Jason L. Sperry

Genomic responses in mouse models poorly mimic human inflammatory diseases

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

A genomic storm in critically injured humans

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes.

An FFP: PRBC transfusion ratio >/=1:1.5 is associated with a lower risk of mortality after massive transfusion.

OBJECTIVE The detrimental effects of coagulopathy, hypothermia, and acidosis are well described as markers for mortality after traumatic hemorrhage. Recent military experience suggests that a high fresh frozen plasma (FFP):packed red blood cell (PRBC) transfusion ratio improves outcome; however, the appropriate ratio these transfusion products should be given remains to be established in a civilian trauma population. METHODS Data were obtained from a multicenter prospective cohort study evaluating clinical outcomes in blunt injured adults with hemorrhagic shock. Those patients who required >/=8 units PRBCs within the first 12 hours postinjury were analyzed (n = 415). RESULTS Patients who received transfusion products in >/=1:1.50 FFP:PRBC ratio (high F:P ratio, n = 102) versus <1:1.50 FFP:PRBC ratio (low F:P, n = 313) required significantly less blood transfusion at 24 hours (16 +/- 9 units vs. 22 +/- 17 units, p = 0.001). Crude mortality differences between the groups did not reach statistical significance (high F:P 28% vs. low F:P 35%, p = 0.202); however, there was a significant difference in early (24 hour) mortality (high F:P 3.9% vs. low F:P 12.8%, p = 0.012). Cox proportional hazard regression revealed that receiving a high F:P ratio was independently associated with 52% lower risk of mortality after adjusting for important confounders (HR 0.48, p = 0.002, 95% CI 0.3-0.8). A high F:P ratio was not associated with a higher risk of organ failure or nosocomial infection, however, was associated with almost a twofold higher risk of acute respiratory distress syndrome, after controlling for important confounders. CONCLUSIONS In patients requiring >/=8 units of blood after serious blunt injury, an FFP:PRBC transfusion ratio >/=1:1.5 was associated with a significant lower risk of mortality but a higher risk of acute respiratory distress syndrome. The mortality risk reduction was most relevant to mortality within the first 48 hours from the time of injury. These results suggest that the mortality risk associated with an FFP:PRBC ratio <1:1.5 may occur early, possibly secondary to ongoing coagulopathy and hemorrhage. This analysis provides further justification for the prospective trial investigation into the optimal FFP:PRBC ratio required in massive transfusion practice.

Fresh frozen plasma is independently associated with a higher risk of multiple organ failure and acute respiratory distress syndrome.

BACKGROUND Blood transfusion is known to be an independent risk factor for mortality, multiple organ failure (MOF), acute respiratory distress syndrome (ARDS), and nosocomial infection after injury. Less is known about the independent risks associated with plasma-rich transfusion components including fresh frozen plasma (FFP), platelets (PLTS), and cryoprecipitate (CRYO) after injury. We hypothesized that plasma-rich transfusion components would be independently associated with a lower risk of mortality but result in a greater risk of morbid complications. METHODS Data were obtained from a multicenter prospective cohort study evaluating clinical outcomes in bluntly injured adults with hemorrhagic shock. All patients required blood transfusion for enrollment. Patients with isolated traumatic brain injury and those not surviving beyond 48 hours were excluded. Cox proportional hazard regression models were used to estimate the outcome risks (per unit) associated with plasma-rich transfusion requirements during the initial 24 hours after injury after controlling for important confounders. RESULTS For the entire study population (n = 1,175), 65%, 41%, and 28% of patients received FFP, PLTS and CRYO, respectively. There was no association with plasma-rich transfusion components and mortality or nosocomial infection. For every unit given, FFP was independently associated with a 2.1% and 2.5% increased risk of MOF and ARDS, respectively. CRYO was associated with a 4.4% decreased risk of MOF (per unit), and PLTS were not associated with any of the outcomes examined. When early deaths (within 48 hours) were included in the model, FFP was associated with a 2.9% decreased risk of mortality per unit transfused. CONCLUSIONS In patients who survive their initial injury, FFP was independently associated with a greater risk of developing MOF and ARDS, whereas CRYO was associated with a lower risk of MOF. Further investigation into the mechanisms by which these plasma-rich component transfusions are associated with these effects are required.

Early use of vasopressors after injury: caution before constriction.

