Jeffrey H. Pruitt

Interleukin-1 and interleukin-1 antagonism in sepsis, systemic inflammatory response syndrome, and septic shock.

Interleukin-1 (IL-1) is one of several proinflammatory cytokines produced during infection, sepsis, and the systemic inflammatory response syndrome (SIRS) that serves to initiate the host inflammatory response and to integrate nonspecific immunity. Many of IL-1s biologic effects are beneficial to the host in times of stress, but when produced for extended periods of time or in excessive quantities, IL-1 contributes to morbidity and mortality. In fact, excessive IL-1 production has been directly linked to the development of hypotension, shock, multi-organ system failure, hematologic dyscrasia, and death in patients and animals with sepsis, SIRS, and septic shock. Recent research interest has focused on IL-1 inhibition to improve outcome in sepsis and septic shock. This article will review the role for IL-1 in sepsis and septic shock, and the function and status of the IL-1 receptors and IL-1 receptor antagonist in modulating IL-1 actions. The results of investigations of IL-1 inhibition in animal models and in human subjects with sepsis and septic shock will also be reviewed.

A matrix metalloproteinase inhibitor prevents processing of tumor necrosis factor α (TNFα) and abrogates endotoxin-induced lethality

Excessive tumor necrosis factor α (TNFα) production in response to Gram-negative bacteremia or endotoxemia can often lead to hypotension, shock, and increased mortality. Current approaches used to block the deleterious effects of exaggerated TNFα production rely on monoclonal antibodies or immunoadhesins that bind TNFα and thus prevent the interaction with its cellular receptors. This report examines whether a previously described inhibitor of matrix metalloproteinases, GM-6001, can inhibit TNFα processing and release and attenuate endotoxin-induced mortality. In human peripheral blood mononuclear cells stimulated in vitro with 1 μg/mL endotoxin, GM-6001 at concentrations <5 μg/mL blocked release of TNFα, but did not affect the release of either IL-1β or IL-6. GM-6001 also inhibited the release of soluble TNF receptor (p75) from peripheral blood mononuclear cells stimulated with endotoxin and/or TNFα. To confirm the role of secreted TNFα in endotoxic shock-induced mortality, C57BL/6 mice were challenged with either endotoxin alone (500 μg/mouse) or endotoxin (100 ng/mouse) plus D-galactosamine (8 mg/mouse). GM-6001 pretreatment (100 mg/kg) significantly attenuated the 90-minute plasma TNFα response in both models and improved survival in mice treated with low-dose endotoxin plus D-galactosamine. However, plasma IL-1β and IL-6 concentrations at 90 min after endotoxin treatment were unaffected by GM-6001 following lethal endotoxin challenge, confirming the in vivo specificity of this matrix metalloproteinase inhibitor for TNFα processing. These findings demonstrate that a novel inhibitor of matrix metalloproteinases can prevent the release of TNFα both in vitro and in vivo, and can abrogate the harmful sequelae of endotoxemic shock.

American Association for the Surgery of Trauma grade 4 renal injury substratification into grades 4a (low risk) and 4b (high risk).

PURPOSE We identified computerized tomography findings associated with the need for urgent intervention for hemostasis after traumatic renal injury to update and refine the American Association for the Surgery of Trauma Organ Injury Scale for renal trauma. MATERIALS AND METHODS We retrospectively reviewed the records of consecutive patients presenting to our level I trauma center from 1999 to 2008 with American Association for the Surgery of Trauma grades 3 and 4 renal injury. In all patients initial abdominal computerized tomography was done soon after presentation to the emergency department before renal intervention. All images were interpreted by a staff radiologist and urologist blinded to clinical outcomes. Novel radiographic features (perirenal hematoma size, intravascular contrast extravasation and renal laceration site) were analyzed and correlated with the invasive intervention rate to control life threatening bleeding. RESULTS Of 299 patients hospitalized with renal injury 102 met study inclusion criteria. Increased perirenal hematoma size (perirenal hematoma rim distance greater than 3.5 cm), intravascular contrast extravasation and a medial renal laceration site were important radiographic risk factors significantly associated with intervention for bleeding after renal trauma. Analyzing these radiographic characteristics collectively showed that patients with 0 or 1 risk factor were at 7.1% risk for intervention and those with 2 or 3 were at remarkably higher risk, that is 66.7% (OR 26.0, 95% CI 7.20-93.9, p <0.0001). CONCLUSIONS On radiography a large perirenal hematoma, intravascular contrast extravasation and medial renal laceration are important risk factors associated with the need for urgent hemostatic intervention after renal trauma. Assessing these computerized tomography characteristics collectively shows that American Association for the Surgery of Trauma grade 4 renal injuries can and should be substratified into grades 4a (low risk) and 4b (high risk).

