Jonathan A. Sosnov

Retrospective Analysis of Long-Term Outcomes After Combat Injury: A Hidden Cost of War.

Background— During the conflicts in Iraq and Afghanistan, 52 087 service members have been wounded in combat. The long-term sequelae of these injuries have not been carefully examined. We sought to determine the relation between markers of injury severity and the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. Methods and Results— Retrospective cohort study of critically injured US military personnel wounded in Iraq or Afghanistan from February 1, 2002 to February 1, 2011. Patients were then followed until January 18, 2013. Chronic disease outcomes were assessed by International Classification of Diseases, 9th edition codes and causes of death were confirmed by autopsy. From 6011 admissions, records were excluded because of missing data or if they were for an individual’s second admission. Patients with a disease diagnosis of interest before the injury date were also excluded, yielding a cohort of 3846 subjects for analysis. After adjustment for other factors, each 5-point increment in the injury severity score was associated with a 6%, 13%, 13%, and 15% increase in incidence rates of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease, respectively. Acute kidney injury was associated with a 66% increase in rates of hypertension and nearly 5-fold increase in rates of chronic kidney disease. Conclusions— In Iraq and Afghanistan veterans, the severity of combat injury was associated with the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease.

Early Acute Kidney Injury in Military Casualties

BACKGROUND While acute kidney injury (AKI) has been well studied in a variety of patient settings, there is a paucity of data in patients injured in the course of the recent wars in Iraq and Afghanistan. We sought to establish the rate of early AKI in this population and to define risk factors for its development. METHODS We combined the results of two studies performed at combat support hospitals in Afghanistan. Only US service members who required care in the intensive care unit were included for analysis. Data on age, race, sex, Injury Severity Score (ISS), first available lactate, and requirement for massive transfusion were collected. Univariate analyses were performed to identify factors associated with the subsequent development of early AKI. Multivariable Cox regression was used to adjust for potential confounders. RESULTS The two observational cohorts yielded 134 subjects for analysis. The studies had broadly similar populations but differed in terms of age and need for massive transfusion. The rate of early AKI in the combined cohort was 34.3%, with the majority (80.5%) occurring within the first two hospital days. Patients with AKI had higher unadjusted mortality rates than those without AKI (21.7% vs. 2.3%, p < 0.001). After adjustment, ISS (hazard ratio, 1.02; 95% confidence interval, 1.00–1.03; p = 0.046) and initial lactate (hazard ratio, 1.16; 95% confidence interval, 1.03–1.31; p = 0.015) were independently associated with the development of AKI. CONCLUSION AKI is common in combat casualties enrolled in two prospective intensive care unit studies, occurring in 34.3%, and is associated with crude mortality. ISS and initial lactate are independently associated with the subsequent development of early AKI. LEVEL OF EVIDENCE Prognostic and epidemiologic study, level III.

Rhabdomyolysis among critically ill combat casualties: Associations with acute kidney injury and mortality.

BACKGROUND Rhabdomyolysis has been associated with poor outcomes in patients with traumatic injury, especially in the setting of acute kidney injury (AKI). However, rhabdomyolysis has not been systematically examined in a large cohort of combat casualties injured in the wars in Iraq and Afghanistan. METHODS We conducted a retrospective study of casualties injured during combat operations in Iraq and Afghanistan who were initially admitted to the intensive care unit from February 1, 2002, to February 1, 2011. Information on age, sex, Abbreviated Injury Scale (AIS) score, Injury Severity Score (ISS), mechanism of injury, shock index, creatine kinase, and serum creatinine were collected. These variables were examined via multivariate logistic and Cox regression analyses to determine factors independently associated with rhabdomyolysis, AKI, and death. RESULTS Of 6,011 admissions identified, a total of 2,109 patients met inclusion criteria and were included for analysis. Rhabdomyolysis, defined as creatine kinase greater than 5,000 U/L, was present in 656 subjects (31.1%). Risk factors for rhabdomyolysis identified on multivariable analysis included injuries to the abdomen and extremities, increased ISS, male sex, explosive mechanism of injury, and shock index greater than 0.9. After adjustment, patients with rhabdomyolysis had a greater than twofold increase in the odds of AKI. In the analysis for mortality, rhabdomyolysis was significantly associated with death until AKI was added, at which point it lost statistical significance. CONCLUSION We found that rhabdomyolysis is associated with the development of AKI in combat casualties. While rhabdomyolysis was strongly associated with mortality on the univariate model and in conjunction with both ISS and age, it was not associated with mortality after the inclusion of AKI. This suggests that the effect of rhabdomyolysis on mortality may be mediated by AKI. LEVEL OF EVIDENCE Prognostic and epidemiologic study, level III.

