Central Venous Waveform Analysis and Cardiac Output in a Porcine Model of Endotoxemic Hypotension and Resuscitation.

BACKGROUND: Cardiac output (CO) is a valuable proxy for perfusion, and governs volume responsiveness during resuscitation from distributive shock. The underappreciated venous system has nuanced physiology that confers valuable hemodynamic information. In this investigation, deconvolution of the central venous waveform by the fast Fourier transformation (FFT) algorithm is performed to assess its ability to constitute a CO surrogate in a porcine model of endotoxemia-induced distributive hypotension and resuscitation. STUDY DESIGN: Ten pigs were anesthetized, catheterized, and intubated. A lipopolysaccharides infusion protocol was used to precipitate low systemic vascular resistance hypotension. Four crystalloid boluses (10 cc/kg) were then given in succession, after which heart rate, mean arterial pressure, thermodilution-derived CO, central venous pressure (CVP), and the central venous waveform were collected, the last undergoing fast Fourier transformation analysis. The amplitude of the fundamental frequency of the central venous waveform's cardiac wave (f0-CVP) was obtained. Heart rate, mean arterial pressure, CVP, f0-CVP, and CO were plotted over the course of the boluses to determine whether f0-CVP tracked with CO better than the vital signs, or than CVP itself. RESULTS: Distributive hypotension to a 25% mean arterial pressure decrement was achieved, with decreased systemic vascular resistance (mean 918 ± 227 [SD] dyne/s/cm-5 vs 685 ± 180 dyne/s/cm-5; p = 0.038). Full hemodynamic parameters characterizing this model were reported. Slopes of linear regression lines of heart rate, mean arterial pressure, CVP, f0-CVP, and CO were -2.8, 1.7, 1.8, 0.40, and 0.35, respectively, demonstrating that f0-CVP values closely track with CO over the 4-bolus range. CONCLUSIONS: Fast Fourier transformation analysis of the central venous waveform may allow real-time assessment of CO during resuscitation from distributive hypotension, possibly offering a venous-based approach to clinical estimation of volume responsiveness.

Perioperative Coagulation Changes in Total Pancreatectomy and Islet Autotransplantation.

OBJECTIVES: Thrombotic complications after total pancreatectomy with islet autotransplantation (TPIAT) are common. However, the systemic changes to coagulation in the perioperative period have not been well studied. Our objective was to evaluate the derangements in coagulation in the perioperative period for this procedure. METHODS: This was a prospective observational study of patients undergoing elective TPIAT for chronic pancreatitis. Multiple methods of evaluating coagulation, including 2 viscoelastic assays and standard laboratory assays were obtained at defined intraoperative and postoperative intervals. RESULTS: Fifteen patients were enrolled. Laboratory values demonstrated initial intraoperative hypercoagulability before significant systemic anticoagulation after islet infusion with heparin. Hypercoagulability is again seen at postoperative days 3 and 7. Subgroup analysis did not identify any major coagulation parameters associated with portal vein thrombosis formation. CONCLUSIONS: Apart from the immediate period after islet cell and heparin infusion, patients undergoing TPIAT are generally hypercoagulable leading to a high rate of thrombotic complications. Portal vein thrombosis development had minimal association with systemic derangements in coagulation as it is likely driven by localized inflammation at the time of islet cell infusion. This study may provide the groundwork for future studies to identify improvements in thrombotic complications.

Circulating miRNA in Patients Undergoing Total Pancreatectomy and Islet Autotransplantation.

