Somatostatin: a possible mediator of the long-term effects of experimental vertical gastrectomy on glucose metabolism in rats?

BACKGROUND: Sleeve gastrectomy (SG) is one of the most commonly performed bariatric surgeries. SG treats type 2 diabetes mellitus better than several drugs. The mechanisms that underlie this phenomenon are not clear. This study proposed that somatostatin (SST) isoforms SST-14 and SST-28 are key in the carbohydrate after SG. METHODS: Surgeries were performed on 3 groups of Wistar rats: the fasting, surgery control, and SG groups. Plasma levels of glucose, insulin, SST-14, and SST-28 were measured at 2 survival periods after surgery. Islet SST receptor (SSTR) and cell populations were studied. We performed a pasireotide (SST-28 analogue) infusion assay in another group of rats to confirm the influence of SST-28 plasma levels on the delta-cell population. RESULTS: This study found an elevation in the insulin response after SG in animals but a decrease in the insulin response over the long term with a loss of beta-cell mass. An increase in duodenal SST-28-producing cells in the duodenum and a loss of pancreatic SST-14-producing cells were observed after SG in animals but not in controls. The expression of SSTR type 5 in delta-cell populations from each group and the ability of the pasireotide infusion assay to decrease the delta-cell population indicated the effect of SST-28 plasma levels on delta-cell maintenance. CONCLUSION: After SG initiates a compensatory response in the duodenum, beta-cell mass is depleted after loss of the brake that regulates SST-14 at the paracrine level in a nonobese, normoglycemic rat model. This was an experimental model, with no clinical translation to the human clinic, with a preliminary importance regarding new pathophysiologic perspectives or pathways.

The role of glucagon after bariatric/metabolic surgery: much more than an "anti-insulin" hormone.

The biological activity of glucagon has recently been proposed to both stimulate hepatic glucose production and also include a paradoxical insulinotropic effect, which could suggest a new role of glucagon in the pathophysiology type 2 diabetes mellitus (T2DM). An insulinotropic role of glucagon has been observed after bariatric/metabolic surgery that is mediated through the GLP-1 receptor on pancreatic beta cells. This effect appears to be modulated by other members of the proglucagon family, playing a key role in the beneficial effects and complications of bariatric/metabolic surgery. Glucagon serves a dual role after sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB). In addition to maintaining blood glucose levels, glucagon exhibits an insulinotropic effect, suggesting that glucagon has a more complex function than simply an "anti-insulin hormone".

Dual effect of RYGB on the entero-insular axis: How GLP-1 is enhanced by surgical duodenal exclusion.

BACKGROUND: The role of the ileum and Glucagon Like Peptide-1 (GLP-1) secretion in the pathophysiological processes underlying the effects of Roux-en-Y gastric bypass (RYGB) on type 2 Diabetes mellitus (T2DM) improvement has been previously determined. However, the roles of duodenal exclusion and Glucose Insulinotropic Peptide (GIP) secretion change is not clear. To clarify this aspect, we compared the pathophysiological mechanisms triggered by RYGB, which implies the early arrival of food to the ileum with duodenal exclusion, and through pre-duodenal ileal transposition (PdIT), with early arrival of food to the ileum but without duodenal exclusion, in a nondiabetic rodent model. METHODS: We compared plasma and insulin, glucose (OGTT), GIP and GLP-1 plasma levels, ileal and duodenal GIP and GLP-1 tissue expression and beta-cell mass for n = 12 Sham-operated, n = 6 RYGB-operated, and n = 6 PdIT-operated Wistar rats. RESULTS: No surgery induced changes in blood glucose levels after the OGTT. However, RYGB induced a significant and strong insulin response that increased less in PdIT animals. Increased beta-cell mass was found in RYGB and PdIT animals as well as similar GLP-1 secretion and GLP-1 intestinal expression. However, differential GIP secretion and GIP duodenal expression were found between RYGB and PdIT. CONCLUSION: The RYGB effect on glucose metabolism is mostly due to early ileal stimulation; however, duodenal exclusion potentiates the ileal response within RYGB effects through enhanced GIP secretion.

