James G. Chandler

Three spectra of laparoscopic entry access injuries1

BACKGROUND Procedure-based surveys oflaparoscopic entry access injuries show a reassuringly low incidence, varying from 5 per 10,000 to 3 per 1,000, and, consequently, can provide only limited specific injury data. The current study uses existing injury-based reporting systems to access a uniquely large number of entry injuries to define the nature and outcomes of such events. STUDY DESIGN Claims arising from US and non-US entry access injuries, between 1980 and 1999, reported to the Physicians Insurers Association of America by their member and affiliate companies and entry-injury medical device reports to the US FDA, from 1995 through October 1997, were analyzed to determine operative procedures, physician specialties, entry devices, and techniques associated with specific injuries. Individual injuries were analyzed for their relative incidence and potential to cause disability and death. RESULTS Five hundred ninety-four structures or organs were injured in 506 patients, resulting in 65 deaths (13%). General surgical procedures made up at least 67% of combined medical device reports and US Physicians Insurers Association of America cases, and gynecologic procedures accounted for 63% of non-US claims. Bowel and retroperitoneal vascular injuries comprised 76% of all injuries incurred in the process of establishing a primary port. Nearly 50% of both small and large bowel injuries were unrecognized for 24 hours or longer. Delayed recognition, along with age greater than 59 years and major visceral vascular injuries, were each independent significant predictors of death. CONCLUSIONS No entry technique or device is absolutely safe. Avoidance of entry injuries depends on patient-specific anatomic orientation and control of entry axial force. Certain entry devices can be facilitating in controlling axial force. Overall, this large aggregate of entry access injuries shows them to be more serious and, along with other data, implies that they might be more common than reported in procedure-based studies.

Overwhelming tPA release, not PAI-1 degradation, is responsible for hyperfibrinolysis in severely injured trauma patients.

BACKGROUND Trauma-induced coagulopathy (TIC) is associated with a fourfold increased risk of mortality. Hyperfibrinolysis is a component of TIC, but its mechanism is poorly understood. Plasminogen activation inhibitor (PAI-1) degradation by activated protein C has been proposed as a mechanism for deregulation of the plasmin system in hemorrhagic shock, but in other settings of ischemia, tissue plasminogen activator (tPA) has been shown to be elevated. We hypothesized that the hyperfibrinolysis in TIC is not the result of PAI-1 degradation but is driven by an increase in tPA, with resultant loss of PAI-1 activity through complexation with tPA. METHODS Eighty-six consecutive trauma activation patients had blood collected at the earliest time after injury and were screened for hyperfibrinolysis using thrombelastography (TEG). Twenty-five hyperfibrinolytic patients were compared with 14 healthy controls using enzyme-linked immunosorbent assays for active tPA, active PAI-1, and PAI-1/tPA complex. Blood was also subjected to TEG with exogenous tPA challenge as a functional assay for PAI-1 reserve. RESULTS Total levels of PAI-1 (the sum of the active PAI-1 species and its covalent complex with tPA) are not significantly different between hyperfibrinolytic trauma patients and healthy controls: median, 104 pM (interquartile range [IQR], 48–201 pM) versus 115 pM (IQR, 54–202 pM). The ratio of active to complexed PAI-1, however, was two orders of magnitude lower in hyperfibrinolytic patients than in controls. Conversely, total tPA levels (active + complex) were significantly higher in hyperfibrinolytic patients than in controls: 139 pM (IQR, 68–237 pM) versus 32 pM (IQR, 16–37 pM). Hyperfibrinolytic trauma patients displayed increased sensitivity to exogenous challenge with tPA (median LY30 of 66.8% compared with 9.6% for controls). CONCLUSION Depletion of PAI-1 in TIC is driven by an increase in tPA, not PAI-1 degradation. The tPA-challenged TEG, based on this principle, is a functional test for PAI-1 reserves. Exploration of the mechanism of up-regulation of tPA is critical to an understanding of hyperfibrinolysis in trauma. LEVEL OF EVIDENCE Prognostic and epidemiologic study, level II.

The "Death Diamond": Rapid thrombelastography identifies lethal hyperfibrinolysis.

