Optimal strategies for assessing and managing pain, agitation, and delirium in the critically ill surgical patient: What you need to know.

ABSTRACT: Pain, agitation, and delirium (PAD) are primary drivers of outcome in the ICU, and expertise in managing these entities successfully is crucial to the intensivist's toolbox. In addition, there are unique aspects of surgical patients that impact assessment and management of PAD. In this review, we address the continuous spectrum of assessment, and management of critically ill surgical patients, with a focus on limiting PAD, particularly incorporating mobility as an anchor to ICU liberation. Finally, we touch on the impact of PAD in specific populations, including opioid use disorder, traumatic brain injury, pregnancy, obesity, alcohol withdrawal, and geriatric patients. The goal of the review is to provide rapid access to information regarding PAD and tools to assess and manage these important elements of critical care of surgical patients.

Does Practice Match Training? Consultation Practices in Surgical Critical Care.

INTRODUCTION: Intensive care unit (ICU) patient and provider attributes may prompt specialty consultation. We sought to determine practice patterns of surgical critical care (SCC) physicians for ICU consultation. METHODS: We surveyed American Association for the Surgery of Trauma members. Various diagnoses were listed under each of nine related specialties. Respondents were asked for which conditions they would consult a specialist. Conditions were cross-referenced with the SCC fellowship curriculum. Other perspectives on practice and consultation were queried. RESULTS: 314 physicians (18.6%) responded (68% male; 79% White; 96.2% surgical intensivist); 284 (16.8%) completed all questions. Percentage of clinical time practicing SCC was 26-50% in 57% and >50% in 14.5%. ICUs were closed (39%), open (25%), or hybrid (36%). Highest average confidence ratings (1 = least, 5 = most) for managing select conditions were ventilator, 4.64; palliative care, 4.51; infections, 4.44; organ donation, hemodynamics (tie), 4.31; lowest rating was myocardial ischemia, 3.85. Consults were more frequent for Cardiology, Hematology, and Neurology; less frequent for nephrology, palliative care, gastroenterology, infectious disease, and pulmonary; and low for curriculum topics (<25%) except for infectious diseases and palliative care. Attending staffing 24 h/day was associated with a lower mean number of topics for consultation (mean 24.03 versus 26.31, P = 0.015). CONCLUSIONS: ICU consultation practices vary based on consultant specialty and patient diagnosis. Consultation is most common for specialty-specific diseases and specialist interventions, but uncommon for topics found in the SCC curriculum, suggesting that respondents' scope of practice closely matched their training.

Laparoscopy is associated with decreased all-cause mortality in patients undergoing emergency general surgery procedures in a regional health system.

BACKGROUND: The aim of this study was to evaluate the use of laparoscopic surgery for common emergency general surgery (EGS) procedures within an integrated Acute Care Surgery (ACS) network. We hypothesized that laparoscopy would be associated with improved outcomes. METHODS: Our integrated health care system's EGS registry created from AAST EGS ICD-9 codes was queried from January 2013 to October 2015. Procedures were grouped as laparoscopic or open. Standard descriptive and univariate tests were performed, and a multivariable logistic regression controlling for open status, age, BMI, Charlson Comorbidity Index (CCI), trauma tier, and resuscitation diagnosis was performed. Laparoscopic procedures converted to open were identified and analyzed using concurrent procedure billing codes across episodes of care. RESULTS: Of 60,604 EGS patients identified over the 33-month period, 7280 (12.0%) had an operation and 6914 (11.4%) included AAST-defined EGS procedures. There were 4813 (69.6%) surgeries performed laparoscopically. Patients undergoing a laparoscopic procedure tended to be younger (45.7 ± 18.0 years vs. 57.2 ± 17.6, p < 0.001) with similar BMI (29.7 ± 9.0 kg/m2 vs. 28.8 ± 8.3, p < 0.001). Patients in the laparoscopic group had lower mean CCI score (1.6 ± 2.3 vs. 3.4 ± 3.2, p ≤ 0.0001). On multivariable analysis, open surgery had the highest association with inpatient mortality (OR 8.67, 4.23-17.75, p < 0.0001) and at all time points (30-, 90-day, 1-, 3-year). At all time points, conversion to open was found to be a statistically significant protective factor. CONCLUSION: Use of laparoscopy in EGS is common and associated with a decreased risk of all-cause mortality at all time points compared to open procedures. Conversion to open was protective at all time points compared to open procedures.