Anticipatory Antifungal Treatment in Critically Ill Patients with SARS-CoV-2 Pneumonia.

BACKGROUND: The aim of this study was to investigate the incidence of COVID-19-associated pulmonary aspergillosis (CAPA) in critically ill patients and the impact of anticipatory antifungal treatment on the incidence of CAPA in critically ill patients. METHODS: Before/after observational study in a mixed intensive care unit (ICU) of a university teaching hospital. The study took place between March 2020 and June 2022. Inclusion criteria were critically ill patients with severe SARS-CoV-2 pneumonia requiring invasive mechanical ventilation. Two analysis periods were compared according to whether or not antifungal therapy was given early. RESULTS: A total of 160 patients with severe SARS-CoV-2 pneumonia and invasive mechanical ventilation were included. The incidence of CAPA in the first study period was 19 out of 58 patients (32.75%); during the second period, after implementation of the intervention (anticipatory antifungal therapy), the incidence of CAPA decreased to 10.78% (11 out of 102 patients). In patients with CAPA under invasive mechanical ventilation, the mortality rate decreased from 100% to 64%. CONCLUSIONS: Anticipating antifungal treatment in patients with SARS-CoV-2 pneumonia under invasive mechanical ventilation was associated with a decrease in the incidence and mortality of pulmonary aspergillosis.

Somatostatin: From a supporting actor to the protagonist to explain the long-term effect of sleeve gastrectomy on glucose metabolism.

BACKGROUND: Bariatric/metabolic surgery has become the most effective treatment against type 2 Diabetes mellitus (T2DM). The role of many gastrointestinal hormones in T2DM has been proposed, but the pathophysiological models described vary greatly depending on the anatomical rearrangements after surgery. We focus on somatostatin as a common factor in two of the most commonly performed surgical procedures in a healthy rodent model. We performed sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGB) and also an experimental surgery without gastric involvement (intestinal resection of 50 % jejunum-ileum portion -IR50 %). METHODS: We used five groups of Wistar rats: fasting control, sham-operated, SG-operated, RYGB-operated and IR50-operated. We analysed several parameters 4 and 23 weeks after surgery: plasma SST-14/28 fractions, plasma glucose, insulin release and SST-producing cell expression in the duodenum and pancreatic islets. RESULTS: Numerous SST-producing cells in the duodenum but a low number in the pancreas and a long-term loss of glucose tolerance were observed in SG and RYGB animals. Additionally, a high plasma SST-28 fraction was found in animals after SG but not after RYGB. Finally, IR50 animals showed no differences versus controls. CONCLUSIONS: In our SG model the amplitude of insulin response after metabolic surgeries, is mediated by SST-28 plasma levels derived from the proportional compensatory effect of gastric SST-producing tissue ablation. In addition, a strong compensatory response to the surgical loss of gastric SST-producing cells, leads to long-term loss of insulin production after SG but not in the others.

Peptide Tyrosine-Tyrosine Triggers GLP-2-Mediated Intestinal Hypertrophy After Roux-en-Y Gastric Bypass.

PURPOSE : Intestinal remodeling and adaptation of the alimentary limb after Roux-en-Y gastric bypass (RYGB) play an important role in the pathophysiological events that lead to type 2 diabetes mellitus (T2DM) improvement. Intestinal absorptive loop hypertrophy and growth following surgery have been related to GLP-2 secretion by ileal L-cells. The secretion of peptide tyrosine-tyrosine (PYY) enterohormone after a meal has been proposed as a trigger for ileal secretion of GLP-1. Our aim is to determine the role of PYY as a GLP-2 secretion modulator as an adaptation result in the alimentary limb after RYGB. METHOD: We used a non-obese euglycemic rodent model. Circulating glucose, insulin, PYY, and GLP-2 were measured in the experimental and control groups. We used four groups: fasting control, Sham-operated, RYGB-operated (RYGB), and RYGB-operated and treated with BIIE0246 (RYGB + BII). BIIE0246 is a NPY2 receptor antagonist in L-cells. Intestinal glucose transporters and GLP-1 and PYY gut expression and hypertrophy were analyzed after 12 weeks of surgery. RESULTS: RYGB increased PYY3-36 plasma levels in rats with or without BII treatment. A high-insulin response was observed in the RYGB group but not in the control or RYGB + BII groups. BIIE0246 treatment limited plasma GLP-2 levels. In the alimentary intestinal limb, hypertrophy and SGLT1 and GLUT1 expression appeared to be reduced after RYGB compared to controls. CONCLUSION: The postprandial ileal PYY secretion is enhanced after RYGB. This increase mediates GLP-2 release through its binding to the Y2 receptor on L-cells. This mechanism plays a role in alimentary limb hypertrophy after surgery.

