Lee Ann Zarzabal

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.

Increased platelet:RBC ratios are associated with improved survival after massive transfusion.

BACKGROUND Several recent military and civilian trauma studies demonstrate that improved outcomes are associated with early and increased use of plasma-based resuscitation strategies. However, outcomes associated with platelet transfusions are poorly characterized. We hypothesized that increased platelet:red blood cells (RBC) ratios would decrease hemorrhagic death and improve survival after massive transfusion (MT). METHODS A transfusion database of patients transported from the scene to 22 Level I Trauma Centers over 12 months in 2005 to 2006 was reviewed. MT was defined as receiving ≥ 10 RBC units within 24 hours of admission. To mitigate survival bias, 25 patients who died within 60 minutes of arrival were excluded from analysis. Six random donor platelet units were considered equal to a single apheresis platelet unit. Admission and outcome data associated with the low (>1:20), medium (1:2), and high (1:1) platelet:RBC ratios were examined. These groups were based on the median value of the tertiles for the ratio of platelets:RBC units. RESULTS Two thousand three hundred twelve patients received at least one unit of blood and 643 received an MT. Admission vital signs, INR, temperature, pH, Glasgow Coma Scale, Injury Severity Score, and age were similar between platelet ratio groups. The average admission platelet counts were lower in the patients who received the high platelet:RBC ratio versus the low ratio (192 vs. 216, p = 0.03). Patients who received MT were severely injured, with a mean (± standard deviation) Injury Severity Score of 33 ± 16 and received 22 ± 15 RBCs and 11 ± 14 platelets within 24 hours of injury. Increased platelet ratios were associated with improved survival at 24 hours and 30 days (p < 0.001 for both). Truncal hemorrhage as a cause of death was decreased (low: 67%, medium: 60%, high: 47%, p = 0.04). Multiple organ failure mortality was increased (low: 7%, medium: 16%, high: 27%, p = 0.003), but overall 30-day survival was improved (low: 52%, medium: 57%, high: 70%) in the high ratio group (medium vs. high: p = 0.008; low vs. high: p = 0.007). CONCLUSION Similar to recently published military data, transfusion of platelet:RBC ratios of 1:1 was associated with improved early and late survival, decreased hemorrhagic death and a concomitant increase in multiple organ failure-related mortality. Based on this large retrospective study, increased and early use of platelets may be justified, pending the results of prospective randomized transfusion data.

Evidence for an Unanticipated Relationship between Undifferentiated Pleomorphic Sarcoma and Embryonal Rhabdomyosarcoma

Embryonal rhabdomyosarcoma (eRMS) shows the most myodifferentiation among sarcomas, yet the precise cell of origin remains undefined. Using Ptch1, p53 and/or Rb1 conditional mouse models and controlling prenatal or postnatal myogenic cell of origin, we demonstrate that eRMS and undifferentiated pleomorphic sarcoma (UPS) lie in a continuum, with satellite cells predisposed to giving rise to UPS. Conversely, p53 loss in maturing myoblasts gives rise to eRMS, which have the highest myodifferentiation potential. Regardless of origin, Rb1 loss modifies tumor phenotype to mimic UPS. In human sarcomas that lack pathognomic chromosomal translocations, p53 loss of function is prevalent, whereas Shh or Rb1 alterations likely act primarily as modifiers. Thus, sarcoma phenotype is strongly influenced by cell of origin and mutational profile.

Effect of temporary shunting on extremity vascular injury: An outcome analysis from the Global War on Terror vascular injury initiative

