Carrie A. Sims

Ringer's ethyl pyruvate solution ameliorates ischemia/reperfusion-induced intestinal mucosal injury in rats.

ObjectivePyruvate has been shown to be protective in numerous in vitro and in vivo models of oxidant-mediated cellular or organ system injury. Unfortunately, the usefulness of pyruvate as a therapeutic agent is abrogated by its very poor stability in solution. In an effort to take advantage of the ability of pyruvate to scavenge reactive oxygen species while avoiding the problems associated with the instability of pyruvate in solution, we sought to determine whether a simple derivative, ethyl pyruvate, would be protective in an animal model of reactive oxygen species-mediated tissue injury, namely mesenteric ischemia and reperfusion in rats. DesignProspective, randomized trial. SettingAnimal research center. SubjectsMale Sprague-Dawley rats. InterventionsUnder general anesthesia, rats were subjected to 60 mins of mesenteric ischemia followed by 60 mins of reperfusion. Controls (n = 6) received intravenous lactated Ringer’s solution according this dosing schedule: 1.5 mL/kg bolus before ischemia, 3.0 mL/kg bolus before resuscitation, and 1.5 mL·kg−1·hr−1 by continuous infusion. Two experimental groups received similar volumes of either pyruvate (n = 6 each) or ethyl pyruvate (n = 9) solution made up exactly like lactated Ringer’s solution except for the substitution of eitherpyruvate or ethyl pyruvate for lactate, respectively. Measurements and Main Results To obtain tissues for assessing mucosal permeability and histology, five 10-cm long segments of small intestine were obtained at the following time points: baseline, after 30 and 60 mins of ischemia, and after 30 and 60 mins of reperfusion. Mucosal permeability to fluorescein isothiocyanate dextran (molecular weight 4000 Da) was assessed ex vivo by using an everted gut sac method. Compared with controls, treatment of rats with either pyruvate solution or ethyl pyruvate solution significantly ameliorated the development of intestinal mucosal hyperpermeability during the reperfusion. Treatment with ethyl pyruvate solution also significantly decreased the extent of histologic mucosal damage after mesenteric reperfusion. ConclusionsTreatment with Ringer’s ethyl pyruvate solution ameliorated structural and functional damage to the intestinal mucosa in a rat model of mesenteric ischemia/reperfusion. Ethyl pyruvate solution warrants further evaluation as a novel therapeutic agent for preventing oxidant-mediated injury in various disease states.

Essential role of mitochondrial energy metabolism in Foxp3+ T-regulatory cell function and allograft survival

Conventional T (Tcon) cells and Foxp3+ T‐regulatory (Treg) cells are thought to have differing metabolic requirements, but little is known of mitochondrial functions within these cell populations in vivo. In murine studies, we found that activation of both Tcon and Treg cells led to myocyte enhancer factor 2 (Mef2)‐induced expression of genes important to oxidative phosphorylation (OXPHOS). Inhibition of OXPHOS impaired both Tcon and Treg cell function compared to wild‐type cells but disproportionally affected Treg cells. Deletion of Pgc1α or Sirt3, which are key regulators of OXPHOS, abrogated Treg‐dependent suppressive function and impaired allograft survival. Mef2 is inhibited by histone/protein deacetylase‐9 (Hdac9), and Hdac9 deletion increased Treg suppressive function. Hdac9‐/‐ Treg showed increased expression of Pgc1α and Sirt3, and improved mitochondrial respiration, compared to wild‐type Treg cells. Our data show that key OXPHOS regulators are required for optimal Treg function and Treg‐dependent allograft acceptance. These findings provide a novel approach to increase Treg function and give insights into the fundamental mechanisms by which mitochondrial energy metabolism regulates immune cell functions in vivo.—Beier, U. H., Angelin, A., Akimova, T., Wang, L., Liu, Y., Xiao, H., Koike, M. A., Hancock, S. A., Bhatti, T. R., Han, R., Jiao, J., Veasey, S. C., Sims, C. A., Baur, J. A., Wallace, D. C., Hancock, W. W. Essential role of mitochondrial energy metabolism in Foxp3+ T‐regulatory cell function and allograft survival. FASEB J. 29, 2315‐2326 (2015). www.fasebj.org

Skeletal muscle acidosis correlates with the severity of blood volume loss during shock and resuscitation.

