effect of cranioplasty timing on functional outcome was evaluated with multivariable ordinal regression and with propensity score matching (PSM) in a sensitivity analysis of functional outcome (Glasgow Outcome Scale-Extended [GOSE] score) and quality of life (Quality of Life After Brain Injury [QOLIBRI] instrument) at 12 months following DC. RESULTS: Among 173 eligible patients, 73 (42%) underwent early cranioplasty and 100 (58%) underwent delayed cranioplasty. In the ordinal logistic regression and PSM, similar 12-month GOSE scores were found between the two groups (adjusted odds ratio [aOR] 0.87, 95% CI 0.61-1.21 and 0.88, 95% CI 0.48-1.65, respectively). In the ordinal logistic regression, early cranioplasty was associated with a higher risk for hydrocephalus than that with delayed cranioplasty (aOR 4.0, 95% CI 1.2-16). Postdischarge seizure rates (early cranioplasty: aOR 1.73, 95% CI 0.7-4.7) and QOLIBRI scores (ß -1.9, 95% CI -9.1 to 9.6) were similar between the two groups. CONCLUSIONS: Functional outcome and quality of life were similar between early and delayed cranioplasty in patients who had undergone DC for TBI. Neurosurgeons may consider performing cranioplasty during the index admission (early) to simplify the patient's chain of care and prevent readmission for cranioplasty but should be vigilant for an increased possibility of hydrocephalus. Clinical trial registration nos.: CENTER-TBI, NCT02210221 (clinicaltrials.gov); Net-QuRe, NTR6003 (trialsearch.who.int) and NL5761 (onderzoekmetmensen.nl).

Treatment-limiting decisions in patients with severe traumatic brain injury in the Netherlands.

Introduction: Treatment-limiting decisions (TLDs) can be inevitable severe traumatic brain injury (s-TBI) patients, but data on their use remain scarce. Research question: To investigate the prevalence, timing and considerations of TLDs in s-TBI patients. Material and methods: s-TBI patients between 2008 and 2017 were analysed retrospecively. Patient data, timing, location, involvement of proxies, and reasons for TLDs were collected. Baseline characteristics and in-hospital outcomes were compared between s-TBI patients with and without TLDs. Results: TLDs were reported in 117 of 270 s-TBI patients (43.3%) and 95.9% of deaths after s-TBI were preceded by a TLD. The majority of TLDs (68.4%) were categorized as withdrawal of therapy, of which withdrawal of organ-support in 64.1%. Neurosurgical intervention was withheld in 29.9%. The median time from admission to TLD was 2 days [IQR, 0-8] and 50.4% of TLDs were made within 3 days of admission. The main reason for a TLD was that the patients were perceived as unsalvageable (66.7%). Nearly all decisions were made multidisciplinary (99.1%) with proxies involvement (75.2%). The predicted mortality (CRASH-score) between patients with and without TLDs were 72.6 vs. 70.6%. The percentage of TLDs in s-TBI patients increased from 20.0% in 2008 to 42.9% in 2012 and 64.3% in 2017. Discussion and conclusion: TLDs occurred in almost half of s-TBI patients and were instituted more frequently over time. Half of TLDs were made within 3 days of admission in spite of baseline prognosis between groups being similar. Future research should address whether prognostic nihilism contributes to self-fulfilling prophecies.

Early surgery versus conservative treatment in patients with traumatic intracerebral hematoma: a CENTER-TBI study.

