Does an early, balanced resuscitation strategy reduce the incidence of hypofibrinogenemia in hemorrhagic shock?

Objectives: Some centers have recommended including concentrated fibrinogen replacement in massive transfusion protocols (MTPs). Given our center's policy of aggressive early balanced resuscitation (1:1:1), beginning prehospital, we hypothesized that our rates of hypofibrinogenemia may be lower than those previously reported. Methods: In this retrospective cohort study, patients presenting to our trauma center November 2017 to April 2021 were reviewed. Patients were defined as hypofibrinogenemic (HYPOFIB) if admission fibrinogen <150 or rapid thrombelastography angle <60. Univariate and multivariable analyses assessed risk factors for HYPOFIB. Inverse probability of treatment weighting analyses assessed the relationship between cryoprecipitate administration and outcomes. Results: Of 29 782 patients, 6618 level 1 activations, and 1948 patients receiving emergency release blood, <1%, 2%, and 7% were HYPOFIB. HYPOFIB patients were younger, had higher head Abbreviated Injury Scale value, and had worse coagulopathy and shock. HYPOFIB had lower survival (48% vs 82%, p<0.001), shorter time to death (median 28 (7, 50) vs 36 (14, 140) hours, p=0.012), and were more likely to die from head injury (72% vs 51%, p<0.001). Risk factors for HYPOFIB included increased age (OR (95% CI) 0.98 (0.96 to 0.99), p=0.03), head injury severity (OR 1.24 (1.06 to 1.46), p=0.009), lower arrival pH (OR 0.01 (0.001 to 0.20), p=0.002), and elevated prehospital red blood cell to platelet ratio (OR 1.20 (1.02 to 1.41), p=0.03). Among HYPOFIB patients, there was no difference in survival for those that received early cryoprecipitate (within 2 hours; 40 vs 47%; p=0.630). On inverse probability of treatment weighted analysis, early cryoprecipitate did not benefit the full cohort (OR 0.52 (0.43 to 0.65), p<0.001), nor the HYPOFIB subgroup (0.28 (0.20 to 0.39), p<0.001). Conclusions: Low rates of hypofibrinogenemia were found in our center which treats hemorrhage with early, balanced resuscitation. Previously reported higher rates may be partially due to unbalanced resuscitation and/or delay in resuscitation initiation. Routine empiric inclusion of concentrated fibrinogen replacement in MTPs is not supported by the currently available data. Level of evidence: Level III.

Mortality and outcomes by blood group in trauma patients: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Blood group O contains lower levels of factor VIII and von Willebrand factor. Higher incidence of bleeding among group O is reported in multiple contexts. Results of studies vary regarding outcomes stratified by blood group in trauma. We systematically reviewed the literature for outcomes related to blood group in trauma patients. Meta-analysis of studies evaluating mortality related to blood group was performed. MATERIALS AND METHODS: The PubMed and Embase databases were searched for studies analysing relationships between blood group and outcomes in trauma patients. Preferred Reporting Items in Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. We synthesized outcomes data related to blood group. Meta-analysis compared mortality rates between group O and non-O patients. RESULTS: Inclusion criteria were met by 13 studies. Statistically significant differences by blood group were reported in 3 of 10 (30%) studies evaluating mortality, 2 of 3 (66.7%) evaluating mortality from haemorrhage and 2 of 9 (22.2%) evaluating transfusion requirement. Meta-analysis was performed on seven studies evaluating mortality (total n = 11,835). There was significant heterogeneity among studies (I2 = 86%, p < 0.00001). No difference was found in mortality between group O and non-O patients (relative risk = 1.21, 95% confidence interval = 0.89-1.64, p = 0.23). CONCLUSION: Existing literature does not consistently demonstrate a mortality difference between trauma patients with O and non-O blood groups. High variability in the methods and results among studies limits this conclusion, and further research is needed to delineate under what circumstances blood group may influence outcomes.

Predicting Futility in Severely Injured Patients: Using Arrival Lab Values and Physiology to Support Evidence-Based Resource Stewardship.