Visceral ischemia-reperfusion injury promotes tumor necrosis factor (TNF) and interleukin-1 (IL-1) dependent organ injury in the mouse

Acute visceral ischemia and subsequent reperfusion injury, which accompanies the surgical repair of a thoracoabdominal aorta aneurysm, is associated with high rates of morbidity and mortality. The purpose of the present study was to determine whether endogenous tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) production contributes to organ dysfunction in animals subjected to visceral ischemia secondary to 30 min of supraceliac aortic occlusion. C57BL6/j mice were treated with either a TNF binding protein (TNF-bp-10 mg/kg) or an anti-IL-1 receptor type 1 antibody (150 μg) 2 h prior to 30 min of supraceliac aortic occlusion. An additional group of mice received 30 min of infrarenal aortic occlusion to determine the contribution of lower torso ischemia-reperfusion injury to the changes seen following supraceliac aortic occlusion. Visceral organ ischemia for 30 min produced by supraceliac aortic occlusion followed by 2 h of reperfusion produced measurable TNF-α in 38% of untreated mice, but TNF-α was undetectable in both sham-operated mice and following infrarenal aortic occlusion. After 2 h of reperfusion, lung myeloperoxidase levels were significantly elevated in the mice experiencing visceral ischemia-reperfusion compared with either a sham operation or infrarenal ischemia-reperfusion (11.6 ± 1.3 U/g vs. 3.4 ± .2 U/g and 3.7 ± 1.0 U/g, respectively, p < .05). Pretreatment with TNF-bp and anti-IL-1 antibody decreased lung neutrophil recruitment (7.2 ± 1.2 U/g and 4.6 ± 1.1 U/g) and capillary membrane permeability changes in mice following visceral ischemia-reperfusion. The present study demonstrates that brief (30 min) clinically relevant visceral ischemia produces TNF-α and IL-1 dependent lung injury.

Radiographic predictors of need for angiographic embolization after traumatic renal injury

BACKGROUND Although the American Association of the Surgery for Trauma Organ Injury Scale is the gold standard for staging renal trauma, it does not address characteristics of perirenal hematomas that may indicate significant hemorrhage. Angiographic embolization has become well established as an effective method for achieving hemostasis. We evaluated two novel radiographic indicators--perirenal hematoma size and intravascular contrast extravasation (ICE)--to test their association with subsequent angiographic embolization. METHODS Among 194 patients with renal trauma between 1999 and 2004, 52 having a grade 3 (n = 33) or grade 4 (n = 19) renal laceration were identified. Computed tomography scans were reviewed by a staff radiologist and urologist blinded to outcomes. ICE was defined as contrast within the perirenal hematoma during the portal venous phase having signal density matching contrast in the renal artery. Hematoma size was determined in four ways: hematoma area (HA), hematoma to kidney area ratio (HKR), difference between hematoma and kidney area (HKD), and perirenal hematoma rim distance (PRD). RESULTS Of the 52 patients, 8 had ICE and 4 of these (50%) required embolization, whereas none of the 42 (0%) patients without ICE needed embolization (p = 0.001). Likewise, all four measures of perirenal hematoma size assessed were significantly greater in patients receiving embolization [HA (128.3 vs. 75.4 cm, p = 0.009), HKR (2.75 vs. 1.65, p = 0.008), HKD (76.5 vs. 30.2 cm, p = 0.006), and PRD (4.0 vs. 2.5 cm, p = 0.041)]. CONCLUSION Perirenal hematoma size and ICE are readily detectible radiographic features and are associated with the need for angiographic embolization.