PURPOSE: Evidence regarding the effect of surgery in traumatic intracerebral hematoma (t-ICH) is limited and relies on the STITCH(Trauma) trial. This study is aimed at comparing the effectiveness of early surgery to conservative treatment in patients with a t-ICH. METHODS: In a prospective cohort, we included patients with a large t-ICH (< 48 h of injury). Primary outcome was the Glasgow Outcome Scale Extended (GOSE) at 6 months, analyzed with multivariable proportional odds logistic regression. Subgroups included injury severity and isolated vs. non-isolated t-ICH. RESULTS: A total of 367 patients with a large t-ICH were included, of whom 160 received early surgery and 207 received conservative treatment. Patients receiving early surgery were younger (median age 54 vs. 58 years) and more severely injured (median Glasgow Coma Scale 7 vs. 10) compared to those treated conservatively. In the overall cohort, early surgery was not associated with better functional outcome (adjusted odds ratio (AOR) 1.1, (95% CI, 0.6-1.7)) compared to conservative treatment. Early surgery was associated with better outcome for patients with moderate TBI and isolated t-ICH (AOR 1.5 (95% CI, 1.1-2.0); P value for interaction 0.71, and AOR 1.8 (95% CI, 1.3-2.5); P value for interaction 0.004). Conversely, in mild TBI and those with a smaller t-ICH (< 33 cc), conservative treatment was associated with better outcome (AOR 0.6 (95% CI, 0.4-0.9); P value for interaction 0.71, and AOR 0.8 (95% CI, 0.5-1.0); P value for interaction 0.32). CONCLUSIONS: Early surgery in t-ICH might benefit those with moderate TBI and isolated t-ICH, comparable with results of the STITCH(Trauma) trial.

Comparative effectiveness of decompressive craniectomy versus craniotomy for traumatic acute subdural hematoma (CENTER-TBI): an observational cohort study.

Background: Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. Methods: We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014-2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). Findings: Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12-26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% [IQR increase] more DC in a centre = 0.9 [95% CI 0.7-1.1], n = 200). Primary DC was associated with more follow-on surgeries and complications [secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%]; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 [95% CI (1.0-3.4), n = 200]). Interpretation: We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling. Funding: Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.

Tackling Neuroinflammation After Traumatic Brain Injury: Complement Inhibition as a Therapy for Secondary Injury.

Traumatic brain injury (TBI) is a leading cause of mortality, sensorimotor morbidity, and neurocognitive disability. Neuroinflammation is one of the key drivers causing secondary brain injury after TBI. Therefore, attenuation of the inflammatory response is a potential therapeutic goal. This review summarizes the most important neuroinflammatory pathophysiology resulting from TBI and the clinical trials performed to attenuate neuroinflammation. Studies show that non-selective attenuation of the inflammatory response, in the early phase after TBI, might be detrimental and that there is a gap in the literature regarding pharmacological trials targeting specific pathways. The complement system and its crosstalk with the coagulation system play an important role in the pathophysiology of secondary brain injury after TBI. Therefore, regaining control over the complement cascades by inhibiting overshooting activation might constitute useful therapy. Activation of the complement cascade is an early component of neuroinflammation, making it a potential target to mitigate neuroinflammation in TBI. Therefore, we have described pathophysiological aspects of complement inhibition and summarized animal studies targeting the complement system in TBI. We also present the first clinical trial aimed at inhibition of complement activation in the early days after brain injury to reduce the risk of morbidity and mortality following severe TBI.

Preperitoneal Pelvic Packing is Associated With Increased Risk of Venous Thromboembolism.

INTRODUCTION: Preperitoneal pelvic packing (PPP) is an important intervention for control of severe pelvic hemorrhage in blunt trauma patients. We hypothesized that PPP is associated with an increased incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE). METHODS: A retrospective cohort analysis of blunt trauma patients with severe pelvic fractures (AIS ≥4) using the 2015-2017 American College of Surgeons-Trauma Quality Improvement Program database was performed. Patients who underwent PPP within four hours of admission were matched to patients who did not using propensity score matching. Matching was performed based on demographics, comorbidities, injury- and resuscitation-related parameters, vital signs at presentation, and initiation and type of prophylactic anticoagulation. The rates of DVT and PE were compared between the matched groups. RESULTS: Out of 5129 patients with severe pelvic fractures, 157 (3.1%) underwent PPP within four h of presentation and were matched with 157 who did not. No significant differences were detected between the two matched groups in any of the examined baseline variables. Similarly, mortality and end-organ failure rates were not different. However, PPP patients were significantly more likely to develop DVT (12.7% versus 5.1%, P = 0.028) and PE (5.7% versus 0.0%, P = 0.003). CONCLUSIONS: PPP in severe pelvic fractures secondary to blunt trauma is associated with an increased risk of DVT and PE. A high index of suspicion and a low threshold for screening for these conditions should be maintained in patients who undergo PPP.

