Center for Translational Injury Research

We sought to examine the improvement in renal function with preserved immunosuppression consequent to reducing de novo cyclosporine (CsA) doses combined with sirolimus and induction antibody treatment. 408 renal recipients treated de novo with CsA-sirolimus included 91 patients who received high (> 5); 125, medium (2.5-5.0); or 192, low CsA doses (< 2.5 mg/kg/day) together with induction antibody among 5, 48 and 68% of subjects, respectively. At 2 years we excluded 21 (23), 30 (24) and 49 (25%) subjects who experienced the composite end-point, yielding 70 (71), 95 (76) and 143 (74%) cases, whose mean de novo CsA C2 values were 725, 400 and 306 ng/ml; for all cohorts, sirolimus C0 = 10-15 de novo and 8-12 ng/ml during maintenance treatment. The primary end-point--mean 4-year GFR by aMDRD--ascribed "0" to patients who experienced death or graft loss after 2 years. Although low-dose subjects were older (p = 0.008) and heavier (p < 0.001) with grafts exposed to longer cold ischemia times (p < 0.001), they displayed greater GFR: 64.8 versus 48.4 among the high and 54.1 ml/min/1.73 m(2) in the medium dose arms (p = 0.002). Polychotomous logistic regression revealed significant GFR predictors to be CsA dose (p = 0.015) and younger donor age (p < 0.001). Between 2 and 4 years, the incidences of the composite end-point were 17, 14 and 16%; including 13, 10 and 11% rejections. 80% reduction in de novo CsA exposure with antibody induction improved renal function at 4 years compared with 50 or 66% reductions.

Damage control laparotomy (DCL) is a lifesaving technique initially employed to minimize the lethal triad of coagulopathy, hypothermia, and acidosis. Recently, it has been recognized that DCL itself carries significant morbidity and may be overutilized. The purpose of this study was to determine (1) whether early fascial closure is associated with a reduction in postoperative complications and (2) whether patients at our institution met traditional DCL indications (acidosis, hypothermia, and coagulopathy). This is a retrospective review of all patients undergoing immediate laparotomy at a Level I trauma center between 2004 and 2008. DCL was defined as temporary abdominal closure at the initial surgery. Early closure was defined as primary fascial closure at initial take back laparotomy. Patients were excluded if they died before first take back. Acidosis (pH <7.30), hypothermia (temperature <95.0°F), and coagulopathy (international normalized ratio >1.5) were measured on intensive care unit (ICU) arrival. Totally, 925 patients were eligible. Thirty percent had DCL employed. Of these, 86 subjects (34%) were closed at first take back while 161 (66%) were not. Both groups were similar in demographics, injury severity score, resuscitation volumes, blood products, and prehospital, emergency department, and operating room vital signs. Univariate analyses noted that intra-abdominal abscesses (8.4% vs. 21.3%), respiratory failure (14.4% vs. 37.1%), sepsis (8.4% vs. 25.1%), and renal failure (3.6% vs. 25.1%) were lower in patients closed at first take back (all <0.05). Controlling for age, gender, injury severity score, and transfusions, logistic regression analysis noted that closure at the first take back was associated with a reduction in infectious (odds ratio, 0.28; 95% confidence interval [CI], 0.12-0.66; p = 0.004) and noninfectious abdominal complications (odds ratio, 0.23; 95% CI, 0.09-0.56; p = 0.001) as well as wound (odds ratio, 0.31; 95% CI, 0.13-0.72; p = 0.007) and pulmonary complications (odds ratio, 0.35; CI, 0.20-0.62; p < 0.001). Of patients closed at the initial take back, 78% were acidotic (35%), coagulopathic (49%), or hypothermic (44%) on initial ICU admission. Early fascial closure is an independent predictor of reduced complications in DCL patients. One in five patients closed at initial take back did not meet any of the traditional indications for DCL upon initial ICU admission. This may represent an overutilization of this valuable technique, exposing patients to increased complications. Further efforts should be directed at achieving both early facial closure as well as redefining the appropriate indications for DCL.