BACKGROUND Postinjury hyperfibrinolysis (HF), defined as LY30 of 3% or greater on rapid thrombelastography (rTEG), is associated with high mortality and large use of blood products. We observed that some cases of HF are reversible and are associated with patients who respond to hemostatic resuscitation; however, other cases of severe HF seem to be associated with these patients’ inevitable demise. We therefore sought to define this unsurvivable subtype of HF as a recognizable rTEG tracing pattern. METHODS We queried our trauma registry for patients who either died or spent at least 1 day in the intensive care unit, received at least 1 U of packed red blood cells, and had an admission rTEG. Within this group of 572 patients, we identified 42 pairs of nonsurvivors and survivors who matched on age, sex, injury mechanism, and New Injury Severity Score (NISS). We inspected the rTEG tracings to ascertain if any pattern was found exclusively within the nonsurviving group and applied these findings to the cohort of 572 patients to assess the predictive value for mortality. RESULTS Within the matched group, 17% of the patients developed HF. Within the HF subgroup, a unique rTEG pattern was present in 14 HF patients who died and in none of the survivors. This pattern was a “diamond-shaped” tracing with a short time to maximum amplitude of 14 minutes or shorter and complete lysis before the LY30 point. When these criteria are applied to the 572 unmatched patients, this pattern had a 100% positive predictive value for mortality. CONCLUSION Patients displaying the “death diamond” pattern on their admission rTEG are at higher risk for mortality. Given the volume of blood products and other resources that these patients consume, this thrombelastography pattern may represent an objective criterion to discontinue efforts at hemostatic resuscitation. LEVEL OF EVIDENCE Prognostic/epidemiologic study, level III.

It’s not your grandfather’s field plasma

Initiating prehospital resuscitation with plasma in patients with trauma-associated hemorrhagic shock will result in more rapid and durable clot formation and, thus, the need for fewer packed cell infusions, less frequent use of cryoprecipitate, and more ventilator-free hospital days compared with those of patients randomized to standard crystalloid field resuscitation.

Combat: Initial Experience with a Randomized Clinical Trial of Plasma-Based Resuscitation in the Field for Traumatic Hemorrhagic Shock.

ABSTRACT The existing evidence shows great promise for plasma as the first resuscitation fluid in both civilian and military trauma. We embarked on the Control of Major Bleeding After Trauma (COMBAT) trial with the support of the Department of Defense to determine if plasma-first resuscitation yields hemostatic and survival benefits. The methodology of the COMBAT study represents not only 3 years of development work but also the integration of nearly two decades of technical experience with the design and implementation of other clinical trials and studies. Herein, we describe the key features of the study design, critical personnel and infrastructural elements, and key innovations. We will also briefly outline the systems engineering challenges entailed by this study. The COMBAT trial is a randomized, placebo-controlled, semiblinded, prospective, phase IIB clinical trial conducted in a ground ambulance fleet based at a level I trauma center and part of a multicenter collaboration. The primary objective of the COMBAT trial is to determine the efficacy of field resuscitation with plasma first compared with standard of care (normal saline). To date, we have enrolled 30 subjects in the COMBAT study. The ability to achieve intervention with a hemostatic resuscitation agent in the closest possible temporal proximity to injury is critical and represents an opportunity to forestall the evolution of the “bloody vicious cycle.” Thus, the COMBAT model for deploying plasma in first-response units should serve as a model for randomized clinical trials of other hemostatic resuscitative agents.

Exploring ethical conflicts in emergency trauma research: The COMBAT (Control of Major Bleeding after Trauma) study experience

BACKGROUND Up to 25% of severely injured patients develop trauma-induced coagulopathy. To study interventions for this vulnerable population for whom consent cannot be obtained easily, the Food and Drug Administration issued regulations for emergency research with an exception from informed consent (ER-EIC). We describe the community consultation and public disclosure (CC/PD) process in preparation for an ER-EIC study, namely the Control Of Major Bleeding After Trauma (COMBAT) study. METHODS The CC/PD was guided by the four bioethical principles. We used a multimedia approach, including one-way communications (newspaper ads, brochures, television, radio, and web) and two-way communications (interactive in-person presentations at community meetings, printed and online feedback forms) to reach the trials catchment area (Denver Countys population: 643,000 and the Denver larger metro area where commuters reside: 2.9 million). Particular attention was given to special-interests groups (eg, Jehovah Witnesses, homeless) and to Spanish-speaking communities (brochures and presentations in Spanish). Opt-out materials were available during on-site presentations or via the COMBAT study website. RESULTS A total of 227 community organizations were contacted. Brochures were distributed to 11 medical clinics and 3 homeless shelters. The multimedia campaign had the potential to reach an estimated audience of 1.5 million individuals in large metro Denver area, the majority via one-way communication and 1900 in two-way communications. This resource intensive process cost more than

Plasma succinate is a predictor of mortality in critically injured patients

84,000. CONCLUSION The CC/PD process is resource-intensive, costly, and complex. Although the multimedia CC/PD reached a large audience, the effectiveness of this process remains elusive. The templates can be helpful to similar ER-EIC studies.