Platelet Aggregation, Mitochondrial Function and Morphology in Cold Storage: Impact of Resveratrol and Cytochrome c Supplementation.

Donated platelets are critical components of hemostasis management. Extending platelet storage beyond the recommended guidelines (5 days, 22 °C) is of clinical significance. Platelet coagulation function can be prolonged with resveratrol (Res) or cytochrome c (Cyt c) at 4 °C. We hypothesized that storage under these conditions is associated with maintained aggregation function, decreased reactive oxygen species (ROS) production, increased mitochondrial respiratory function, and preserved morphology. Donated platelets were stored at 22 °C or 4 °C supplemented with 50 µM Res or 100 µM Cyt c and assayed on days 0 (baseline), 5, 7 and 10 for platelet aggregation, morphology, intracellular ROS, and mitochondrial function. Declining platelet function and increased intracellular ROS were maintained by Res and Cyt c. Platelet respiratory control ratio declined during storage using complex I + II (CI + CII) or CIV substrates. No temperature-dependent differences (4 °C versus 22 °C) in respiratory function were observed. Altered platelet morphology was observed after 7 days at 22 °C, effects that were blunted at 4 °C independent of exposure to Res or Cyt c. Storage of platelets at 4 °C with Res and Cyt c modulates ROS generation and platelet structural integrity.

Use of Thromboelastography in the Evaluation and Management of Patients With Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Traumatic brain injury is associated with coagulopathy that increases mortality risk. Viscoelastic hemostatic assays such as thromboelastography (Haemonetics SA, Signy, Switzerland) provide rapid coagulopathy assessment and may be particularly useful for goal-directed treatment of traumatic brain injury patients. We conducted a systematic review to assess thromboelastography in the evaluation and management of coagulopathy in traumatic brain injury patients. DATA SOURCES: MEDLINE, PubMed Central, Embase, and CENTRAL. STUDY SELECTION: Clinical studies of adult patients with traumatic brain injury (isolated or polytrauma) who were assessed by either standard thromboelastography or thromboelastography with platelet mapping plus either conventional coagulation assays or platelet function assays from January 1999 to June 2021. DATA EXTRACTION: Demographics, injury mechanism and severity, diagnostic, laboratory data, therapies, and outcome data were extracted for analysis and comparison. DATA SYNTHESIS: Database search revealed 1,169 sources; eight additional articles were identified by the authors. After review, 31 publications were used for qualitative analysis, and of these, 16 were used for quantitative analysis. Qualitative and quantitative analysis found unique patterns of thromboelastography and thromboelastography with platelet mapping parameters in traumatic brain injury patients. Patterns were distinct compared with healthy controls, nontraumatic brain injury trauma patients, and traumatic brain injury subpopulations including those with severe traumatic brain injury or penetrating traumatic brain injury. Abnormal thromboelastography K-time and adenosine diphosphate % inhibition on thromboelastography with platelet mapping are associated with decreased survival after traumatic brain injury. Subgroup meta-analysis of severe traumatic brain injury patients from two randomized controlled trials demonstrated improved survival when using a viscoelastic hemostatic assay-guided resuscitation strategy (odds ratio, 0.39; 95% CI, 0.17-0.91; p = 0.030). CONCLUSIONS: Thromboelastography and thromboelastography with platelet mapping characterize coagulopathy patterns in traumatic brain injury patients. Abnormal thromboelastography profiles are associated with poor outcomes. Conversely, treatment protocols designed to normalize abnormal parameters may be associated with improved traumatic brain injury patient outcomes. Current quality of evidence in this population is low; so future efforts should evaluate viscoelastic hemostatic assay-guided hemostatic resuscitation in larger numbers of traumatic brain injury patients with specific focus on those with traumatic brain injury-associated coagulopathy.

Platelet Dysfunction after Traumatic Brain Injury: A Review.