BACKGROUND Continuous assessment of tissue perfusion and oxygen utilization may allow for early recognition and correction of hemorrhagic shock. We hypothesized that continuously monitoring skeletal muscle (SM) PO2, PCO2, and pH during shock would provide an easily accessible method for assessing the severity of blood loss and the efficacy of resuscitation. METHODS Thirteen anesthetized pigs (25-35 kg) underwent laparotomy and femoral vessel cannulation. Multiparameter fiberoptic sensors were placed in the deltoid (SM) and femoral artery. Ventilation was maintained at a PaCO2 of 40-45 mm Hg. Total blood volume (TBV) was measured using an Evans blue dye technique. Animals were bled for 15 minutes, maintained at a mean arterial pressure (MAP) of 40 mm Hg for 1 hour, resuscitated (shed blood + 2 times shed volume in normal saline) and observed for 1 hour. Four animals served as controls (sham hemorrhage). Blood and tissue samples were taken at each time point. RESULTS Blood loss ranged from 28.5-56% of TBV. SM pH and SM PO2 levels fell rapidly with shock. SM PO2 returned to normal with resuscitation; however, SM pH did not return to baseline. SM PCO2 significantly rose with shock, but returned to baseline promptly with resuscitation. There was a significant correlation between SM pH and blood volume loss at end shock (r2 = 0.73, p < 0.001) and recovery (r2 = 0.84, p < 0.001). Animals (n = 2) whose SM pH did not recover to 7.2 were found to have ongoing blood loss from biopsy sites and persistent tissue hypercarbia despite normal MAP. CONCLUSION Continuous multiparameter monitoring of SM provides a minimally invasive method for assessing severity of shock and efficacy of resuscitation. Both PCO2 and PO2 levels change rapidly with shock and resuscitation. SM pH is directly proportional to lost blood volume. Persistent SM acidosis (pH < 7.2) and elevated PCO2 levels suggest incomplete resuscitation despite normalized hemodynamics.

Methylene blue and vasoplegia: who, when, and how?

Systemic inflammatory response can be associated with clinically significant and, at times, refractory hypotension. Despite the lack of uniform definitions, this condition is frequently called vasoplegia or vasoplegic syndrome (VS), and is thought to be due to dysregulation of endothelial homeostasis and subsequent endothelial dysfunction secondary to direct and indirect effects of multiple inflammatory mediators. Vasoplegia has been observed in all age groups and in various clinical settings, such as anaphylaxis (including protamine reaction), sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery. Among mechanisms thought to be contributory to VS, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway appears to play a prominent role. In search of effective treatment for vasoplegia, methylene blue (MB), an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase (GC), has been found to improve the refractory hypotension associated with endothelial dysfunction of VS. There is evidence that MB may indeed be effective in improving systemic hemodynamics in the setting of vasoplegia, with reportedly few side effects. This review describes the current state of clinical and experimental knowledge relating to MB use in the setting of VS, highlighting the potential risks and benefits of therapeutic MB administration in refractory hypotensive states.

Factors associated with mortality and brain injury after falls from the standing position.

BACKGROUND Trauma centers are increasingly tasked with evaluating patients who have sustained low-acuity mechanisms of injury, such as fall from standing (FFS). Previous studies have shown that low-level falls are associated with a high incidence of injury in certain patient groups. The purpose of the current study was to assess risk factors associated with brain injury and death after fall from the standing position only. MATERIALS A retrospective analysis was performed on all patients who presented with FFS as the mechanism of injury from 2000 to 2005. Demographic variables, past medical history, use of warfarin, blood-alcohol level, initial vital signs, injuries, disposition, and mortality outcome were recorded. Data were analyzed to determine risk factors associated with brain injury, need for intensive care unit (ICU) admission, need for emergency operation, and mortality. RESULTS A total of 808 patients were identified. Risk factors associated with brain injury, the need for ICU admission, and death included: Injury Severity Score, age >or=60 years, blood-alcohol level greater than 80 mg/dL, warfarin use, systolic blood pressure <100 mm Hg, and Glasgow Coma Scale <or=12. These risk factors had an additive effect for propensity for brain injury, ICU admission, and death. Increasing Injury Severity Score and use of warfarin had an independent association with mortality. CONCLUSION FFS is a potentially morbid mechanism of injury in those who are using warfarin, those with Glasgow Coma Scale score <or=12, and those who are not inebriated. Age more than 60 years is an additive, but not independent, risk factor for injury.

Monitoring skeletal muscle and subcutaneous tissue acid-base status and oxygenation during hemorrhagic shock and resuscitation.

