Propensity weighted analysis of chemical venous thromboembolism prophylaxis agents in isolated severe traumatic brain injury: An EAST sponsored multicenter study.

BACKGROUND: In patients with severe traumatic brain injury (TBI), clinicians must balance preventing venous thromboembolism (VTE) with the risk of intracranial hemorrhagic expansion (ICHE). We hypothesized that low molecular weight heparin (LMWH) would not increase risk of ICHE or VTE as compared to unfractionated heparin (UH) in patients with severe TBI. METHODS: Patients ≥ 18 years of age with isolated severe TBI (AIS ≥ 3), admitted to 24 level I and II trauma centers between January 1, 2014 to December 31, 2020 and who received subcutaneous UH and LMWH injections for chemical venous thromboembolism prophylaxis (VTEP) were included. Primary outcomes were VTE and ICHE after VTEP initiation. Secondary outcomes were mortality and neurosurgical interventions. Entropy balancing (EBAL) weighted competing risk or logistic regression models were estimated for all outcomes with chemical VTEP agent as the predictor of interest. RESULTS: 984 patients received chemical VTEP, 482 UH and 502 LMWH. Patients on LMWH more often had pre-existing conditions such as liver disease (UH vs LMWH 1.7 % vs. 4.4 %, p = 0.01), and coagulopathy (UH vs LMWH 0.4 % vs. 4.2 %, p < 0.001). There were no differences in VTE or ICHE after VTEP initiation. There were no differences in neurosurgical interventions performed. There were a total of 29 VTE events (3 %) in the cohort who received VTEP. A Cox proportional hazards model with a random effect for facility demonstrated no statistically significant differences in time to VTE across the two agents (p = 0.44). The LMWH group had a 43 % lower risk of overall ICHE compared to the UH group (HR = 0.57: 95 % CI = 0.32-1.03, p = 0.062), however was not statistically significant. CONCLUSION: In this multi-center analysis, patients who received LMWH had a decreased risk of ICHE, with no differences in VTE, ICHE after VTEP initiation and neurosurgical interventions compared to those who received UH. There were no safety concerns when using LMWH compared to UH. LEVEL OF EVIDENCE: Level III, Therapeutic Care Management.

Early VTE prophylaxis in severe traumatic brain injury: A propensity score weighted EAST multicenter study.

BACKGROUND: Patients with traumatic brain injury (TBI) are at high risk of venous thromboembolism events (VTE). We hypothesized that early chemical VTE prophylaxis initiation (≤24 hours of a stable head CT) in severe TBI would reduce VTE without increasing risk of intracranial hemorrhage expansion (ICHE). METHODS: A retrospective review of adult patients 18 years or older with isolated severe TBI (Abbreviated Injury Scale score, ≥ 3) who were admitted to 24 Level I and Level II trauma centers from January 1, 2014 to December 31 2020 was conducted. Patients were divided into those who did not receive any VTE prophylaxis (NO VTEP), who received VTE prophylaxis ≤24 hours after stable head CT (VTEP ≤24) and who received VTE prophylaxis >24 hours after stable head CT (VTEP>24). Primary outcomes were VTE and ICHE. Covariate balancing propensity score weighting was utilized to balance demographic and clinical characteristics across three groups. Weighted univariate logistic regression models were estimated for VTE and ICHE with patient group as predictor of interest. RESULTS: Of 3,936 patients, 1,784 met inclusion criteria. Incidences of VTE was significantly higher in the VTEP>24 group, with higher incidences of DVT in the group. Higher incidences of ICHE were observed in the VTEP≤24 and VTEP>24 groups. After propensity score weighting, there was a higher risk of VTE in patients in VTEP >24 compared with those in VTEP≤24 (odds ratio, 1.51; 95% confidence interval, 0.69-3.30; p = 0.307), however was not significant. Although, the No VTEP group had decreased odds of having ICHE compared with VTEP≤24 (odds ratio, 0.75; 95% confidence interval, 0.55-1.02, p = 0.070), the result was not statistically significant. CONCLUSION: In this large multi-center analysis, there were no significant differences in VTE based on timing of initiation of VTE prophylaxis. Patients who never received VTE prophylaxis had decreased odds of ICHE. Further evaluation of VTE prophylaxis in larger randomized studies will be necessary for definitive conclusions. LEVEL OF EVIDENCE: Therapeutic Care Management; Level III.

Enterocyte expression of epidermal growth factor receptor is not required for intestinal adaptation in response to massive small bowel resection.

PURPOSE: Intestinal adaptation after massive small bowel resection (SBR) permits improved absorption of enteral nutrition despite significant loss of bowel length. Epidermal growth factor (EGF) and its receptor (EGFR) have previously been established to play major roles in the pathogenesis of adaptation. This study tested the hypothesis that EGFR signaling within the epithelial cell compartment (enterocytes) is required for intestinal adaptation. METHODS: We developed a tamoxifen-inducible Villin-Cre/LoxP recombinant system for enterocyte-directed EGFR deletion using EGFR-floxed mice. Epidermal growth factor receptor-null mice and wild-type littermates underwent either 50% proximal SBR or sham operation. Ileal tissue was harvested on postoperative day 7. To assess for adaptation, villus height and crypt depth as well as rates of crypt cell proliferation and apoptosis were measured. RESULTS: Adaptation after SBR occurred normally, as demonstrated by significant increases in villus height, crypt depth, and crypt proliferative and apoptotic index in both the wild-type and EGFR-null mice. CONCLUSION: Enterocyte EGFR expression is not required for the adaptation response to massive SBR. This novel finding suggests that enterocyte proliferation during adaptation is regulated by EGFR signaling in cells other than enterocytes, perhaps within the mesenchymal cell compartment of the bowel wall via factor(s) that are presently unknown.

p38 MAPK regulates Bax activity and apoptosis in enterocytes at baseline and after intestinal resection.

