Effect of external dead space removal on CO2 homeostasis in mechanically ventilated adult Covid-19 patients.

BACKGROUND: Patients with Covid-19 respiratory failure present with hypoxemia, often in combination with hypercapnia. In this prospective, observational study we examined the effect of removing external dead space (DS) on CO2 -homeostasis in mechanically ventilated Covid-19 patients. In addition, volumetric capnography was validated for its ability to estimate external DS volume using in vitro measured DS volumes as reference. METHODS: In total, 10 patients with acute respiratory distress syndrome from Covid-19 were included. Volumetric capnography, mechanical ventilation, and arterial blood gas data were analyzed before and after removal of external DS and analyzed for potentially significant changes in response to DS removal. Measurements of external DS were obtained in circuit using volumetric capnography and compared to actual measured DS volumes off the circuit. RESULTS: After the removal of external DS, the alveolar minute ventilation and CO2 elimination improved, notwithstanding unchanged respiratory rate and tidal volumes. The increase in CO2 elimination was associated with a decrease in arterial CO2 partial pressure (PaCO2 ). The volumetric capnography method for assessment of external DS showed a low bias of -9 mL (lower limit of agreement -40, 95% CI -60 to -20 mL, upper limit of agreement 21 mL, 95% CI: 1-40 mL) and a percentage error of 48% compared to absolute values measured in vitro. CONCLUSION: Removal of external DS increased alveolar minute ventilation and CO2 elimination in Covid-19 patients with respiratory failure in the current study. This was associated with a decrease in PaCO2 . This may indicate a decreased CO2 production due to decreased work of breathing and more effective gas-exchange in response to DS removal. In addition, volumetric capnography appears to be a clinically feasible method for continuous measurement of external DS in the current study and may be of value in optimizing ventilator treatment.

Perioperative fluid balance and major postoperative complications in surgery for advanced epithelial ovarian cancer.

OBJECTIVE: Appropriate fluid balance in the perioperative period is important as both hypo- and hypervolemia are associated with increased risk of complications. Women undergoing cytoreductive surgery (CRS) for advanced epithelial ovarian cancer (EOC) may have major fluid shifts. The optimal perioperative fluid balance in these women is yet to be determined. Our objective was to investigate the association between perioperative fluid balance and major postoperative complications. METHODS: Women with advanced stage EOC who underwent surgery at Karolinska University Hospital, Stockholm, Sweden were identified from the institutional database. Women subjected to surgery with curative intent were included in the analysis. Additional data were retrieved from medical records. The association between perioperative fluid balance and major postoperative complications was investigated by multivariable regression and adjusted for predefined confounders. RESULTS: Of the 270 women identified in the institutional database during 2014-2017, 184 women were included in the analyses. Of these women, 22% (n = 40) experienced a major postoperative complication. The fully adjusted odds of major postoperative complications increased when perioperative fluid balance exceeded >3000 mL, (Odds Ratio (OR) 4.85, 95% Confidence Interval (CI) 1.23-19.2, p = 0.02) and > 5000 mL (OR 33.7, 95% CI 4.13-275, p < 0.01). There was no association between negative fluid balance and major postoperative complications (OR 3.33, 95% CI 0.25-44.1, p = 0.36). CONCLUSIONS: Fluid balance >3000 mL perioperatively during surgery for advanced EOC increased the odds of major postoperative complications. Management of perioperative fluid balance in advanced EOC surgery remains a challenge.

Surgery performed later in the week is associated with inferior survival in advanced ovarian cancer.

BACKGROUND: Complete macroscopic resection without any residual tumour after completion of surgery is a strong prognostic factor in advanced epithelial ovarian cancer (EOC). It has previously been reported that surgery performed later in the week is associated with failure to achieve complete macroscopic resection. Our objective was to examine if weekday of surgery influences oncologic outcome. MATERIALS AND METHODS: This population-based observational study included 100% of all women diagnosed with advanced-stage invasive epithelial ovarian cancer between 2009-2011 and 2014-2016 in the Stockholm/Gotland County of Sweden. The association between weekday of surgery and survival was analysed with proportional hazards regression yielding hazard ratios (HR) with 95% confidence intervals (CI), adjusted for predefined confounders. RESULTS: Out of 1066 identified women, 524 with advanced stage EOC treated with surgery were included in the final analysis. Surgery performed Wednesday to Thursday was associated with an increased hazard of death (HR 1.28, 95% CI 1.04-1.58, p-value 0.02). The trend of the hazard of surgery performed throughout the week from Monday through Thursday was also significant (p = 0.01). CONCLUSION: The increased mortality associated with surgery that is performed later in the week suggests that surgery for advanced ovarian cancer is best conducted early in the week.