Safety and efficacy of C1-inhibitor in traumatic brain injury (CIAO@TBI): study protocol for a randomized, placebo-controlled, multi-center trial.

BACKGROUND: Traumatic brain injury (TBI) is a major cause of death and disability across all ages. After the primary impact, the pathophysiologic process of secondary brain injury consists of a neuroinflammation response that critically leads to irreversible brain damage in the first days after the trauma. A key catalyst in this inflammatory process is the complement system. Inhibiting the complement system could therefore be a therapeutic target in TBI. OBJECTIVE: To study the safety and efficacy of C1-inhibitor (C1-INH) compared to placebo in patients with TBI. By temporarily blocking the complement system, we hypothesize a decrease in the posttraumatic neuroinflammatory response resulting in a less unfavorable clinical outcome for TBI patients. METHODS: CIAO@TBI is a multicenter, randomized, blinded, phase II placebo-controlled trial. Adult TBI patients with GCS < 13 requiring intracranial pressure (ICP) monitoring will be randomized, using block randomization, within 12 h after trauma to one dose 6000 IU C1-INH or placebo. A total of 106 patients will be included, and follow-up will occur up to 12 months. The primary endpoints are (1) Therapy Intensity Level (TIL) Scale, (2) Glasgow Outcome Scale-Extended (GOSE) at 6 months, and (3) complication rate during hospitalization. Outcomes will be determined by a trial nurse blinded for the treatment allocation. Analyses will be conducted in an intention-to-treat analysis. DISCUSSION: We expect that C1-INH administration will be safe and potentially effective to improve clinical outcomes by reducing neuroinflammation in TBI patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04489160. Registered on 27 July 2020. EudraCT 2020-000140-58.

Low-molecular-weight heparin versus unfractionated heparin in pediatric traumatic brain injury.

OBJECTIVE: The incidence of venous thromboembolism (VTE) in patients with traumatic brain injury (TBI) has increased significantly. The Eastern Association for the Surgery of Trauma recommends using low-molecular-weight heparin (LMWH) over unfractionated heparin (UH) in pediatric patients requiring VTE prophylaxis, although this strategy is unsupported by the literature. In this study, the authors compare the outcomes of pediatric TBI patients receiving LMWH versus UH. METHODS: The authors performed a 4-year (2014-2017) analysis of the pediatric American College of Surgeons Trauma Quality Improvement Program. All trauma patients (age ≤ 18 years) with TBI requiring thromboprophylaxis with UH or LMWH were potentially eligible for inclusion. Patients who had been transferred, had died in the emergency department, or had penetrating trauma were excluded. Patients were stratified into either the LMWH or the UH group on the basis of the prophylaxis they had received. Patients were matched on the basis of demographics, injury characteristics, vital signs, and transfusion requirements using propensity score matching (PSM). The study endpoints were VTE, death, and craniotomy after initiation of prophylaxis. Univariate analysis was performed after PSM to compare outcomes. RESULTS: A total of 2479 patients met the inclusion criteria (mean age 15.5 ± 3.7 years and 32.0% female), of which 1570 (63.3%) had received LMWH and 909 (36.7%) had received UH. Before PSM, patients receiving UH were younger, had a lower Glasgow Coma Scale score, and had a higher Injury Severity Score. Patients treated in pediatric hospitals were more likely to receive UH (12.9% vs 9.0%, p < 0.001) than patients treated in adult hospitals. Matched patients receiving UH had a higher incidence of VTE (5.1% vs 2.9%, p = 0.03). CONCLUSIONS: LMWH prophylaxis in pediatric TBI appears to be more effective than UH in preventing VTE. Large, multicenter prospective studies are warranted to confirm the superiority of LMWH over UH in pediatric patients with TBI. Moreover, outcomes of VTE prophylaxis in the very young remain understudied; therefore, dedicated studies to evaluate this population are needed.

Comparison of outcomes in non-head injured trauma patients using pre-injury warfarin or direct oral anticoagulant therapy.

