Frederick A. Gage

Heterotopic Ossification in High-energy Wartime Extremity Injuries: Prevalence and Risk Factors

BACKGROUND Heterotopic ossification in the extremities remains a common complication in the setting of high-energy wartime trauma, particularly in blast-injured amputees and in those in whom the definitive amputation was performed within the zone of injury. The purposes of this cohort study were to report the experience of one major military medical center with high-energy wartime extremity wounds, to define the prevalence of heterotopic ossification in these patients, and to explore the relationship between heterotopic ossification and other potential independent predictors. METHODS We retrospectively reviewed the records and radiographs of all combat-wounded patients admitted to this institution between March 1, 2003, and December 31, 2006. Patients with a minimum of two months of radiographic follow-up who underwent at least one orthopaedic procedure on an extremity constituted our study group; those who underwent at least one orthopaedic procedure but had not had heterotopic ossification develop constituted the control group. Variables recorded for each study subject included age and sex, location and mechanism of injury, method(s) of fracture fixation, number of débridement procedures, duration of negative pressure therapy, location of heterotopic ossification, presence and severity of traumatic brain injury, and Injury Severity Scores. RESULTS During the study period, 1213 war-wounded patients were admitted. Of those patients, 243 (157 in the heterotopic ossification group and eighty-six controls) met the inclusion criteria. The observed rate of heterotopic ossification was 64.6%. A significant relationship was detected between heterotopic ossification and the presence (p = 0.006) and severity (p = 0.003) of a traumatic brain injury. Risk factors for the development of heterotopic ossification were found to be an age of less than thirty years (p = 0.007, odds ratio = 3.0), an amputation (p = 0.048, odds ratio = 2.9), multiple extremity injuries (p = 0.002, odds ratio = 3.9), and an Injury Severity Score of >or=16 (p = 0.02, odds ratio = 2.2). CONCLUSIONS The prevalence of heterotopic ossification in war-wounded patients is higher than that in civilian trauma. Although trends associated with local wound conditions were identified, the risk factors for the development of heterotopic ossification found in this study suggest that systemic causes predominate.

Inflammatory biomarkers in combat wound healing.

Background:Modern war ballistics and blast injuries inflict devastating extremity injuries, violating soft tissue, bone, and neurovascular structures. Despite advances in complex wound management, appropriate timing of war wound closure remains subjective. In addition, the pathophysiology of acute wound failure is poorly defined. Methods:Patients with penetrating extremity wounds sustained during combat were prospectively studied and followed for 30 days after definitive wound closure. The primary outcome was wound healing. Wound dehiscence was defined as spontaneous partial or complete wound disruption after closure. Serum, wound effluent, and wound bed tissue biopsy were collected at each surgical wound debridement. Serum and wound effluent were analyzed with a multiplex array of 22 cytokines and chemokines, and wound tissue for corresponding gene transcript expression. Results:Fifty-two penetrating extremity war wounds in 33 male patients were investigated. Nine (17%) wounds dehisced. Concomitant vascular injury, increased wound size, and higher injury severity score correlated with wound dehiscence. Both serum and wound effluent cytokine and chemokine protein profiles were statistically associated with healing outcome at various time points. Wound biopsy gene transcript expression demonstrated increased tissue inflammation associated with wound failure. Multiple protein and gene transcript biomarkers predictive of wound healing were identified. Conclusions:The cytokine and chemokine protein and gene transcript expression patterns demonstrate a condition of inflammatory dysregulation associated with war wound failure. A molecular biomarker panel may predict combat wound healing outcome and warrants prospective validation.

Metalloproteinase Expression is Associated with Traumatic Wound Failure

BACKGROUND Matrix metalloproteinases (MMPs) are crucial in the inflammatory and remodeling phases of wound healing. We previously reported the correlation between pro-inflammatory cytokines and timing of successful combat-wound closure. We now extend our studies to investigate the correlation between wound-remodeling MMP expression and wound healing. METHODS Thirty-eight wounds in 25 patients with traumatic extremity combat wounds were prospectively studied. Surgical debridement with vacuum-assisted closure (VAC) device application was repeated every 48 to 72h until surgical wound closure. Wound effluent and patient serum were collected at each wound debridement and analyzed for five matrix metalloproteinases using the Luminex multiplex system; Millipore Corp, Billerica, MA. The primary outcome was wound healing within 30 d of definitive wound closure. Impairment was defined as delayed wound closure (>21 d from injury) or wound dehiscence. MMP expression was compared between impaired and normal healing wounds. RESULTS Elevated levels of serum MMP-2 and MMP-7 and reduced levels of effluent MMP3 were seen in impaired wounds (n = 9) compared with wounds that healed (n = 29; P<0.001). Receiver operating characteristic (ROC) curve analysis yielded area-under-the-curve (AUC) of 0.744, 0.783, and 0.805, respectively. CONCLUSIONS Impaired wound healing is characterized by pro-inflammatory MMP-2 and MMP-7. Serum and effluent concentrations of MMP-2, MMP-3, and MMP-7 can effectively predict the outcome of traumatic war wounds and can potentially provide decision-supportive, objective evidence for the timing of wound closure.