Hypertension after injury among burned combat veterans: A retrospective cohort study.

BACKGROUND The long-term health effects of burn are poorly understood. We sought to evaluate the relationship between burn and the subsequent development of hypertension. METHODS Retrospective cohort study of patients admitted to our burn center from 2003 to 2010. Data collected included demographic variables, burn size, injury severity score, presence of inhalation injury, serum creatinine, need for renal replacement therapy, as well as days spent in the hospital, in the intensive care unit and on mechanical ventilation. Data for the subsequent diagnosis of hypertension was obtained from medical records. Cox proportional hazard regression models were performed to determine what factors were associated with hypertension. RESULTS Of the 711 patients identified, 670 were included for analysis after exclusions. After adjustment, only age (HR 1.06 per one year increase, 95% confidence interval 1.03-1.08; p<0.001), percentage of total body surface area burned (HR 1.11 per 5% increase, 95% confidence interval 1.04-1.19; p=0.002) and acute kidney injury (HR 1.68, 95% confidence interval 1.05-2.69; p=0.03) were associated with hypertension. CONCLUSION Burn size is independently associated with the subsequent risk of hypertension in combat casualties. Clinical support for primary prevention techniques to reduce the incidence of hypertension specific to burn patients may be warranted.

Acute Kidney Injury in Critically Injured Combat Veterans: A Retrospective Cohort Study

BACKGROUND Acute kidney injury (AKI) has been associated with mortality after traumatic injury. However, there is a paucity of data for military service members with injuries received in combat. We sought to identify risk factors for AKI after combat trauma and evaluate whether AKI is a predictor of mortality. STUDY DESIGN Retrospective observational study. SETTINGS & PARTICIPANTS US service members who were critically wounded in Iraq or Afghanistan from February 1, 2002, to February 1, 2011, and survived until evacuation to Landstuhl Regional Medical Center, Germany. PREDICTORS Demographic variables, vital signs, injury severity score, presence of burn injury, and mechanism of injury as defined at the time of initial injury, as well as the presence of AKI ascertained within the first 7 days using KDIGO (Kidney Disease: Improving Global Outcomes) serum creatinine criteria. OUTCOMES Logistic regression models were used to identify risk factors for both AKI and death. RESULTS Of 6,011 records, 3,807 were included for analysis after excluding patients with missing data. AKI occurred in 474 (12.5%) patients and 112 (2.9%) died. More patients with versus without AKI died (n=62 [13.1%] vs n=50 [1.5%]; P<0.001). After adjustment, AKI was a predictor of mortality (OR, 5.14; 95% CI, 3.33-7.93; P<0.001). Predictors of AKI were age, African American race, injury severity score, amputations, burns, and presenting vital signs. LIMITATIONS AKI diagnoses limited to creatinine-based definitions. CONCLUSIONS AKI predicted mortality in combat veterans injured in the wars in Iraq and Afghanistan.