OBJECTIVE Extremity vascular injury during the current war has been defined by anecdotal description and case series. These reports focused on estimation of short-term limb viability and technical description of commonly used adjuncts. Temporary vascular shunting (TVS) has been advocated in current care structures, yet mostly due to war environments, broader statistical scrutiny is lacking. This studys purpose is to provide perspective on TVSs impact on limb salvage, and estimate longer-term freedom from amputation. METHODS Data from the Joint Theater Trauma Registry (JTTR), Balad Vascular Registry (BVR), Walter Reed Vascular Registry (WRVR), electronic medical records, and patient interviews were collected on American Troops sustaining extremity vascular injury from June 2003 through December 2007. Those in whom arterial TVS utilization was identified comprise the TVS group. These were compared with controls with similar injury date and anatomic location managed without TVS. Descriptive statistics were employed establishing overall univariate predictors of amputation and comparison between groups. Proportional-hazards modeling, with propensity score adjustment for systemic injury severity and Level 2 care, characterized risk factors of limb loss and effect of TVS. Freedom from amputation was estimated using Kaplan Meier log-rank methods. RESULTS Cases and controls consisted of 64 and 61 extremity arterial injuries, respectively. Mean follow-up was 22 months (range: 1-54 months). The TVS group was more severely injured (mean injury severity score [ISS]: 18 [SD = 10] TVS vs. 15 [SD = 10] control, P = .05) and more likely to receive Level 2 care (TVS: 26%; control: 10%, P = .02). Overall, a total of 26 amputations occurred (21%). Penetrating blasts, compared with gunshot wounds, were associated with amputation (30% vs. 6%, P = .002). After propensity score adjustment, use of TVS suggested a reduced risk of amputation (relative risk [RR] = 0.47; 95% confidence interval [CI] [0.18-1.19]; P = .11). Venous repair was associated with limb salvage (RR = 0.2; 95% CI [0.04-0.99], P = .05). Associated fracture (RR = 5.0; 95% CI [1.45-17.28], P = .01), and elevated mangled extremity severity score (MESS) ([MESS 5-7] RR = 3.5, 95% CI [0.97-12.36], P = .06; [MESS 8-12] RR = 16.4; 95% CI (3.79-70.79), P < .001) predicted amputation. Amputation-free survival was 78% in the TVS group and 77% in the control group at three years (P = .5). CONCLUSION Temporary vascular shunting used as a damage control adjunct in management of wartime extremity vascular injury does not lead to worse outcomes. Benefit from TVS is suggested, but not statistically significant. Injury specific variables of venous ligation, associated fracture, and penetrating blast mechanism are associated with amputation. Amputation-free survival after vascular injury in Operation Iraqi Freedom is 79% at three years. Further studies to statistically define any possible benefits of TVS are needed.

Less Is More: Improved Outcomes in Surgical Patients with Conservative Fluid Administration and Central Venous Catheter Monitoring

BACKGROUND The ARDS Clinical Trials Network Fluid and Catheter Treatment Trial (FACTT) addressed fluid management and central monitoring of patients with acute respiratory distress syndrome/acute lung injury (ARDS/ALI). Because surgical patients may have been fundamentally different from the overall FACTT cohort, we set out to separately analyze the surgery patients in the trial. STUDY DESIGN We performed a posthoc, surgical subgroup analysis of 1,000 patients enrolled in the FACTT. Patients were randomized using a 2x2 factorial design comparing a conservative (CON) versus a liberal (LIB) strategy of fluid management and the use of a pulmonary artery catheter (PAC) or a central venous catheter (CVC). The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days, ICU-free days, and dialysis-free days until hospital discharge up to day 90. We defined surgical patients as those admitted to a surgical ICU, burn ICU, or cardiac surgical ICU; trauma patients; or those with an APACHE III surgical admission type. RESULTS There were 244 surgical patients. Risk of death within 60 days of randomization did not vary with catheter or fluid management, and a corresponding lack of effect was evident with regard to dialysis-free days. Ventilator-free days were increased in the fluid-conservative group (LIB, 13+/-1 days; CON, 15+/-1 days; p=0.04) at 28 days. CVC patients had more ventilator-free days at 28 and 90 days (28 days: CVC, 16+/-1 days; PAC, 13+/-1 days; p=0.03; 90 days: CVC, 64+/-3 days; PAC, 57+/-4 days; p=0.03). CVC patients had more ICU-free days at 90 days (90 days: CVC, 63+/-3 days; PAC, 55+/-3 days; p=0.04). CONCLUSIONS The risk of death did not vary with fluid management or catheter. A conservative fluid-administration strategy and central venous catheter monitoring resulted in more ventilator-free and ICU-free days in surgical patients with acute lung injury, and conservative fluid administration did not result in more renal failure.

Toxic epidermal necrolysis: Five years of treatment experience from a burn unit

BACKGROUND Toxic epidermal necrolysis (TEN) is a serious drug eruption that results in death in approximately 25% to 50% of patients. There is controversy over whether SCORTEN accurately predicts mortality or if treatment interventions such as intravenous immunoglobulin (IVIg) can alter mortality. OBJECTIVES We sought to determine whether SCORTEN accurately predicts mortality in this cohort, whether IVIg improved survival, and which drugs and medical comorbidities impacted mortality. METHODS We summarize our experience prospectively over 5 years and 82 patients. Patients either received supportive care, intravenous immunoglobulin, or cyclosporine as treatment. All patients had a SCORTEN on admission, an offending drug on record, and a list of medical comorbidities. RESULTS Of the 82 patients, 29% died from TEN. SCORTEN accurately predicted mortality in this cohort with an area under the curve (AUC) of 0.83 in a receiver operator curve (ROC) analysis. A Kaplan-Meier curve did not show improved mortality if patients received IVIg versus supportive care (P = .9). Medications most often responsible for TEN were trimethoprim/sulfamethoxazole, followed by anticonvulsants, nonsteroidal anti-inflammatories, and allopurinol. LIMITATIONS This prospective cohort study design is not as ideal as patients presenting for a randomized controlled trial. CONCLUSIONS SCORTEN was an accurate predictor of mortality in this cohort. Age older than 40 years, the presence of metabolic syndrome and/or gout, higher body surface area involvement, higher SCORTEN, and higher number of medical comorbidities statistically significantly increased risk of death. IVIg did not significantly alter mortality. Although the highest number of cases was due to trimethoprim/sulfamethoxazole, the greatest proportion of deaths was due to allopurinol.

