David Bar-Or

A randomized double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of two doses of the tramadol orally disintegrating tablet for the treatment of premature ejaculation within less than 2 minutes.

BACKGROUND Premature ejaculation (PE) is a widely observed male sexual dysfunction with a major impact on quality of life for many men and their sexual partners. OBJECTIVE To assess the safety of tramadol orally disintegrating tablet (ODT) (Zertane) and its efficacy in prolonging intravaginal ejaculation latency time (IELT) and improving Premature Ejaculation Profile (PEP) scores. DESIGN, SETTING, AND PARTICIPANTS We conducted an integrated analysis of two identical 12-wk randomized double-blind, placebo-controlled phase 3 trials across 62 sites in Europe. Healthy men 18-65 yr of age with a history of lifelong PE according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, and an IELT ≤ 120 s were included. There were 604 intent-to-treat subjects included in the analysis. INTERVENTION Subjects were randomized to receive 1:1:1 placebo (n=200), 62 mg tramadol ODT (n=206), or 89 mg tramadol ODT (n=198). MEASUREMENTS We measured overall change and fold increase in median IELT and the mean change in all four measures of the PEP. Differences across treatment groups were analyzed using Wilcoxon rank-sum tests, analysis of variance, and chi-square analyses. RESULTS AND LIMITATIONS Tramadol ODT resulted in significant increases in median IELT compared with placebo; increases were 0.6 min (1.6 fold), 1.2 min (2.4 fold), and 1.5 min (2.5 fold) for placebo, 62 mg tramadol ODT, and 89 mg tramadol ODT, respectively (p<0.001 for all comparisons). Men saw significantly greater improvement in all four measures of the PEP in both doses compared with placebo (p<0.05 for all comparisons). Tramadol ODT was well tolerated; study discontinuation occurred in 0%, 1.0%, and 1.6% of subjects in placebo, 62 mg, and 89 mg tramadol ODT groups, respectively. Limitations include study inclusion for men with IELT up to 120 s. CONCLUSIONS On-demand 62mg tramadol ODT is an effective treatment for PE in a low and safe therapeutic dose and provides a new option for managing mild to severe PE.

Oxidative stress in severe acute illness

The overall redox potential of a cell is primarily determined by oxidizable/reducible chemical pairs, including glutathione–glutathione disulfide, reduced thioredoxin–oxidized thioredoxin, and NAD+–NADH (and NADP–NADPH). Current methods for evaluating oxidative stress rely on detecting levels of individual byproducts of oxidative damage or by determining the total levels or activity of individual antioxidant enzymes. Oxidation–reduction potential (ORP), on the other hand, is an integrated, comprehensive measure of the balance between total (known and unknown) pro-oxidant and antioxidant components in a biological system. Much emphasis has been placed on the role of oxidative stress in chronic diseases, such as Alzheimers disease and atherosclerosis. The role of oxidative stress in acute diseases often seen in the emergency room and intensive care unit is considerable. New tools for the rapid, inexpensive measurement of both redox potential and total redox capacity should aid in introducing a new body of literature on the role of oxidative stress in acute illness and how to screen and monitor for potentially beneficial pharmacologic agents.

Commercial human albumin preparations for clinical use are immunosuppressive in vitro.

Objective:We previously reported significant variations in oxidation status and molecular length among sources and lots of human serum albumin (HSA) commercial preparations intended for clinical use. In this report, we investigated what effect the presence of HSA products have on the immune response in vitro. Design:Laboratory study. Setting:Trauma research basic science laboratory. Subjects:Activated human peripheral blood mononuclear cells. Interventions:Six commercial HSA preparations were tested for their effect on cytokine release from activated human peripheral blood mononuclear cells (PBMCs) and T-lymphocytes. Mass spectrometry analysis of aspartyl-alanyl diketopiperazine (DA-DKP) content of HSA and percentage of HSA having lost its amino terminal dipeptide aspartyl alanyl (HSA-DA) were correlated. Measurements and Main Results:Human PBMCs were cultured in the presence of six commercial HSA preparations and activated via the T-cell receptor complex. A cloned T-lymphocyte cell line, activated with specific antigen, was also cultured with both synthetic DA-DKP and small molecular weight extracts from the commercial HSA tested. Supernatants were quantified by enzyme-linked immunosorbent assay for interferon-γ and tumor necrosis factor-α content. DA-DKP was extracted from HSA by centrifugal filters and quantified by anion exchange liquid chromatography coupled to negative electrospray ionization mass spectrometry. HSA species were determined by reverse phase liquid chromatography coupled to positive electrospray ionization, time of flight mass spectrometry. All HSA preparations significantly inhibited the in vitro production of interferon-γ and tumor necrosis factor-α by activated PBMCs. DA-DKP was detected in all HSA sources at concentrations ranging between 42.0 and 79.6 &mgr;M. A synthetic form of DA-DKP possessed similar immunosuppressive qualities in a dose-dependent manner on T lymphocytes. Conclusions:DA-DKP was present in significant concentrations in all HSA sources tested and was partially responsible for the immunosuppressive effects of HSA on activated PBMCs and T-lymphocytes in vitro. In view of these findings, administering HSA to immunocompromised critically ill patients might be reevaluated.