OBJECTIVE Recent evidence suggests that overly aggressive crystalloid resuscitation is associated with poor outcome. This has led to a renewed interest in the use of vasopressors for hemodynamic support during resuscitation after injury. We sought to characterize early vasopressor (EV) use and aggressive early crystalloid resuscitation (ECR) and their association with mortality in severely injured patients. METHODS Data were obtained from a multicenter, prospective, cohort study designed to evaluate the outcome of blunt injured adults in hemorrhagic shock. Early deaths (<48 hours) were excluded from the analysis. A single Cox proportional hazard regression model was used to evaluate the effects of EV use (levophed, phenylephrine, dopamine, or vasopressin) and aggressive ECR on mortality at 12 and 24 hours postinjury, while controlling for important physiologic, injury, resuscitation, and patient demographic confounders. RESULTS Cox proportional hazard regression revealed that EV use within 12 hours after injury was independently associated with over an 80% higher risk of mortality (hazard ratio [HR] 1.81, 95% confidence interval [CI] 1.1-2.9, p = 0.013), and was independently associated with over a twofold higher risk of mortality at 24 hours (HR 2.15, 95% CI 1.4-3.4, p = 0.001). These findings were consistent across all vasopressor subtypes. Aggressive ECR was independently associated with a 40% reduction in mortality (HR 0.594, 95% CI 0.37-0.95, p = 0.030). CONCLUSION These findings provide evidence that the early use of vasopressors for hemodynamic support after hemorrhagic shock may be deleterious, and should be used cautiously and not in place of aggressive crystalloid resuscitation after severe blunt injury.

Western Trauma Association critical decisions in trauma: resuscitative thoracotomy.

BACKGROUND In the past three decades, there has been a significant clinical shift in the performance of resuscitative thoracotomy (RT), from a nearly obligatory procedure before declaring any trauma patient deceased to a more selective application of RT. We have sought to formulate an evidence-based guideline for the current indications for RT after injury in the patient. METHODS The Western Trauma Association Critical Decisions Committee queried the literature for studies defining the appropriate role of RT in the trauma patient. When good data were not available, the Committee relied on expert opinion. RESULTS There are no published PRCT and it is not likely that there will be; recommendations are based on published prospective observational and retrospective studies, as well as expert opinion of Western Trauma Association members. Patients undergoing cardiopulmonary resuscitation (CPR) on arrival to the hospital should be stratified based on injury and transport time. Indications for RT include the following: blunt trauma patients with less than 10 minutes of prehospital CPR, penetrating torso trauma patients with less than 15 minutes of CPR, patients with penetrating trauma to the neck or extremity with less than 5 minutes of prehospital CPR, and patients in profound refractory shock. After RT, the patient’s intrinsic cardiac activity is evaluated; patients in asystole without cardiac tamponade are declared dead. Patients with a cardiac wound, tamponade, and associated asystole are aggressively treated. Patients with an intrinsic rhythm following RT should be treated according to underlying primary pathology. Following several minutes of such treatment as well as generalized resuscitation, salvageability is reassessed; we define this as the patient’s ability to generate a systolic blood pressure of greater than 70 mm Hg with an aortic cross-clamp if necessary. CONCLUSION The success of RT approximates 35% for the patient arriving in shock with a penetrating cardiac wound and 15% for all patients with penetrating wounds. Conversely, patient outcome is relatively poor when RT is performed for blunt trauma, 2% survival for patients in shock and less than 1% survival for patients with no vital signs. Patients undergoing CPR on arrival to the hospital should be stratified based on injury and transport time to determine the utility of RT. This algorithm represents a rational approach that could be followed at trauma centers with the appropriate resources; it may not be applicable at all hospitals caring for the injured. There will be patient, personnel, institutional, and situational factors that may warrant deviation from the recommended guideline. The annotated algorithm is intended to serve as a quick bedside reference for clinicians.

Accuracy of cardiac function and volume status estimates using the bedside echocardiographic assessment in trauma/critical care.

BACKGROUND Critically ill patients often require invasive monitoring to evaluate and optimize cardiac function and preload. With questionable outcomes associated with pulmonary artery catheters (PACs), some have evaluated the role of less invasive monitors. We hypothesized that the Bedside Echocardiographic Assessment in Trauma (BEAT) examination would generate cardiac index (CI) and central venous pressure (CVP) estimates that correlate with that of a PAC. METHODS BEAT was performed on all SICU patients with a PAC in place. Prospective data included stroke volume and the inferior vena cava (IVC) diameter. The CI was calculated and correlated with that from the PAC. Each CI was then categorized as low, normal, or high. The IVC diameter was used to estimate the CVP. The association between the BEAT and PAC estimates of CI and CVP was evaluated using chi. RESULTS Eighty-five BEAT examinations were performed, 57% on trauma and 37% on general surgery patients. Fifty-nine percent of the CI examinations and 97% of the IVC examinations contained quality images. Of these, the overall correlation coefficient was 0.70 (p < 0.0001). When CI was categorized, there was a significant association between the BEAT and PAC (p = 0.021). There was a significant association between the CVP estimate from the BEAT examination and the PAC (p = 0.031). CONCLUSION Our data show a significant correlation between the CI and CVP estimates obtained from the BEAT examination and that from a PAC. BEAT provides a noninvasive method of evaluating cardiac function and volume status. Bedside echocardiography is teachable and should become a part of future critical care curricula.

