Mark A. Wilson

Evolution in the Management of Hepatic Trauma: A 25-Year Perspective

ObjectiveTo define the changes in demographics of liver injury during the past 25 years and to document the impact of treatment changes on death rates. Summary Background DataNo study has presented a long-term review of a large series of hepatic injuries, documenting the effect of treatment changes on outcome. A 25-year review from a concurrently collected database of liver injuries documented changes in treatment and outcome. MethodsA database of hepatic injuries from 1975 to 1999 was studied for changes in demographics, treatment patterns, and outcome. Factors potentially responsible for outcome differences were examined. ResultsA total of 1,842 liver injuries were treated. Blunt injuries have dramatically increased; the proportion of major injuries is approximately 16% annually. Nonsurgical therapy is now used in more than 80% of blunt injuries. The death rates from both blunt and penetrating trauma have improved significantly through each successive decade of the study. The improved death rates are due to decreased death from hemorrhage. Factors responsible include fewer major venous injuries requiring surgery, improved outcome with vein injuries, better results with packing, and effective arterial hemorrhage control with arteriographic embolization. ConclusionsThe treatment and outcome of liver injuries have changed dramatically in 25 years. Multiple modes of therapy are available for hemorrhage control, which has improved outcome.

Hemorrhagic Shock Induces NAD(P)H Oxidase Activation in Neutrophils: Role of HMGB1-TLR4 Signaling

Hemorrhagic shock/resuscitation (HS/R)-induced generation of reactive oxygen species (ROS) plays an important role in posthemorrhage inflammation and tissue injury. We have recently reported that HS/R-activated neutrophils (PMN), through release of ROS, serve an important signaling function in mediating alveolar macrophage priming and lung inflammation. PMN NAD(P)H oxidase has been thought to be an important source of ROS following HS/R. TLR4 sits at the interface of microbial and sterile inflammation by mediating responses to both bacterial endotoxin and multiple endogenous ligands, including high-mobility group box 1 (HMGB1). Recent studies have implicated HMGB1 as an early mediator of inflammation after HS/R and organ ischemia/reperfusion. In the present study, we tested the hypothesis that HS/R activates NAD(P)H oxidase in PMN through HMGB1/TLR4 signaling. We demonstrated that HS/R induced PMN NAD(P)H oxidase activation, in the form of phosphorylation of p47phox subunit of NAD(P)H oxidase, in wild-type mice; this induction was significantly diminished in TLR4-mutant C3H/HeJ mice. HMGB1 levels in lungs, liver, and serum were increased as early as 2 h after HS/R. Neutralizing Ab to HMGB1 prevented HS/R-induced phosphorylation of p47phox in PMN. In addition, in vitro stimulation of PMN with recombinant HMGB1 caused TLR4-dependent activation of NAD(P)H oxidase as well as increased ROS production through both MyD88-IRAK4-p38 MAPK and MyD88-IRAK4-Akt signaling pathways. Thus, PMN NAD(P)H oxidase activation, induced by HS/R and as mediated by HMGB1/TLR4 signaling, is an important mechanism responsible for PMN-mediated inflammation and organ injury after hemorrhage.

Trial of Short-Course Antimicrobial Therapy for Intraabdominal Infection

BACKGROUND The successful treatment of intraabdominal infection requires a combination of anatomical source control and antibiotics. The appropriate duration of antimicrobial therapy remains unclear. METHODS We randomly assigned 518 patients with complicated intraabdominal infection and adequate source control to receive antibiotics until 2 days after the resolution of fever, leukocytosis, and ileus, with a maximum of 10 days of therapy (control group), or to receive a fixed course of antibiotics (experimental group) for 4±1 calendar days. The primary outcome was a composite of surgical-site infection, recurrent intraabdominal infection, or death within 30 days after the index source-control procedure, according to treatment group. Secondary outcomes included the duration of therapy and rates of subsequent infections. RESULTS Surgical-site infection, recurrent intraabdominal infection, or death occurred in 56 of 257 patients in the experimental group (21.8%), as compared with 58 of 260 patients in the control group (22.3%) (absolute difference, -0.5 percentage point; 95% confidence interval [CI], -7.0 to 8.0; P=0.92). The median duration of antibiotic therapy was 4.0 days (interquartile range, 4.0 to 5.0) in the experimental group, as compared with 8.0 days (interquartile range, 5.0 to 10.0) in the control group (absolute difference, -4.0 days; 95% CI, -4.7 to -3.3; P<0.001). No significant between-group differences were found in the individual rates of the components of the primary outcome or in other secondary outcomes. CONCLUSIONS In patients with intraabdominal infections who had undergone an adequate source-control procedure, the outcomes after fixed-duration antibiotic therapy (approximately 4 days) were similar to those after a longer course of antibiotics (approximately 8 days) that extended until after the resolution of physiological abnormalities. (Funded by the National Institutes of Health; STOP-IT ClinicalTrials.gov number, NCT00657566.).

