Myung S. Park

Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients

Objective:To determine the effect of blood component ratios in massive transfusion (MT), we hypothesized that increased use of plasma and platelet to red blood cell (RBC) ratios would result in decreased early hemorrhagic death and this benefit would be sustained over the ensuing hospitalization. Summary Background Data:Civilian guidelines for massive transfusion (MT ≥10 units of RBC in 24 hours) have typically recommend a 1:3 ratio of plasma:RBC, whereas optimal platelet:RBC ratios are unknown. Conversely, military data shows that a plasma:RBC ratio approaching 1:1 improves long term outcomes in MT combat casualties. There is little consensus on optimal platelet transfusions in either civilian or military practice. At present, the optimal combinations of plasma, platelet, and RBCs for MT in civilian patients is unclear. Methods:Records of 467 MT trauma patients transported from the scene to 16 level 1 trauma centers between July 2005 and June 2006 were reviewed. One patient who died within 30 minutes of admission was excluded. Based on high and low plasma and platelet to RBC ratios, 4 groups were analyzed. Results:Among 466 MT patients, survival varied by center from 41% to 74%. Mean injury severity score varied by center from 22 to 40; the average of the center means was 33. The plasma:RBC ratio ranged from 0 to 2.89 (mean ± SD: 0.56 ± 0.35) and the platelets:RBC ratio ranged from 0 to 2.5 (0.55 ± 0.50). Plasma and platelet to RBC ratios and injury severity score were predictors of death at 6 hours, 24 hours, and 30 days in multivariate logistic models. Thirty-day survival was increased in patients with high plasma:RBC ratio (≥1:2) relative to those with low plasma:RBC ratio (<1:2) (low: 40.4% vs. high: 59.6%, P < 0.01). Similarly, 30-day survival was increased in patients with high platelet:RBC ratio (≥1:2) relative to those with low platelet:RBC ratio (<1:2) (low: 40.1% vs. high: 59.9%, P < 0.01). The combination of high plasma and high platelet to RBC ratios were associated with decreased truncal hemorrhage, increased 6-hour, 24-hour, and 30-day survival, and increased intensive care unit, ventilator, and hospital-free days (P < 0.05), with no change in multiple organ failure deaths. Statistical modeling indicated that a clinical guideline with mean plasma:RBC ratio equal to 1:1 would encompass 98% of patients within the optimal 1:2 ratio. Conclusions:Current transfusion practices and survival rates of MT patients vary widely among trauma centers. Conventional MT guidelines may underestimate the optimal plasma and platelet to RBC ratios. Survival in civilian MT patients is associated with increased plasma and platelet ratios. Massive transfusion practice guidelines should aim for a 1:1:1 ratio of plasma:platelets:RBCs.

Thromboelastography as a Better Indicator of Hypercoagulable State After Injury Than Prothrombin Time or Activated Partial Thromboplastin Time

OBJECTIVES To investigate the hemostatic status of critically ill, nonbleeding trauma patients. We hypothesized that a hypercoagulable state exists in patients early after severe injury and that the pattern of clotting and fibrinolysis are similar between burned and nonburn trauma patients. MATERIALS Patients admitted to the surgical or burn intensive care unit within 24 hours after injury were enrolled. Blood samples were drawn on days 0 through 7. Laboratory tests included prothrombin time (PT), activated partial thromboplastin time (aPTT), levels of activated factor XI, D-dimer, protein C percent activity, antithrombin III percent activity, and thromboelastography (TEG). RESULTS Study subjects were enrolled from April 1, 2004, to May 31, 2005, and included nonburn trauma patients (n = 33), burned patients (n = 25), and healthy (control) subjects (n = 20). Despite aggressive thromboprophylaxis, three subjects (2 burned and 1 nonburn trauma patients [6%]) had pulmonary embolism during hospitalization. Compared with controls, all patients had prolonged PT and aPTT (p < 0.05). The rate of clot formation (alpha angle) and maximal clot strength were higher for patients compared with those of controls (p < 0.05), indicating a hypercoagulable state. Injured patients also had lower protein C and antithrombin III percent activities and higher fibrinogen levels (p < 0.05 for all). Activated factor XI was elevated in 38% of patients (control subjects had undetectable levels). DISCUSSION Thromboelastography analysis of whole blood showed that patients were in a hypercoagulable state; this was not detected by plasma PT or aPTT. The high incidence of pulmonary embolism indicated that our current prophylaxis regimen could be improved.

