Jeffrey L. Johnson

Genomic responses in mouse models poorly mimic human inflammatory diseases

A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R2 between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.

A genomic storm in critically injured humans

Critical injury in humans induces a genomic storm with simultaneous changes in expression of innate and adaptive immunity genes.

Plasma and lipids from stored packed red blood cells cause acute lung injury in an animal model.

Transfusion-related acute lung injury (TRALI) is a serious complication of hemotherapy. During blood storage, lipids are generated and released into the plasma. In this study, the role of these lipids in TRALI was investigated using an isolated, perfused rat lung model. Rats were pretreated with endotoxin (LPS) or saline in vivo and the lungs were isolated, ventilated, and perfused with saline, or (a) 5% (vol/ vol) fresh human plasma, (b) plasma from stored blood from the day of isolation (D.0) or from the day of outdate (D.42), (c) lipid extracts from D.42 plasma, or (d) purified lysophosphatidylcholines. Lungs from saline or LPS-pretreated rats perfused with fresh (D.0) plasma showed no pulmonary damage as compared with saline perfused controls. LPS pretreatment/D.42 plasma perfusion caused acute lung injury (ALI) manifested by dramatic changes in both pulmonary artery pressure and edema. Incubation of LPS pre-tx rats with mibefradil, a Ca2+ channel blocker, or WEB 2170, a platelet-activating factor (PAF) receptor antagonist, inhibited ALI caused by D.42 plasma. Lung histology showed neutrophil sequestration without ALI with LPS pretreatment/saline or D.0 plasma perfusion, but ALI with LPS pretreatment/D.42 plasma perfusion, and inhibition of D.42 plasma induced ALI with WEB 2170 or mibefradil. A significant increase in leukotriene E4 was present in LPS-pretreated/D.42 plasma-perfused lungs that was inhibited by WEB 2170. Lastly, significant pulmonary edema was produced when lipid extracts of D.42 plasma or lysophosphatidylcholines were perfused into LPS-pretreated lungs. Lipids caused ALI without vasoconstriction, except at the highest dose employed. In conclusion, both plasma and lipids from stored blood produced pulmonary damage in a model of acute lung injury. TRALI, like the adult respiratory distress syndrome, may be the result of two insults: one derived from stored blood and the other from the clinical condition of the patient.

Randomized Comparison of ABVD and MOPP/ABV Hybrid for the Treatment of Advanced Hodgkin’s Disease: Report of an Intergroup Trial

PURPOSE In a series of trials, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP/ABV) have been identified as effective treatments for Hodgkins disease. We compared these regimens as initial chemotherapy for Hodgkins disease. PATIENTS AND METHODS Adult patients (N = 856) with advanced Hodgkins disease were randomly assigned to treatment with ABVD or MOPP/ABV. The major end points were failure-free and overall survival, life-threatening acute toxicities, and serious long-term toxicities, including cardiomyopathy, pulmonary toxicity, myelodysplastic syndromes (MDS), and secondary malignancies. RESULTS The rates of complete remission (76% v 80%, P =.16), failure-free survival at 5 years (63% v 66%, P =.42), and overall survival at 5 years (82% v 81%, P =.82) were similar for ABVD and MOPP/ABV, respectively. Clinically significant acute pulmonary and hematologic toxicity were more common with MOPP/ABV (P =.060 and.001, respectively). There was no difference in cardiac toxicity. There were 24 deaths attributed to initial treatment: nine with ABVD and 15 with MOPP/ABV (P =.057). There have been 18 second malignancies associated with ABVD and 28 associated with MOPP/ABV (P =.13). Thirteen patients have developed MDS or acute leukemia: 11 were initially treated with MOPP/ABV, and two were initially treated with ABVD but subsequently received MOPP-containing regimens and radiotherapy before developing leukemia (P =.011). CONCLUSION ABVD and the MOPP/ABV hybrid are effective therapies for Hodgkins disease. MOPP/ABV is associated with a greater incidence of acute toxicity, MDS, and leukemia. ABVD should be considered the standard regimen for treatment of advanced Hodgkins disease.

Abdominal perfusion pressure: a superior parameter in the assessment of intra-abdominal hypertension.