ASA classification and surgical severity grading used to identify a high-risk population, a multicenter prospective cohort study in Swedish tertiary hospitals.

BACKGROUND: Identification of surgical populations at high risk for negative outcomes is needed for clinical and research purposes. We hypothesized that combining two classification systems, ASA (American Society of Anesthesiology physical status) and surgical severity, we could identify a high-risk population before surgery. We aimed to describe postoperative outcomes in a population selected by these two classifications system. METHODS: Data were collected in a Swedish multicentre, time-interrupted prospective, consecutive cohort study. Eligibility criteria were age ≥18 years, ASA ≥3, elective or emergent, major to Xmajor/complex (Specialist Procedure Codes used in United Kingdom), gastrointestinal, urogenital or orthopaedic procedures. Postoperative morbidity was identified by the Postoperative Morbidity Survey on postoperative days 3 ± 1, 7 ± 1, 10 + 5 and graded for severity by the Clavien-Dindo system. Mortality was assessed at 30, 180 and 360 days. RESULTS: Postoperative morbidity was 78/48/47 per cent on postoperative days 3/7/10. Majority of morbidities (67.5 per cent) were graded as >1 by Clavien-Dindo. Any type of postoperative morbidity graded >1 was associated with increased risk for death up to one year. The mortality was 5.7 per cent (61/1063) at 30 days, 13.3 per cent (142/1063) at 6 months and 19.1 per cent (160/1063) at 12 months. CONCLUSION: Severity classification as major to Xmajor/complex and ASA ≥3 could be used to identify a high-risk surgical population concerning postoperative morbidity and mortality before surgery. Combining the two systems future electronic data extraction is possible of a high-risk population in tertiary hospitals.

Comparison between capnodynamic and thermodilution method for cardiac output monitoring during major abdominal surgery: An observational study.

BACKGROUND: Cardiac output (CO) monitoring is the basis of goal-directed treatment for major abdominal surgery. A capnodynamic method estimating cardiac output (COEPBF) by continuously calculating nonshunted pulmonary blood flow has previously shown good agreement and trending ability when evaluated in mechanically ventilated pigs. OBJECTIVES: To compare the performance of the capnodynamic method of CO monitoring with transpulmonary thermodilution (COTPTD) in patients undergoing major abdominal surgery. DESIGN: Prospective, observational, method comparison study. Simultaneous measurements of COEPBF and COTPTD were performed before incision at baseline and before and after increased (+10 cmH2O) positive end-expiratory pressure (PEEP), activation of epidural anaesthesia and intra-operative events of hypovolemia and low CO. The first 25 patients were ventilated with PEEP 5 cmH2O (PEEP5), while in the last 10 patients, lung recruitment followed by individual PEEP adjustment (PEEPadj) was performed before protocol start. SETTING: Karolinska University Hospital, Stockholm, Sweden. PATIENTS: In total, 35 patients (>18 years) scheduled for major abdominal surgery with advanced hemodynamic monitoring were included in the study. MAIN OUTCOME MEASURES AND ANALYSIS: Agreement and trending ability between COEPBF and COTPTD at different clinical moments were analysed with Bland--Altman and four quadrant plots. RESULTS: In total, 322 paired values, 227 in PEEP5 and 95 in PEEPadj were analysed. Respectively, the mean COEPBF and COTPTD were 4.5 ±â€Š1.0 and 4.8 ±â€Š1.1 in the PEEP5 group and 4.9 ±â€Š1.2 and 5.0 ±â€Š1.0 l min-1 in the PEEPadj group. Mean bias (levels of agreement) and percentage error (PE) were -0.2 (-2.2 to 1.7) l min-1 and 41% for the PEEP5 group and -0.1 (-1.7 to 1.5) l min-1 and 31% in the PEEPadj group. Concordance rates during changes in COEPBF and COTPTD were 92% in the PEEP5 group and 90% in the PEEPadj group. CONCLUSION: COEPBF provides continuous noninvasive CO estimation with acceptable performance, which improved after lung recruitment and PEEP adjustment, although not interchangeable with COTPTD. This method may become a tool for continuous intra-operative CO monitoring during general anaesthesia in the future. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03444545.