Elderly patients may benefit from tight glucose control

BACKGROUND Trauma is the leading cause of mortality under the age of 40 years. Recent observations on metabolic reprogramming during hypoxia and ischemia indicate that hypoxic mitochondrial uncoupling promotes the generation of succinate, which in turn mediates reperfusion injury and inflammatory sequelae upon reoxygenation. Plasma levels of succinate significantly increase in response to trauma and hemorrhage in experimental models and clinical samples, suggesting that succinate may represent a candidate marker of systemic perfusion in trauma. METHODS Quantitative mass spectrometry-based metabolomics was used to quantify succinate and lactate in 595 plasma samples from severely injured patients enrolled at the Denver Health Medical Center, a Level I trauma center in Denver, Colorado. RESULTS A total of 95 severely injured patients were sampled for up to 10 time points (595 total samples), from field blood to 7 days postinjury. Results indicate that plasma levels of succinate increased up to 25.9-fold in deceased patients versus the median of the surviving patients (p = 2.75e-100; receiver operating characteristic area under the curve, 0.911). On the other hand, only 2.4-fold changes increases in lactate were observed (p = 5.8e-21; area under the curve, 0.874). CONCLUSION Succinate represents a uniquely sensitive biomarker of postshock metabolic derangement and may be an important mediator of sequelae. Level of evidence Prognostic study, level III.

Fibrinolysis shutdown is associated with a fivefold increase in mortality in trauma patients lacking hypersensitivity to tissue plasminogen activator

BACKGROUND While minimizing hyperglycemia in critically injured patients improves outcomes, it is debatable whether postinjury glucose control should aim for conventional glucose control levels (≤180 mg/dL) or tight glucose control levels (81-108 mg/dL). We queried our 17-year prospective database of patients at risk for postinjury multiple organ failure to examine the association between glucose levels and adverse outcomes. METHODS Acutely injured patients admitted to a Level I trauma center intensive care unit from 1992 to 2008 who were more than 15 years of age, had Injury Severity Scores >15, and who survived >48 hours were eligible for the study. Multiple logistic regression was used to determine the independent association of glucose control with adverse outcomes (death, ventilator-free days, intensive care unit-free days, and major infections), adjusted for Injury Severity Score, age, and red blood cell transfusion in the first 12 hours. RESULTS Overall, 2,231 patients were eligible, of whom 153 (6.9%) died. The mean age was 37.8 ± 0.4 years, and the median Injury Severity Score was 27 (interquartile range, 21-35). The majority (77%) of these patients maintained mean glucose within conventional glucose control levels and only 10% achieved mean glucose levels within tight glucose control levels. Nonsurvivors required greater doses of insulin to control glucose levels and had greater mean insulin to glucose ratios (t test; P = .025). After adjusting for confounders, mean glucose remained significantly associated with the studied adverse outcomes. Age significantly modified all these associations with older patients seeming to benefit more from tight glucose control levels than their younger counterparts. CONCLUSION Age is an effect modifier of the association between glucose levels and adverse outcomes. Future studies including larger samples of elderly trauma patients are needed to determine the ideal levels for glucose control in this growing population.

Direct blood transfusions

BACKGROUND Fibrinolysis shutdown (SD) is an independent risk factor for increased mortality in trauma. High levels of plasminogen activator inhibitor-1 (PAI-1) directly binding tissue plasminogen activator (t-PA) is a proposed mechanism for SD; however, patients with low PAI-1 levels present to the hospital with a rapid TEG (r-TEG) LY30 suggestive SD. We therefore hypothesized that two distinct phenotypes of SD exist, one, which is driven by t-PA inhibition, whereas another is due to an inadequate t-PA release in response to injury. METHODS Trauma activations from our Level I center between 2014 and 2016 with blood collected within an hour of injury were analyzed with r-TEG and a modified TEG assay to quantify fibrinolysis sensitivity using exogenous t-PA (t-TEG). Using the existing r-TEG thresholds for SD (<0.9%), physiologic (LY30 0.9–2.9%), and hyperfibrinolysis (LY30 > 2.9%) patients were stratified into phenotypes. A t-TEG LY30 greater than 95th percentile of healthy volunteers (n = 140) was classified as t-PA hypersensitive and used to subdivide phenotypes. A nested cohort had t-PA and PAI-1 activity levels measured in addition to proteomic analysis of additional fibrinolytic regulators. RESULTS This study included 398 patients (median New Injury Severity Score, 18), t-PA-Sen was present in 27% of patients. Shutdown had the highest mortality rate (20%) followed by hyperfibinolysis (16%) and physiologic (9% p = 0.020). In the non–t-PA hypersensitive cohort, SD had a fivefold increase in mortality (15%) compared with non-SD patients (3%; p = 0.003) which remained significant after adjusting for Injury Severity Score and age (p = 0.033). Overall t-PA activity (p = 0.002), PAI-1 (p < 0.001), and t-PA/PAI-1 complex levels (p = 0.006) differed between the six phenotypes, and 54% of fibrinolytic regulator proteins analyzed (n = 19) were significantly different. CONCLUSION In conclusion, acute fibrinolysis SD is not caused by a single etiology, and is clearly associated with PAI-1 activity. The differential phenotypes require an ongoing investigation to identify the optimal resuscitation strategy for these patients. Level of Evidence Prognostic, level III.