Joseph P. Minei

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.

Allogeneic blood transfusion increases the risk of postoperative bacterial infection: A meta-analysis

Background: Immunosuppression is a consequence of allogeneic (homologous) blood transfusion (ABT) in humans and is associated with an increased risk in cancer recurrence rates after potentially curative surgery as well as an increase in the frequency of postoperative bacterial infections. Although a meta-analysis has been reported demonstrating the relationship between ABT and colon cancer recurrence, no meta-analysis has been reported demonstrating the relationship of ABT to postoperative bacterial infection. Methods: Twenty peer-reviewed articles published from 1986 to 2000 were included in a meta-analysis. Criteria for inclusion included a clearly defined control group (nontransfused) compared with a treated (transfused) group and statistical analysis of accumulated data that included stepwise multivariate logistic regression analysis. In addition, a subgroup of publications that included only the traumatically injured patient was included in a separate meta-analysis. A fixed effects analysis was conducted with odds ratios obtained by using the conditional maximum likelihood method and 95% confidence intervals on the obtained odds ratios were determined using the mid-p technique. Results: The total number of subjects included in this meta-analysis was 13,152 (5,215 in the transfused group and 7,937 in the nontransfused group). The common odds ratio for all articles included in this meta-analysis evaluating the association of ABT to the incidence of postoperative bacterial infection was 3.45 (range, 1.43-15.15), with 17 of the 20 studies demonstrating a value of p < or = 0.05. These results provide overwhelming evidence that ABT is associated with a significantly increased risk of postoperative bacterial infection in the surgical patient. The common odds ratio of the subgroup of trauma patients was 5.263 (range, 5.03-5.43), with all studies showing a value of p < 0.05 (0.005-0.0001). These results demonstrate that ABT is associated with a greater risk of postoperative bacterial infection in the trauma patient when compared with those patients receiving ABT during or after elective surgery. Conclusion: These results demonstrate that ABT is an associated and apparently significant and frequently overlooked risk factor for the development of postoperative bacterial infection in the surgical patient. Allogeneic blood transfusion is a greater risk factor in the traumatically injured patient when compared with the elective surgical patient for the development of postoperative bacterial infection.

Blunt splenic injury in adults: Multi-institutional study of the Eastern Association for the Surgery of Trauma

BACKGROUND Nonoperative management of blunt injury to the spleen in adults has been applied with increasing frequency. However, the criteria for nonoperative management are controversial. The purpose of this multi-institutional study was to determine which factors predict successful observation of blunt splenic injury in adults. METHODS A total of 1,488 adults (>15 years of age) with blunt splenic injury from 27 trauma centers in 1997 were studied through the Multi-institutional Trials Committee of the Eastern Association for the Surgery of Trauma. Statistical analysis was performed with analysis of variance and extended chi2 test. Data are expressed as mean +/- SD; a value of p < 0.05 was considered significant. RESULTS A total of 38.5 % of patients went directly to the operating room (group I); 61.5% of patients were admitted with planned nonoperative management. Of the patients admitted with planned observation, 10.8% failed and required laparotomy; 82.1% of patients with an Injury Severity Score (ISS) < 15 and 46.6% of patients with ISS > 15 were successfully observed. Frequency of immediate operation correlated with American Association for the Surgery of Trauma (AAST) grades of splenic injury: I (23.9%), II (22.4%), III (38.1%), IV (73.7%), and V (94.9%) (p < 0.05). Of patients initially managed nonoperatively, the failure rate increased significantly by AAST grade of splenic injury: I (4.8%), II (9.5%), III (19.6%), IV (33.3%), and V (75.0%) (p < 0.05). A total of 60.9% of the patients failed nonoperative management within 24 hours of admission; 8% failed 9 days or later after injury. Laparotomy was ultimately performed in 19.9% of patients with small hemoperitoneum, 49.4% of patients with moderate hemoperitoneum, and 72.6% of patients with large hemoperitoneum. CONCLUSION In this multicenter study, 38.5% of adults with blunt splenic injury went directly to laparotomy. Ultimately, 54.8% of patients were successfully managed nonoperatively; the failure rate of planned observation was 10.8%, with 60.9% of failures occurring in the first 24 hours. Successful nonoperative management was associated with higher blood pressure and hematocrit, and less severe injury based on ISS, Glasgow Coma Scale, grade of splenic injury, and quantity of hemoperitoneum.

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.

External fixation or arteriogram in bleeding pelvic fracture: initial therapy guided by markers of arterial hemorrhage.