Dynamic Arterial Elastance During Experimental Endotoxic Septic Shock: A Potential Marker of Cardiovascular Efficiency.

Dynamic arterial elastance (Eadyn), the ratio between pulse pressure variation (PPV) and stroke volume variation (SVV), has been suggested as a dynamic parameter relating pressure and flow. We aimed to determine the effects of endotoxic septic shock and hemodynamic resuscitation on Eadyn in an experimental study in 18 New Zealand rabbits. Animals received placebo (SHAM, n = 6) or intravenous lipopolysaccharide (E. Coli 055:B5, 1 mg⋅kg - 1) with or without (EDX-R, n = 6; EDX, n = 6) hemodynamic resuscitation (fluid bolus of 20 ml⋅kg - 1 and norepinephrine for restoring mean arterial pressure). Continuous arterial pressure and aortic blood flow measurements were obtained simultaneously. Cardiovascular efficiency was evaluated by the oscillatory power fraction [%Osc: oscillatory work/left ventricular (LV) total work] and the energy efficiency ratio (EER = LV total work/cardiac output). Eadyn increased in septic animals (from 0.73 to 1.70; p = 0.012) and dropped after hemodynamic resuscitation. Eadyn was related with the %Osc and EER [estimates: -0.101 (-0.137 to -0.064) and -9.494 (-11.964 to -7.024); p < 0.001, respectively]. So, the higher the Eadyn, the better the cardiovascular efficiency (lower %Osc and EER). Sepsis resulted in a reduced %Osc and EER, reflecting a better cardiovascular efficiency that was tracked by Eadyn. Eadyn could be a potential index of cardiovascular efficiency during septic shock.

Noradrenaline modifies arterial reflection phenomena and left ventricular efficiency in septic shock patients: A prospective observational study.

PURPOSE: To determine whether noradrenaline alters the arterial pressure reflection phenomena in septic shock patients and the effects on left ventricular (LV) efficiency. MATERIAL AND METHODS: Thirty-seven septic shock patients with a planned change in noradrenaline dose. Timing and magnitude (Reflection Magnitude and Augmentation Index) of arterial reflections were evaluated. Total, steady, and oscillatory LV power (also expressed as fraction of the total power), subendocardial viability ratio (SEVR), energy efficiency and transmission ratios were used as a marker of LV efficiency. RESULTS: An incremental change in noradrenaline increased Reflection Magnitude [0.28(0.09) to 0.31(0.1], Augmentation Index [-6.4(23.6) to 4.8(20.7)%], and LV total power [0.79(IQR:0.47-1) to 0.98(IQR:0.57-1.27)W], all p < 0.001; whereas decreased arrival time of reflected waves [from 95(87 to 121) to 83(79 to 101)ms; p < 0.001]. Variables of LV performance showed a decreased efficiency: oscillatory fraction and energy efficiency ratio increased [20.9(5.7) to 22.8(4.9)%, and 8.2(1.7) to 10.1(2) mW.min.litre-1; p < 0.001, respectively]; and energy transmission ratio and SEVR decreased [73.8(9.9) to 72(9.8)% and 146(IQR:113-188) to 143(IQR:109-172)%, p = 0.003 and p = 0.041, respectively]. CONCLUSIONS: Noradrenaline increased reflection phenomena, increasing LV workload and worsening LV performance in septic shock patients. These conditions could explain the detrimental effects during long-term use of noradrenaline.

