J. Jason Hoth

Early Identification of Patients at Risk of Acute Lung Injury: Evaluation of Lung Injury Prediction Score in a Multicenter Cohort Study

RATIONALE Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. OBJECTIVES To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). METHODS In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. MEASUREMENTS AND MAIN RESULTS Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1-4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78-0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9-5.7). CONCLUSIONS ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772).

Injury-associated hypothermia: an analysis of the 2004 National Trauma Data Bank.

Severe injury and shock are frequently associated with abnormalities in patient body temperature. Substantial increases in mortality have been associated with profound hypothermia, especially below 35°C. The purpose of this study was to further characterize the impact of hypothermia in a large dataset of trauma patients. This study was a retrospective analysis of the 2004 version of the National Trauma Data Bank (NTDB), which contains approximately 1.1 million patients from over 400 trauma centers. Admission temperature was analyzed with respect to mortality, injury severity score (ISS), base deficit (BD), Glasgow Coma Score (GCS), and hospital outcomes. The NTDB contained 701,491 patients with temperatures recorded upon trauma center admission. Of these, 11,026 patients had admission temperatures <35°C, and 802 had temperatures <32°C. Comparison of core temperature versus mortality revealed that as temperature decreased, the mortality rate increased, reaching approximately 39% at 32°C, and remained constant at lower temperatures. Surprisingly, 477 patients (59.5%) survived with temperatures <32°C. Similarly, BD increased as hypothermia worsened until body temperature reached 31°C, below which there was little further increase. Patients with admission temperatures less than 35°C had significantly greater mortality (25.5% vs. 3.0%, P < 0.001) and BD (7.8 vs. 3.7, P < 0.001) when compared with patients with temperatures ≥35°C. In survivors, average ventilator days and intensive care unit (ICU) days were 14.4 and 12.8, respectively, for patients with temperatures <35°C as opposed to more normothermic patients who demonstrated an average of 9.5 ventilator days and 9.1 ICU days (P < 0.001). When grouped by individual ISS, BD level, and GCS motor score, mortality was significantly greater when admission temperature was below 35°C (ISS mean difference = 11.4%, BD mean difference = 22.8%, and GCS motor mean difference = 9.85%). Logistic regression revealed that hypothermia remains an independent determinant of mortality after correction for confounding variables (odds ratio = 1.54, 95% confidence interval 1.40-1.71). Admission hypothermia is associated with greater mortality, increased injury severity, more profound acidosis, and prolonged ICU/ventilator courses. However, although mortality at <32°C is high, patients with temperatures this low do survive. As temperatures drop below 32°C, mortality rates remain constant, which may indicate a threshold below which physiologic mechanisms are unable to correct body temperature regardless of injury severity. Although shock severity is highly indicative of outcome, hypothermia independently contributes to the substantial mortality associated with severe injury.

Prophylactic antibiotics adversely affect nosocomial pneumonia in trauma patients.

BACKGROUND Little data are available regarding the impact that prolonged prophylactic antibiotic use (>48 hours) has on the development of nosocomial pneumonia. This retrospective study was conducted to assess the effect that prolonged prophylactic antibiotic use has on the development of nosocomial pneumonia and antibiotic use complications. METHODS The records of patients who contracted nosocomial pneumonia during mechanical ventilation were retrospectively reviewed. These patients then were classified into two groups: those who received prolonged prophylactic antibiotics before the diagnosis of pneumonia and those who did not receive antibiotics. RESULTS For the patients who received prolonged prophylactic antibiotics, the first pneumonia was diagnosed later, the causative organisms were more likely to be resistant or Gram-negative bacteria, and the incidence of antibiotic complications were two times greater than for patients who did not receive extended antibiotic prophylaxis. CONCLUSION Justification for the use and duration of prolonged (>48 hours) prophylactic antibiotics requires careful reevaluation because this practice is associated with significant clinical complications that lead to increased use of patient resources, lengthened hospital stay, and higher cost.

Prospective Trial of Angiography and Embolization for All Grade III to V Blunt Splenic Injuries: Nonoperative Management Success Rate Is Significantly Improved

BACKGROUND Nonoperative management (NOM) of blunt splenic injury is well accepted. Substantial failure rates in higher injury grades remain common, with one large study reporting rates of 19.6%, 33.3%, and 75% for grades III, IV, and V, respectively. Retrospective data show angiography and embolization can increase salvage rates in these severe injuries. We developed a protocol requiring referral of all blunt splenic injuries, grades III to V, without indication for immediate operation for angiography and embolization. We hypothesized that angiography and embolization of high-grade blunt splenic injury would reduce NOM failure rates in this population. STUDY DESIGN This was a prospective study at our Level I trauma center as part of a performance-improvement project. Demographics, injury characteristics, and outcomes were compared with historic controls. The protocol required all stable patients with grade III to V splenic injuries be referred for angiography and embolization. In historic controls, referral was based on surgeon preference. RESULTS From January 1, 2010 to December 31, 2012, there were 168 patients with grades III to V spleen injuries admitted; NOM was undertaken in 113 (67%) patients. The protocol was followed in 97 patients, with a failure rate of 5%. Failure rate in the 16 protocol deviations was 25% (p = 0.02). Historic controls from January 1, 2007 to December 31, 2009 were compared with the protocol group. One hundred and fifty-three patients with grade III to V injuries were admitted during this period, 80 (52%) patients underwent attempted NOM. Failure rate was significantly higher than for the protocol group (15%, p = 0.04). CONCLUSIONS Use of a protocol requiring angiography and embolization for all high-grade spleen injuries slated for NOM leads to a significantly decreased failure rate. We recommend angiography and embolization as an adjunct to NOM for all grade III to V splenic injuries.