BACKGROUND Bleeding pelvic fractures (BPF) carry mortality as high as 60%, yet controversy remains over optimal initial management. Some base initial intervention on fracture pattern, with immediate external fixation (EX FIX) in amenable fractures aimed at controlling venous bleeding. Others feel ongoing hemodynamic instability indicates arterial bleeding, and prefer early angiography (ANGIO) before EX-FIX. Our aim was to evaluate markers of arterial bleeding in patients with BPF, thus identifying patients requiring early ANGIO regardless of fracture pattern. METHODS Patients with pelvis fracture were identified from a Level I trauma center registry over a 7-year period and records reviewed. From this group, two subsets were analyzed: those with initial hypotension related to pelvic fracture, and those without hypotension who underwent pelvic ANGIO. Data included hemodynamics, response to resuscitation, presence of contrast blush on CT, fracture treatment and outcome. Adequate response to initial resuscitation (R) was defined as a sustained (>2 hours) improvement of systolic blood pressure to >90 mm Hg systolic after the administration of < or = 2 units packed red blood cells. Those with repeated episodes of hypotension despite resuscitation were classified as non-responders (NR) RESULTS: From 1/94-1/01, 1171 patients were admitted with pelvic ring fracture. Thirty-five (0.3%) had hypotension attributable to pelvis fracture. 28 fell into the NR group, and 26 of these underwent ANGIO. Nineteen (73%) showed arterial bleeding while 3 resuscitation response patients underwent ANGIO with none demonstrating bleeding (p = 0.03). Sensitivity and specificity of inadequate response to initial resuscitation for predicting the presence of arterial bleeding on ANGIO were 100% and 30% respectively while negative and positive predictive value were 100% and 73%. In patients with fractures amenable to external fixation (n = 16), 44% had arterial bleeding on ANGIO, and all were in the NR group. An additional 17 patients without hypotension also underwent ANGIO. Contrast blush on admission CT was seen in 4, 3 of which had arterial bleeding seen on ANGIO (75%). Sensitivity and specificity for contrast blush in predicting bleeding on ANGIO were 60% and 92% with positive and negative predictive value being 75% and 85%. CONCLUSIONS In patients with hypotension and pelvic fracture, therapy selection based on initial response to resuscitation in BPF yields a 73% positive ANGIO rate in NR patients. Delay in ANGIO for EX FIX in patients with amenable fractures would have delayed embolization in the face of ongoing arterial bleeding in 44% of patients. In stable patients with pelvic fracture, contrast blush also indicates a high likelihood of arterial injury and ANGIO is indicated. Optimal therapy in the face of BPF requires early determination of the presence of arterial bleeding so that ANGIO can be rapidly obtained, and response to initial resuscitation as well as the presence of contrast blush aid in this decision.

Out-of-Hospital Hypertonic Resuscitation Following Severe Traumatic Brain Injury: A Randomized Controlled Trial

CONTEXT Hypertonic fluids restore cerebral perfusion with reduced cerebral edema and modulate inflammatory response to reduce subsequent neuronal injury and thus have potential benefit in resuscitation of patients with traumatic brain injury (TBI). OBJECTIVE To determine whether out-of-hospital administration of hypertonic fluids improves neurologic outcome following severe TBI. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, randomized, placebo-controlled clinical trial involving 114 North American emergency medical services agencies within the Resuscitation Outcomes Consortium, conducted between May 2006 and May 2009 among patients 15 years or older with blunt trauma and a prehospital Glasgow Coma Scale score of 8 or less who did not meet criteria for hypovolemic shock. Planned enrollment was 2122 patients. INTERVENTION A single 250-mL bolus of 7.5% saline/6% dextran 70 (hypertonic saline/dextran), 7.5% saline (hypertonic saline), or 0.9% saline (normal saline) initiated in the out-of-hospital setting. MAIN OUTCOME MEASURE Six-month neurologic outcome based on the Extended Glasgow Outcome Scale (GOSE) (dichotomized as >4 or ≤4). RESULTS The study was terminated by the data and safety monitoring board after randomization of 1331 patients, having met prespecified futility criteria. Among the 1282 patients enrolled, 6-month outcomes data were available for 1087 (85%). Baseline characteristics of the groups were equivalent. There was no difference in 6-month neurologic outcome among groups with regard to proportions of patients with severe TBI (GOSE ≤4) (hypertonic saline/dextran vs normal saline: 53.7% vs 51.5%; difference, 2.2% [95% CI, -4.5% to 9.0%]; hypertonic saline vs normal saline: 54.3% vs 51.5%; difference, 2.9% [95% CI, -4.0% to 9.7%]; P = .67). There were no statistically significant differences in distribution of GOSE category or Disability Rating Score by treatment group. Survival at 28 days was 74.3% with hypertonic saline/dextran, 75.7% with hypertonic saline, and 75.1% with normal saline (P = .88). CONCLUSION Among patients with severe TBI not in hypovolemic shock, initial resuscitation with either hypertonic saline or hypertonic saline/dextran, compared with normal saline, did not result in superior 6-month neurologic outcome or survival. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00316004.