Coagulopathy is a known sequela of traumatic brain injury (TBI) and can lead to increased morbidity and mortality. Platelet dysfunction has been identified as one of several etiologies of coagulopathy following TBI and has been associated with poor outcomes. Regardless of whether the platelet dysfunction occurs as a direct consequence of the injury or because of pre-existing medical comorbidities or medication use, accurate detection and monitoring of response to therapy is key to optimal patient care. Platelet transfusion has been proposed as a potential therapeutic intervention to treat platelet dysfunction, with several studies using platelet function assays to monitor response. The development of increasingly precise diagnostic testing is providing enhanced understanding of the specific derangement in the hemostatic process, allowing clinicians to provide patient-specific treatment plans. There is wide variability in the currently available literature on the incidence and clinical significance of platelet dysfunction following TBI, which creates challenges with developing evidence-based management guidelines. The relatively high prevalence of platelet inhibitor therapy serves as an additional confounding factor. In addition, the data are largely retrospective in nature. We performed a literature review to provide clarity on this clinical issue. We reviewed 348 abstracts, and included 97 manuscripts in our final literature review. Based on the currently available research, platelet dysfunction has been consistently demonstrated in patients with moderate-severe TBI. We recommend the use of platelet functional assays to evaluate patients with TBI. Platelet transfusion directed at platelet dysfunction may lead to improved clinical outcome. A randomized trial guided by implementation science could improve the applicability of these practices.

The Effect of Outcome Selection on the Performance of Prediction Models in Patients at Risk for Sepsis.

IMPORTANCE: Risk prediction models for patients with suspected sepsis have been derived on and applied to various outcomes, including readily available outcomes such as hospital mortality and ICU admission as well as longer-term mortality outcomes that may be more important to patients. It is unknown how selecting different outcomes influences model performance in patients at risk for sepsis. OBJECTIVES: Evaluate the impact of outcome selection on risk model performance and weighting of individual predictor variables. DESIGN SETTING AND PARTICIPANTS: We retrospectively analyzed adults hospitalized with suspected infection from January 2014 to September 2017 at 12 hospitals. MAIN OUTCOMES AND MEASURES: We used routinely collected clinical data to derive logistic regression models for four outcomes: hospital mortality, composite ICU length of stay greater than 72 hours or hospital mortality, 30-day mortality, and 90-day mortality. We compared the performance of the models using area under the receiver operating characteristic curve and calibration plots. RESULTS: Among 52,184 admissions, 2,030 (4%) experienced hospital mortality, 6,659 (13%) experienced the composite of hospital mortality or ICU length of stay greater than 72 hours, 3,417 (7%) experienced 30-day mortality, and 5,655 (11%) experienced 90-day mortality. Area under the receiver operating characteristic curves decreased when hospital-based models were applied to predict 30-day (hospital mortality = 0.88-0.85; -0.03, composite ICU length of stay greater than 72 hours or hospital mortality = 0.90-0.81; -0.09) and 90-day mortality (hospital mortality = 0.88-0.81; -0.07, composite ICU length of stay greater than 72 hours or hospital mortality = 0.90-0.76; -0.14; all p < 0.01). Models were well calibrated for derived (root-mean-square error = 5-15) but not alternate outcomes (root-mean-square error = 8-35). CONCLUSIONS AND RELEVANCE: Risk models trained to predict readily available hospital-based outcomes in suspected sepsis show poorer discrimination and calibration when applied to 30- and 90-day mortality. Interpretation and application of risk models for patients at risk of sepsis should consider these findings.

Association between Adherence to Recommended Care and Outcomes for Adult Survivors of Sepsis.

Rationale: Postsepsis care recommendations target specific deficits experienced by sepsis survivors in elements such as optimization of medications, screening for functional impairments, monitoring for common and preventable causes of health deterioration, and consideration of palliative care. However, few data are available regarding the application of these elements in clinical practice.Objectives: To quantify the delivery of postsepsis care for patients discharged after hospital admission for sepsis and evaluate the association between receipt of postsepsis care elements and reduced mortality and hospital readmission within 90 days.Methods: We conducted a retrospective chart review of a random sample of patients who were discharged alive after an admission for sepsis (identified from International Classification of Diseases, 10th Revision discharge codes) at 10 hospitals during 2017. We used a structured chart abstraction to determine whether four elements of postsepsis care were provided within 90 days of hospital discharge, per expert recommendations. We used multivariable logistic regression to evaluate the association between receipt of care elements and 90-day hospital readmission and mortality, adjusted for age, comorbidity, length of stay, and discharge disposition.Results: Among 189 sepsis survivors, 117 (62%) had medications optimized, 123 (65%) had screening for functional or mental health impairments, 86 (46%) were monitored for common and preventable causes of health deterioration, and 110 (58%) had care alignment processes documented (i.e., assessed for palliative care or goals of care). Only 20 (11%) received all four care elements within 90 days. Within 90 days of discharge, 66 (35%) patients were readmitted and 33 (17%) died (total patients readmitted or died, n = 82). Receipt of two (odds ratio [OR], 0.26; 95% confidence interval [95% CI], 0.10-0.69) or more (three OR, 0.28; 95% CI, 0.11-0.72; four OR, 0.12; 95% CI, 0.03-0.50) care elements was associated with lower odds of 90-day readmission or 90-day mortality compared with zero or one element documented. Optimization of medications (no medication errors vs. one or more errors; OR, 0.44; 95% CI, 0.21-0.92), documented functional or mental health assessments (physical function plus swallowing/mental health assessments vs. no assessments; OR, 0.14; 95% CI, 0.05-0.40), and documented goals of care or palliative care screening (OR, 0.52; 95% CI, 0.25-1.05; not statistically significant) were associated with lower odds of 90-day readmission or 90-day mortality.Conclusions: In this retrospective cohort study of data from a single health system, we found variable delivery of recommended postsepsis care elements that were associated with reduced morbidity and mortality after hospitalization for sepsis. Implementation strategies to efficiently overcome barriers to adopting recommended postsepsis care may help improve outcomes for sepsis survivors.

