Surgeons and surgical trainees both have a significant knowledge gap in the safe and effective use of surgical energy devices, regardless of surgical specialty and despite what they feel was adequate training. The knowledge gap is not improved with experience. A formal surgical energy education program should be a requirement for residency training or credentialing.

Both acute stress hyperglycemia and uncontrolled hypoglycemia may serve as indices of disease severity in critically ill patients, yet the mechanisms behind altered glucose control in inflammatory diseases such as acute sepsis is poorly understood. Evidence of the ability of vasopressin to mediate central and peripheral glucose regulation via V1b and V1a receptors has mounted over the years, but the role of vasopressin in glucose homeostasis during sepsis, is unclear. We hypothesized that vasopressin is involved in glycemic control in endotoxin‐induced inflammation seen in sepsis but that this role may be overshadowed by vasopressin's primary role of maintaining blood pressure in the face of septic shock. Thus, we used a piglet model of endotoxin‐induced pulmonary hypertension in the absence of systemic shock to better understand the relationship between vasopressin and glucose homeostasis in a hypoxemia‐induced inflammatory state. The intent was to study effects of vasopressin separate from its role in blood pressure regulation.After hemodynamic equilibration following catheterization of anesthetized Yorkshire cross piglets (8 kg body weight), baseline mean arterial pressure, cardiac output, and blood gasses were assessed, and blood was obtained for measurement of glucose (BG), vasopressin, cortisol, insulin, glucagon, and cytokine profiles. Liver and pancreatic blood flows were assessed via colored microsphere method. E. coli endotoxin (7,500–50,000 units) was administered intravenously to achieve pulmonary hypertension (evidenced by a pulmonary to systemic vascular resistance ratio increase of 120%), which decreased arterial oxygenation to a PaO2 of 78 ± 5 mm Hg without systemic hypotension(ETX, n=16). Piglets were followed for 11 hours after endotoxin administration. Results were compared against control piglets who did not receive endotoxin (CON, n=7). In CON group, all hemodynamics and biomarkers measured remained constant. Endotoxin caused an increase in pro‐inflammatory markers TNFα, IL‐1ra, and IL‐6. Blood glucose levels were elevated at baseline in both CON (189±11 mg/dL) and ETX (199±9 mg/dL), with corresponding elevated vasopressin levels (106 ± 17 pg/ml; and 78 ± 9 pg/ml in CON and ETX, respectively) likely due to piglet susceptibility to anesthesia induction stress. Both BG and vasopressin levels decreased over the duration of the experiment, with no significant changes in cortisol. Liver blood flow tended to decrease and pancreatic blood flow to increase with time in both CON and ETX. Interestingly, insulin increased 6‐fold with endotoxin and then returned toward baseline by 2 hours after endotoxin administration. Glucagon increased after endotoxin and remained elevated over baseline 11 hours later.Stepwise multiple regression analysis was used to determine relationships between BG and vasopressin, cortisol, insulin, glucagon, TNFα, IL‐1ra, and IL‐6, liver and pancreatic blood flows, hemodynamics, and blood oxygenation. BG was most strongly positively associated with circulating vasopressin, liver blood flow and insulin, and negatively correlated with glucagon (r= 0.72, p<0.001). Our results support an important role of vasopressin as a stress hormone regulator of glucose homeostasis both in control conditions and in the response to endotoxin‐induced stress.Support or Funding InformationThis project was funded by the US Army Medical Command. The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Renal function is greatly reduced during hemorrhagic shock and resuscitation with vasopressors. Studies suggest chromatin remodeling may be responsible for pathophysiologic responses to shock and resuscitation; however, whether chromatin remodeling underlies renal hemodynamic changes induced by shock and resuscitation with different types of vasopressors is unknown. We aim to examine the effect of vasopressin or norepinephrine infusion during resuscitation on renal hemodynamics, and the role of epigenetic chromatin remodeling enzymes in this response. We hypothesized that renal hemodynamics and expression of chromatin remodeling enzymes of renal artery will be altered in a vasopressor‐dependent manner in a pig model of hemorrhagic shock and resuscitation. Adult pigs were anesthetized and subjected to hemorrhage (n=16), or maintained as non‐hemorrhaged controls (n=6). One hour post‐hemorrhage, pigs were resuscitated with saline up to 2x shed blood volume (SA; n=5), saline plus vasopressin infusion (VP; n=5), or saline plus norepinephrine infusion (NE; n=6). Animals were euthanized 4 to 5 hours post‐hemorrhage. Resuscitation strategy significantly affected hemodynamic parameters within the first hour of treatment. Only VP increased mean arterial pressure compared to SA (71.80±8.60 versus 54.40±5.30 mmHg, p<0.05). Renal vascular resistance of VP and NE, but not SA pigs was elevated