BACKGROUND: Patients on prehospital anticoagulation with warfarin or direct oral anticoagulants (DOACs) represent a vulnerable subset of the trauma population. While protocolized warfarin reversal is widely available and easily implemented, prehospital anticoagulation with DOAC is cost prohibitive with only a few reversal options. This study aims to compare hospital outcomes of non-head injured trauma patients taking pre-injury DOAC versus warfarin. METHODS: A retrospective cohort study at a level 1 trauma center was performed. All adult trauma patients with pre-injury anticoagulation admitted between January 2015 and December 2018, were stratified into DOAC-using and warfarin-using groups. Patients were excluded if they had traumatic brain injury (TBI). Univariate and multivariable analyses were performed. Outcomes measures included in-hospital mortality, blood transfusion requirements, ICU length of stay (LOS), hospital LOS and discharge disposition. RESULTS: 374 non-TBI trauma patients on anticoagulation were identified, of which 134 were on DOACs and 240 on warfarin. Patients on DOACs had a higher ISS (9 [IQR, 9-10] vs. 9 [IQR, 5-9]; p<0.001), and lower admission INR values (1.2 [IQR, 1.1-1.3] vs 2.4 [IQR, 1.8-2.7]; p<0.001) than warfarin users. Use of reversal agents was higher in warfarin users (p<0.001). Relative to warfarin, DOAC users did not differ significantly with respect to hospital mortality (OR 0.47, 95% CI [0.13-1.73]). Multivariable analysis (not possible for mortality) did not show significant difference for RBC transfusion requirements (OR 0.92 [0.51-1.67]), ICU LOS (OR 1.08 [0.53-2.19]), hospital LOS (OR 1.10 [0.70-1.74]) or discharge disposition (OR 0.56 [0.29-1.11]) between the groups. CONCLUSION: Despite lower reversal rates and higher ISS, non-TBI trauma patients with pre-injury DOAC use had similar outcomes as patients on pre-injury warfarin. There may be equipoise to have larger, prospective studies evaluating the comparative safety of DOACs and warfarin in the population prone to low energy fall type injuries.

Isolated rib cage fractures in the elderly: Do all patients belong to the intensive care unit? A retrospective nationwide analysis.

BACKGROUND: Western Trauma Association guidelines recommend admitting patients 65 years or older with two or more rib fractures diagnosed by chest radiograph to the intensive care unit (ICU). Increased use of computed tomography has led to identification of less severe, "occult" rib fractures. We aimed to evaluate current national trends in disposition of older patients with isolated rib cage fractures and to identify characteristics of patients initially admitted to the ward who failed ward management. METHODS: A retrospective cohort study of patients 65 years or older with isolated two or more blunt rib cage fractures using the 2010 to 2016 American College of Surgeons Trauma Quality Improvement Program database was performed. Ward failure was defined as patients initially admitted to the ward with subsequent need for unplanned ICU admission or intubation. Multivariable analyses were derived to study the independent predictors of failure of ward management. Propensity score matching sub-analysis was used to assess outcomes in patients admitted to the ward versus ICU. RESULTS: There were 5,021 patients included in the analysis. Of these patients, 1,406 (28.0%) were admitted to the ICU. On multivariable analysis, age was an independent predictor of ICU admission. Of the 3,577 patients admitted directly to the ward, 38 (1.1%) patients required unplanned intubation or ICU admission. Independent predictors of failure of ward management included chronic renal failure (odds ratio [OR], 7.20; p ≤ 0.001; 95% confidence interval [CI], 2.50-20.76), traumatic pneumothorax (OR, 8.70; p = 0.008; 95% CI, 1.76-42.93), concurrent sternal fracture (OR, 6.52; p ≤ 0.001; 95% CI, 2.53-16.80), drug use disorder (OR, 6.58; p = 0.032; 95% CI, 1.17-36.96), and emergency department oxygen requirement or oxygen saturation less than 95% (OR, 2.38; p = 0.018; 95% CI, 1.16-4.86). Mortality was higher in patients with delayed ICU care versus patients with successful ward disposition (21.1% vs. 0.8%; p < 0.001). CONCLUSION: Our results suggest that the majority of isolated rib cage fractures in older patients are safely managed on the ward with exceedingly low ward failure rates (1.1%). Patients with failure of ward management have significantly higher mortality, and we have identified predictors of failing the ward. LEVEL OF EVIDENCE: Therapeutic/Care Management, level IV; Prognostic III.