Predictive Accuracy of Quick Sequential Organ Failure Assessment for Hospital Mortality Decreases With Increasing Comorbidity Burden Among Patients Admitted for Suspected Infection.

OBJECTIVES: Evaluate the accuracy of the quick Sequential Organ Failure Assessment tool to predict mortality across increasing levels of comorbidity burden. DESIGN: Retrospective observational cohort study. SETTING: Twelve acute care hospitals in the Southeastern United States. PATIENTS: A total of 52,187 patients with suspected infection presenting to the Emergency Department between January 2014 and September 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was hospital mortality. We used electronic health record data to calculate quick Sequential Organ Failure Assessment risk scores from vital signs and laboratory values documented during the first 24 hours. We calculated Charlson Comorbidity Index scores to quantify comorbidity burden. We constructed logistic regression models to evaluate differences in the performance of quick Sequential Organ Failure Assessment greater than or equal to 2 to predict hospital mortality in patients with no documented (Charlson Comorbidity Index = 0), low (Charlson Comorbidity Index = 1-2), moderate (Charlson Comorbidity Index = 3-4), or high (Charlson Comorbidity Index ≥ 5) comorbidity burden. Among the cohort, 2,030 patients died in the hospital (4%). No comorbidities were documented for 5,038 patients (10%), 9,235 patients (18%) had low comorbidity burden, 12,649 patients (24%) had moderate comorbidity burden, and 25,265 patients (48%) had high comorbidity burden. Overall model discrimination for quick Sequential Organ Failure Assessment greater than or equal to 2 was the area under the receiver operating characteristic curve of 0.71 (95% CI, 0.69-0.72). A model including both quick Sequential Organ Failure Assessment and Charlson Comorbidity Index had improved discrimination compared with Charlson Comorbidity Index alone (area under the receiver operating characteristic curve, 0.77; 95% CI, 0.76-0.78 vs area under the curve, 0.61; 95% CI, 0.59-0.62). Discrimination was highest among patients with no documented comorbidities (quick Sequential Organ Failure Assessment area under the receiver operating characteristic curve, 0.84; 95% CI; 0.79-0.89) and lowest among high comorbidity patients (quick Sequential Organ Failure Assessment area under the receiver operating characteristic curve, 0.67; 95% CI, 0.65-0.68). The strength of association between quick Sequential Organ Failure Assessment and mortality ranged from 30.5-fold increased likelihood in patients with no comorbidities to 4.7-fold increased likelihood in patients with high comorbidity. CONCLUSIONS: The accuracy of quick Sequential Organ Failure Assessment to predict hospital mortality diminishes with increasing comorbidity burden. Patients with comorbidities may have baseline abnormalities in quick Sequential Organ Failure Assessment variables that reduce predictive accuracy. Additional research is needed to better understand quick Sequential Organ Failure Assessment performance across different comorbid conditions with modification that incorporates the context of changes to baseline variables.

A Repeated Measures Pilot Comparison of Trajectories of Fluctuating Endogenous Hormones in Young Women with Traumatic Brain Injury, Healthy Controls.

