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.

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.

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.

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.

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.

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.

Impact of a delirium screening tool and multifaceted education on nurses' knowledge of delirium and ability to evaluate it correctly.

BACKGROUND: The impact of using a validated delirium screening tool and different levels of education on surgical-trauma intensive care unit (STICU) nurses' knowledge about delirium is unclear. OBJECTIVES: To measure the impact of using the Intensive Care Delirium Screening Checklist (ICDSC), with or without a multi-faceted education program, on STICU nurses' knowledge and perceptions of delirium and their ability to evaluate it correctly. METHODS: The knowledge and perceptions of subject nurses about delirium, and agreement between the independent assessments of delirium by the subject nurse and by a validated judge (who always used the ICDSC), were compared across 3 phases. Phase 1: No delirium screening tool and no education. Phase 2: ICDSC and minimal education (ie, ICDSC validation study only). Phase 3: ICDSC and multifaceted education (ie, pharmacist-led didactic lecture, Web-based module, and nurse-led bedside training). RESULTS: Nurses' knowledge (mean [SD] score out of 10 points) was similar (P = .08) in phase 1 (6.1 [1.4]) and phase 2 (6.5 [1.4]) but was greater (P = .001) in phase 3 (8.2 [1.4]). Agreement between nurses and the validated judge in the assessment of delirium increased from phase 1 (κ = 0.40) to phase 2 (κ = 0.62) to phase 3 (κ = 0.74). Nurses perceived use of the ICDSC as improving their ability to recognize delirium. CONCLUSIONS: Use of a multifaceted education program improves both nurses' knowledge about delirium and their perceptions about its recognition. Implementation of the ICDSC improves the ability of STICU nurses to evaluate delirium correctly.

Activated protein C alters inflammation and protects renal function in sepsis.

BACKGROUND: Activated protein C (aPC) confers survival benefit in patients with sepsis, yet its protective mechanism(s) remain unclear. Herein, we determined time-dependent severity of renal dysfunction during polymicrobial sepsis. We hypothesized aPC restores renal function by preserving organ architecture and reducing inflammation. MATERIALS AND METHODS: Sprague-Dawley rats underwent sham operation or cecal ligation and puncture (CLP). At 6 or 24 h post-surgery, kidney function was assessed by plasma electrolytes, blood urea nitrogen (BUN), and creatinine levels. Renal architecture was examined histologically. In the next series of experiments, 24-h post-surgery, animals were treated with vehicle or aPC (1 mg/kg) for 4 d, and kidney function and circulating cytokine levels were measured. Plasma was collected and assayed for BUN, creatinine, and lactate dehydrogenase (LDH) levels. Serum cytokine levels were measured by ELISA. RESULTS: Plasma electrolytes, BUN, creatinine, and renal architecture were altered 6 h after CLP. Treatment with aPC significantly inhibited sepsis-induced elevations in BUN, creatinine, LDH levels, and improved renal architecture. After CLP, interferon gamma (INFγ) decreased, while interleukins-1beta and -10 (IL-1ß and IL-10) increased; these effects were attenuated by aPC treatment. CONCLUSIONS: Our data demonstrate that renal dysfunction occurs as early as 6 h following sepsis and continues thereafter. Treatment with aPC attenuated INFγ and IL-1ß changes, and preserved renal function in sepsis. These data suggest aPC may confer a survival advantage by reducing systemic inflammation and, in doing so, preserving organ function.