Gastric tonometry correlates with the severity of blood loss during shock. However, tonometry is cumbersome, has a slow response time, and is not practical to apply in the acute resuscitation setting. We hypothesized that subcutaneous tissue (SC) and skeletal muscle (SM) pH, pCO2, and pO2 changes are comparable with changes seen in bowel tonometry during shock and resuscitation. Thirteen male mini-swine (25-35 kg; n = 4 control, n = 9 shock) underwent laparotomy and jejunal tonometry. A multisensor probe (Diametrics Medical, Roseville, MN) was placed in the carotid artery, the chest SC, and the adductor muscle of the leg (SM). PaCO2 was maintained between 40 and 45 mmHg. Shocked animals were hemorrhaged and kept at mean arterial pressure of 40 mmHg. Animals were bled until a reinfusion of >10% of the total shed blood was needed to maintain the mean arterial pressure at 40 mmHg. Animals were resuscitated with shed blood plus 2x shed volume in lactated Ringers solution (20 min) and were observed for 3 h. The average blood loss was 47.2% ± 8.7% of calculated blood volume. During the hemorrhagic phase, SM and SC displayed tissue acidosis (r2 = 0.951), tissue hypercapnea (r2 = 0.931), and tissue hypoxia (r2 = 0.748). Overall, pH displayed the best correlation between SM and SC during shock and resuscitation. PCO2 in the jejunum (tonometry), SM, and SC increased during decompensation. However, during resuscitation as tonometric pCO2 normalized, only SC pCO2 decreased to its baseline value, whereas the SM pCO2 decrease tended to lag behind. Bland-Altman analyses demonstrated that the variability of the tissue pH changes in SM and SC are predictable according to the phases of hemorrhage and resuscitation. Changes in tissue pH correlated during bleeding and during resuscitation among SC and SM, and these changes followed the trends in gut tonometry as well. Continuous pCO2 and pO2 monitoring in the SM and SC tissues had significant correlations during the induction of shock only. SM and SC continuous pH and pCO2 monitoring reflect bowel pCO2 values during hemorrhagic shock. The response of these indicators as potential surrogates of impaired tissue metabolism varies among tissues and according to the phases of hemorrhage or resuscitation.

Hyperbaric oxygen therapy in necrotizing soft tissue infections

BACKGROUND Surgical debridement and antibiotics are the mainstays of therapy for patients with necrotizing soft tissue infections (NSTIs), but hyperbaric oxygen therapy (HBO) is often used as an adjunctive measure. Despite this, the efficacy of HBO remains unclear. We hypothesized that HBO would have no effect on mortality or amputation rates. METHODS We performed a retrospective analysis of our institutional experience from 2005 to 2009. Inclusion criteria were age > 18 y and discharge diagnosis of NSTI. We abstracted baseline demographics, physiology, laboratory values, and operative course from the medical record. The primary endpoint was in-hospital mortality; the secondary endpoint was extremity amputation rate. We compared baseline variables using Mann-Whitney, chi-square, and Fishers exact test, as appropriate. Significance was set at P < 0.05. RESULTS We identified 80 cases over the study period. The cohort was 54% male (n = 43) and 53% white (n = 43), and had a mean age of 55 ± 16 y. There were no significant differences in demographics, physiology, or comorbidities between groups. In-hospital mortality was not different between groups (16% in the HBO group versus 19% in the non-HBO group; P = 0.77). In patients with extremity NSTI, the amputation rate did not differ significantly between patients who did not receive HBO and those who did (17% versus 25%; P = 0.46). CONCLUSIONS Hyperbaric oxygen therapy does not appear to decrease in-hospital mortality or amputation rate after in patients with NSTI. There may be a role for HBO in treatment of NSTI; nevertheless, consideration of HBO should never delay operative therapy. Further evidence of efficacy is necessary before HBO can be considered the standard of care in NSTI.

The influence of unit-based nurse practitioners on hospital outcomes and readmission rates for patients with trauma