Toll-like receptor 2 participates in the response to lung injury in a murine model of pulmonary contusion.

ABSTRACT Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We report that Toll-like receptor (TLR) 2 participates in the inflammatory response to lung injury. To show this, we use a model of pulmonary contusion in the mouse that is similar to that observed clinically in humans based on histologic, morphologic, and biochemical criteria of acute lung injury. The inflammatory response to pulmonary contusion in our mouse model is characterized by pulmonary edema, neutrophil transepithelial migration, and increased expression of the innate immunity proinflammatory cytokines IL 1&bgr; and IL 6, the adhesion intracellular adhesion molecule 1, and chemokine (CXC motif) ligand 1. Compared with wild-type animals, contused Tlr2(−/−) mice have significantly reduced pulmonary edema and neutrophilia. These findings are associated with decreased levels of circulating chemokine (CXC motif) ligand 1. In contrast, systemic IL 6 levels remain elevated in the TLR2-deficient phenotype. These results show that TLR2 has a primary role in the neutrophil response to acute lung injury. We suggest that an unidentified noninfectious ligand generated by pulmonary contusion acts via TLR2 to generate inflammatory responses.

Predicting Risk of Postoperative Lung Injury in High-risk Surgical Patients: A Multicenter Cohort Study

Background: Acute respiratory distress syndrome (ARDS) remains a serious postoperative complication. Although ARDS prevention is a priority, the inability to identify patients at risk for ARDS remains a barrier to progress. The authors tested and refined the previously reported surgical lung injury prediction (SLIP) model in a multicenter cohort of at-risk surgical patients. Methods: This is a secondary analysis of a multicenter, prospective cohort investigation evaluating high-risk patients undergoing surgery. Preoperative ARDS risk factors and risk modifiers were evaluated for inclusion in a parsimonious risk-prediction model. Multiple imputation and domain analysis were used to facilitate development of a refined model, designated SLIP-2. Area under the receiver operating characteristic curve and the Hosmer–Lemeshow goodness-of-fit test were used to assess model performance. Results: Among 1,562 at-risk patients, ARDS developed in 117 (7.5%). Nine independent predictors of ARDS were identified: sepsis, high-risk aortic vascular surgery, high-risk cardiac surgery, emergency surgery, cirrhosis, admission location other than home, increased respiratory rate (20 to 29 and ≥30 breaths/min), FIO2 greater than 35%, and SpO2 less than 95%. The original SLIP score performed poorly in this heterogeneous cohort with baseline risk factors for ARDS (area under the receiver operating characteristic curve [95% CI], 0.56 [0.50 to 0.62]). In contrast, SLIP-2 score performed well (area under the receiver operating characteristic curve [95% CI], 0.84 [0.81 to 0.88]). Internal validation indicated similar discrimination, with an area under the receiver operating characteristic curve of 0.84. Conclusions: In this multicenter cohort of patients at risk for ARDS, the SLIP-2 score outperformed the original SLIP score. If validated in an independent sample, this tool may help identify surgical patients at high risk for ARDS.

CD40–CD154 interactions between macrophages and natural killer cells during sepsis are critical for macrophage activation and are not interferon gamma dependent

Natural killer (NK) cell interactions with macrophages have been shown to be important during bacterial sepsis in activating macrophages to improve bacterial clearance. The mechanism for this increased activation, however, is unclear. This study determines the relative roles of interferon (IFN)‐γ and CD40/CD154 direct cell interactions on macrophage and NK cell activation in an experimental model of sepsis. Splenic NK cells and peritoneal macrophages were isolated and cultured alone or in coculture, with and without LPS. CD69 expression on NK cells, phagocytosis ability of macrophages, and cell cytokine production was assessed at 24 and 48 h. Coculture of NK cells and macrophages significantly increased activation levels of both cell types, and through experiments culturing NK cells with supernatants from stimulated macrophages and macrophages with supernatants from stimulated NK cells, this activation was determined to be cell‐contact‐dependent. Similar experiments were conducted using NK cells from IFN‐γ deficient (–/–) mice, as well as anti‐IFN‐γ neutralizing antibody. These experiments determined that IFN‐γ is not required for NK or macrophage activation, although it did augment activation levels. Experiments were again repeated using peritoneal macrophages from CD40‐/– mice or splenic NK cells from CD154‐/– mice. CD40/CD154 interactions were important in the ingestion of bacteria by macrophages, but did not affect NK cell activation at 24 h. There was, however, a protective effect of CD40/CD154 interactions on NK cell activation‐induced cell death that occurred at 48 h. CD40/CD154 interactions between macrophages and NK cells are therefore important in macrophage phagocytosis, and are not dependent on IFN‐γ.