Reciprocal Risk of Acute Kidney Injury and Acute Respiratory Distress Syndrome in Critically Ill Burn Patients

Objective:To evaluate the association between acute respiratory distress syndrome and acute kidney injury with respect to their contributions to mortality in critically ill patients. Design:Retrospective analysis of consecutive adult burn patients requiring mechanical ventilation. Setting:A 16-bed burn ICU at tertiary military teaching hospital. Patients:Adult patients more than 18 years old requiring mechanical ventilation during their initial admission to our burn ICU from January 1, 2003, to December 31, 2011. Interventions:None. Measurements and Main Results:A total 830 patients were included, of whom 48.2% had acute kidney injury (n = 400). These patients had a 73% increased risk of developing acute respiratory distress syndrome after controlling for age, gender, total body surface area burned, and inhalation injury (hazard ratio, 1.73; 95% CI, 1.18–2.54; p = 0.005). In a reciprocal multivariate analysis, acute respiratory distress syndrome (n = 299; 36%) demonstrated a strong trend toward developing acute kidney injury (hazard ratio, 1.39; 95% CI, 0.99–1.95; p = 0.05). There was a 24% overall in-hospital mortality (n = 198). After adjusting for the aforementioned confounders, both acute kidney injury (hazard ratio, 3.73; 95% CI, 2.39–5.82; p < 0.001) and acute respiratory distress syndrome (hazard ratio, 2.16; 95% CI, 1.58–2.94; p < 0.001) significantly contributed to mortality. Age, total body surface area burned, and inhalation injury were also significantly associated with increased mortality. Conclusions:Acute kidney injury increases the risk of acute respiratory distress syndrome in mechanically ventilated burn patients, whereas acute respiratory distress syndrome similarly demonstrates a strong trend toward the development of acute kidney injury. Acute kidney injury and acute respiratory distress syndrome are both independent risks for subsequent death. Future research should look at this interplay for possible early interventions.

Comparison of Military and Civilian Methods for Determining Potentially Preventable Deaths: A Systematic Review

Importance Military and civilian trauma experts initiated a collaborative effort to develop an integrated learning trauma system to reduce preventable morbidity and mortality. Because the Department of Defense does not currently have recommended guidelines and standard operating procedures to perform military preventable death reviews in a consistent manner, these performance improvement processes must be developed. Objectives To compare military and civilian preventable death determination methods to understand the existing best practices for evaluating preventable death. Evidence Review This systematic review followed the PRISMA reporting guidelines. English-language articles were searched from inception to February 15, 2017, using the following databases: MEDLINE (Ovid), Evidence-Based Medicine Reviews (Ovid), PubMed, CINAHL, and Google Scholar. Articles were initially screened for eligibility and excluded based on predetermined criteria. Articles reviewing only prehospital deaths, only inhospital deaths, or both were eligible for inclusion. Information on study characteristics was independently abstracted by 2 investigators. Reported are methodological factors affecting the reliability of preventable death studies and the preventable death rate, defined as the number of potentially preventable deaths divided by the total number of deaths within a specific patient population. Findings Fifty studies (8 military and 42 civilian) met the inclusion criteria. In total, 1598 of 6500 military deaths reviewed and 3346 of 19 108 civilian deaths reviewed were classified as potentially preventable. Among military studies, the preventable death rate ranged from 3.1% to 51.4%. Among civilian studies, the preventable death rate ranged from 2.5% to 85.3%. The high level of methodological heterogeneity regarding factors, such as preventable death definitions, review process, and determination criteria, hinders a meaningful quantitative comparison of preventable death rates. Conclusions and Relevance The reliability of military and civilian preventable death studies is hindered by inconsistent definitions, incompatible criteria, and the overall heterogeneity in study methods. The complexity, inconsistency, and unpredictability of combat require unique considerations to perform a methodologically sound combat-related preventable death review. As the Department of Defense begins the process of developing recommended guidelines and standard operating procedures for performing military preventable death reviews, consideration must be given to the factors known to increase the risk of bias and poor reliability.

Urinary Biomarkers are Associated with Severity and Mechanism of Injury.