BACKGROUND: The recent pandemic exposed a largely unrecognized threat to medical resources, including daily available blood products. Some of the most severely injured patients who arrive in extremis consume tremendous resources yet succumb shortly after arrival. We sought to identify cut points available early in the patient's resuscitation that predicted 100% mortality. STUDY DESIGN: Cut points were developed from a previously collected data set of all level 1 trauma patients admitted January 2010 to December 2016. Objective values available on or shortly after arrival were evaluated. Once generated, we then validated these variables against (1) a prospective data set November 2017 to October 2021 of severely injured patients and (2) a multicenter, randomized trial of hemorrhagic shock patients. Analyses were conducted using STATA 17.0 (College Station, TX), generating positive predictive value (PPV), negative predictive value, sensitivity, and specificity. RESULTS: The development data set consisted of 9,509 patients (17% mortality), with 2,137 (24%) and 680 (24%) in the two validation data sets. Several combinations of arrival vitals and labs had 100% PPV. Patients undergoing CPR in the field or on arrival (with subsequent return of spontaneous circulation) required lower fibrinolysis LY-30 (30%) than those with systolic blood pressures of ≤50 (30 to 50%), ≤70 (80 to 90%), and ≤90 mmHg (90%). Using a combination of these validated variables, the Suspension of Transfusions and Other Procedures (STOP) criteria were developed, with each element predicting 100% mortality, allowing physicians to cease further resuscitative efforts. CONCLUSIONS: The use of evidence-based STOP criteria provides cut points of futility to help guide early decisions for discontinuing aggressive treatment of severely injured patients arriving in extremis.

Perioperative Treatment with a Prolyl Hydroxylase Inhibitor Reduces Necrosis in a Rat Ischemic Skin Flap Model.

BACKGROUND: The hypoxia-inducible factor (HIF) pathway, regulated by prolyl hydroxylase, is central to tissue adaptation to ischemia. The authors tested whether the prolyl hydroxylase inhibitor dimethyloxalylglycine reduces skin flap necrosis. METHODS: Dorsal skin flaps were raised on hairless rats, with dimethyloxalylglycine delivered intraperitoneally and/or topically for 7 days before and after surgery. After 14 treatment days, percentage of flap necrosis was compared grossly and tissue perfusion compared with an in vivo imaging system. Angiogenesis was compared using immunohistochemical CD31 staining and enzyme-linked immunosorbent assay for tissue vascular endothelial growth factor. Expression levels of HIF-1α and terminal deoxynucleotidyl transferase-mediated dUDP end-labeling were compared using immunohistochemical staining. Complete blood counts and gross necropsy specimens were obtained to assess systemic toxicity. RESULTS: Dimethyloxalylglycine administration significantly improved postoperative flap viability, with combined topical and intraperitoneal dimethyloxalylglycine administration leading to reduced necrosis on postsurgical day 7 at 6 mg/kg/day, 12 mg/kg/day, 24 mg/kg/day, and 48 mg/kg/day versus controls (all p < 0.05). Compared with controls (unperfused, 39.9 ± 3.8 percent), dimethyloxalylglycine treatment led to a dose-dependent decrease in unperfused tissue at 6 mg/kg/day (11.4 ± 1.7 percent), 12 mg/kg/day (9.4 ± 4.2 percent), 24 mg/kg/day (4.7 ± 2.6 percent), and 48 mg/kg/day (1.4 ± 0.9 percent) (all p < 0.001). Topical dimethyloxalylglycine application alone administered at 48 mg/kg/day was sufficient to improve flap viability (p = 0.005). Dimethyloxalylglycine-treated flaps exhibited higher CD31 staining (p = 0.004), tissue vascular endothelial growth factor (p = 0.007), HIF-1α staining (p < 0.001), and reduced terminal deoxynucleotidyl transferase-mediated dUDP end-labeling staining (p = 0.045). There were no differences in hematocrit or macroscopic organ changes on gross necropsy. CONCLUSION: Topical and systemic targeting of the HIF-1 pathway may be a promising therapeutic approach to improve flap resistance to ischemia.

The Impact of Ergonomics on Recruitment to Surgical Fields: A Multi-Institutional Survey Study.