compared to non‐hemorrhaged controls (0.20±0.03 and 0.19±0.01, respectively, versus 0.09±0.01 mmHg/ml/min, p<0.05). Gene expression of 84 chromatin remodeling enzymes was tested in renal arteries. SA significantly altered a smaller proportion of chromatin remodeling enzymes than VP or NE (6, 20, and 30 of 84 enzymes, respectively) when compared to non‐hemorrhaged controls. VP and NE upregulated expression of histone deacetylases (HDAC2, HDAC4, HDAC6, HDAC9, HDAC11), SET domain‐containing methyltransferases (SETD7, SETD8, SETDB2, NDS1), methyltransferases (EZH2, PRMT5), and demethylases (KDM5B, KDM6B). Unique to NE, DNA methyltransferases (DNMT1, DNMT3A, DNMT3B) were upregulated. Only SA upregulated expression of SETD4, and NEK6. In all treatment groups, LOC100739818, and RPS6KA3 were upregulated, while SET1B was downregulated. Because we observed renal hemodynamic differences among groups, and HDACs and DNMTs have been shown to regulate nitric oxide synthase 3 (NOS3) expression in vascular cells, we hypothesized that NOS3 gene expression of renal artery will be altered in a vasopressor‐dependent manner. NOS3 expression was not significantly different among resuscitation groups, despite differences in expression of chromatin remodeling enzymes. We are the first to demonstrate that renal hemodynamics and renal artery expression of epigenetic enzymes are regulated differently depending on the type of resuscitation strategy used, thus highlighting the importance of resuscitation strategy in the epigenetic regulation of renal vascular function during treatment of hemorrhagic shock.Support or Funding InformationThe views expressed in this presentation are those of the authors and do not reflect the official policy or position of the Department of the Army, the Department of Defense, or the U.S. government.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Escherichia coli sepsis remains the most mortal cause of early‐onset neonatal sepsis and is characterized by an endotoxin lipopolysaccharide (LPS)‐mediated acute inflammatory response and pulmonary edema. Cytokines are increasingly being evaluated as potential biomarkers for diagnosis of sepsis and monitoring of disease severity but the timing of inflammatory changes in relation to pulmonary hypertension and pulmonary function is unclear.We used a piglet model of endotoxin (ETX)‐induced pulmonary hypertension in the absence of systemic shock to test the hypothesis that pulmonary vasoconstriction versus alveolar gas exchange are mediated by different cytokines. Anesthetized Yorkshire cross piglets (8 kg body weight) were catheterized, and after hemodynamic equilibration, baseline mean arterial pressure, cardiac output, pulmonary arterial pressure, and blood gases were assessed. E. coli endotoxin LPS was administered intravenously (n=10) and carefully titrated (7,500–35,000 units) to achieve pulmonary hypertension without systemic hypotension, and acute lung injury (ALI) criteria of PaO2/FiO2 less than 350 mmHg. Control pigs received normal saline (n=5). Pigs were observed for 18 hours with hemodynamic monitoring and blood was obtained every 2–4 hours for assessment of blood gases and cytokine profiles measured by multiplex magnetic bead assay (Milliplex MAP for Luminex). Hemodynamic measurements, blood oxygenation, and cytokine levels remained constant in the control group. Pulmonary hypertension was seen in the ETX group as evidenced by a mean increase in pulmonary to systemic vascular resistance ratio (PVR/SVR) from 0.16 ± 0.01 to 0.44 ± 0.06 (p<0.05).All 13 inflammatory biomarkers examined (GM‐CSF, INFγ, interleukin (IL)‐1a, IL‐1β, IL‐1ra, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12, IL‐18, and TNF‐α) acutely increased within 2 hours of endotoxin‐induced pulmonary hypertension (ANOVA, p<0.05). Inflammatory marker levels along with PVR/SVR, returned toward baseline levels by 4 hours after ETX exposure and remained no different from controls through 18 hours after ETX. Multiple regression analysis was performed to determine which inflammatory markers in the first 2 hours after ETX may be related to the selective pulmonary vasoactive response to ETX as indicated by the PVR to SVR ratio, versus which markers were associated with reduced pulmonary alveolar gas exchange as reflected by PaO2/FiO2. PVR/SVR was most strongly correlated with IL‐6 and TNF‐α and negatively correlated with IL‐1ra (r=0.92, p<0.01), suggesting that IL‐6 and TNF‐α may be involved in mediating pulmonary vasoconstriction, whereas IL‐1ra antagonizes the vasoactive response to endotoxin. PaO2/FiO2 was positively correlated with IL‐1a, and negatively correlated with INFγ, TNF‐α, IL‐2, and IL‐18 (r=0.93, p<0.01). These findings demonstrate that cytokine changes that accompany endotoxin‐induced pulmonary hypertension occur independent of systemic shock. Further, there appears to be specific differential mediation of the pulmonary vascular response versus pulmonary gas exchange by different cytokines.Support or Funding InformationThis project was funded by the US Army Medical Command. The views expressed in this abstract are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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