Incidence of Pulmonary Embolus in Combat Casualties With Extremity Amputations and Fractures

BACKGROUND The objective of this retrospective study was to determine the incidence of pulmonary embolism (PE) in casualties of wartime extremity wounds and specifically in casualties with a trauma-associated amputation. METHODS Records of all combat-wounded evacuated and admitted between March 1, 2003, and December 31, 2007, were retrospectively reviewed. Continuous and categorical variables were studied with the Students t test, Fishers exact test or χ² test; multivariate analysis was performed using a stepwise regression logistic model. RESULTS A total of 1,213 records were reviewed; 263 casualties met the inclusion criteria. One hundred three (41.5%) had amputations and 145 (58.5%) had long-bone fractures not requiring amputation. The observed rate of PE in these 263 casualties was 5.7%. More casualties with amputations, 10 (3.7%), developed PE than those with long-bone fractures in the absence of amputation, 5 (1.9%) (p = 0.045). Casualties with bilateral lower extremity trauma-associated amputations had a significantly higher incidence of PE compared with those sustaining a single amputation (p = 0.023), and the presence of bilateral lower extremity amputations was an independent risk factor for development of a PE (p = 0.007, odds ratio 5.9) (univariate and multivariate analysis, respectively). CONCLUSION The cumulative incidence of PE was 5.7%. The incidence of PE is significantly higher with trauma-associated amputation than with extremity long-bone fracture without amputation. Bilateral amputations, multiple long-bone fractures, and pelvic fractures are independent risk factors for the development of PE. The use of aggressive prophylaxis, deep venous thrombosis screening with ultrasound, and use of prophylactic inferior vena cava filters should be considered in this patient population.

Room Temperature Pulsatile Perfusion of Renal Allografts With Lifor Compared With Hypothermic Machine Pump Solution

This pilot study compared the use of the Lifor Organ Preservation Medium (RTLF) at room temperature with hypothermic Belzer machine preservation solution (CMPS) and room in vitro temperature Belzer machine preservation solution (RTMPS) in a porcine model of uncontrolled donation after cardiac death (DCD). In this study, 5 porcine kidneys for each perfusate group were recovered under a DCD protocol. The kidneys were recovered, flushed, and placed onto a renal preservation system following standard perfusion procedures. The average flow rate for CMPS was 36.2 +/- 7.2549 mL/min, RTMPS was 90.2 +/- 9.7159 mL/min, and RTLF was 103.1 +/- 5.1108 mL/min. The average intrarenal resistance for CMPS was 1.33 +/- 0.1709 mm Hg/mL per minute, RTMPS was 0.84 +/- 0.3586 and RTLF was 0.39 +/- 0.04. All perfusion parameters were statistically significant (P < .05) at all time points for the CMPS when compared with both RTMPS and RTLF. All perfusion parameters for RTMPS and RTLF were equivalent for the first 12 hours; thereafter, RTLF became significantly better than RTMPS at 18 and 24 hours. It appears that both RTMPS and RTLF have equivalent perfusion characteristic for the initial 12 hours of perfusion, but LF continues to maintain a low resistance and high flow up to 24 hours. The results of this pilot study indicate that RTLF may represent a better alternative to pulsatile perfusion with CMPS and requires validation in an in vivo large animal transplant model.

Non-invasive monitoring of tissue oxygenation during laparoscopic donor nephrectomy.

BackgroundStandard methods for assessment of organ viability during surgery are typically limited to visual cues and tactile feedback in open surgery. However, during laparoscopic surgery, these processes are impaired. This is of particular relevance during laparoscopic renal donation, where the condition of the kidney must be optimized despite considerable manipulation. However, there is no in vivo methodology to monitor renal parenchymal oxygenation during laparoscopic surgery.MethodsWe have developed a method for the real time, in vivo, whole organ assessment of tissue oxygenation during laparoscopic nephrectomy to convey meaningful biological data to the surgeon during laparoscopic surgery. We apply the 3-CCD (charge coupled device) camera to monitor qualitatively renal parenchymal oxygenation with potential real-time video capability.ResultsWe have validated this methodology in a porcine model across a range of hypoxic conditions, and have then applied the method during clinical laparoscopic donor nephrectomies during clinically relevant pneumoperitoneum. 3-CCD image enhancement produces mean region of interest (ROI) intensity values that can be directly correlated with blood oxygen saturation measurements (R2 > 0.96). The calculated mean ROI intensity values obtained at the beginning of the laparoscopic nephrectomy do not differ significantly from mean ROI intensity values calculated immediately before kidney removal (p > 0.05).ConclusionHere, using the 3-CCD camera, we qualitatively monitor tissue oxygenation. This means of assessing intraoperative tissue oxygenation may be a useful method to avoid unintended ischemic injury during laparoscopic surgery. Preliminary results indicate that no significant changes in renal oxygenation occur as a result of pneumoperitoneum.