A retrospective analysis of geriatric trauma patients: venous lactate is a better predictor of mortality than traditional vital signs

BackgroundTraditional vital signs (TVS), including systolic blood pressure (SBP), heart rate (HR) and their composite, the shock index, may be poor prognostic indicators in geriatric trauma patients. The purpose of this study is to determine whether lactate predicts mortality better than TVS.MethodsWe studied a large cohort of trauma patients age ≥ 65 years admitted to a level 1 trauma center from 2009-01-01 - 2011-12-31. We defined abnormal TVS as hypotension (SBP < 90 mm Hg) and/or tachycardia (HR > 120 beats/min), an elevated shock index as HR/SBP ≥ 1, an elevated venous lactate as ≥ 2.5 mM, and occult hypoperfusion as elevated lactate with normal TVS. The association between these variables and in-hospital mortality was compared using Chi-square tests and multivariate logistic regression.ResultsThere were 1987 geriatric trauma patients included, with an overall mortality of 4.23% and an incidence of occult hypoperfusion of 20.03%. After adjustment for GCS, ISS, and advanced age, venous lactate significantly predicted mortality (OR: 2.62, p < 0.001), whereas abnormal TVS (OR: 1.71, p = 0.21) and SI ≥ 1 (OR: 1.18, p = 0.78) did not. Mortality was significantly greater in patients with occult hypoperfusion compared to patients with no sign of circulatory hemodynamic instability (10.67% versus 3.67%, p < 0.001), which continued after adjustment (OR: 2.12, p = 0.01).ConclusionsOur findings demonstrate that occult hypoperfusion was exceedingly common in geriatric trauma patients, and was associated with a two-fold increased odds of mortality. Venous lactate should be measured for all geriatric trauma patients to improve the identification of hemodynamic instability and optimize resuscitative efforts.

The impact of the AIS 2005 revision on injury severity scores and clinical outcome measures

BACKGROUND The abbreviated injury scale (AIS) was updated in 2005 from the AIS 1998 version. The purpose of this study is to describe the effects of this change on injury severity scoring and outcome measures. MATERIALS AND METHODS Analyses were performed on all trauma patients consecutively admitted over a 6-month period at two geographically separate Level I trauma centers. Injuries were manually double-coded according to the AIS 05 and the AIS 98. Changes in AIS, ISS, and new ISS (NISS) were analysed using paired t-tests. Apparent differences in outcome by ISS strata (<16, 16-24, >24) were compared for AIS 05 versus AIS 98 using the Wald-type statistic. Lastly, the percent of patients with a change in ISS strata are reported. RESULTS There were 2250 patients included in the study. Nearly half (46.4%) of AIS codes changed, resulting in a different AIS score for 18.9% of all codes. The mean ISS was significantly lower using the AIS 05 (11.7) versus the AIS 98 (13.3, p<0.001). Similarly, the mean NISS was significantly lower (16.3 versus 18.7, p<0.001). In the ISS strata 16-24 an apparent increase in mortality, length of stay, and percent of patients not discharged home was observed for the AIS 05 versus AIS 98. Changes in outcome measures for this stratum were as follows (AIS 98 versus AIS 05): mortality, 4.3% versus 7.7% (p=0.002); hospital length of stay, 5.2 days versus 7.3 days (p<0.001); percent of patients not discharged home, 39.2% versus 49.3% (p<0.001). Finally, there was a 20.5% reduction in patients with an ISS>or=16 and a 26.2% reduction in patients with an ISS>or=25 using the AIS 05. CONCLUSIONS The AIS revision had a significant impact on overall injury severity measures, clinical outcome measures, and percent of patients in each ISS strata. Therefore, the AIS revision affects the ability to directly compare data generated using AIS 05 and AIS 98 which has implications in trauma research, reimbursement and ACS accreditation.