OBJECTIVE: To compare baseline and 72-hour hormone levels in women with traumatic brain injury (TBI) and controls. SETTING: Hospital emergency department. PARTICIPANTS: 21 women ages 18-35 with TBI and 21 controls. DESIGN: Repeated measures. MAIN MEASURES: Serum samples at baseline and 72 hours; immunoassays for estradiol (E2), progesterone (PRO), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and cortisol (CORT); and health history. RESULTS: Women with TBI had lower E2 (p = 0.042) and higher CORT (p = 0.028) levels over time. Lower Glasgow Coma Scale (GSC) and OCs were associated with lower FSH (GCS p = 0.021; OCs p = 0.016) and higher CORT (GCS p = 0.001; OCs p = 0.008). CONCLUSION: Acute TBI may suppress E2 and increase CORT in young women. OCs appeared to independently affect CORT and FSH responses. Future work is needed with a larger sample to characterize TBI effects on women's endogenous hormone response to injury and OC use's effects on post-TBI stress response and gonadal function, as well as secondary injury.

Impact of Multiprofessional Rounds on Critical Care Outcomes in the Surgical Trauma Intensive Care Unit.

Multiprofessional rounds (MPR) represent a mechanism for the coordination of care in critically ill patients. Herein, we examined the impact of MPR on ventilator days (Vent-day), ICU length of stay (LOS), hospital LOS (HLOS), and mortality. A team developed guidelines for MPR, which began in February 2016. Patients admitted between November 2015 and March 2017 with Acute Physiology and Chronic Health Evaluation (APACHE) IV and injury severity scores were included. Outcome data consisted of Vent-day, Vent-day observed/expected ratio (O/E), ICU LOS, ICU LOS O/E, HLOS, HLOS-O/E, and mortality. Linear regression models are constructed to assess statistical significance. A total of 3372 patients were included. Among surgical patients (n = 343 pre-MPR, n = 1675 post-MPR), MPR was associated with decreases in Vent-day O/E (0.74 pre, 0.59 post, P = 0.03), ICU LOS O/E (0.67 pre, 0.61 post, P = 0.01), and HLOS-O/E (1.47 pre, 1.22 post, P = 0.0005). No mortality difference was observed. For trauma patients (n = 221 pre, n = 1133 post), MPR resulted in a reduction in Vent-days (2.2 days pre, 1.6 days post, P = 0.05). However, no differences were observed for Vent-day O/E, ICU LOS O/E, HLOS-O/E, and mortality. Implementation of MPR was associated with improved outcomes for surgical trauma ICU patients. Sustainability of MPR remains a challenge and requires education and engagement.

Enhanced platelet function in cold stored whole blood supplemented with resveratrol or cytochrome C.

BACKGROUND: Limited availability and use of whole blood (WB) following trauma is driven by perceptions that hemostatic function is limited by platelet dysfunction within 5 days storage. We sought to define the hemostatic function of WB stored at 4°C for up to 25 days, elucidate changes in metabolic parameters and mitochondrial dysfunction in platelets in WB, and the effect of supplementation using resveratrol (Res) or cytochrome c (Cyt c). METHODS: Whole blood was collected, aliquoted, and stored at 4°C without agitation. Resveratrol or Cyt c was supplemented before storage, or 10 days post-storage. Serial samples were collected and analyzed for hemostatic function by platelet mapping thromboelastography. Platelets isolated from WB were counted and mitochondrial function assessed by oxygen consumption, mitochondrial membrane potential, and biochemical parameters. RESULTS: Platelet function of WB was maintained up to 15 days at 4°C before a significant decrease was observed at 25 days. Resveratrol or Cyt c improved WB aggregation potential when supplemented 10 days post-storage. Platelet oxygen consumption was maintained until 10-day storage but significantly decreased thereafter in the absence of change in platelet count. Cytochrome c increased oxygen consumption on Day 15 and platelet mitochondrial membrane potential steadily decreased over time, an effect attenuated by Res or Cyt c supplementation 10 days post-storage. Potassium and lactate levels increased during storage, while pH levels decreased, with no observed effect following Res or Cyt c supplementation. CONCLUSION: Storing cold WB with Res or Cyt c supplementation enhances ex vivo aggregation by improving platelet function, thereby extending overall storage life. These findings have potential significance for improving WB availability in immediate trauma situations, including treatment in a battlefield trauma setting. LEVEL OF EVIDENCE: Translational study, diagnostic test or criteria, level II.

Effect of Systemic Triphenylphosphonium on Organ Function and Oxidative Stress.