Circulating microRNAs (miRNAs) can be biomarkers for diagnosis and progression of several pathophysiological conditions. In a cohort undergoing total pancreatectomy with islet autotransplantation (TPIAT) from the multicenter Prospective Observational Study of TPIAT (POST), we investigated associations between a panel of circulating miRNAs (hsa-miR-375, hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-216a-5p, hsa-miR-320d, hsa-miR-200c, hsa-miR-125b, hsa-miR-7-5p, hsa-miR-221-3p, hsa-miR-122-5p) and patient, disease and islet-isolation characteristics. Plasma samples (n = 139) were collected before TPIAT and miRNA levels were measured by RTPCR. Disease duration, prior surgery, and pre-surgical diabetes were not associated with circulating miRNAs. Levels of hsa-miR-29b-3p (P = 0.03), hsa-miR-148a-3p (P = 0.04) and hsa-miR-221-3p (P = 0.01) were lower in those with genetic risk factors. Levels of hsa-miR-148a-3p (P = 0.04) and hsa-miR-7-5p (P = 0.04) were elevated in toxic/metabolic disease. Participants with exocrine insufficiency had lower hsa-miR-29b-3p, hsa-miR-148a-3p, hsa-miR-320d, hsa-miR-221-3p (P < 0.01) and hsa-miR-375, hsa-miR-200c-3p, and hsa-miR-125b-5p (P < 0.05). Four miRNAs were associated with fasting C-peptide before TPIAT (hsa-miR-29b-3p, r = 0.18; hsa-miR-148a-3p, r = 0.21; hsa-miR-320d, r = 0.19; and hsa-miR-221-3p, r = 0.21; all P < 0.05), while hsa-miR-29b-3p was inversely associated with post-isolation islet equivalents/kg and islet number/kg (r = -0.20, P = 0.02). Also, hsa-miR-200c (r = 0.18, P = 0.03) and hsa-miR-221-3p (r = 0.19, P = 0.03) were associated with islet graft tissue volume. Further investigation is needed to determine the predictive potential of these miRNAs for assessing islet autotransplant outcomes.

MG53 as a Novel Therapeutic Protein to Treat Acute Lung Injury.

INTRODUCTION: Lung injury has several inciting etiologies ranging from trauma (contusion and hemorrhage) to ischemia reperfusion injury. Reflective of the injury, tissue and cellular injury increases proportionally with the injury stress and is an area of potential intervention to mitigate the injury. This study aims to evaluate the therapeutic benefits of recombinant human MG53 (rhMG53) protein in porcine models of acute lung injury (ALI). MATERIALS AND METHODS: We utilized live cell imaging to monitor the movement of MG53 in cultured human bronchial epithelial cells following mechanical injury. The in vivo efficacy of rhMG53 was evaluated in a porcine model of hemorrhagic shock/contusive lung injury. Varying doses of rhMG53 (0, 0.2, or 1 mg/kg) were administered intravenously to pigs after induction of hemorrhagic shock/contusive induced ALI. Ex vivo lung perfusion system enabled assessment of the isolated porcine lung after a warm ischemic induced injury with rhMG53 supplementation in the perfusate (1 mg/mL). RESULTS: MG53-mediated cell membrane repair is preserved in human bronchial epithelial cells. rhMG53 mitigates lung injury in the porcine model of combined hemorrhagic shock/contusive lung injury. Ex vivo lung perfusion administration of rhMG53 reduces warm ischemia-induced injury to the isolated porcine lung. CONCLUSIONS: MG53 is an endogenous protein that circulates in the bloodstream. Therapeutic treatment with exogenous rhMG53 may be part of a strategy to restore (partially or completely) structural morphology and/or functional lung integrity. Systemic administration of rhMG53 constitutes a potential effective therapeutic means to combat ALI.

Correction: Chronic Alcohol Ingestion Increases Mortality and Organ Injury in a Murine Model of Septic Peritonitis.

[This corrects the article DOI: 10.1371/journal.pone.0062792.].

Omental Pouch Technique for Combined Site Islet Autotransplantation Following Total Pancreatectomy.