Predicting the Need to Pack Early for Severe Intra-abdominal Hemorrhage

OBJECTIVE To determine if the decision to pack for hemorrhage could be refined. MATERIALS AND METHODS Seventy consecutive trauma patients for whom packing was used to control hemorrhage were studied. The patients had liver injuries, abdominal vascular injuries, and bleeding retroperitoneal hematomas. Preoperative variables were analyzed and survivors compared with nonsurvivors. RESULTS Packing controlled hemorrhage in 37 (53%) patients. Significant differences (p < 0.05) between survivors and nonsurvivors were Injury Severity Score (29 vs. 38), initial pH (7.3 vs. 7.1), platelet count (229,000 vs. 179,000/mm3), prothrombin time (14 vs. 22 seconds), partial thromboplastin time (42 vs. 69 seconds), and duration of hypotension (50 vs. 90 minutes). Nonsurvivors received 20 units of packed red blood cells before packing compared to 13 units for survivors. CONCLUSION Patients who suffer severe injury, hypothermia, refractory hypotension, coagulopathy, and acidosis need early packing if they are to survive. Failure to control hemorrhage is related to severity of injury and delay in the use of pack tamponade. A specific protocol that mandates packing when parameters reach a critical limit should be considered.

Is the timing of fracture fixation important for the patient with multiple trauma

Objective The effect of timing of femur fracture fixation for patients with multiple trauma was studied to determine the effect of operative timing on eventual outcome. Methods The relationship between timing of intramedullary rod (IMR) placement, degree of injury, and pulmonary complications was studied in 424 consecutive patients. The authors focused on 105 patients undergoing IMR placement with an Injury Severity score (ISS) of greater than or equal to 18, The effects of timing of IMR placement on various pulmonary complications, organ failure, intensive care unit (ICU) admission, and ventilatory assistance were studied for various time intervals. Results Of the 424 patients, pulmonary complications increased slightly in the more seriously injured group (ISS > 18) but were not influenced by the timing of IMR placement. Of the 105 patients undergoing IMR placement with an ISS ≥ 18, only 2 patients died. Both patients had an IMR placed in less than 24 hours and died later of head injury and delayed hemorrhage. The incidence of organ failure, number of ventilator days, and length of ICU stay did not differ between the groups based on timing of fracture fixation. The incidence of severe head injuries was higher in the group undergoing delayed IMR placement (>48 hours). Conclusions Modest delays in IMR placement did not adversely affect patient outcome. Pulmonary complications were related to the severity of injury rather than to timing of fracture fixation. In a well‐integrated trauma system, clinical judgment regarding the timing of IMR placement was the most important determinant of outcome. Delays that were made to stabilize the patient, treat associated injuries, and plan orthopedic reconstruction did not adversely affect patient outcome.

Hemorrhagic Shock Activation of NLRP3 Inflammasome in Lung Endothelial Cells

Hemorrhagic shock (HS) due to major trauma and surgery predisposes the host to the development of systemic inflammatory response syndrome (SIRS), including acute lung injury (ALI), through activating and exaggerating the innate immune response. IL-1β is a crucial proinflammatory cytokine that contributes to the development of SIRS and ALI. Lung endothelial cells (EC) are one important source of IL-1β, and the production of active IL-1β is controlled by the inflammasome. In this study, we addressed the mechanism underlying HS activation of the inflammasome in lung EC. We show that high mobility group box 1 acting through TLR4, and a synergistic collaboration with TLR2 and receptor for advanced glycation end products signaling, mediates HS-induced activation of EC NAD(P)H oxidase. In turn, reactive oxygen species derived from NAD(P)H oxidase promote the association of thioredoxin-interacting protein with the nucleotide-binding oligomerization domain-like receptor protein NLRP3 and subsequently induce inflammasome activation and IL-1β secretion from the EC. We also show that neutrophil-derived reactive oxygen species play a role in enhancing EC NAD(P)H oxidase activation and therefore an amplified inflammasome activation in response to HS. The present study explores a novel mechanism underlying HS activation of EC inflammasome and thus presents a potential therapeutic target for SIRS and ALI induced after HS.

SELECTIVE MICROVASCULAR ENDOTHELIAL CELL DYSFUNCTION IN THE SMALL INTESTINE FOLLOWING RESUSCITATED HEMORRHAGIC SHOCK

Following resuscitation (RES) from hemorrhagic shock (HEM), intestinal microvessels develop progressive vasoconstriction that impairs mucosal blood flow, despite central hemodynamic RES. These events might have clinical consequences secondary to occult intestinal ischemia. We hypothesized that the microvascular impairments were due to progressive endothelial cell dysfunction and an associated reduction in the dilator, nitric oxide (NO), following HEM/RES. Male Sprague-Dawley rats, were monitored for central hemodynamics and the terminal ileum was studied with in vivo videomicroscopy. HEM was 50% of baseline mean arterial pressure (MAP) for 60 min, and RES was with shed blood + 1 volume of normal saline (NS), Following HEM/RES, acetylcholine (10-7, 10-5 M) was topically applied and ileal inflow (A1) and premucosal arteriolar diameters were measured to assess endothelial-cell function at 60 and 120 min post-RES. Normalization of MAP, cardiac output, and heart rate demonstrated adequate systemic resuscitation. Post-RES vasoconstriction developed in A1 (-25%) and premucosal (-28%) arterioles with an associated reduction in A1 flow (-47%). However, there was a selective impairment of endothelialdependent dilation that was manifested only in the smaller premucosal arterioles and not in the inflow, A1 arterioles. This suggests that multiple mechanisms are involved in the development of the post-RES vasoconstriction. The premucosal response was likely mediated by endothelial cell dysfunction, while the A1 response was probably the result of enhanced vasoconstrictor forces. This early microvascular dysfunction might contribute to the late sequelae of intestinal ischemia and might alter microvascular responses to subsequent systemic insults.