OBJECTIVE To assess the clinical utility of abdominal perfusion pressure (mean arterial pressure minus intra-abdominal pressure) as both a resuscitative endpoint and predictor of survival in patients with intra-abdominal hypertension. METHODS 144 surgical patients treated for intra-abdominal hypertension between May 1997 and June 1999 were retrospectively reviewed. Multivariate logistic regression and receiver operating characteristic curve analysis of common physiologic variables and resuscitation endpoints were performed to determine the decision thresholds for each variable that predict patient survival. RESULTS Abdominal perfusion pressure was statistically superior to both mean arterial pressure and intravesicular pressure in predicting patient survival from intra-abdominal hypertension and abdominal compartment syndrome. Multiple regression analysis demonstrated that abdominal perfusion pressure was also superior to other common resuscitation endpoints, including arterial pH, base deficit, arterial lactate, and hourly urinary output. CONCLUSION Abdominal perfusion pressure appears to be a clinically useful resuscitation endpoint and predictor of patient survival during treatment for intra-abdominal hypertension and abdominal compartment syndrome.

Postinjury life threatening coagulopathy: is 1:1 fresh frozen plasma:packed red blood cells the answer?

BACKGROUND Recent military experience suggests that immediate 1:1 fresh frozen plasma (FFP); red blood cells (RBC) for casualties requiring >10 units packed red blood cells (RBC) per 24 hours reduces mortality, but no clinical trials exist to address this issue. Consequently, we reviewed our massive transfusion practices during a 5-year period to test the hypothesis that 1:1 FFP:RBC within the first 6 hours reduces life threatening coagulopathy. METHODS We queried our level I trauma centers prospective registry from 2001 to 2006 for patients undergoing massive transfusion. Logistic regression was used to evaluate the independent effect of FFP:RBC in 133 patients who received >10 units RBC in 6 hours on (1) Coagulopathy (international normalized ratio [INR] >1.5 at 6 hours), controlling for our previously described risk factors predictive of coagulopathy, as well as RBC, FFP, and platelet administration (2) Death (controlling for all variables plus age, crystalloids per 24 hours, INR >1.5 at 6 hours). RESULTS Overall mortality was 56%; 50% died from acute blood loss in the operating room. Over 80% of the RBC transfusions were completed in the first 6 hours: (Median RBC: 18 units) Median FFP:RBC survivors, 1:2, nonsurvivors: 1:4. (p < 0.001) INR >1.5 at 6 hours occurred in 30 (23%); 81% died. Regarding mortality, logistic regression showed significant variables (p < 0.05) included: RBC per 6 hours (OR = 1.248, 95%CI: 1.957-53.255), INR at 6 hours >1.5 (OR = 10.208, 95% CI: 1.957-53.255), ED temperature <34 degrees C (OR = 15.491, 95% CI 1.376-174.396), and age >55 years (OR = 40.531, CI 5.315-309.077). The adjusted OR for FFP:RBC ratio including the quadratic term was found to follow a U-shaped association (quadratic term estimate 0.6737 +/- 0.0345, p = 0.0189). CONCLUSION Although our data suggest that 1:1 FFP:RBC reduced coagulopathy, this did not translate into a survival benefit. Our findings indicate that the relationship between coagulopathy and mortality is more complex, and further clinical investigation is necessary before recommending routine 1:1 in the exsanguinating trauma patient.

Treatment-related outcomes from blunt cerebrovascular injuries: importance of routine follow-up arteriography.

ObjectiveTo assess the impact of routine follow-up arteriography on the management and outcome of patients with acute blunt cerebrovascular injuries (BCVI). Summary Background DataDuring the past 5 years there has been increasing recognition of BCVI, but the management of these lesions remains controversial. The authors previously proposed a grading system for BCVI, with grade-specific management guidelines. The authors have noted that a significant number of injuries evolve within 7 to 10 days, warranting alterations in therapy. MethodsA prospective database of a regional trauma center’s experience with BCVI has been maintained since 1990. A policy of arteriographic screening for BCVI based on injury mechanism (e.g., cervical hyperextension) and injury patterns (e.g., cervical and facial fractures) was instituted in 1996. A grading system was devised to develop management protocols: I = intimal irregularity; II = dissection/flap/thrombus; III = pseudoaneurysm; IV = occlusion; V = transection. ResultsFrom June 1990 to October 2001, 171 patients (115 male, age 36 ± 1 years) were diagnosed with BCVI. Mean injury severity score was 28 ± 1; associated injuries included brain (57%), spine (44%), chest (43%), and face (34%). Mechanism was motor vehicle crash in 50%, fall in 11%, pedestrian struck in 11%, and other in 29%. One hundred fourteen patients had 157 carotid artery injuries (43 bilateral), and 79 patients had 97 vertebral artery injuries (18 bilateral). The breakdown of injury grades was 137 grade I, 52 grade II, 32 grade III, 25 grade IV, and 8 grade V. One hundred fourteen (73%) carotid and 65 (67%) vertebral arteries were restudied with arteriography 7 to 10 days after the injury. Eight-two percent of grade IV and 93% of grade III injuries were unchanged. However, grade I and II lesions changed frequently. Fifty-seven percent of grade I and 8% of grade II injuries healed, allowing cessation of therapy, whereas 8% of grade I and 43% of grade II lesions progressed to pseudoaneurysm formation, prompting interventional treatment. There was no significant difference in healing or in progression of injuries whether treated with heparin or antiplatelet therapy or untreated. However, heparin may improve the neurologic outcome in patients with ischemic deficits and may prevent stroke in asymptomatic patients. ConclusionsRoutine follow-up arteriography is warranted in patients with grade I and II BCVIs because most of these patients (61% in this series) will require a change in management. A prospective randomized trial will be necessary to identify the optimal treatment of BCVI.