Development of a Bayesian model to estimate health care outcomes in the severely wounded

Background: Graphical probabilistic models have the ability to provide insights as to how clinical factors are conditionally related. These models can be used to help us understand factors influencing health care outcomes and resource utilization, and to estimate morbidity and clinical outcomes in trauma patient populations. Study design: Thirty-two combat casualties with severe extremity injuries enrolled in a prospective observational study were analyzed using step-wise machine-learned Bayesian belief network (BBN) and step-wise logistic regression (LR). Models were evaluated using 10-fold cross-validation to calculate area-under-the-curve (AUC) from receiver operating characteristics (ROC) curves. Results: Our BBN showed important associations between various factors in our data set that could not be developed using standard regression methods. Cross-validated ROC curve analysis showed that our BBN model was a robust representation of our data domain and that LR models trained on these findings were also robust: hospital-acquired infection (AUC: LR, 0.81; BBN, 0.79), intensive care unit length of stay (AUC: LR, 0.97; BBN, 0.81), and wound healing (AUC: LR, 0.91; BBN, 0.72) showed strong AUC. Conclusions: A BBN model can effectively represent clinical outcomes and biomarkers in patients hospitalized after severe wounding, and is confirmed by 10-fold cross-validation and further confirmed through logistic regression modeling. The method warrants further development and independent validation in other, more diverse patient populations.

Bilateral lower-extremity amputation wounds are associated with distinct local and systemic cytokine response

BACKGROUND Approximately 25% of U.S. military members sustaining extremity amputations in recent military conflicts have bilateral lower-extremity amputations (BLA). We investigated among combat-related extremity wounds whether BLA exhibit different bacterial burden, inflammatory response, and local complications. METHODS A total of 75 patients with combat-related extremity wounds (19 BLA) were evaluated for age, tobacco use, body mass index, Injury Severity Score, Acute Physiology and Chronic Health Evaluation II, and delayed primary closure time. Blood, wound exudates, and muscle biopsies were obtained and analyzed for cytokine and quantitative bacteriology, excluding patients using nonsteroidal anti-inflammatory medications and corticosteroids, due to potential effects on their inflammatory profile. RESULTS BLA was not associated with differences in age, tobacco use, body mass index, and delayed primary closure time, but these patients had increased Injury Severity Score, Acute Physiology and Chronic Health Evaluation II, and rates of critical colonization. Proinflammatory cytokines including tumor necrosis factor-α (exudate), interleukin (IL)-1 (exudate) and IL-6 (serum) were increased in BLA patients. They also had serum and exudate increased IL-8 and decreased IL-13 and granulocyte-macrophage colony-stimulating factor. Both wound dehiscence (WD) and heterotopic ossification (HO) were more common in BLA patients. CONCLUSION BLA patients were more likely to exhibit critical bacterial colonization, a distinct inflammatory response, and develop WD and HO. Modulating this response represents an attractive target in an effort to prevent complications such as WD and HO.

Evidence of a heterogeneous tissue oxygenation: renal ischemia/reperfusion injury in a large animal model.

Abstract. Renal ischemia that occurs intraoperatively during procedures requiring clamping of the renal artery (such as renal procurement for transplantation and partial nephrectomy for renal cancer) is known to have a significant impact on the viability of that kidney. To better understand the dynamics of intraoperative renal ischemia and recovery of renal oxygenation during reperfusion, a visible reflectance imaging system (VRIS) was developed to measure renal oxygenation during renal artery clamping in both cooled and warm porcine kidneys. For all kidneys, normothermic and hypothermic, visible reflectance imaging demonstrated a spatially distinct decrease in the relative oxy-hemoglobin concentration (%HbO2) of the superior pole of the kidney compared to the middle or inferior pole. Mean relative oxy-hemoglobin concentrations decrease more significantly during ischemia for normothermic kidneys compared to hypothermic kidneys. VRIS may be broadly applicable to provide an indicator of organ ischemia during open and laparoscopic procedures.