BACKGROUND: Awareness of ergonomics in surgery is growing, but whether musculoskeletal (MSK) injuries in surgery influence trainee career choices remains unknown. This study aimed to characterize medical students' MSK pain during surgical rotations and determine whether ergonomics influence student interest in surgical fields. METHODS: An online survey was administered to medical students in North Carolina. Students were asked about specialty interest, MSK pain on surgical rotations, and deterrents from surgical fields. Students were exposed to literature about ergonomics in surgery then queried again about relative specialty interest (medical versus surgical). Differences in specialty interest before and after the exposure were compared using a Wilcoxon signed-rank test. RESULTS: Of 243 participants, 44.0% were interested in pursuing a surgical specialty. Overall, 75.3% reported MSK pain during their surgical rotation, with the average daily pain score highest during surgery rotations compared to all other clinical rotations. The worst pain was reported in the feet and low back while "standing in the operating room" (81.2%) or "retracting" (59.4%). Among students initially interested in surgery but whose interest changed to a medical specialty during medical school, "physical demands of the field" was a common deterrent (36.4%). After exposure to literature regarding the incidence of MSK injuries in surgery, student interest in surgical fields on a 10-point scale significantly decreased (average -0.5 points; P < 0.01). CONCLUSIONS: High incidence of MSK injury among surgeons may be one factor deterring medical students from surgical careers. Ergonomic interventions may be important both to improve surgeon longevity and maintain the surgical workforce.

Rate of instrumentation changes on postoperative and follow-up radiographs after primary complex spinal fusion (five or more levels) for adult deformity correction.

OBJECTIVEIn the United States, healthcare expenditures have been soaring at a concerning rate. There has been an excessive use of postoperative radiographs after spine surgery and this has been a target for hospitals to reduce unnecessary costs. However, there are only limited data identifying the rate of instrumentation changes on radiographs after complex spine surgery involving ≥ 5-level fusions.METHODSThe medical records of 136 adult (≥ 18 years old) patients with spine deformity undergoing elective, primary complex spinal fusion (≥ 5 levels) for deformity correction at a major academic institution between 2010 and 2015 were reviewed. Patient demographics, comorbidities, and intra- and postoperative complication rates were collected for each patient. The authors reviewed the first 5 subsequent postoperative and follow-up radiographs, and determined whether revision of surgery was performed within 5 years postoperatively. The primary outcome investigated in this study was the rate of hardware changes on follow-up radiographs.RESULTSThe majority of patients were female, with a mean age of 53.8 ± 20.0 years and a body mass index of 27.3 ± 6.2 kg/m2 (parametric data are expressed as the mean ± SD). The median number of fusion levels was 9 (interquartile range 7-13), with a mean length of surgery of 327.8 ± 124.7 minutes and an estimated blood loss of 1312.1 ± 1269.2 ml. The mean length of hospital stay was 6.6 ± 3.9 days, with a 30-day readmission rate of 14.0%. Postoperative and follow-up change in stability on radiographs (days from operation) included: image 1 (4.6 ± 9.3 days) 0.0%; image 2 (51.7 ± 49.9 days) 3.0%; image 3 (142.1 ± 179.8 days) 5.6%; image 4 (277.3 ± 272.5 days) 11.3%; and image 5 (463.1 ± 525.9 days) 15.7%. The 3rd year after surgery had the highest rate of hardware revision (5.55%), followed by the 2nd year (4.68%), and the 1st year (4.54%).CONCLUSIONSThis study suggests that the rate of instrumentation changes on radiographs increases over time, with no changes occurring at the first postoperative image. In an era of cost-conscious healthcare, fewer orders for early radiographs after complex spinal fusions (≥ 5 levels) may not impact patient care and can reduce the overall use of healthcare resources.

Characterization of Perinatal Risk Factors and Complications Associated With Nonsyndromic Craniosynostosis.