Copper stimulates the synthesis and release of interleukin-8 in human endothelial cells: A possible early role in systemic inflammatory responses

Endogenous copper can play an important role in postischemic reperfusion injury, a condition associated with endothelial cell activation and increased interleukin 8 (IL-8) production. Excessive endothelial IL-8 secreted during trauma, major surgery, and sepsis may contribute to the development of systemic inflammatory response syndrome (SIRS), adult respiratory distress syndrome (ARDS), and multiple organ failure (MOF). No previous reports have indicated that copper has a direct role in stimulating human endothelial IL-8 secretion. Increased IL-8 in the culture medium of human umbilical vein (HUVEC), lung microvascular, and iliac artery endothelial cells was observed 24 h after the addition of 10 to 50 &mgr;M CuCl2 (cupric ions). HUVEC IL-8 induction by copper was higher than by 50 pg/mL tumor necrosis factor-&agr;, whereas 50 pg/mL IL-1&bgr; and 1 ng/mL platelet-activating factor did not stimulate IL-8 production or release. HUVEC IL-8 mRNA increased 3 h after CuCl2 stimulation and remained elevated after 24 h, implying sustained transcriptional activation. Copper did not stimulate HUVECs to secrete other cytokines. Cu(II) appeared to be the primary copper ion responsible for the observed increase in IL-8 because a specific high-affinity Cu(II)-binding peptide, d-Asp-d-Ala-d-His-d-Lys (d-DAHK), completely abolished this effect in a dose-dependent manner. These results suggest that Cu(II) may induce endothelial IL-8 by a mechanism independent of known Cu(I) generation of reactive oxygen species. Furthermore, in vivo studies are warranted to determine if copper is involved in the pathogenesis of systemic inflammation and if Cu(II) chelation can reduce this IL-8-induced endothelial inflammatory response.

The Effect of Age on Glasgow Coma Scale Score in Patients With Traumatic Brain Injury

IMPORTANCE The Glasgow Coma Scale (GCS) is used frequently to define the extent of neurologic injury in patients with a traumatic brain injury (TBI). Whether age affects the predictive ability of the GCS for severity of TBI (determined by the Abbreviated Injury Scale [AIS] score) remains unknown. OBJECTIVE To investigate the effect of age on the association between the GCS and anatomic TBI severity. DESIGN, SETTING, AND PARTICIPANTS We examined all patients with a TBI, defined by diagnostic codes 850 to 854 from the International Classification of Diseases, Ninth Revision, Clinical Modification, who were admitted to 2 level I trauma centers from January 1, 2008, through December 31, 2012. EXPOSURES We compared elderly (≥65 years) and younger (18-64 years) adults with TBI. MAIN OUTCOMES AND MEASURES We examined differences by age in GCS category (defined by emergency department GCS as severe [3-8], moderate [9-12], or mild [13-15]) at each level of TBI severity (head AIS score, 1 [minor] to 5 [critical]). Cochran-Armitage χ² trend tests and stepwise multivariate linear and logistic regression models were used. RESULTS During the study period, 6710 patients had a TBI (aged <65 years, 73.17%). Significant differences in GCS category by age occurred at each AIS score (P ≤ .01 for all). In particular, among patients with an AIS score of 5, most of the elderly patients (56.33%) had a mild neurologic deficit (GCS score, 13-15), whereas most of the younger patients (63.28%) had a severe neurologic deficit (GCS score, 3-8). After adjustment, the younger adults had increased odds of presenting with a severe neurologic deficit (GCS score, 3-8) at each of the following AIS scores: 1, 4.2 (95% CI, 1.0-17.6; P = .05); 2, 2.0 (1.0-3.7; P = .04); 3, 2.0 (1.2-3.5; P = .01); 4, 4.6 (2.8-7.5; P < .001); and 5, 3.1 (2.1-4.6; P < .001). The interaction between age and GCS for anatomic TBI severity remained significant after adjustment (estimate, -0.11; P = .005). CONCLUSIONS AND RELEVANCE Age affects the relationship between the GCS score and anatomic TBI severity. Elderly TBI patients have better GCS scores than younger TBI patients with similar TBI severity. These findings have implications for TBI outcomes research and for protocols and research selection criteria that use the GCS.