A Reduction in Clot Formation Rate and Strength Assessed by Thrombelastography Is Indicative of Transfusion Requirements in Patients With Penetrating Injuries

BACKGROUND Bleeding is a major cause of death in patients with traumatic injuries. Recently, thrombelastography (TEG) has been suggested as an additional means of evaluating coagulation in trauma patients. We hypothesized that TEG data would aid in defining the coagulopathy of trauma in patients with penetrating traumatic injuries. METHODS A retrospective study was performed of patients (n = 44) with penetrating injuries admitted to a combat support hospital during a 2-month period in 2004. Recorded data included standard laboratory data, TEG parameters, and blood product use in the first 24 hours after admission. Values were compared with clinically accepted ranges and those obtained from the Haemoscope Corporation. RESULTS At admission, International Normalization Ratio, prothrombin time, and partial thromboplastin time were increased in 39% (>or=1.5), 31% (>16 seconds), and 37% (>40 seconds) of patients, respectively, suggesting hypocoagulation, but these variables did not correlate with the use of blood products (p > 0.05). TEG values obtained within 24 hours of admission (6 hours +/- 5.7 hours; median of 4.5 hours) demonstrated hypocoagulation based on delayed propagation of the clot (increased K time and reduced alpha-angle) and decreased clot strength (reduced maximal amplitude [MA]). MA correlated (r = 0.57, p < 0.01) with blood product use as well as platelet count (r = 0.61, p < 0.01). Patients with reduced MA (n = 23) used more blood products and had reduced platelet counts and hematocrit. CONCLUSION Thrombelastography was a more accurate indicator of blood product requirements in our patient population than prothrombin time, partial thromboplastin time, and International Normalization Ratio. Thrombelastography enhanced by platelet count and hematocrit can guide blood transfusion requirements.

Thrombelastography is better than PT, aPTT, and activated clotting time in detecting clinically relevant clotting abnormalities after hypothermia, hemorrhagic shock and resuscitation in pigs.

BACKGROUND Hypothermia and hemorrhagic shock contribute to coagulopathy after trauma. In this study, we investigated the independent and combined effects of hypothermia and hemorrhage with resuscitation on coagulation in swine and evaluated clinically relevant tests of coagulation. METHODS Pigs (n = 24) were randomized into four groups of six animals each: sham control, hypothermia, hemorrhage with resuscitation, and hypothermia, hemorrhage with resuscitation combined. Hypothermia to 32 degrees C was induced with a cold blanket. Hemorrhage was induced by bleeding 35% of total blood volume followed by resuscitation with lactated Ringers solution. Coagulation was assessed by thrombin generation, prothrombin time (PT), activated partial thromboplastin time (aPTT), activated clotting time (ACT), and thrombelastography (TEG) from blood samples taken at baseline and 4 hour after hypothermia and/or hemorrhage with resuscitation. Data were compared with analysis of variance. RESULTS Baseline values were similar among groups. There were no changes in any measurements in the control group. Compared with baseline values, hemorrhage with resuscitation increased lactate to 140% +/- 15% (p < 0.05). Hypothermia decreased platelets to 73% +/- 3% (p < 0.05) with no effect on fibrinogen. Hemorrhage with resuscitation reduced platelets to 72% +/- 4% and fibrinogen to 71% +/- 3% (both p < 0.05), with similar decreases in platelets and fibrinogen observed in the combined group. Thrombin generation was decreased to 75% +/- 4% in hypothermia, 67% +/- 6% in hemorrhage with resuscitation, and 75% +/- 10% in the combined group (all p < 0.05). There were no significant changes in PT or aPTT by hemorrhage or hypothermia. ACT was prolonged to 122% +/- 1% in hypothermia, 111% +/- 4% in hemorrhage with resuscitation, and 127% +/- 3% in the combined group (all p < 0.05). Hypothermia prolonged the initial clotting time (R) and clot formation time (K), and decreased clotting rapidity (alpha) (all p < 0.05). Hemorrhage with resuscitation only decreased clot strength (maximum amplitude [MA], p < 0.05). TEG parameters in the combined group reflected the abnormal R, K, MA, and alpha observed in the other groups. CONCLUSION Hypothermia inhibited clotting times and clotting rate, whereas hemorrhage impaired clot strength. Combining hypothermia with hemorrhage impaired all these clotting parameters. PT, aPTT were not sensitive whereas ACT was not specific in detecting these coagulation defects. Only TEG differentiated mechanism related to clotting abnormalities, and thus may allow focused treatment of clotting alterations associated with hypothermia and hemorrhagic shock.