Intensive Chemotherapy and Immunotherapy in Patients With Newly Diagnosed Primary CNS Lymphoma: CALGB 50202 (Alliance 50202)

PURPOSE Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome. PATIENTS AND METHODS Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial. RESULTS The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age > 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival. CONCLUSION CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.

The abdominal compartment syndrome is a morbid complication of postinjury damage control surgery.

BACKGROUND The abdominal compartment syndrome (ACS) is a recognized complication of damage control surgery (DCS). The purposes of this study were to (1) determine the effect of ACS on outcome after DCS, (2) identify patients at high risk for the development of ACS, and (3) determine whether ACS can be prevented by preemptive intravenous bag closure during DCS. METHODS Patients requiring postinjury DCS at our institution from January 1996 to June 2000 were divided into groups depending on whether or not they developed ACS. ACS was defined as an intra-abdominal pressure (IAP) greater than 20 mm Hg in association with increased airway pressure or impaired renal function. RESULTS ACS developed in 36% of the 77 patients who underwent DCS with a mean IAP prior to decompression of 26 +/- 1 mm Hg. The ACS versus non-ACS groups were not significantly different in patient demographics, Injury Severity Score, emergency department vital signs, or intensive care unit admission indices (blood pressure, temperature, base deficit, cardiac index, lactate, international normalized ratio, partial thromboplastin time, and 24-hour fluid). The initial peak airway pressure after DCS was higher in those patients who went on to develop ACS. The development of ACS after DCS was associated with increased ICU stays, days of ventilation, complications, multiorgan failure, and mortality. CONCLUSIONS ACS after postinjury DCS worsens outcome. With the exception of early elevation in peak airway pressure, we could not identify patients at higher risk for ACS; moreover, preemptive abdominal bag closure during initial DCS did not prevent this highly morbid complication.

Primary Fibrinolysis Is Integral in the Pathogenesis of the Acute Coagulopathy of Trauma

Background:The existence of primary fibrinolysis (PF) and a defined mechanistic link to the “Acute Coagulopathy of Trauma” is controversial. Rapid thrombelastography (r-TEG) offers point of care comprehensive assessment of the coagulation system. We hypothesized that postinjury PF occurs early in severe shock, leading to postinjury coagulopathy, and ultimately hemorrhage-related death. Methods:Consecutive patients over 14 months at risk for postinjury coagulopathy were stratified by transfusion requirements into massive (MT) >10 units/6 hours (n = 32), moderate (Mod) 5 to 9 units/6 hours (n = 15), and minimal (Min) <5 units/6 hours (n = 14). r-TEG was performed by adding tissue factor to uncitrated whole blood. r-TEG estimated percent lysis was categorized as PF when >15% estimated percent lysis was detected. Coagulopathy was defined as r-TEG clot strength = G < 5.3 dynes/cm2. Logistic regression was used to define independent predictors of PF. Results:A total of 34% of injured patients requiring MT had PF, which was associated with lower emergency department systolic blood pressure, core temperature, and greater metabolic acidosis (analysis of variance, P < 0.0001). The risk of death correlated significantly with PF (P = 0.026). PF occurred early (median, 58 minutes; interquartile range, 1.2–95.9 minutes); every 1 unit drop in G increased the risk of PF by 30%, and death by over 10%. Conclusions:Our results confirm the existence of PF in severely injured patients. It occurs early (<1 hour), and is associated with MT requirements, coagulopathy, and hemorrhage-related death. These data warrant renewed emphasis on the early diagnosis and treatment of fibrinolysis in this cohort.