Damage-control laparotomy (DCL) is a lifesaving technique but carries significant morbidity. If DCL is over used and the factors that predict early fascial closure have not been fully evaluated. The purpose of the current study was to determine (1) the current rate of DCL, (2) the percentage of DCLs that are closed at first take-back, and (3) possible physiologic and resuscitative parameters predicting early fascial closure. A retrospective review of all trauma laparotomies from a Level I trauma center between January 2004 and December 2008 was performed. Patients were excluded if they died before first take-back. Univariate and multivariate analyses were performed. Nine hundred thirty patients were eligible, 278 (30%) underwent DCL, 36 excluded for death before first take-back. Of the remaining 242 DCL patients, 83 (34%) were closed at first take-back and 159 (66%) were not closed at first take-back. These two groups were similar in injury severity, demographics, and prehospital and emergency department fluids and vitals. Median emergency department international normalized ratio (INR; 1.13 vs. 1.29, p = 0.010), post-op INR (1.4 vs. 1.5, p = 0.028), 24-hour fluids (11.9 L vs. 15.5 L, p = 0.006), peak post-op intra-abdominal pressure (IAP; 15 vs. 18, p < 0.001), and mortality (1.2% vs. 8.2%, p = 0.027) were different between groups. Multivariate analysis noted vacuum-assisted closure at initial laparotomy (Odds ratio, 3.1; 95% confidence interval [CI], 1.42-6.63; p = 0.004) was an independent predictor of closure at first take-back. However, post-op INR (Odds ratio, 0.18; 95% CI, 0.03-0.97; p = 0.04) and post-op peak IAP (Odds ratio, 0.85; 95% CI, 0.76-0.95; p = 0.005) predicted failure to close fascia at first take-back. In similarly injured DCL patients, increased post-op INR and IAP predicted inability to achieve primary fascial closure on first take-back, while use of the vacuum-assisted closure was associated with increased likelihood of early fascial closure. At a busy academic Level I trauma center, the current rate of DCL among those undergoing emergent laparotomy is 30%. Whether this represents optimal use or overutilization of this technique still needs to be determined.

Recognition of trauma-induced coagulopathy by conventional coagulation testing (CCT) is limited by their slow results, incomplete characterization, and their poor predictive nature. Rapid thrombelastography (r-TEG) delivers a more comprehensive assessment of the coagulation system but has not been prospectively validated in trauma patients. The purpose of this pilot study was to evaluate the timeliness of r-TEG results, their correlation with CCTs, and the ability of r-TEG to predict early blood transfusion. Over a 5-month period, 583 consecutive major trauma activations were prospectively entered into a database, of which 272 met entry criteria. r-TEG and CCTs (prothrombin time, international normalized ratio, partial thromboplastin time, and platelet count) were obtained on all patients. Graphical results for r-TEG were displayed "real time" in the trauma bay. Spearman's correlation and regression models were used to compare r-TEG and CCTs. Early r-TEG values (activated clotting time [ACT], k-time, and r-value) were available within 5 minutes, late r-TEG values (maximal amplitude and α-angle) within 15 minutes, and CCTs within 48 minutes (p < 0.001). ACT, r-value, and k-time showed strong correlation with prothrombin time, international normalized ratio, and partial thromboplastin time (all r >0.70; p < 0.001), whereas maximal amplitude (r = -0.49) and α-angle (r = 0.40) correlated with platelet count (both p < 0.001). Linear regression demonstrated ACT predicted red blood cells (coef. 0.05; 95% confidence interval [CI], 0.04-0.06; p < 0.001), plasma (coef. 0.03; 95% CI, 0.02-0.04; p < 0.001), and platelet (coef. 0.06; 95% CI, 0.04-0.07; p < 0.001) transfusions within the first 2 hours of arrival. Controlling for all demographics and Emergency Department vitals, ACT >128 predicted massive transfusion (≥10 U) in the first 6 hours (odds ratio, 5.15; 95% CI, 1.36-19.49; p = 0.01). In addition, ACT <105 predicted patients who did not receive any transfusions in the first 24 hours (odds ratio, 2.80; CI, 1.02-7.07; p = 0.04). Graphical r-TEG results are available within minutes, correlate with conventional coagulation test that are not as rapidly available, and are predictive of early transfusions of packed red blood cells, plasma, and platelets.