Conditions of systemic stress can lead to increased reactive oxygen species production, mitochondrial dysfunction, systemic inflammation, and multiorgan dysfunction. Triphenylphosphonium (TPP+) is a lipophilic cation used to target therapeutics to mitochondria. We sought to determine the effects of TPP+ on mitochondrial integrity. Male rats were anesthetized and TPP+ (5 mg/kg) or vehicle (saline) was administered intravenously 30-minutes after anesthesia initiation and intraperitoneally (20 mg/kg) 60-minutes later. Rats were exsanguinated 2-hours postinjection. Cardiac, pulmonary, hepatic, splenic, and renal tissues were analyzed for inflammation, lipid peroxidation, endogenous antioxidant activity, cytokine expression, and mitochondrial function. In vitro modeling was performed using freshly isolated hepatocytes subjected to 8-hours hypoxia/30-minutes reoxygenation in the absence or presence of TPP+. TPP+ increased lipid peroxidation in the liver, lung, and kidney as well as antioxidant activity in the liver, kidney, and spleen. Conversely, antioxidant activity decreased in the lung with TPP+. In addition, TPP+ altered hepatic inflammatory mediators. In vitro, TPP+ attenuated oxygen consumption and, when combined with hypoxic injury, depolarized mitochondrial membranes in hepatocytes. TPP+ induces systemic responses associated with oxidative stress and worsening pathologies in animals. Caution should be exercised when employing TPP+ for therapeutics.

Cytochrome c and resveratrol preserve platelet function during cold storage.

BACKGROUND: Donated platelets are stored at 22°C and discarded within 5 days because of diminished function and risk of bacterial contamination. Decline of platelet function has been attributed to decreased mitochondrial function and increased oxidative stress. Resveratrol (Res) and cytochrome c (Cyt c), in combination with hypothermic storage, may extend platelet viability. METHODS: Platelets from 20 donors were pooled into four independent sets and stored at 22°C or 4°C in the absence or presence of Res (50 µM) or Cyt c (100 µM) for up to 10 days. Sequential measurement of platelet counts, coagulation function (thromboelastography), oxygen consumption, lipid peroxidation, glucose-lactate levels, pH, TCO2, and soluble platelet activation markers (CD62P/PF-4) was performed. RESULTS: Platelet function diminished rapidly over time at 22°C versus 4°C (adenosine diphosphate, day 10 [0.6 ± 0.5] vs. [7.8 ± 3.5], arachidonic acid: day 10 [0.5 ± 0.5] vs. [30.1 ± 27.72]). At 4°C, storage treatment with Res or Cyt c limited deterioration in platelet function up to day 10, an effect not observed at 22°C (day 10, 4°C, Con [7.8 ± 3.5] vs. Res [37.3 ± 24.19] vs. Cyt c [45.83 ± 43.06]). Mechanistic analysis revealed oxygen consumption increased in response to Cyt c at 22°C, whereas neither Cyt c or Res affected oxygen consumption at 4°C. Lipid peroxidation was only reduced at 22°C (day 7 and day 10), but remained unchanged at 4°C, or when Res or Cyt c was added. Cytosolic ROS was significantly reduced by pretreatment with Res at 4°C. Total platelet count and soluble activation markers were unchanged during storage and not affected by Res, Cyt c, or temperature. Glucose concentration, pH and TCO2 decreased while lactate levels increased during storage at 22°C but not 4°C. CONCLUSION: Platelet function is preserved by cold storage for up to 10 days. This function is enhanced by treatment with Res or Cyt c, which supports mitochondrial activity, thus potentially extending platelet shelf life.

Cytochrome c limits oxidative stress and decreases acidosis in a rat model of hemorrhagic shock and reperfusion injury.

BACKGROUND: Hemorrhagic shock and reperfusion (HSR) injury leads to a cascade of reactive oxygen species (ROS) production and mitochondrial dysfunction, which results in energy failure, cell death, and multiple organ dysfunction. Cytochrome c (cyt c) is the final electron carrier in the mitochondrial electron transport chain providing the electrochemical force for ATP production. We sought to determine whether exogenous cyt c administration would improve parameters of organ dysfunction and/or mitochondrial stability in a rat model of HSR. METHODS: Male rats were hemorrhaged to a mean arterial pressure (MAP) of 33 ± 2.0 mm Hg for 1 hour before resuscitation. Saline or cyt c (0.8 mg [HSR-LoCC] or 3.75 mg [HSR-HiCC]) was administered (i.v.) 30 minutes before resuscitation. Rats were euthanized by cardiac puncture 2 hours post-surgery and tissue collected and analyzed for lipid peroxidation, endogenous antioxidant activity (glutathione peroxidase (GPx) and catalase), TNF-α expression, mitochondrial function (complex-I activity), and circulating mitochondrial DNA (mtDNA). RESULTS: Cyt c administration improved lactate clearance, decreased hepatic lipid peroxidation, increased hepatic GPx activity, restored pulmonary TNF-α to sham activity levels, and increased hepatic complex-I activity. Furthermore, addition of exogenous cyt c decreased circulating levels of mtDNA. CONCLUSIONS: These studies demonstrate that cyt c reduces markers of physiologic stress, decreases oxidative stress, and lowers levels of circulating mtDNA. The impact of cytochrome c is organ specific. Further studies remain to determine the sum of the effects of cytochrome c on overall outcome.