Increased apoptosis in crypt enterocytes is a key feature of intestinal adaptation following massive small bowel resection (SBR). Expression of the proapoptotic factor Bax has been shown to be required for resection-induced apoptosis. It has also been demonstrated that p38-α MAPK (p38) is necessary for Bax activation and apoptosis in vitro. The present studies were designed to test the hypothesis that p38 is a key regulator of Bax activation during adaptation after SBR in vivo. Enterocyte expression of p38 was deleted by tamoxifen administration to activate villin-Cre in adult mice with a floxed Mapk14 (p38-α) gene. Proximal 50% SBR or sham operations were performed on wild-type (WT) and p38 intestinal knockout (p38-IKO) mice under isoflurane anesthesia. Mice were killed 3 or 7 days after operation, and adaptation was analyzed by measuring intestinal morphology, proliferation, and apoptosis. Bax activity was quantified by immunoprecipitation, followed by Western blotting. After SBR, p38-IKO mice had deeper crypts, longer villi, and accelerated proliferation compared with WT controls. Rates of crypt apoptosis were significantly lower in p38-IKO mice, both at baseline and after SBR. Levels of activated Bax were twofold higher in WT mice after SBR relative to sham. In contrast, activated Bax levels were reduced by 67% in mice after p38 MAPK deletion. Deleted p38 expression within the intestinal epithelium leads to enhanced adaptation and reduced levels of enterocyte apoptosis after massive intestinal resection. p38-regulated Bax activation appears to be an important mechanism underlying resection-induced apoptosis.

Extent of small bowel resection does not influence the magnitude of intestinal adaptation in the mouse.

PURPOSE: The magnitude of intestinal adaptation is considered to correlate with the extent of small bowel resection (SBR). However, this association has never been tested in mice. We sought to test the hypothesis that a greater SBR will induce a greater adaptation response. METHODS: C57/B6 mice underwent 50% SBR, 75% SBR, or sham operation and were killed on postoperative day 7. The magnitude of adaptation was compared between 50% SBR and 75% SBR as changes in villus height, crypt depth, as well as rates of apoptosis and proliferation. RESULTS: Seventy-five percent SBR led to decreased survival and increased weight loss compared with 50% SBR. The remnant ileum of both 50% SBR and 75% SBR displayed similar crypt expansion, enhanced villi, and increased apoptotic indices. Proliferation rates increased after 50% and 75% SBR equally. CONCLUSION: Models of resection greater than 50% in mice result in greater morbidity and mortality and do not magnify the adaptation response to massive SBR. The use of more extreme resection models does not appear to provide added benefit for investigating mechanisms of intestinal adaptation.

Epidermal growth factor receptor signaling modulates chemokine (CXC) ligand 5 expression and is associated with villus angiogenesis after small bowel resection.

BACKGROUND: Adaptive villus growth after a massive small bowel resection (SBR) is an important response to the loss of intestinal surface area and is regulated via epidermal growth factor receptor (EGFR) signaling. Increased levels of the proangiogenic chemokine ligand 5 (CXCL5) have been found within the adapting bowel in which angiogenesis is increased. We sought to determine whether CXCL5 was expressed specifically in the villus mesenchymal zone (area of increased blood vessel growth) and whether this expression was affected by EGF. METHODS: C57BL/6J mice were subjected to sham operation (bowel transaction with reanastomosis) or 50% proximal SBR. The remnant intestine was harvested, and the villus lamina propria was isolated by laser capture microdissection. The expression of CXCL5 messenger RNA (mRNA) was analyzed using real-time polymerase chain reaction (RT-PCR). Furthermore, CXCL5 mRNA levels were determined in EGF-stimulated human umbilical vein endothelial cells (HUVECs). RESULTS: A 2.39-fold increase (P < .05) in CXCL5 mRNA occurred in the lamina propria after SBR. In addition, villus height was found to be related directly to the degree of CXCL5 mRNA (R(2) = 0.97) expression. HUVECs treated with EGF demonstrated a 9-fold increase in CXCL5 mRNA expression. CONCLUSION: The villus growth observed in resection-induced adaptation is associated with increased expression of the chemokine CXCL5 within the lamina propria. Because EGF enhances CXCL5 expression directly in endothelial cells, EGFR-directed proangiogenic gene expression may be a critical mechanism for adaptive ileal villus growth.

Growth factors: possible roles for clinical management of the short bowel syndrome.

The structural and functional changes during intestinal adaptation are necessary to compensate for the sudden loss of digestive and absorptive capacity after massive intestinal resection. When the adaptive response is inadequate, short bowel syndrome (SBS) ensues and patients are left with the requirement for parenteral nutrition and its associated morbidities. Several hormones have been studied as potential enhancers of the adaptation process. The effects of growth hormone, insulin-like growth factor-1, epidermal growth factor, and glucagon-like peptide 2 on adaptation have been studied extensively in animal models. In addition, growth hormone and glucagon-like peptide 2 have shown promise for the treatment of SBS in clinical trials in human beings. Several lesser studied hormones, including leptin, corticosteroids, thyroxine, testosterone, and estradiol, are also discussed.