Nitric oxide synthase inhibition aggravates intestinal microvascular vasoconstriction and hypoperfusion of bacteremia.

Nitric oxide (NO) is an important hemodynamic mediator of sepsis; however, its visceral microcirculatory effects are largely unknown. To determine the role of systemic nitric oxide synthase (NO-S) inhibition on the microcirculation of the small intestine (SI), an intact loop of SI was exteriorized from decerebrate rats into a controlled tissue bath. Videomicroscopy was used to measure arteriolar diameters (A1, A3) and optical Doppler velocimetry was used to quantitate flow. In nonbacteremic controls inhibition of NO-S by N omega-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg IV) caused vasoconstriction (A1 = -7%; A3 = -24% baseline values) and reduced A1 flow by 26%. Bacteremic controls received 10(9) Escherichia coli IV, which resulted in arteriolar constriction and hypoperfusion (A1 = -16%; A3 = -21%; A1 flow = -44%), despite increased cardiac output (+33%). Treatment of bacteremic rats with L-NAME corrected the increased cardiac output (-3%), but exacerbated vasoconstriction (A1 = -24%; A3 = -27%) and did not improve A1 flow (-49%). These data indicate that (1) NO mediates basal microvascular tone of the SI; (2) hyperdynamic bacteremia causes arteriolar constriction and hypoperfusion of the SI; and (3) although systemic NO-S inhibition normalizes cardiac output and increases blood pressure, it aggravates vasoconstriction in the SI and does not improve hypoperfusion.

Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis

Macrophages can be activated and regulated by high-mobility group box 1 (HMGB1), a highly conserved nuclear protein. Inflammatory functions of HMGB1 are mediated by binding to cell surface receptors, including the receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, TLR4, and TLR9. Pyroptosis is a caspase-1-dependent programmed cell death, which features rapid plasma membrane rupture, DNA fragmentation, and release of proinflammatory intracellular contents. Pyroptosis can be triggered by various stimuli, however, the mechanism underlying pyroptosis remains unclear. In this study, we identify a novel pathway of HMGB1-induced macrophage pyroptosis. We demonstrate that HMGB1, acting through RAGE and dynamin-dependent signaling, initiates HMGB1endocytosis, which in turn induces cell pyroptosis. The endocytosis of HMGB1 triggers a cascade of molecular events, including cathepsin B release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation. We further confirm that HMGB1-induced macrophage pyroptosis also occurs in vivo during endotoxemia, suggesting a pathophysiological significance for this form of pyroptosis in the development of inflammation. These findings shed light on the regulatory role of ligand-receptor internalization in directing cell fate, which may have an important role in the progress of inflammation following infection and injury.

Alternatives in the Management of Penetrating Injuries to the Iliac Vessels

BACKGROUND The high mortality and morbidity rates after iliac vessel injuries remain a challenging problem for trauma surgeons. Several controversial issues surround the management of iliac vessel injuries, including the value of abbreviated laparotomy, the role of extra-anatomic bypass reconstruction (EABR), the use of vascular prostheses in the presence of contamination, and the need and timing for fasciotomy. METHODS Retrospective review of the records of patients who sustained an injury to the iliac vessel between 1987 and 1996. RESULTS A total of 64 patients were treated, including 23 with isolated iliac vein injuries, 17 with arterial injuries, and 24 with combined arteriovenous injuries. Vascular prostheses were placed in 17 patients with arterial injuries, including 12 with associated intestinal wounds. Graft infection did not occur. Of the 24 patients with combined injuries, 11 underwent abbreviated laparotomy and 1 died. Five deaths, however, occurred in 13 patients in whom no attempts were made for damage control laparotomy. Significant differences between survivors and nonsurvivors included final arterial pH, final prothrombin time, length of hypotension, and number of transfusions. Arterial ligation with EABR was performed in five patients and failed in two. Deep venous thrombosis and pulmonary embolism occurred in four patients, in three of them after venous injuries were ligated. The overall mortality rate was 23%. CONCLUSION Our findings show that (1) abbreviated laparotomy reduces mortality in iliac injuries; (2) EABR should be performed early after stabilization to prevent limb ischemia; (3) the use of vascular prostheses with associated intestinal injuries did not appear to increase the incidence of graft infection; and (4) after vein ligation, early fasciotomy and prophylaxis against extremity swelling, deep venous thrombosis, and pulmonary embolism should be considered.