Total pancreatectomy and islet autotransplantation (TPIAT) is an effective treatment for selected patients with chronic pancreatitis. The portal circulation is the standard infusion site for islet transplant, but marked elevation of portal pressures may prevent complete islet infusion. Herein we report a novel technique of combined site islet autotransplantation using an omental pouch. This technique may be useful when technical limitations prevent complete intraportal transplantation. In four TPIAT recipients with intraoperative issues precluding the complete intraportal infusion of islets, an omental pouch was created to contain the remaining islet mass. Patients were monitored for complications, and islet graft function was assessed using mixed meal tolerance testing and compared with matched controls who received only intraportally transplanted islets. All patients had decreasing insulin requirements as their recovery progressed. At 3 months follow-up there were no significant differences in glycemic control or graft function for the combined site recipients compared with their matched controls who only received an intraportal islet infusion. The omentum has potentially desirable qualities such as accessibility, capacity, and systemic/portal vascularity comparable to the native pancreas. The omental pouch technique may represent a safe and effective alternate site for islet autotransplantation. Further study is needed to confirm these findings.

Tissue oxygen saturation in dogs with acute hemorrhage.

OBJECTIVE: To evaluate initial tissue hemoglobin oxygen saturation (StO2 ) in dogs presenting to an emergency room (ER) for acute hemorrhage. DESIGN: Prospective, observational study. SETTING: University veterinary teaching hospital. ANIMALS: Thirty-eight dogs with acute hemorrhage were enrolled between July 2009 and October 2010. Seventy-eight normal dogs from a previous observational study were included to represent healthy controls ("no shock"). INTERVENTIONS: Tissue oxygen saturation measurement was obtained at enrollment on dogs presented to the ER for acute hemorrhage. Baseline clinicopathologic (CBC, serum biochemical profile, prothrombin time, and activated partial thromboplastin time) and physiologic (plasma lactate concentration, venous blood gas, blood pressure, and hemoglobin oxygen saturation by pulse oximetry) data were recorded from all patients with hemorrhage. An ER clinician blinded to the StO2 value guided patient management. Patient survival to discharge from the hospital in the study group was recorded. Once data collection was complete, 3 emergency and critical care clinicians blinded to the StO2 data retrospectively classified patients into 1 of 4 shock categories (no shock, mild, moderate, or severe shock). MEASUREMENTS AND MAIN RESULTS: The historical group of healthy dogs had higher StO2 concentrations compared to the dogs classified with shock at all 3 levels (mild, moderate, and severe, P = 0.0006, <0.0001, and 0.0018, respectively); however, there was no statistical difference in StO2 between the levels of shock. A cut-off StO2 value of 87.6% identified a patient as having shock (area under the curve: 0.824, 95% confidence interval 0.749, 0.899). CONCLUSIONS: Dogs with hemorrhagic shock have lower StO2 than a population of healthy dogs.

Surgical treatment of pain in chronic pancreatitis.

PURPOSE OF REVIEW: Patients suffering from chronic pancreatitis often require surgical intervention to treat their disease. This review discusses surgical options as well as reviews current trends and research in the operative management of chronic pancreatitis. RECENT FINDINGS: Relevant current topics in the field include the appropriate timing of surgery as well as the relative benefits of various procedures, particularly duodenum-preserving pancreatic head resection versus pancreaticoduodenectomy. Multiple studies have found that surgery earlier in the disease course results in improved outcomes. Furthermore, the recent literature reports similar outcomes of duodenum-preserving pancreatic head resection when compared with pancreaticoduodenectomy. SUMMARY: It is important for treating clinicians to be well versed on the interplay of medical, endoscopic, and surgical strategies to carefully tailor a patient's treatment plan. Each patient warrants careful consideration and an individualized approach in collaboration with multidisciplinary colleagues.

Inducing Different Brain Injury Levels Using Shock Wave Lithotripsy.