Comparison Between Civilian Burns and Combat Burns From Operation Iraqi Freedom and Operation Enduring Freedom

Objective:To assess outcome differences between locally burned civilians and military personnel burned in a distant combat zone treated in the same facility. Summary Background Data:The United States Army Institute of Surgical Research (USAISR) Burn Center serves as a referral center for civilians and is the sole center for significant burns in military personnel. We made the hypothesis that outcomes for military personnel burned in the current conflict in Iraq and Afghanistan would be poorer because of delays to definitive treatment, other associated injury, and distance of evacuation. Methods:We reviewed the civilian and military records of patients treated at the USAISR from the outset of hostilities in Iraq in April 2003 to May 2005. Demographics, injury data, mortality, and clinical outcomes were compared. Results:We cared for 751 patients during this time period, 273 of whom were military (36%). Military injuries occurred in a younger population (41 ± 19 vs. 26 ± 7 years for civilian and military respectively, P < 0.0001) with a longer time from injury to burn center arrival (1 ± 5 days vs. 6 ± 5, P < 0.0001), a higher Injury Severity Score (ISS 5 ± 8 vs. 9 ± 11, P < 0.0001), and a higher incidence of inhalation injury (8% vs. 13%, P = 0.024). Total burn size did not differ. Mortality was 7.1% in the civilian and 3.8% in the military group (P = 0.076). When civilians outside the age range of the military cohort were excluded, civilian mortality was 5.0%, which did not differ from the military group (P = 0.57). Total body surface area (TBSA) burned, age ≥40 years, presence of inhalation injury, and ventilator days were found to be important predictors of mortality by stepwise regression, and were used in a final predictive model with the area under receiver operator characteristic curve of 0.97 for both populations considered together. No significant effect of either group was identified during development. Conclusions:Mortality does not differ between civilians evacuated locally and military personnel injured in distant austere environments treated at the same center.

Assessment of severity of ovine smoke inhalation injury by analysis of computed tomographic scans.

BACKGROUND Our goal was to evaluate computed tomographic (CT) scans of the chest as a means of stratifying smoke inhalation injury (SII) severity. METHODS Twenty anesthetized sheep underwent graded SII: group I, no smoke; group II, 5 smoke units; group III, 10 units; and group IV, 16 units. CT scans were obtained at 6, 12, and 24 hours after injury. Each quadrant of each slice was scored subjectively: 0 = normal, 1 = interstitial markings, 2 = ground-glass appearance, and 3 = consolidation. The sum of all scores was the radiologists score (RADS) for that scan. Computerized analysis of three-dimensional reconstructed scans was also performed, based on Hounsfield unit ranges: hyperinflated, -1,000 to -900; normal, -899 to -500; poorly aerated, -499 to -100; and nonaerated, -99 to +100. The fraction of abnormal lung tissue (FALT) was computed from poorly aerated, nonaerated, and total volumes. Mean gray-scale density (DENS) was also computed. RESULTS SII resulted in severity- and time-related changes in oxygenation (alveolar-arterial gradient), ventilation (respiratory rate-pressure product), DENS, FALT, and RADS. Ordinal logistic regression generated a predictive model for severity of injury (r2 = 0.623, p = 0.001), retaining RADS at 24 hours and rejecting the other variables. CONCLUSION At 24 hours, CT scanning enabled SII severity stratification; qualitative evaluation (RADS) outperformed current semiautomated methods (DENS, FALT).