BACKGROUND With the increased restrictions on resident work hours, hospitals increasingly are relying on advance practice nurses and physician assistants to help meet the patient care demand. We have created a workflow model wherein unit-based nurse practitioners (UBNPs) provide the minute-to-minute care for patients with trauma in one specific unit in our hospital, with supervision by the attending surgeons. Patients with trauma may also be admitted to other units, where the care model is a traditional resident-run (RR) service, again with supervision by the attending staff. Our aim was to determine if there were differences between the care provided by UBNPs and residents. METHODS We queried our trauma database for all patients admitted to our urban, academic, Level I trauma center from January 1, 2007, to August 31, 2010. Patients discharged alive from the trauma service were identified and cross-referenced with an administrative database to collect demographics, injury characteristics, comorbidities, complications, and discharge information. Patients cared for by the UBNPs were compared with those cared for by the RR service. &khgr;2, Fisher’s exact, and Student’s t tests were used to determine significance. Significant factors were then tested with a multivariate linear regression analysis. p < 0.05 was considered significant. RESULTS During the study period, 3,859 patients were discharged alive from the trauma service, 2,759 (71.5%) from the UBNPs service, and 1,100 (28.5%) from the RR service. Demographic data and mean Injury Severity Score (11.6 vs. 11.1, p = 0.24) were similar for the two groups, although mean abdominal Abbreviated Injury Score was higher for the UBNP group (0.6 vs. 0.5, p = 0.02). UBNP patients were more likely to be diagnosed with deep venous thrombosis (4% vs. 2.5%, p = 0.02) and were more likely to be discharged to home (67% vs. 60%, p = 0.002). Mean (SD) length of stay for UBNP patients was 6.5 (8.8) days compared with 7 (10.8) days for RR patients, although this difference did not reach statistical significance ( p = 0.17). The 30-day hospital readmission rates were similar for both groups (4.0% vs. 4.4%, p = 0.63). CONCLUSION Care provided by UBNPs is equivalent to that provided by residents. With the restriction on resident work hours and greater reliance on nurse practitioners, patient care does not suffer. Moreover, a difference of 0.5 days in mean length of stay for the UBNP patients equates with more than 1,300 fewer patient care days. This difference, although not statistically significant, may be clinically relevant to physicians and administrators and may offset the cost of hiring UBNPs to help meet the patient care demand. LEVEL OF EVIDENCE Therapeutic study, level IV.

Reduced brain tissue oxygen in traumatic brain injury: Are most commonly used interventions successful?

BACKGROUND Brain tissue oxygenation (PbtO2)-guided management facilitates treatment of reduced PbtO2 episodes potentially conferring survival and outcome advantages in severe traumatic brain injury (TBI). To date, the nature and effectiveness of commonly used interventions in correcting compromised PbtO2 in TBI remains unclear. We sought to identify the most common interventions used in episodes of compromised PbtO2 and to analyze which were effective. METHODS A retrospective 7-year review of consecutive severe TBI patients with a PbtO2 monitor was conducted in a Level I trauma centers intensive care unit or neurosurgical registry. Episodes of compromised PbtO2 (defined as <20 mm Hg for 0.25-4 hours) were identified, and clinical interventions conducted during these episodes were analyzed. Response to treatment was gauged on how rapidly (ΔT) PbtO2 normalized (>20 mm Hg) and how great the PbtO2 increase was (ΔPbtO2). Intracranial pressure (ΔICP) and cerebral perfusion pressure (ΔCPP) also were examined for these episodes. RESULTS Six hundred twenty-five episodes of reduced PbtO2 were identified in 92 patients. Patient characteristics were: age 41.2 years, 77.2% men, and Injury Severity Score and head or neck Abbreviated Injury Scale score of 34.0 ± 9.2 and 4.9 ± 0.4, respectively. Five interventions: narcotics or sedation, pressors, repositioning, FIO2/PEEP increases, and combined sedation or narcotics + pressors were the most commonly used strategies. Increasing the number of interventions resulted in worsening the time to PbtO2 correction. Triple combinations resulted in the lowest ΔICP and dual combinations in the highest ΔCPP (p < 0.05). CONCLUSION Clinicians use a limited number of interventions when correcting compromised PbtO2. Using strategies employing many interventions administered closely together may be less effective in correcting PbO2, ICP, and CPP deficits. Some PbtO2 deficits may be self-limited.

Differences in outcomes between ICU attending and senior resident physician led medical emergency team responses

INTRODUCTION Although rapid response systems (RRS) have been shown to decrease the incidence of cardiac arrest (CA), there are no studies evaluating optimal staffing. We hypothesize that there are no outcome differences between ICU physician and senior resident led events. METHODS A retrospective study of the RRS database at a single, academic hospital was performed from July 1, 2006 to May 31, 2010. Surgical patients and those in the ICU were excluded. Daytime (D) was defined as 7 am-5 pm Monday through Friday, and weekends were defined as 5 pm on Friday to 6:59 am on Monday. The nurse to patient ratio is constant during all shifts. An ICU physician leads daytime events on weekdays whereas night/weekend (NW) events are led by residents. NW events were compared against D events using chi square or Fischers exact test. Significance was defined as p<0.05. RESULTS A total of 1404 events were reviewed with 534 (38%) D and 870 (62%) NW events. Respiratory and staff concerns were more likely during NW compared to D (50% vs. 39% and 46% vs. 34%, p<0.001, respectively). Following RRS activation, no difference was noted between D and NW periods in the incidence of progression to CA, transfer to ICU, or hospital mortality. Invasive procedures were more common in the NW period. CONCLUSION Resident-led RRS may have similar outcomes to attending intensivist led events. Prospective studies are needed to determine the ideal team composition.