OBJECTIVES: To assess the feasibility of inducing different severities of shock wave (SW)-induced traumatic brain injury (TBI) using lithotripsy. METHODS: Wistar rats (n = 36) were divided into 2 groups: group 1 (n = 20) received 5 SW pulses, and group 2 (n = 16) received 15 SWs pulses. The SW pulses were delivered to the right side of the frontal cortex. Neurologic and behavioral assessments (Garcia test, beam walking, rotarod, and elevated plus maze) were performed at the baseline and at 3, 6, 24, 72, and 168 hours after injury. At day 7 after injury (168 hours), we performed cerebral angiography to assess the presence of cerebral vasospasm and vascular damage due to SW-induced TBI. At the conclusion of the study, the animals were euthanized to assess damage to brain tissue using an overall histologic severity score. RESULTS: The Garcia score was significantly higher, and the anxiety index (based on the elevated plus maze) was significantly lower in group 1 compared to group 2 (P < .05). The anxiety index for group 1 returned to the baseline level in a fast nonlinear fashion, whereas the anxiety index for group 2 followed a distinct slow linear reduction. Cerebral angiograms revealed a more severe vasospasm for the animals in group 2 compared to group 1 (P = .027). We observed a statistically significant difference in the overall histologic severity scores between the groups. The median (interquartile range) overall histologic severity scores for groups 1 and 2 were 3.0 (2.75) and 6.5 (6.0), respectively (P = .023). CONCLUSIONS: We have successfully established different SW-induced TBI severities in our SW-induced TBI model by delivering different numbers of SW pulses to brain tissue.

Characteristics of Combat-Associated Small Bowel Injuries.

INTRODUCTION: Although there are multiple studies regarding the management and outcomes of colonic injuries incurred in combat, the literature is limited with regard to small bowel injuries. This study seeks to provide the largest reported review of the characteristics of combat-associated small bowel injuries. MATERIALS AND METHODS: The Department of Defense Trauma Registry was queried for U.S. Armed Forces members who sustained hollow viscus injuries in the years 2007-2012 during Operations Enduring Freedom, Iraqi Freedom, and New Dawn. Concomitant injuries, procedures, and complications were delineated. Fisher's exact test was used to analyze the relationship of bowel injury pattern to rates of repeat laparotomy, fecal diversion, and complications. RESULTS: One hundred seventy-one service members had small bowel injuries. The mean age was 25.8 ± 6.6 yr with a mean injury severity score of 27.9 ± 12.4. The majority of injuries were penetrating (94.2%, n = 161) as a result of explosive devices (61.4%, n = 105). The median blood transfusion requirement in the first 24 h was 6.0 units (interquartile range 1.0-17.3 units). The most frequent concomitant injuries were large bowel (64.3%, n = 110), pelvic fracture (35.7%, n = 61), and perineal (26.3%, n = 45). Fifty patients (29.2%) had a colostomy, and nine patients (5.3%) had an ileostomy; 62.6% (n = 107) of soldiers underwent more than one laparotomy. The mortality rate was 1.8% (n = 3). The most common complications were pneumonia (15.2%, n = 26), deep vein thrombosis (14.6%, n = 25), and wound infection (14.6%, n = 25). The need for repeat laparotomy and fecal diversion was found to be significantly associated with injury pattern (p = 0.00052 and p < 0.0001, respectively). CONCLUSION: We found that two-thirds of service members with small bowel injuries also had a large bowel injury. One-third of the patients required diversion and two-thirds had more than one laparotomy. The pattern of bowel injury significantly affected the need for repeat laparotomy and fecal diversion.

Assessment of prehospital hemorrhage and airway care using a simulation model.