Posttraumatic contrast-induced acute kidney injury: minimal consequences or significant threat?

BACKGROUND Recent enthusiasm for the use of iodinated contrast media and progressive adaption of modern imaging techniques suggests an increased risk of contrast-induced acute kidney injury (CIAKI) in trauma patients. We hypothesized that CIAKI incidence would be higher than that previously reported. METHODS A 1-year retrospective review of our prospective database was performed. Low-osmolar, nonionic, iodinated intravascular (IV) contrast was used exclusively. CIAKI was defined as serum creatinine>0.5 mg/dL, or >25% increase from baseline within 72 hours of admission. The association between CIAKI and risk factors was explored. RESULTS Of 3,775 patients, 1,184 (31.4%) received IV contrast and had baseline and follow-up serum creatinine. Median age was 38 years (range, 18-95 years) and median Injury Severity Score (ISS) was 16. A total of 8% of patients had history of diabetes mellitus. CIAKI was identified in 78 (6.6%). One patient required long-term hemodialysis. In univariable analysis, age>65 years (p=0.01), history of diabetes mellitus (p=0.01), initial creatinine>1.5 mg/dL (p=0.01), ISS≥16 (p=0.04), and initial systolic blood pressure<90 mm Hg (p=0.01) were identified as risk factors for CIAKI. Of note, no association with the dose of IV contrast≥250 mL and CIAKI was identified (p=0.95). A multiple logistic regression model identified higher age, male gender, systolic blood pressure<90 mm Hg, and higher ISS as risk factors for CIAKI. In-hospital mortality was significantly higher in the CIAKI group (9.0% vs. 3.2%, p=0.02). After adjusting for covariates, CIAKI was not significantly associated with in-hospital mortality. CONCLUSION Current trauma management places patients at substantial risk for CIAKI, and risk stratification can be assessed by common clinical criteria. IV contrast dose alone is not an independent associated risk factor. How these data would be extrapolated to an older cohort remains to be determined.

Does Isolated Traumatic Subarachnoid Hemorrhage Merit a Lower Intensity Level of Observation Than Other Traumatic Brain Injury

Evidence is emerging that isolated traumatic subarachnoid hemorrhage (ITSAH) may be a milder form of traumatic brain injury (TBI). If true, ITSAH may not benefit from intensive care unit (ICU) admission, which would, in turn, decrease resource utilization. We conducted a retrospective review of all TBI admissions to our institution between February 2010 and November 2012 to compare the presentation and clinical course of subjects with ITSAH to all other TBI. We then performed descriptive statistics on the subset of ITSAH subjects presenting with a Glasgow Coma Score (GCS) of 13-15. Of 698 subjects, 102 had ITSAH and 596 had any other intracranial hemorrhage pattern. Compared to all other TBI, ITSAH had significantly lower injury severity scores (p<0.0001), lower head abbreviated injury scores (p<0.0001), higher emergency department GCS (p<0.0001), shorter ICU stays (p=0.007), higher discharge GCS (p=0.005), lower mortality (p=0.003), and significantly fewer head computed tomography scans (p<0.0001). Of those ITSAH subjects presenting with a GCS of 13-15 (n=77), none underwent placement of an intracranial monitor or craniotomy. One subject (1.3%) demonstrated a change in exam (worsened headache and dizziness) concomitant with a progression of his intracranial injury. His symptoms resolved with readmission to the ICU and continued observation. Our results suggest that ITSAH are less-severe brain injuries than other TBI. ITSAH patients with GCS scores of 13-15 demonstrate low rates of clinical progression, and when progression occurs, it resolves without further intervention. This subset of TBI patients does not appear to benefit from ICU admission.

TBI risk stratification at presentation: a prospective study of the incidence and timing of radiographic worsening in the Parkland Protocol.