Does history of substance use disorder predict acute traumatic brain injury rehabilitation outcomes?

BACKGROUND/OBJECTIVE: The study explored whether premorbid substance use disorder (SUD) predicts acute traumatic brain injury (TBI) outcomes. METHODS: 143 participants with moderate (34.2%) and severe (65.8%) TBI were enrolled at two Level 1 trauma center inpatient brain injury rehabilitation units. Acute outcomes were measured with the Disability Rating Scale (DRS), the FIMTM; self and informant ratings of the Patient Competency Rating Scale (PCRS); self and family rating of the Frontal Systems Behavioral Scale (FrSBe), and the Neurobehavioral Rating Scale-Revised (NRS-R). RESULTS: Hierarchical linear modeling revealed that SUD history significantly predicted trajectories of PCRS clinician ratings, PCRS self-family and PCRS self-clinician discrepancy scores, and more negative FrSBE family ratings. These findings indicate comparatively greater post-injury executive functions (EF) impairments, particularly self-awareness (SA) of injury-related deficits, for those with SUD history. No significant SUD*time interaction effect was found for FIM or NRS-R scores. CONCLUSIONS: SUD history and TBI are associated with impaired SA and EF but their co-occurrence is not a consistent predictor of acute post-injury functional outcomes. Pre-morbid patient characteristics and rater expectations and biases may moderate associations between SA and recovery after TBI.

MitoQ modulates oxidative stress and decreases inflammation following hemorrhage.

BACKGROUND: Oxidative stress associated with hemorrhagic shock and reperfusion (HSR) results in the production of superoxide radicals and other reactive oxygen species, leading to cell damage and multiple-organ dysfunction. We sought to determine if MitoQ, a mitochondria-targeted antioxidant, reduces morbidity in a rat model of HSR by limiting oxidative stress. METHODS: HSR was achieved in male rats by arterial blood withdrawal to a mean arterial pressure of 25 ± 2 mm Hg for 1 hour before resuscitation. MitoQ (5 mg/kg), TPP (triphenylphosphonium, 5 mg/kg) or saline (0.9% vol./vol.) was administered intravenously 30 minutes before resuscitation, followed by an intraperitoneal administration (MitoQ, 20 mg/kg) immediately after resuscitation (n = 5 per group). Morbidity was assessed based on cumulative markers of animal distress (0-10 scale). Rats were sacrificed 2 hours after procedure completion, and liver tissue was collected and processed for histology or assayed for lipid peroxidation (thiobarbituric acid reactive substance [TBARS]) or endogenous antioxidant (catalase, glutathione peroxidase [GPx], and superoxide dismutase) activity. RESULTS: HSR significantly increased morbidity as well as TBARS and catalase activities versus sham. Conversely, no difference in GPx or superoxide dismutase activity was measured between sham, HSR, and TPP, MitoQ administration reduced morbidity versus HSR (5.8 ± 0.3 vs. 7.6 ± 0.3; p < 0.05), while TPP administration significantly reduced hepatic necrosis versus both HSR and HSR-MitoQ (1.2 ± 0.1 vs. 2.0 ± 0.2 vs. 1.9 ± 0.2; p < 0.05, n = 5). Analysis of oxidative stress demonstrated increased TBARS and GPx in HSR-MitoQ versus sham (12.0 ± 1.1 µM vs. 6.2 ± 0.5 µM and 37.9 ± 3.0 µmol/min/mL vs. 22.9 ± 2.7 µmol/min/mL, TBARS and GPx, respectively, n = 5; p < 0.05). Conversely, catalase activity in HSR-MitoQ was reduced versus HSR (1.96 ± 1.17 mol/min/mL vs. 2.58 ± 1.81 mol/min/mL; n = 5; p < 0.05). Finally, MitoQ treatment decreased tumor necrosis factor α (0.66 ± 0.07 pg/mL vs. 0.92 ± 0.08 pg/mL) and interleukin 6 (7.3 ± 0.8 pg/mL vs. 11 ± 0.9 pg/mL) versus HSR as did TPP alone (0.58 ± 0.05 pg/mL vs. 0.92 ± 0.08 pg/mL; 6.7 ± 0.6 pg/mL vs. 11 ± 0.9 pg/mL; n = 5; p < 0.05). CONCLUSION: Our data demonstrate that MitoQ treatment following hemorrhage significantly limits morbidity and decreases hepatic tumor necrosis factor α and interleukin 6. In addition, MitoQ differentially modulates oxidative stress and hepatic antioxidant activity.