BACKGROUND: The quality of prehospital care impacts patient outcomes. Military efforts have focused on training revision and the creation of high-fidelity simulation models to address potentially survivable injuries. We sought to investigate the applicability of models emphasizing hemorrhage control and airway management to a civilian population. METHODS: Prehospital health care providers (PHPs) undergoing their annual training were enrolled. A trauma scenario was simulated with two modules: hemorrhage control and airway management. Experienced raters used a validated tool to assess performance. Pearson correlation, logistic regression, and χ tests were used for analysis. RESULTS: Ninety-five PHPs participated with a mean experience of 15.9 ± 8.3 years, and 7.4% reported past military training. The PHPs' overall execution rate of the six hemorrhage control measures varied from 38.9% to 88.4%. The median blood loss was 1,700 mL (interquartile range, 1,043-2,000), and the mean global rater score was 25.0 ± 7.4 (scale, 5-40). There was a significant relationship between PHP profession and past military experience to their consideration of blood transfusion and tranexamic acid. An inverse relationship between blood loss and global rater score was found (r = -0.59, n = 88, p = 1.93 × 10). After simulated direct laryngoscope failure in the airway module, 58% of PHPs selected video laryngoscopy over placement of a supraglottic airway. Eighty-six percent of participants achieved bilateral chest rise in the manikin regardless of management method. Participants reported improved comfort with skills after simulation. CONCLUSION: Our data reveal marginal performance in hemorrhage control regardless of the PHP's prior experience. The majority of PHPs were able to secure an advanced airway if direct laryngoscope was unavailable with a predisposition for video laryngoscopy over supraglottic airway. Our findings support the need for continued training for PHPs highlighting hemorrhage control maneuvers and increased familiarity with airway management options. Improved participant confidence posttraining gives credence to simulation training. LEVEL OF EVIDENCE: Prognostic/epidemiological study, level III.

Vasopressors in Sepsis.

BACKGROUND: Sepsis accounts for 10% of intensive care unit admissions and significant healthcare costs. Although the mortality rate from sepsis has been decreasing with better critical care, early identification of septic patients, and prompt interventions, the mortality rate remains 20%-30%. METHOD: Review of the English-language literature. RESULTS: Norepinephrine is the first-line vasopressor in shock and is associated with a lower mortality rate as well as fewer adverse effects. Dopamine has similar actions but is associated with significantly more tachydysrhythmias and should be reserved for patients with bradycardia. Epinephrine and vasopressin are appropriate second-line vasopressors and may enable use of lower doses of norepinephrine while improving hemodynamics. Inotropes may be added in patients with cardiac dysfunction. CONCLUSION: Appropriate treatment of sepsis includes prompt identification, early antimicrobial drug therapy, appropriate fluid resuscitation, and initiation of vasopressors in the presence of continued septic shock. Further research needs to be done to better understand the ideal timing of the addition of a second agent and the optimal combinations of vasopressors for individual patients.

Total Pancreatectomy With Intraportal Islet Autotransplantation as a Treatment of Chronic Pancreatitis in Patients With CFTR Mutations.

OBJECTIVES: Chronic pancreatitis (CP) is an infrequent but debilitating complication associated with CFTR mutations. Total pancreatectomy with islet autotransplantation (TPIAT) is a treatment option for CP that provides pain relief and preserves ß-cell mass, thereby minimizing the complication of diabetes mellitus. We compared outcomes after TPIAT for CP associated with CFTR mutations to CP without CTFR mutations. METHODS: All TPIATs performed between 2002 and 2014 were retrospectively reviewed: identifying 20 CFTR homozygotes (cystic fibrosis [CF] patients), 19 CFTR heterozygotes, and 20 age-/sex-matched controls without CFTR mutations. Analysis of variance and χ tests were used to compare groups. RESULTS: Baseline demographics were not different between groups. Postoperative glycosylated hemoglobin and C-peptide levels were similar between groups, as were islet yield and rate of postoperative complications. At 1 year, 40% of CF patients, 22% of CFTR heterozygotes, and 35% of control patients were insulin independent. CONCLUSION: Total pancreatectomy with islet autotransplantation is a safe, effective treatment option for CF patients with CP, giving similar outcomes for those with other CP etiologies.

Metabolomics in COPD Acute Respiratory Failure Requiring Noninvasive Positive Pressure Ventilation.