Emergency department length of stay is an independent predictor of hospital mortality in trauma activation patients

BACKGROUND The early resuscitation occurs in the emergency department (ED) where intensive care unit protocols do not always extend and monitoring capabilities vary. Our hypothesis is that increased ED length of stay (LOS) leads to increased hospital mortality in patients not undergoing immediate surgical intervention. METHODS We examined all trauma activation admissions from January 2002 to July 2009 admitted to the Trauma Service (n = 3,973). Exclusion criteria were as follows: patients taken to the operating room within the first 2 hours of ED arrival, nonsurvivable brain injury, and ED deaths. Patients spending >5 hours in the ED were not included in the analysis because of significantly lower acuity and mortality. RESULTS Patients spent a mean of 3.2 hours ± 1 hour in the ED during their initial evaluation. Hospital mortality increases for each additional hour a patient spends in the ED, with 8.3% of the patients staying in the ED between 4 hours and 5 hours ultimately dying (p = 0.028). ED LOS measured in minutes is an independent predictor of mortality (odds ratio, 1.003; 95% confidence interval, 1.010-1.006; p = 0.014) when accounting for Injury Severity Score, Revised Trauma Score, and age. Linear regression showed that a longer ED LOS was associated with anatomic injury pattern rather than physiologic derangement. CONCLUSION In this patient population, a longer ED LOS is associated with an increased hospital mortality even when controlling for physiologic, demographic, and anatomic factors. This highlights the importance of rapid progression of patients through the initial evaluation process to facilitate placement in a location that allows implementation of early goal directed trauma resuscitation.

Toll-like receptor 4-dependent responses to lung injury in a murine model of pulmonary contusion.

Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We previously demonstrated that toll-like receptor 2 (TLR-2) participates in the inflammatory response to lung injury. We hypothesized that the TLR-4, in an MyD88-dependent manner, may also participate in the response to lung injury. To investigate this, we used a model of pulmonary contusion in the mouse that is similar to that observed clinically in humans and evaluated postinjury lung function, pulmonary neutrophil recruitment, and the systemic innate immune response. Comparisons were made between wild-type mice and mice deficient in TLR-4 or MyD88. We found TLR-4-dependent responses to pulmonary contusion that include hypoxemia, edema, and neutrophil infiltration. Increased expression of IL-6 and chemokine (C-X-C motif) ligand 1 in the bronchoalveolar lavage and serum was also dependent on TLR-4 activation. We further demonstrated that these responses to pulmonary contusion were dependent on MyD88, an adapter protein in the signal transduction pathway mediated by TLRs. These results show that TLRs have a primary role in the response to acute lung injury. Lung inflammation and systemic innate immune responses are dependent on TLR activation by pulmonary contusion.

Characterization of crash-induced thoracic loading resulting in pulmonary contusion

BACKGROUND Pulmonary contusion (PC) is commonly sustained in motor vehicle crash. This study utilizes the Crash Injury Research and Engineering Network (CIREN) database and vehicle crash tests to characterize the occupants and loading characteristics associated with PC. A technique to match CIREN cases to vehicle crash tests is applied to quantify the thoracic loading associated with this injury. METHODS The CIREN database and crash test data from the National Highway Traffic Safety Administration were used in this study. An analysis of CIREN data were conducted between three study cohorts: patients that sustained PC and any other chest injury (PC+ and chest+), patients with chest injury and an absence of PC (PC- and chest+), and a control group without chest injury and an absence of PC (PC- and chest-). Forty-one lateral impact crash tests were analyzed and thoracic loading data from onboard crash tests dummies were collected. RESULTS The incidence of PC in CIREN data were 21.7%. Crashes resulting in PC demonstrated significantly greater mortality (23.9%) and Injury Severity Score (33.1 +/- 15.7) than the control group. The portion of lateral impacts increased from 27% to 48% between the control group and PC+ and chest+ cohort, prompting the use of lateral impact crash tests for the case-matching portion of the study. Crash tests were analyzed in two configurations; vehicle-to-vehicle tests and vehicle-to-pole tests. The average maximum chest compression and deflection velocity from the dummy occupants were found to be 25.3% +/- 2.6% and 4.6 m/s +/- 0.42 m/s for the vehicle-to-pole tests and 23.0% +/- 4.8% and 3.9 m/s +/- 1.1 m/s for the vehicle-to-vehicle tests. Chest deflection versus time followed a roughly symmetric and sinusoidal profile. Sixteen CIREN cases were identified that matched the vehicle crash tests. Of the 16 matched cases, 12 (75%) sustained chest injuries, with half of these patients presenting with PC. CONCLUSIONS Quantified loading at the chest wall indicative of PC and chest injury in motor vehicle crash is valuable boundary condition data for bench-top studies or computer simulations focused on this injury. In addition, because PC often exhibits a delayed onset, knowing the population and crash modes highly associated with this injury may promote earlier detection and improved management of this injury.