ABSTRACT Combat-related blast trauma results in massive tissue injury and tends to involve multiple systems. Further, an acute measure of injury severity based on underlying biological mechanisms may be important for the triage and treatment of these types of patients. We hypothesized that urinary biomarkers (UBs) would reflect severity of injury and that they would be elevated for blast injuries compared with gunshot wounds (GSW) in a cohort of combat casualties. We also postulated that UBs would be higher in patients with burns compared with patients with non-burn trauma in a civilian cohort. Among 80 service members who sustained combat-related injuries, we performed generalized estimating equations to compare differences in log-transformed concentrations of the UBs by both injury severity and injury mechanism. Among 22 civilian patients, we performed Kruskal–Wallis tests to compare differences for the UBs stratified by burn and non-burn trauma. In the military cohort, with the exception of IL-18, all UBs were significantly (P <0.05) higher for patients with a severe combat-related injury (Injury Severity Score ≥25). In addition, all crude UBs concentrations were significantly higher for blast versus GSW patients (P < 0.05). After adjusting for injury severity score and time of UB draw, KIM-1 (2.80 vs. 2.31; P = 0.03) and LFABP (−1.11 vs. −1.92; P = 0.02) were significantly higher for patients with a blast mechanism of injury. There were no significant differences in UBs between burn and non-burn civilian trauma patients. Future studies are needed to understand the physiologic response to trauma and the extent that UBs reflect these underlying processes.

Vasopressin, Sepsis, and Renal Perfusion - A VASST Deficit in Our Understanding

Abstract : In this issue of Critical Care Medicine, Guarido et al (1) present their fascinating work in a model of endotoxemia in rats. Consistent with prior studies, they found that vasopressin could increase blood pressure in animals refractory to phenylephrine. What is provocative about this work is the presumptive mechanism for these findings. In septic animals, this improvement in blood pressure could not be explained by improvements in cardiac function or vasoconstriction from large vessels. The effect appeared to be a result of vasoconstriction within the renal vascular bed as evidenced by decreased renal blood flow (RBF) in vivo and increased renal vascular perfusion pressure in vitro. These effects were attenuated by Y-27632, implying that signaling via the Rho-A/Rho-kinase pathway plays a role. Presumably, this decrease in renal perfusion could potentially result in acute kidney injury (AKI), a syndrome that has been associated with increased mortality in the ICU setting (2). The implication is that in the setting of refractory shock, similar physiology may apply to patients resulting in an increase in AKI with vasopressin.

Associations of Initial Injury Severity and Posttraumatic Stress Disorder Diagnoses With Long-Term Hypertension Risk After Combat Injury

The associations between injury severity, posttraumatic stress disorder (PTSD), and development of chronic diseases, such as hypertension, among military service members are not understood. We sought to (1) estimate the prevalence and incidence of PTSD within a severely injured military cohort, (2) assess the association between the presence and chronicity of PTSD and hypertension, and (3) determine whether or not initial injury severity score and PTSD are independent risk factors for hypertension. Administrative and clinical databases were used to conduct a retrospective cohort study of 3846 US military casualties injured in the Iraq and Afghanistan conflicts between February 1, 2002, and February 1, 2011. Development of PTSD and hypertension after combat injury were determined using the International Classification of Diseases, Ninth Revision codes. Multivariable competing risk regression models were used to assess associations between injury severity score, PTSD, and hypertension, while controlling for covariates. Overall prevalence of PTSD was 42.4%, and prevalence of hypertension was 14.3%. Unadjusted risk of hypertension increased significantly with chronicity of PTSD (1–15 diagnoses: hazard ratio, 1.77; 95% confidence interval, 1.46–2.14; P<0.001; >15 diagnoses: hazard ratio, 2.29; 95% confidence interval, 1.85–2.84; P<0.001) compared with patients never diagnosed with PTSD. The association between injury severity score (hazard ratio, 1.06 per 5-U increment; 95% confidence interval, 1.03–1.10; P<0.001) and hypertension was significant, with little change in effect in the multivariable model (hazard ratio, 1.05 per 5-U increment; 95% confidence interval, 1.01–1.09; P=0.03). In a cohort of service members injured in combat, we found that chronicity of PTSD diagnoses and injury severity were independent risk factors for hypertension.