Effects of fluid administration on arterial load in septic shock patients.

PURPOSE: To determine the effects of fluid administration on arterial load in critically ill patients with septic shock. METHODS: Analysis of septic shock patients monitored with an oesophageal Doppler and equipped with an indwelling arterial catheter in whom a fluid challenge was performed because of the presence of systemic hypoperfusion. Measures of arterial load [systemic vascular resistance, SVR = mean arterial pressure (MAP)/cardiac output (CO); net arterial compliance, C = stroke volume (SV)/arterial pulse pressure; and effective arterial elastance, Ea = 90% of systolic arterial pressure/SV] were studied both before and after volume expansion (VE). RESULTS: Eighty-one patients were analysed, 54 (67%) increased their CO by at least 10% after VE (preload responders). In the whole population, 29 patients (36%) increased MAP by at least 10 % from preinfusion level (pressure responders). In the preload responder group, only 24 patients (44%) were pressure responders. Fluid administration was associated with a significant decrease in Ea [from 1.68 (1.11-2.11) to 1.57 (1.08-1.99) mmHg/mL; P = 0.0001] and SVR [from 1035 (645-1483) to 928 (654-1452) dyn s cm(-5); P < 0.01]. Specifically, in preload responders in whom arterial pressure did not change, VE caused a reduction in Ea from 1.74 (1.22-2.24) to 1.55 (1.24-1.86) mmHg/mL (P < 0.0001), affecting both resistive [SVR: from 1082 (697-1475) to 914 (624-1475) dyn s cm(-5); P < 0.0001] and pulsatile [C: from 1.11 (0.84-1.49) to 1.18 (0.99-1.44) mL/mmHg; P < 0.05] components. There was no relationship between preinfusion arterial load parameters and VE-induced increase in arterial pressure. CONCLUSION: Fluid administration significantly reduced arterial load in critically patients with septic shock and acute circulatory failure, even when increasing cardiac output. This explains why some septic patients increase their cardiac output after fluid administration without improving blood pressure.

The use of pulse pressure variation and stroke volume variation in spontaneously breathing patients to assess dynamic arterial elastance and to predict arterial pressure response to fluid administration.

BACKGROUND: Dynamic arterial elastance (Eadyn), defined as the pulse pressure variation (PPV) to stroke volume variation (SVV) ratio, has been suggested as a predictor of the arterial pressure response to fluid administration. In this study, we assessed the effectiveness of Eadyn to predict the arterial blood pressure response to a fluid challenge (FC) in preload-dependent, spontaneously breathing patients. METHODS: Patients admitted postoperatively and monitored with the Nexfin monitor (BMEYE, Amsterdam, The Netherlands) were enrolled in the study. Patients were included in the analysis if they were spontaneously breathing and had an increase in cardiac output ≥10% during an FC. Patients were classified according to the increase in mean arterial blood pressure (MAP) after FC into MAP-responders (MAP increase ≥10%) and MAP-nonresponders (MAP increase <10%). Eadyn was continuously calculated from the PPV and SVV values obtained from the monitor. RESULTS: Thirty-four FCs from 26 patients were studied. Seventeen FCs (50%) induced a positive MAP response. Preinfusion Eadyn was significantly higher in MAP-responders (1.39 ± 0.41 vs 0.85 ± 0.23; P = 0.0001). Preinfusion Eadyn predicted a positive MAP response to FC with an area under the receiver-operating characteristic curve of 0.92 ± 0.04 of standard error (95% confidence interval, 0.78-0.99; P < 0.0001). A preinfusion Eadyn value ≥1.06 (gray zone: 0.9-1.15) discriminated MAP-responders with a sensitivity and specificity of 88.2% (approximate 95% confidence interval, 64%-99%), respectively. CONCLUSIONS: Noninvasive Eadyn, defined as the PPV to SVV ratio, predicted the arterial blood pressure increase to fluid administration in spontaneously breathing, preload-dependent patients.

Non-invasive assessment of fluid responsiveness by changes in partial end-tidal CO2 pressure during a passive leg-raising maneuver.