Pre-peritoneal pelvic packing for early hemorrhage control reduces mortality compared to resuscitative endovascular balloon occlusion of the aorta in severe blunt pelvic trauma patients: A nationwide analysis.

BACKGROUND: Early hemorrhage control after severe blunt pelvic trauma is life-saving. The aim of this study is to compare the efficacy and outcomes of pre-peritoneal packing (PPP) and Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) with a subsequent hemorrhage control procedure to control life-threatening pelvic hemorrhage in trauma patients. METHODS: A 3-year (2015-2017) retrospective analysis of the Trauma Quality Improvement Program (TQIP) was performed. All blunt trauma patients (aged ≥15 years) who underwent PPP or Zone 3 REBOA placement were included while deaths on arrival and transfers were excluded. Patients were matched on clinical characteristics using propensity score matching (PSM). Univariate analysis was performed to compare mortality, time to procedure, time in ED, transfusion requirements, complications rates, and ICU and hospital length of stay (LOS) amongst patient groups. RESULTS: Of 420 trauma patients, 307 underwent PPP and 113 REBOA. Patients had similar hemodynamics and ISS upon presentation, but PPP patients had a higher GCS (P = 0.037) and more blunt kidney injuries (P = 0.015). After PSM, 206 trauma patients were included in the analysis. There were no significant differences in blood transfusion, LOS, or major complications. Time to REBOA was shorter than time to PPP (52 vs 77.5 min; P<0.001) with longer time in ED (65 vs 51 min; p = 0.023). The 24-hour (32.4 vs 17.7%; P = 0.23) and in-hospital mortality (52.0 vs 37.3%; P = 0.048) were higher after REBOA. CONCLUSION: PPP is associated with improved survival compared to REBOA placement. Delay in definitive hemorrhage control may provide a potential explanation, but causation remains unresolved. This data suggests that early PPP may offer a benefit over REBOA in the setting of hemorrhage after blunt pelvic trauma. Further, large, multi-institutional studies are warranted to support these findings. LEVEL OF EVIDENCE: Prognostic study, level III.

Decision making in very severe traumatic brain injury (Glasgow Coma Scale 3-5): a literature review of acute neurosurgical management.

INTRODUCTION: Patients presenting with an early Glasgow Coma Scale (GCS) Score of 3-5 after blunt or penetrating skull-brain assaults are categorized as having sustained a very severe traumatic brain injury (vs-TBI). This category is often overlooked in literature. Impact on patients and families lives however is huge and the question "whether to surgically treat or not" frequently poses a dilemma to treating physicians. Little is known about mortality and outcome, compared to what is known for the group of severe TBI patients (s-TBI) (GCS 3-8). The main goal of this review was creating more awareness for the neurosurgical treatment of this patient group. EVIDENCE ACQUISITION: A literature search (2000-2017) was conducted discussing "severe TBI (GCS 3-8)", "(neuro)surgical management" and "outcome". Ultimately 45 out of 2568 articles were included for further analysis. EVIDENCE SYNTHESIS: Mortality rates and unfavorable outcome are high for s-TBI patients and as expected higher for vs-TBI patients. Mortality rates reach up to 100% for specific subgroups with GCS=3 and bilaterally fixed dilated pupils. Functional outcome was generally poor, but sometimes, although seldom, favorable in specific groups of vs-TBI patients after neurosurgical intervention. Factors like initial GCS, pupillary abnormalities and age seem to be associated with worse outcome. CONCLUSIONS: Overall this literature review showed high rates of unfavorable outcome and mortality for vs-TBI patients. However, some studies, reporting relatively low mortality rates, reported "good" outcome for specific groups of vs-TBI patients. It is concluded that clinical decision making, in particular those on treatment limitations, should never be taken based on the GCS alone.