Renal allograft glomerular filtration rate (GFR) was measured at 4-month intervals for up to 1 year in 43 CsA-treated patients using x-ray fluorescence determination of plasma iohexol clearance. Study patients were divided into cohorts based on time (years) after transplantation at study entry (0-1; 1-2; 2-3; and > 3 years) and entry GFR levels (20-29; 30-39; 40-49; and > or = 50 ml/min/1.73 m2). GFR at study entry was 42 +/- 2 and was comparable in CAD (n = 31) versus LRD (n = 12) allografts (42 +/- 2 and 44 +/- 4 ml/min/1.73 m2, respectively). Range of entry GFR levels was similar in each of the "time at entry" cohorts defined above. Serum creatinine concentrations of 1.5-2.5 mg% were associated with GFR levels of 20-60 ml/min/1.73 m2. Serial GFR levels obtained at 4-month intervals for 1 year (n = 34 patients) were not consistent with a pattern of progressively declining GFR occurring as a function of either time after transplantation or absolute GFR level at study entry (intraindividual coefficient of variation 10.3 +/- 1.0%). Patients in the lower quartile of "entry GFR" levels (< 34 ml/min/1.73 m2) were more likely than their counterparts to have had a history of acute rejection. Results are consistent with retrospective population studies of aggregate serum creatinine levels, indicating that long-term CsA use is not uniformly associated with accelerated loss of renal allograft function consequent to a progressive, toxic nephropathy. The data also suggest that neither absolute GFR level nor time after transplantation represent indications for routine dose reduction or conversion to AZA.

Distribution of cadaveric donor kidneys, based upon the donor-recipient HLA match grade, remains one of the major controversies in transplantation. To determine whether matching results in fewer rejection episodes and better graft survival, we retrospectively studied our single-center patient population of 683 cyclosporine-prednisone-treated primary cadaveric renal allograft recipients. For 237 recipients of well-matched HLA A, B kidneys (< or = 2 HLA A, B mismatches [MM]) the 1-, 3-, 5-, and 7-year graft survivals of 76%, 66%, 62%, and 61%, respectively, were not significantly different from those of 71%, 65%, 63%, and 63%, respectively, for the 446 poorly matched HLA A, B (> 2 HLA A, B MM) recipients. Similarly, the 1-, 3-, 5-, and 7-year graft survivals for the 307 recipients of well-matched HLA-DR kidneys (0 or 1 DR MM) of 74%, 65%, 63%, and 61%, respectively, were not significantly different from those of 72%, 65%, 63%, and 62%, respectively, for the 366 poorly matched (2 DR MM) recipients. Patient survivals were comparable at each time point for well- vs. poorly matched recipients. Similarly, donor-recipient HLA A, B, and DR matching was not beneficial in retransplant recipients who were transplanted following negative NIH and antiglobulin (AHG) crossmatches when testing both historical (high-PRA) and pretransplant sera. Since rejection episodes may be a more sensitive indicator of immune response than graft loss, we also analyzed the relationship between donor-recipient HLA match grade and posttransplant rejections. A total of 60% (n = 413) of recipients experienced no rejections and had 1-, 3-, 5-, and 7-year graft survivals of 82%, 78%, 74%, and 73%, respectively; 32% (n = 215) of patients who experienced 1 rejection had 1-, 3-, 5-, and 7-year graft survivals of 58%, 48%, 44%, and 43%, respectively (P < 0.001 for graft survival of 0 vs. 1 rejection). The remaining 8% (n = 55) of recipients experienced more than 1 (> 1) rejection and had 1-, 3-, 5-, and 7-year graft survivals of 62%, 38%, 36%, and 36%, respectively (P < 0.001 for graft survival of 0 vs. > 1 rejection and P < 0.01 for graft survival of 1 vs. > 1 rejection). The mean numbers of rejections/patient experienced by well-matched vs. poorly matched recipients were comparable and not significantly different.(ABSTRACT TRUNCATED AT 400 WORDS)

... Auteur(s) / Author(s). PODDER H. (1) ; PODBIELSKI J. (1) ; HUSSEIN I. (1) ; KATZ SM (1) ; VANBUREN CT (1) ; KAHAN BD (1) ; Affiliation(s) du ou des auteurs / Author(s) Affiliation(s). ... Anglais Editeur / Publisher. Elsevier, Amsterdam, PAYS-BAS (1969) (Revue) ...