Resveratrol attenuates hypoxic injury in a primary hepatocyte model of hemorrhagic shock and resuscitation.

BACKGROUND: Oxidative stress following hemorrhagic shock and resuscitation (HSR) is regulated, in part, by inflammatory and apoptotic mediators such as necrosis factor κB (NF-κB) and p53. Sirtuin 1 (Sirt-1) is a metabolic intermediary that regulates stress responses by suppressing NF-κB and p53 activity. Resveratrol is a naturally occurring polyphenolic antioxidant and Sirt-1 agonist. The aim of this study was to determine whether resveratrol protects hepatocytes following HSR or hypoxia. METHODS: In vivo, HSR was achieved in male rats by arterial blood withdrawal to 30 ± 2 mm Hg for 1 hour before resuscitation with or without resveratrol (Res, 30 mg/kg). Hepatic tissue was stained and scored for necrosis, interleukin 6, and Sirt-1 expression. In vitro, primary rat hepatocytes were subjected to 8 hours of hypoxia without or with Res (100 µM). Cells were analyzed immediately or after 6 hours of normoxia, for survival and markers of injury (lactate dehydrogenase assay, lipid peroxidation, and mitochondrial integrity). Cell lysates were collected for cytochrome c analysis and immunoprecipitated using antibodies against NF-κB (p65) or p53. RESULTS: In vivo, animals subject to HSR exhibited increased expression of markers of hepatocyte damage compared with those sham operated, concomitant with lower Sirt-1 expression. In vitro, hypoxia followed by normoxia resulted in increased cell death, an effect that was blunted by Res. Analysis of cell and mitochondrial function demonstrated that Res inhibited the detrimental effects of hypoxia in isolated hepatocytes. CONCLUSION: Resveratrol prevents cell death in HSR and exerts a protective effect on the mitochondria in a hepatocyte model of hypoxic injury-reoxygenation possibly via Sirt-1 modulation of p53 and NF-κB activity.

Pyrrolidine dithiocarbamate improves mortality in a rat model of severe hemorrhage.

BACKGROUND: Hemorrhagic shock is a life threatening condition characterized by diminishing organ function. The aim of this study was to determine whether an effective pyrrolidine dithiocarbamate (PDTC) treatment protocol could be established to decrease organ dysfunction and mortality in a lethal hemorrhagic shock-resuscitation (HSR) model. MATERIALS AND METHODS: Sprague-Dawley rats were randomized into three experimental groups; HSR alone (HSR), PDTC (100 mg/kg) administered 12 h pre-HSR (PDTC-12), and PDTC administered 1 h post-shock prior to resuscitation (PDTC+1). Hemorrhage was induced by arterial blood withdrawal to a mean arterial pressure (MAP) of 25 ± 5 mmHg for 1 h. Resuscitation was performed until pre-HSR MAP was attained. Blood was collected immediately prior to HSR, 1 h post-shock, and at protocol end. Measurements of base excess, lactate, arterial partial pressure of carbon dioxide (PaCO(2)) and oxygen (PaO(2)), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, blood urea nitrogen (BUN), and lipase were performed. RESULTS: In PDTC+1 animals, PDTC was ineffective in improving survival. In contrast, survival was significantly increased in the PDTC-12 animals versus PDTC+1 and HSR groups. Analysis of physiologic parameters demonstrated that elevations in base deficit and lactate levels following hemorrhage were blunted by PDTC administration in the PDTC-12 group. At time of death, creatinine, ALT, and AST levels were significantly higher in HSR versus PDTC-12 animals. CONCLUSIONS: Administration of PDTC 12 h prior to HSR significantly improves survival through preservation of organ function.