BACKGROUND: The passive leg-raising (PLR) maneuver provides a dynamic assessment of fluid responsiveness inducing a reversible increase in cardiac preload. Since its effects are sudden and transitory, a continuous cardiac output (CO) monitoring is required to appropriately assess the hemodynamic response of PLR. On the other hand, changes in partial end-tidal CO2 pressure (PETCO2) have been demonstrated to be tightly correlated with changes in CO during constant ventilation and stable tissue CO2 production (VCO2). In this study we tested the hypothesis that, assuming a constant VCO2 and under fixed ventilation, PETCO2 can track changes in CO induced by PLR and can be used to predict fluid responsiveness. METHODS: Thirty-seven mechanically ventilated patients with acute circulatory failure were monitored with the CardioQ-ODM esophageal Doppler. A 2-minutes PLR maneuver was performed. Fluid responsiveness was defined according to CO increase (responders ≥ 15%) after volume expansion. RESULTS: PLR-induced increases in CO and PETCO2 were strongly correlated (R2 = 0.79; P < 0.0001). The areas under the receiver-operating characteristics (ROC) curve for a PLR-induced increase in CO and PETCO2 (0.97 ± 0.03 SE; CI 95%: 0.85 to 0.99 and 0.94 ± 0.04 SE; CI 95%: 0.82 to 0.99; respectively) were not significantly different. An increase ≥ 5% in PETCO2 or ≥ 12% in CO during PLR predicted fluid responsiveness with a sensitivity of 90.5% (95% CI: 69.9 to 98.8%) and 95.2% (95% CI: 76.2 to 99.9%), respectively, and a specificity of 93.7% (95% CI: 69.8 to 99.8%). CONCLUSION: Induced changes in PETCO2 during a PLR maneuver could be used to track changes in CO for prediction of fluid responsiveness in mechanically ventilated patients with acute circulatory failure, under fixed minute ventilation and assuming a constant tissue CO2 production.

Dynamic arterial elastance to predict arterial pressure response to volume loading in preload-dependent patients.

INTRODUCTION: Hemodynamic resuscitation should be aimed at achieving not only adequate cardiac output but also sufficient mean arterial pressure (MAP) to guarantee adequate tissue perfusion pressure. Since the arterial pressure response to volume expansion (VE) depends on arterial tone, knowing whether a patient is preload-dependent provides only a partial solution to the problem. The objective of this study was to assess the ability of a functional evaluation of arterial tone by dynamic arterial elastance (Ea(dyn)), defined as the pulse pressure variation (PPV) to stroke volume variation (SVV) ratio, to predict the hemodynamic response in MAP to fluid administration in hypotensive, preload-dependent patients with acute circulatory failure. METHODS: We performed a prospective clinical study in an adult medical/surgical intensive care unit in a tertiary care teaching hospital, including 25 patients with controlled mechanical ventilation who were monitored with the Vigileo(®) monitor, for whom the decision to give fluids was made because of the presence of acute circulatory failure, including arterial hypotension (MAP ≤65 mmHg or systolic arterial pressure <90 mmHg) and preserved preload responsiveness condition, defined as a SVV value ≥10%. RESULTS: Before fluid infusion, Ea(dyn) was significantly different between MAP responders (MAP increase ≥15% after VE) and MAP nonresponders. VE-induced increases in MAP were strongly correlated with baseline Ea(dyn) (r(2) = 0.83; P < 0.0001). The only predictor of MAP increase was Ea(dyn) (area under the curve, 0.986 ± 0.02; 95% confidence interval (CI), 0.84-1). A baseline Ea(dyn) value >0.89 predicted a MAP increase after fluid administration with a sensitivity of 93.75% (95% CI, 69.8%-99.8%) and a specificity of 100% (95% CI, 66.4%-100%). CONCLUSIONS: Functional assessment of arterial tone by Ea(dyn), measured as the PVV to SVV ratio, predicted arterial pressure response after volume loading in hypotensive, preload-dependent patients under controlled mechanical ventilation.