We aimed to investigate whether metabolomic analysis can discriminate acute respiratory failure due to COPD exacerbation from respiratory failure due to heart failure and pneumonia. Since COPD exacerbation is often overdiagnosed, we focused on those COPD exacerbations that were severe enough to require noninvasive mechanical ventilation. We enrolled stable COPD subjects and patients with acute respiratory failure requiring noninvasive mechanical ventilation due to COPD, heart failure, and pneumonia. We excluded subjects with history of both COPD and heart failure and patients with obstructive sleep apnea and obstructive lung disease other than COPD. We performed metabolomics analysis using NMR. We constructed partial least squares discriminant analysis (PLS-DA) models to distinguish metabolic profiles. Serum (p=0.001, R2 = 0.397, Q2 = 0.058) and urine metabolic profiles (p < 0.001, R2 = 0.419, Q2 = 0.142) were significantly different between the four diagnosis groups by PLS-DA. After excluding stable COPD patients, the metabolomes of the various respiratory failure groups did not cluster separately in serum (p=0.2, R2 = 0.631, Q2 = 0.246) or urine (p=0.065, R2 = 0.602, Q2 = -0.134). However, several metabolites in the serum were reduced in patients with COPD exacerbation and pneumonia. We did not find a metabolic profile unique to COPD exacerbation, but we were able to clearly and reliably distinguish stable COPD patients from patients with respiratory failure in both serum and urine.

Assessment of key plasma metabolites in combat casualties.

BACKGROUND: Previous studies have indicated that hemorrhagic shock and injury cause significant early changes in metabolism. Recently, global changes in metabolism have been described using metabolomics in animal models and civilian trauma. We evaluated metabolic changes associated with combat injury to identify early biomarkers and aid in triage. METHODS: Plasma obtained at emergency department presentation and intervals thereafter from patients injured during combat operations in Iraq (n = 78) were compared with healthy control subjects (n = 40). Using proton Nuclear Magnetic Resonance (NMR), water-soluble metabolites were detected and quantified. Resulting metabolic profiles were analyzed with partial least squares discriminant analysis, Receiver Operating Characteristic (ROC), and cluster analyses to identify features of combat injury and mortality. RESULTS: Significant alterations to metabolism resulted from traumatic injury. Metabolic profiles of injured patients differed from those of healthy controls, driven by increased 5-aminolevulinate and hypoxanthine that persisted through 24 hours. Among combat-injured patients, increased succinate and malonate best discriminated between those who survived from those who did not. Higher levels of succinate and hypoxanthine were associated with increased injury severity. ROC analysis showed that these metabolites had equivalent or superior performance to lactate in distinguishing the presence of trauma, injury severity, and mortality. CONCLUSION: Combat injury is associated with several changes at the metabolic level compared with healthy individuals. Novel potential biomarkers of mortality (succinate, malonate), injury severity (succinate, hypoxanthine), and the presence of trauma (hypoxanthine, 5-aminolevulinate) perform as well as or better than the common clinical standard, lactate. LEVEL OF EVIDENCE: Prognostic study, level III.

CXCR5(+) follicular cytotoxic T cells control viral infection in B cell follicles.

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.

A Case of Pseudocholinesterase Deficiency Resulting From Malnutrition.

Pseudocholinesterase deficiencies occur because of both genetic and acquired factors. We present the case of a patient with a history of bariatric surgery and severe malnutrition who subsequently developed prolonged neuromuscular blockade after succinylcholine administration. She had markedly decreased pseudocholinesterase levels at the time of the incident, but her motor function returned to normal with supportive care. After aggressive nutritional support over multiple weeks, her pseudocholinesterase levels drastically improved. For those patients in a poor nutritional state who experience an unexpected episode of apnea or prolonged neuromuscular blockade, practitioners must always consider malnutrition-induced pseudocholinesterase deficiency as a possible etiology.