Out-of-hospital Hypertonic Resuscitation After Traumatic Hypovolemic Shock A Randomized, Placebo Controlled Trial

Objective: To determine whether out-of-hospital administration of hypertonic fluids would improve survival after severe injury with hemorrhagic shock. Background: Hypertonic fluids have potential benefit in the resuscitation of severely injured patients because of rapid restoration of tissue perfusion, with a smaller volume, and modulation of the inflammatory response, to reduce subsequent organ injury. Methods: Multicenter, randomized, blinded clinical trial, May 2006 to August 2008, 114 emergency medical services agencies in North America within the Resuscitation Outcomes Consortium. Inclusion criteria: injured patients, age ≥ 15 years with hypovolemic shock (systolic blood pressure ⩽ 70 mm Hg or systolic blood pressure 71–90 mm Hg with heart rate ≥ 108 beats per minute). Initial resuscitation fluid, 250 mL of either 7.5% saline per 6% dextran 70 (hypertonic saline/dextran, HSD), 7.5% saline (hypertonic saline, HS), or 0.9% saline (normal saline, NS) administered by out-of-hospital providers. Primary outcome was 28-day survival. On the recommendation of the data and safety monitoring board, the study was stopped early (23% of proposed sample size) for futility and potential safety concern. Results: A total of 853 treated patients were enrolled, among whom 62% were with blunt trauma, 38% with penetrating. There was no difference in 28-day survival—HSD: 74.5% (0.1; 95% confidence interval [CI], −7.5 to 7.8); HS: 73.0% (−1.4; 95% CI, −8.7–6.0); and NS: 74.4%, P = 0.91. There was a higher mortality for the postrandomization subgroup of patients who did not receive blood transfusions in the first 24 hours, who received hypertonic fluids compared to NS [28-day mortality—HSD: 10% (5.2; 95% CI, 0.4–10.1); HS: 12.2% (7.4; 95% CI, 2.5–12.2); and NS: 4.8%, P < 0.01]. Conclusion: Among injured patients with hypovolemic shock, initial resuscitation fluid treatment with either HS or HSD compared with NS, did not result in superior 28-day survival. However, interpretation of these findings is limited by the early stopping of the trial. Clinical Trial Registration: Clinical Trials.gov, NCT00316017

Quantitative proteome analysis of human plasma following in vivo lypopolysaccharide administration using 16O/18O labeling and the accurate mass and time tag approach

Identification of novel diagnostic or therapeutic biomarkers from human blood plasma would benefit significantly from quantitative measurements of the proteome constituents over a range of physiological conditions. Herein we describe an initial demonstration of proteome-wide quantitative analysis of human plasma. The approach utilizes postdigestion trypsin-catalyzed 16O/18O peptide labeling, two-dimensional LC-FTICR mass spectrometry, and the accurate mass and time (AMT) tag strategy to identify and quantify peptides/proteins from complex samples. A peptide accurate mass and LC elution time AMT tag data base was initially generated using MS/MS following extensive multidimensional LC separations to provide the basis for subsequent peptide identifications. The AMT tag data base contains >8,000 putative identified peptides, providing 938 confident plasma protein identifications. The quantitative approach was applied without depletion of high abundance proteins for comparative analyses of plasma samples from an individual prior to and 9 h after lipopolysaccharide (LPS) administration. Accurate quantification of changes in protein abundance was demonstrated by both 1:1 labeling of control plasma and the comparison between the plasma samples following LPS administration. A total of 429 distinct plasma proteins were quantified from the comparative analyses, and the protein abundances for 25 proteins, including several known inflammatory response mediators, were observed to change significantly following LPS administration.

High Dynamic Range Characterization of the Trauma Patient Plasma Proteome

Although human plasma represents an attractive sample for disease biomarker discovery, the extreme complexity and large dynamic range in protein concentrations present significant challenges for characterization, candidate biomarker discovery, and validation. Herein we describe a strategy that combines immunoaffinity subtraction and subsequent chemical fractionation based on cysteinyl peptide and N-glycopeptide captures with two-dimensional LC-MS/MS to increase the dynamic range of analysis for plasma. Application of this “divide-and-conquer” strategy to trauma patient plasma significantly improved the overall dynamic range of detection and resulted in confident identification of 22,267 unique peptides from four different peptide populations (cysteinyl peptides, non-cysteinyl peptides, N-glycopeptides, and non-glycopeptides) that covered 3654 different proteins with 1494 proteins identified by multiple peptides. Numerous low abundance proteins were identified, exemplified by 78 “classic” cytokines and cytokine receptors and by 136 human cell differentiation molecules. Additionally a total of 2910 different N-glycopeptides that correspond to 662 N-glycoproteins and 1553 N-glycosylation sites were identified. A panel of the proteins identified in this study is known to be involved in inflammation and immune responses. This study established an extensive reference protein database for trauma patients that provides a foundation for future high throughput quantitative plasma proteomic studies designed to elucidate the mechanisms that underlie systemic inflammatory responses.