Early versus delayed restoration of flow with temporary vascular shunt reduces circulating markers of injury in a porcine model.

BACKGROUND Temporary vascular shunting to restore flow after vascular injury has been advocated. The effectiveness of this adjunct in protecting against ischemic injury has not been established. This study will assess the temporal impact of shunts on ischemic injury and arterial flow. METHODS A porcine model of hind-limb ischemia via iliac artery occlusion was used (N = 36; weight [kg] +/- SD: 89 +/- 4.4). Animals were randomized into one control (Iscctrl) and four study groups (Isc0, Isc1, Isc3, and Isc6) according to ischemic time. Shunt placement followed ischemia, and flow and circulating injury markers were collected incrementally during 18 hours of reperfusion. Flow proportions and a calculated Ischemia Injury Index were used to characterize group differences. RESULTS There were no intergroup differences concerning initial weight, hemodynamic, or laboratory values. Shunt patency was 92% in the absence of anticoagulation. The proportion of common femoral arterial flow to baseline flow in the Isc6 group was lower than the Iscctrl group (p = 0.02). There was a similar trend with the Isc1 and Isc3 groups. The Ischemia Injury Index demonstrated that there was a difference in the Isc3 and Isc6 groups (late shunt placement) compared with the Iscctrl, Isc0, and Isc1 groups (early shunt placement) (p < 0.001). CONCLUSION This study provides physiologic insight into the benefit of shunts in a model of extremity ischemia. Early shunting protects the extremity from further ischemic insult and reduces circulating markers of tissue injury. Additionally, the presence of a shunt does not increase the Ischemic Injury Index and patency is maintained in the absence of heparinization.

IL-4R drives dedifferentiation, mitogenesis, and metastasis in rhabdomyosarcoma.

Purpose: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. The alveolar subtype of rhabdomyosarcoma (ARMS) is a paradigm for refractory and incurable solid tumors because more than half of the children at diagnosis have either regional lymph node or distant metastases. These studies follow our previous observation that Interleukin-4 receptor α (IL-4Rα) is upregulated in both human and murine ARMS, and that the IL-4R signaling pathway may be a target for abrogating tumor progression. Experimental Design: By in vitro biochemical and cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of IL-4 and IL-13 in IL-4R–mediated mitogenesis, myodifferentiation, and tumor progression. Results: IL-4 and IL-13 ligands accelerated tumor cell growth and activated STAT6, Akt, or MAPK signaling pathways in the human RMS cell lines, RD and Rh30, as well as in mouse primary ARMS cell cultures. IL-4 and IL-13 treatment also decreased protein expression of myogenic differentiation factors MyoD and Myogenin, indicating a loss of muscle differentiation. Using a genetically engineered mouse model of ARMS, we have shown that inhibition of IL-4R signaling pathway with a neutralizing antibody has a profound effect on the frequency of lymph node and pulmonary metastases, resulting in significant survival extension in vivo. Conclusions: Our results indicate that an IL-4R-dependent signaling pathway regulates tumor cell progression in RMS, and inhibition of this pathway could be a promising adjuvant therapeutic approach. Clin Cancer Res; 17(9); 2757–66. ©2011 AACR.

Lineage of origin in rhabdomyosarcoma informs pharmacological response

Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.

Growth in children with acute lymphoblastic leukemia during treatment

Obesity is increasingly prevalent in affluent societies and portends considerable morbidity. This is especially true in children with acute lymphoblastic leukemia (ALL) in whom the metabolic syndrome may begin during therapy, demanding clarification of the trajectory of weight gain so that effective interventions may be developed. In this retrospective study of body mass index from a single institution over a 20-year period, almost 15% of children with ALL were at risk of overweight or frankly overweight (body mass index >85th centile) at diagnosis. This proportion increased steadily, reaching 40% at the end of treatment. Strategies to limit weight gain will have to be instituted early in the management of children with ALL, and will probably have to be maintained throughout and after the completion of active treatment.