BACKGROUND We have created a theoretical algorithm for venous thromboembolism prophylaxis after traumatic brain injury (TBI) known as the Parkland Protocol, which stratifies patients into low-, medium-, and high-risk categories for spontaneous progression of hemorrhage. This prospective study characterizes the incidence and timing of radiographic progression of the TBI patterns in these categories. METHODS Inclusion criterion was presentation with intracranial blood between February 2010 and March 2011; exclusion was receipt of only one computed tomographic scan of the head during the inpatient stay or preinjury warfarin. At admission, all patients were preliminarily categorized per the Parkland Protocol as follows: low risk (LR), patients meeting the modified Berne-Norwood criteria; moderate risk (MR), injuries larger than the modified Berne-Norwood criteria without requiring a neurosurgical procedure; high risk (HR), any patient with a craniotomy/monitor. RESULTS A total of 245 patients with intracranial hemorrhage were enrolled during the 13-month study period. Of patients preliminarily classified as LR at admission (n = 136), progression was seen in 25.0%. Spontaneous worsening was seen in 7.4% of LR patients at 24 hours after injury, and no LR patients progressed at 72 hours after injury. In patients initially classified as MR at admission (n = 42), progression was seen in 42.9%, with 91.5% of patients demonstrating stable computed tomographic head scans at 72 hours after injury. In patients initially classified as HR (n = 67), 64.2% demonstrated spontaneous progression of their TBI patterns, with 10.5% continuing to progress at 72 hours after injury. Most repeat scans were performed as routinely scheduled studies (81–91%). CONCLUSION Increases in the incidence of spontaneous worsening were seen as severities of injury progressed from the Parkland Protocol’s LR to MR to HR arms. The time frames for these spontaneous worsenings seem to be such that the protocol’s theoretical recommendations for venous thromboembolism prophylaxis are worth pursuing as future points of investigation. LEVEL OF EVIDENCE Prognostic study, level III.

Aortic Aneurysm Repair Is Associated with a Lower Inflammatory Response Compared with Surgery for Inflammatory Bowel Disease

Background: Since the plasma cytokine profile reflects the body’s inflammatory response to injury, this study was designed to prospectively observe the plasma cytokine levels in response to the degree of different sorts of abdominal surgical trauma. Methods: Plasma levels of TNF-α, type I TNF receptor (p55), type II TNF receptor (p75), IL-6, IL-8, IL-10, phospholipase A2 (PLA2), and haptoglobin were measured peri-operatively in patients undergoing bowel resection for inflammatory bowel disease or diverticulitis (IBD) (n = 9), elective repair of abdominal aortic aneurysm (AAA) (n = 9), or laparoscopic cholecystectomy (lap chole) (n = 9). Results: The IBD patients showed a significant (p < 0.05) post-operative elevation in plasma IL-6, p55, p75, and PLA2 levels, but no significant change in TNF-α, IL-8, IL-10 or haptoglobin levels. The AAA patients had a significant post-operative rise in IL-10 levels and a significant decrease in plasma haptoglobin levels, but no significant change of TNF-α, IL-6, IL-8, p55, p75, or PLA2 concentrations. The lap chole patients demonstrated no significant change in any of these parameters. Conclusion: These data show that IL-6, IL-10, p55, and p75 are markers to measure the degree of inflammatory stress associated with abdominal operative procedures and demonstrate the relative lack of a cytokine response to laparoscopic cholecystectomy.

Can CT imaging of the chest, abdomen, and pelvis identify all vertebral injuries of the thoracolumbar spine without dedicated reformatting?

BACKGROUND The main objective of this study was to compare detection rates of clinically significant thoracolumbar spine (TLS) fracture between computed tomography (CT) imaging of the chest, abdomen, and spine (CT CAP) and CT for the thoracolumbar spine (CT TL). METHODS We retrospectively identified patients at our institution with a TLS fracture over a two-year period that had both CT CAP and reformatted CT TL imaging. The sensitivity of CT CAP to identify fracture was calculated for each fracture type. RESULTS A total of 516 TLS fractures were identified in 125 patients using reformatted CT TL spine imaging. Overall, 69 of 512 fractures (13%) were missed on CT CAP that were identified on CT TL. Of those, there were no clinically significant missed fractures. CONCLUSIONS CT CAP could potentially be used as a screening tool for clinically significant TLS injuries.