BACKGROUND: Certain intrauterine risk factors are known to increase the risk of premature cranial suture fusion and may cause complications during birth. Some of these risk factors may be modifiable. Therefore, the authors sought to characterize the institutional patterns of prenatal risk factors and perinatal complications in nonsyndromic craniosynostosis patients compared to normal births from the surrounding area to identify areas for possible intervention or prevention. METHODS: The medical records of all infants with nonsyndromic craniosynostosis and full birth records born at Duke University Health System from 2006 to 2017 were retrospectively reviewed. Maternal comorbidities, prenatal risk factors, and perinatal complications were collected. The North Carolina State Center for Health Statistics was queried for perinatal statistics from Durham county and the Northeastern Perinatal Care Region to represent a control cohort of normal births from the same time period and region. The primary outcome investigated was the incidence of prenatal risk factors and complications at birth associated with premature fusion of cranial sutures. RESULTS: Eighty births with nonsyndromic craniosynostosis were included in this study. The majority of these patients were males (61.7%) and born via cesarean section (55.0%). Intrauterine growth restriction occurred in 10.0% and head trauma during delivery occurred in 2.5%. Twinning (14.8% vs 3.6%, P < 0.0001), cesarean births (55.5% vs 30.0%, P < 0.0001), and breech presentation (17.3% vs 3.2%, P < 0.0001) were significantly more common in craniosynostosis patients. Prenatally, mothers of craniosynostosis infants had higher incidence of gestational diabetes (13.5% vs 5.0%, P < 0.0001) and oligohydramnios (6.1% vs 1.3%, P < 0.0001) compared to regional controls. CONCLUSION: This study demonstrates that premature suture fusion is associated with prenatal risk factors such as gestational diabetes and oligohydramnios. Continued research into potentially modifiable prenatal risk factors and more refined prenatal diagnostic tools has the potential to reduce both the incidence of premature suture fusion and the sequelae of birth complications in this population.

Extracellular Mitochondrial DNA and N-Formyl Peptides in Trauma and Critical Illness: A Systematic Review.

OBJECTIVES: Extracellular mitochondrial DNA and N-formyl peptides released following tissue damage may contribute to systemic inflammation through stimulation of the innate immune system. In this review, we evaluate existing in vivo human data regarding a role for mitochondrial DNA and N-formyl peptides in producing systemic inflammation in trauma and critical illness, investigate the utility of these molecules in risk prediction and clinical decision support, and provide suggestions for standardization of future research. DATA SOURCES: PubMed, Embase (1971-2017). STUDY SELECTION: Studies measuring extracellular mitochondrial DNA and/or N-formyl peptides in acutely ill patients. DATA EXTRACTION: Fifty-four studies were analyzed. Data extracted included article characteristics, methods, results, and performance in clinical prediction. DATA SYNTHESIS: The most common patient types investigated were trauma (19 studies) and sepsis (eight). In studies comparing patient mitochondrial DNA or N-formyl peptide levels to healthy controls, 38 (90.5%) reported significantly elevated mitochondrial DNA levels in patients at first reported time point, as did the one study making this comparison for N-formyl peptides. Nine studies (81.8%) reported significantly elevated plasma/serum mitochondrial DNA levels in at least one time point in patients who developed inflammatory complications of their primary pathology compared with patients without inflammatory complications. For the ability of mitochondrial DNA to predict complications or outcomes, the area under the curve was 0.7 or greater in 84.6% of receiver operating characteristic curves, and 92.9% of odds, adjusted odds, risk, and hazard ratios were statistically significant. CONCLUSIONS: Extracellular mitochondrial DNA levels are elevated early in patients' hospital courses in many acute illnesses and are higher in patients who develop inflammatory complications. Elevated mitochondrial DNA levels may be clinically useful in risk prediction and clinical decision support systems. Further research is needed to determine the role of extracellular N-formyl peptides in systemic inflammation and their possible clinical utility.

Thirty-day complication and readmission rates associated with resection of metastatic spinal tumors: a single institutional experience.