Quantification of hypercoagulable state after blunt trauma: Microparticle and thrombin generation are increased relative to injury severity, while standard markers are not

BACKGROUND Major trauma is an independent risk factor for developing venous thromboembolism. While increases in thrombin generation and/or procoagulant microparticles have been detected in other patient groups at greater risk for venous thromboembolism, such as cancer or coronary artery disease, this association has yet to be documented in trauma patients. This pilot study was designed to characterize and quantify thrombin generation and plasma microparticles in individuals early after traumatic injury. METHODS Blood was collected in the trauma bay from 52 blunt injured patients (cases) and 19 uninjured outpatients (controls) and processed to platelet poor plasma to allow for (1) isolation of microparticles for identification and quantification by flow cytometry, and (2) in vitro thrombin generation as measured by calibrated automatic thrombography. Data collected are expressed as either mean ± standard deviation or median with interquartile range. RESULTS Among the cases, which included 39 men and 13 women (age, 40 ± 17 years), the injury severity score was 13 ± 11, the international normalized ratio was 1.0 ± 0.1, the thromboplastin time was 25 ± 3 seconds, and platelet count was 238 ± 62 (thousands). The numbers of total (cell type not specified) procoagulant microparticles, as measured by Annexin V staining, were increased compared to nontrauma controls (541 ± 139/μL and 155 ± 148/μL, respectively; P < .001). There was no significant difference in the amount of thrombin generated in trauma patients compared to controls; however, peak thrombin was correlated to injury severity (Spearman correlation coefficient R, 0.35; P = .02). CONCLUSION Patients with blunt trauma have greater numbers of circulating procoagulant microparticles and increased in vitro thrombin generation. Future studies to characterize the cell-specific profiles of microparticles and changes in thrombin generation kinetics after traumatic injury will determine whether microparticles contribute to the hypercoagulable state observed after injury.

Continuous Renal Replacement Therapy Improves Survival in Severely Burned Military Casualties with Acute Kidney Injury

BACKGROUND Acute kidney injury in severely burned patients is associated with high mortality. We wondered whether early use of continuous renal replacement therapy (CRRT) changes outcomes in severely burned military casualties with predetermined criteria for acute kidney injury. METHODS Between November 2005 and June 2007, casualties admitted to our burn intensive care unit after sustaining burns in Iraq and Afghanistan, who subsequently developed acute kidney injury or circulatory shock or both, underwent CRRT. Baseline demographic, laboratory, and hemodynamic parameters were recorded. Both 28-day mortality and in- hospital mortality were evaluated and compared with a consecutive group of burn casualties with greater than 40% total body surface area (TBSA) burns, acute kidney injury, or nephrology consultation in the 2 years before the existence of our CRRT program. RESULTS One hundred forty-seven severely burned military casualties were admitted to our intensive care unit before CRRT program initiation, and 102 were admitted after CRRT program initiation. Before the CRRT program, 16 patients were identified as having >40% TBSA burns with kidney injury with or without nephrology consultation (control group); 18 were treated with CRRT since (CRRT group). Groups were similar for %TBSA, %full-thickness TBSA, incidence of inhalation injury, blood urea nitrogen, creatinine, and Injury Severity Score. Of the CRRT patients, seven soldiers were treated for isolated acute kidney injury, whereas 11 were treated for a combination of acute kidney injury and shock. The dose of therapy was 50.2 +/- 13 mL/kg/h with a treatment course of 5.2 +/- 3 days. Of the 11 patients in the CRRT group treated for shock, eight were off vasopressors by 24 hours and the remaining three within 48 hours. None of the patients in the control group were placed on renal replacement therapy with nephrology consultation in eight patients. Both 28-day mortality (22% vs. 75%, p = 0.002) and in-hospital mortality (56% vs. 88%, p = 0.04) were lower in the CRRT group compared with that in the control group. CONCLUSION Aggressive application of CRRT in severely burned casualties with kidney injury significantly improves survival.