Pharmacologic thromboprophylaxis is a risk factor for hemorrhage progression in a subset of patients with traumatic brain injury.

BACKGROUND Pharmacologic thromboprophylaxis (PTP) may exacerbate intracranial hemorrhage (ICH) in patients with traumatic brain injury (TBI). We examined risk factors for hemorrhage progression in patients with blunt TBI and hypothesized that PTP would increase ICH progression in a subset of these patients. METHODS We retrospectively studied patients with TBI admitted to our level I trauma center during 19 months. Progression of hemorrhage was examined in two populations: patients with a stable initial follow-up (F/U) computed tomography (CT) and patients with hemorrhage progression on initial F/U CT. Risk factors potentially associated with hemorrhage progression were analyzed using logistic regression. Timing of PTP was defined two ways: exposed to PTP versus not exposed; early (<72 hours), late (>or=72 hours), or no PTP. RESULTS Three hundred forty patients with TBI were reviewed and hemorrhage progression occurred in 32.4% (n = 110) of patients of which 59.1% were considered clinically significant. In patients with ICH progression on initial F/U CT, predictors of subsequent hemorrhage progression include exposure to PTP (odds ratio [OR]: 13.07, p = 0.01), extradural/subdural hemorrhage (OR: 5.15, p = 0.03), Glasgow Coma Score 3-8 (OR: 4.64, p = 0.03), and body mass index >or=25 (OR = 4.32, p = 0.03). PTP was not significantly associated with hemorrhage progression in patients with a stable initial F/U CT. CONCLUSIONS These findings suggest that PTP use is associated with a 13-fold increased odds of further hemorrhage progression in patients whose F/U CT within 1 day of admission showed ICH progression; 16% of this risk can be attributed to receiving PTP. Conversely, PTP may be safe in a subgroup of patients with TBI with no ICH progression on initial F/U CT.

The effect of storage on the accumulation of oxidative biomarkers in donated packed red blood cells.

BACKGROUND Transfusion-related acute lung injury (TRALI) is a life-threatening condition characterized by oxidative stress. Longer storage times of packed red blood cells (PRBC) and other blood products have been implicated with an increased risk in developing TRALI in transfused patients. METHODS A total of 10 units of blood containing PRBC stored in citrate-phosphate-dextrose buffer at 4 degrees C were included in the study. At Bonfils Blood Center (Denver, CO), samples were collected on storage day 1 and day 42. Samples were immediately centrifuged, and the supernatants were collected and stored at -80 degrees C until further analysis. Oxidation-reduction potential and protein oxidation were measured in both the day 1 and day 42 samples. RESULTS Oxidation-reduction potential significantly increased (p < 0.05) in the day 42 sample (98.1 mV +/- 21.9 SD) versus the day 1 sample (62.6 mV +/- 21.5 SD). The oxidation of human serum albumin increased by 63.6% during the storage time. Other serum proteins such as apolipoprotein A1 and transthyretin demonstrated similar increases in oxidation. Also, proteins with a cleaved C-terminal amino acid were observed indicating the presence of carboxypeptidase activity, a marker of inflammation. CONCLUSIONS The presence of an oxidative environment in transfused PRBC increases with storage time. This could partially explain the increased risk of developing TRALI related to the transfusion of older blood products.

Transient monocyte release of interleukin-10 in response to traumatic brain injury.

A significant component of the immune response to trauma results in the systemic presence of cytokines which have the potential to suppress the patients immune response to infection and contribute to post-injury complications. We assayed peripheral blood leukocytes obtained from 10 patients with head trauma to determine their production of interleukin (IL). Serum was assayed for the presence of IL-10, TGFbeta1, and IFNgamma by ELISA. Peripheral blood leukocytes were screened for intracellular IL-10 and IFNgamma by fluorescence-activated flow cytometry, and cytokine-specific mRNA was detected by the polymerase chain reaction. We detected an immediate, but transient, presence of IL-10 in the sera of all 10 patients who suffered head trauma. IL-10-specific intracytoplasmic immunofluorescence was also detected immediately after injury in peripheral blood monocytes, but not in lymphocytes or granulocytes. IL-10-specific mRNA was detected in peripheral blood leukocytes in only 50% of patients immediately after injury, when the highest serum levels of IL-10 were observed. Our data indicates that release of pre-formed IL-10 by monocytes contributes to the presence of IL-10 found in patient peripheral blood immediately after head injury.