BACKGROUND: This study aims to assess 30-day complication and unplanned readmission rates associated with resection of metastatic spinal tumors. METHODS: Medical records were reviewed for 135 adults who underwent elective resection of a spinal cord tumor. Patient demographics, comorbidities, and tumor characteristics were collected. Tumor pathology was analyzed and diagnosed by a pathologist. The primary outcomes were intra- and 30-day post-operative complication and readmission rates. RESULTS: Of the 135 spinal tumor resections, 30 (22.2%) cases were metastatic. The most common tumor pathology was bone (13.3%) and the most common locations were thoracic (45.2%), and cervical (32.7%). Most patients had an open surgery (96.7%), with a mean laminectomy/laminoplasty level of 1.9±1.5 and mean operative time of 328.4±658.0 min. There was a 3.3% incidence rate of intraoperative durotomies, with no spinal cord or nerve root injuries. Post-operatively, 44.8% of patients were transferred to the intensive care unit (ICU). The most common post-operative complications were weakness (20.0%), new sensory deficits (16.7%), and hypotension (13.3%). The mean length of stay was 8.8±7.6 days, with the majority of patients discharged home (96.7%). The 30-day readmission rate was 9.7%, with the most common 30-day complications being uncontrolled pain (16.7%), sensory-motor deficits (13.3%), and fever (10.0%). CONCLUSIONS: Our study suggests that weakness, sensory deficits, and uncontrolled pain are the most common complications after resection of spinal metastases, with a relatively high associated 30-day readmission rate. Further studies are necessary to corroborate our findings and identify strategies to reduce complication and readmission rates after resection of spinal metastases.

Socioeconomic Factors, Perioperative Complications, and 30-Day Readmission Rates Associated With Delayed Cranial Vault Reconstruction for Craniosynostosis.

BACKGROUND: Premature fusion of the cranial sutures can lead to significant neurocognitive, developmental, and esthetic consequences, especially if not corrected within the first year of life. This study aimed to identify the drivers of delayed cranial vault reconstruction (CVR) and its impact on complication and 30-day readmission rates among craniosynostosis patients. METHODS: The medical records of all children who underwent CVR for craniosynostosis between 2005 and 2017 at an academic institution were retrospectively reviewed. A delay in operation was defined by surgery performed >12 months of age. Patient demographics, comorbidities, perioperative complication rates, and 30-day readmission rates were collected. RESULTS: A total of 96 patients underwent primary CVR, with 79 (82.3%) patients undergoing nondelayed surgery and 17 (17.7%) patients undergoing surgery >12 months of age. Children undergoing delayed surgery were significantly more likely to be non-White (P < 0.0001), have Medicaid insurance (P = 0.023), and have a non-English primary language (P < 0.005). There was increased incidence of developmental disability identified at first consult (no-delay: 3.9% vs delay: 41.2%, P < 0.0001) and increased intracranial pressure (no-delay: 6.3% vs delay: 29.4%, P < 0.005) among children undergoing delayed surgery. The delayed cohort had a significantly higher unplanned 30-day readmission rate (no-delay: 0.0% vs delay: 5.9%, P = 0.03). CONCLUSION: Our study suggests that craniosynostosis patients who are non-White, have a non-English primary language, and have Medicaid insurance are at risk for delayed primary surgery, which may lead to increased 30-day readmission. Interventions are necessary to reduce craniosynostosis patients' barriers to care to minimize the sequelae associated with delayed surgery.

Neuroprotective pentapeptide CN-105 is associated with reduced sterile inflammation and improved functional outcomes in a traumatic brain injury murine model.

At present, there are no proven pharmacological treatments demonstrated to improve long term functional outcomes following traumatic brain injury(TBI). In the setting of non-penetrating TBI, sterile brain inflammatory responses are associated with the development of cerebral edema, intracranial hypertension, and secondary neuronal injury. There is increasing evidence that endogenous apolipoprotein E(apoE) modifies the neuroinflammatory response through its role in downregulating glial activation, however, the intact apoE holoprotein does not cross the blood-brain barrier due to its size. To address this limitation, we developed a small 5 amino acid apoE mimetic peptide(CN-105) that mimics the polar face of the apoE helical domain involved in receptor interactions. The goal of this study was to investigate the therapeutic potential of CN-105 in a murine model of closed head injury. Treatment with CN-105 was associated with a durable improvement in functional outcomes as assessed by Rotarod and Morris Water Maze and a reduction in positive Fluoro-Jade B stained injured neurons and microglial activation. Administration of CN-105 was also associated with reduction in mRNA expression of a subset of inflammatory and immune-related genes.