Differential expression of the immunoinflammatory response in trauma patients: Burn vs. non-burn

RATIONALE Cytokines are central mediators of the immune-inflammatory response to injury and subsequent multiple organ dysfunction syndrome (MODS). Although previous studies evaluated cytokine levels after trauma, differences between patients with burn and non-burn trauma have not been assessed systematically. METHODS A prospective database of trauma patients admitted between May 2004 and September 2007 to the burn or surgical intensive care units within 24 h of injury with an anticipated stay of at least 72 h was analyzed. Sequential clinical and laboratory parameters were collected in the first week, including multiplex analysis data for plasma levels of inflammatory cytokines (IL-6, and IL-8). Patients with known pre-injury coagulopathy were excluded. A Marshall score of 10 or greater was defined as MODS. RESULTS A total of 179 patients were enrolled (67 burn and 112 non-burn). Plasma IL-6 and IL-8 levels were markedly elevated in both burn and non-burn patients compared to healthy volunteers. Burn subjects had higher levels of IL-6 and IL-8 than the non-burn on days 1 through 7 after injury. Subjects with burns and at least 30% total body surface area were older and had a lower injury severity score, a higher prevalence of MODS, and correspondingly higher mortality. Multivariate analysis of injury type, MODS, and time did not demonstrate an influence of MODS. CONCLUSIONS Burns were associated with a greater and more sustained immune-inflammatory response than non-burn trauma as evidenced by elevated plasma IL-6 and IL-8 levels during the first week. There was no association between MODS and plasma cytokine levels.

Combining Early Coagulation and Inflammatory Status Improves Prediction of Mortality in Burned and Nonburned Trauma Patients

BACKGROUND After injury, there is a synergistic response between inflammation and coagulation systems. We hypothesized that combining markers of these processes and standard clinical indices would improve early prediction of in- hospital mortality in burned and nonburned trauma patients. METHODS Patients admitted to the surgical or burn intensive care unit within 24 hours of injury with an anticipated stay >or=3 days were enrolled during a one year period. Upon admission, blood was drawn for thromboelastography, plasma-based clotting assays, and cytokine levels. Clinical indices and multiple organ dysfunction syndrome (MODS) scores were recorded. Candidate variables evaluated included age, percentage third degree burns, inhalation injury, percentage total body surface area burns, interleukin-6, tumor necrosis factor alpha, interleukin-8, prothrombin time, partial thromboplastin time (PTT), maximal amplitude reflective of clot strength, group (burn or nonburn) and admission MODS. Multiple logistic regression with stepwise selection and likelihood ratio test was performed to identify predictors for mortality. A receiver operating characteristic (ROC) curve was constructed to assess the diagnostic performance of identified predictors. Validation of the model with an additional cohort was performed. RESULTS For model development, we enrolled 25 burned and 33 nonburned trauma patients (20 blunt and 13 penetrating injuries). Fifteen deaths occurred. Multiple logistic regression analysis identified six independent risk factors for death: age, percentage third degree burns, inhalation injury, tumor necrosis factor alpha level, maximal amplitude, and MODS score with an area under ROC curve of 0.961 (95% confidence interval: 0.891, 1.000, p < 0.05). The area under the ROC curve for the validation cohort (n = 66) was 0.936 (95% confidence interval: 0.875, 0.997, p < 0.001). CONCLUSION Our model improves prediction of in-hospital mortality in comparison to previous methods for burn and nonburn trauma patients. Furthermore, our model is equally applicable to all patients regardless of type of traumatic injury (nonburn or burn). This improvement is because of the inclusion of patients early coagulation and inflammatory status in addition to standard clinical indices. These data provide a baseline within which to measure incremental improvements in care.