CTA-Based Screening Reduces Time to Diagnosis and Stroke Rate in Blunt Cervical Vascular Injury

BACKGROUND Advances in computed tomography capabilities have enabled trauma surgeons to screen for and diagnose the severity of blunt cervical vascular injury (BCVI) using computed tomographic angiography (CTA) alone. We hypothesized that the use of CTA-alone screening and diagnostic methods would reduce the time interval from admission to diagnosis and, hence, also reduce the stroke rates associated with these injuries. METHODS All patients admitted to a level I trauma center after December 1999 at risk for BCVI were screened. Until March 2005, patients were screened with cervical catheter angiography (CA). Subsequently, a CTA-alone screening/diagnostic program was initiated simultaneously with standardized interdisciplinary treatment guidelines for BCVI. Data for controls were subsequently obtained by reviewing trauma registry records. RESULTS Of 3012 trauma service admissions from April 2005 to July 2006, 26 patients were found to have BCVI diagnosed by CTA alone. A standardized, injury grade-based set of treatment guidelines were then initiated immediately based on CTA findings. Time to diagnosis and stroke rate in these patients were then compared with 79 patients found to have BCVI from December 1999 to March 2005 during CA-based screening. There were no differences in sex, mean age, Injury Severity Score, head/neck Abbreviated Injury Scale, or arrival Glasgow Coma Scale between the CA and CTA groups. With CA-based screening, the mean +/- SD time from trauma center admission to diagnosis was 31.2 +/- 41.1 hours. After transition to CTA screening in March 2005, this time was reduced to 2.65 +/- 3.3 hours (p < 0.001). During the era of CA-based screening, the overall stroke rate for BCVI at our institution was 15.2% (n = 12 of 79). After the initiation of CTA-based screening, the stroke rate was reduced to 3.8% (n = 1 of 26, p = 0.046). CONCLUSIONS The initiation of a CTA-based screening and diagnostic program, along with interdisciplinary standardized treatment guidelines, reduced the time to diagnosis of BCVI 12-fold and the institutional stroke rate due to BCVI fourfold. This may be due to earlier diagnosis and initiation of definitive therapy.

Scoop and run to the trauma center or stay and play at the local hospital: hospital transfer's effect on mortality.

BACKGROUND Triage attempts to ensure that severely injured patients are transported to a high-level trauma facility to reduce mortality. However, some patients are triaged to the nearest medical facility before transport to a final destination trauma center (TC). We sought to analyze whether initial triage of critically injured patients to a nontrauma center (NTC) is associated with increased mortality. METHODS The Glue Grant Trauma Database of severely injured patients was analyzed. Mortality risk for patients who had an intermediate stop at another facility was compared with patients triaged directly from the scene to the TC. Patient demographics, time from injury to TC arrival, resuscitation volume, transfusions, head injury, initial systolic blood pressure, co-morbidities, and injury severity were included as confounders in a multivariate logistic regression model. RESULTS There were 1,112 patients of whom 318 (29%) were initially triaged to an NTC. After adjusting for confounders, this was associated with an increase in prehospital crystalloids (4.2 L vs. 1.4 L, p < 0.05) and a 12-fold increase in blood transfusions (60% vs. 5%, p < 0.001). Age, injury severity score, Acute Physiology and Chronic Health Evaluation II score, and time from injury to TC arrival were independent predictors of mortality. The odds of death were 3.8 times greater (95% CI, 1.6-9.0) when patients were initially triaged to a nontrauma facility. CONCLUSIONS Triaging severely injured patients to hospitals that are incapable of providing definitive care is associated with increased mortality. Attempts at initial stabilization at an NTC may be harmful. These findings are consistent with a need for continued expansion of regional trauma systems.

The changing pattern and implications of multiple organ failure after blunt injury with hemorrhagic shock

Objectives:To describe the incidence of postinjury multiple organ failure and its relationship to nosocomial infection and mortality in trauma centers using evidence-based standard operating procedures. Design:Prospective cohort study wherein standard operating procedures were developed and implemented to optimize postinjury care. Setting:Seven U.S. level I trauma centers. Patients:Severely injured patients (older than age 16 yrs) with a blunt mechanism, systolic hypotension (<90 mm Hg), and/or base deficit (≥6 mEq/L), need for blood transfusion within the first 12 hrs, and an abbreviated injury score ≥2 excluding brain injury were eligible for inclusion. Measurements and Main Results:One thousand two patients were enrolled and 916 met inclusion criteria. Daily markers of organ dysfunction were prospectively recorded for all patients while receiving intensive care. Overall, 29% of patients had multiple organ failure develop. Development of multiple organ failure was early (median time, 2 days), short-lived, and predicted an increased incidence of nosocomial infection, whereas persistence of multiple organ failure predicted mortality. However, surprisingly, nosocomial infection did not increase subsequent multiple organ failure and there was no evidence of a “second-hit”-induced late-onset multiple organ failure. Conclusions:Multiple organ failure remains common after severe injury. Contrary to current paradigms, the onset is only early, and not bimodal, nor is it associated with a “second-hit”-induced late onset. Multiple organ failure is associated with subsequent nosocomial infection and increased mortality. Standard operating procedure-driven interventions may be associated with a decrease in late multiple organ failure and morbidity. (Crit Care Med 2012; 40:–1135)