Clinical and experimental validation of a capnodynamic method for end-expiratory lung volume assessment.

INTRODUCTION: Lung protective ventilation can decrease post-operative pulmonary complications. The aim of this study was to evaluate a capnodynamic method estimating effective lung volume (ELV) as a proxy for end-expiratory lung volume in response to PEEP changes in patients, healthy subjects and a porcine model. METHODS: Agreement and trending ability for ELV in anaesthetized patients and agreement in awake subjects were evaluated using nitrogen multiple breath wash-out/in and plethysmography as a reference respectively. Agreement and trending ability were evaluated in pigs during PEEP elevations with inert gas wash-out as reference. RESULTS: In anaesthetized patients bias (95% limits of agreement [LoA]) and percentage error (PE) at PEEP 0 cm H2 O were 133 mL (-1049 to 1315) and 71%, at PEEP 5 cm H2 O 161 mL (-1291 to 1613 mL) and 66%. In healthy subjects: 21 mL (-755 to 796 mL) and 26%. In porcines, at PEEP 5-20 cm H2 O bias decreased from 223 mL to 136 mL LoA (34-412) to (-30 to 902) and PE 29%-49%. Trending abilities in anaesthetized patients and porcines were 100% concordant. CONCLUSION: The ELV-method showed low bias but high PE in anaesthetized patients. Agreement was good in awake subjects. In porcines, agreement was good at lower PEEP levels. Concordance related to PEEP changes reached 100% in all settings. This method may become a useful trending tool for monitoring lung function during mechanical ventilation, if findings are confirmed in other clinical contexts.

Performance of a capnodynamic method estimating cardiac output during respiratory failure - before and after lung recruitment.

Respiratory failure may cause hemodynamic instability with strain on the right ventricle. The capnodynamic method continuously calculates cardiac output (CO) based on effective pulmonary blood flow (COEPBF) and could provide CO monitoring complementary to mechanical ventilation during surgery and intensive care. The aim of the current study was to evaluate the ability of a revised capnodynamic method, based on short expiratory holds (COEPBFexp), to estimate CO during acute respiratory failure (LI) with high shunt fractions before and after compliance-based lung recruitment. Ten pigs were submitted to lung lavage and subsequent ventilator-induced lung injury. COEPBFexp, without any shunt correction, was compared to a reference method for CO, an ultrasonic flow probe placed around the pulmonary artery trunk (COTS) at (1) baseline in healthy lungs with PEEP 5 cmH2O (HLP5), (2) LI with PEEP 5 cmH2O (LIP5) and (3) LI after lung recruitment and PEEP adjustment (LIPadj). CO changes were enforced during LIP5 and LIPadj to estimate trending. LI resulted in changes in shunt fraction from 0.1 (0.03) to 0.36 (0.1) and restored to 0.09 (0.04) after recruitment manoeuvre. Bias (levels of agreement) and percentage error between COEPBFexp and COTS changed from 0.5 (- 0.5 to 1.5) L/min and 30% at HLP5 to - 0.6 (- 2.3 to 1.1) L/min and 39% during LIP5 and finally 1.1 (- 0.3 to 2.5) L/min and 38% at LIPadj. Concordance during CO changes improved from 87 to 100% after lung recruitment and PEEP adjustment. COEPBFexp could possibly be used for continuous CO monitoring and trending in hemodynamically unstable patients with increased shunt and after recruitment manoeuvre.

Fluid volume kinetics of 20% albumin.

AIMS: A population kinetic model was developed for the body fluid shifts occurring when 20% albumin is given by intravenous infusion. The aim was to study whether its efficacy to expand the plasma volume is impaired after major surgery. METHODS: An intravenous infusion of 3 mL/kg 20% albumin over 30 minutes was given to 15 volunteers and to 15 patients on the 1st day after major open abdominal surgery. Blood samples and urine were collected during 5 hours. Mixed-effect modelling software was used to develop a fluid volume kinetic model, using blood haemoglobin and urine excretion the estimate body fluid shifts, to which individual-specific covariates were added in sequence. RESULTS: The rise in plasma albumin expanded the plasma volume in excess of the infused volume by relocating noncirculating fluid (rate constant k21 ), but it also increased losses of fluid from the kinetic system (kb ). The balance between k21 and kb maintained the rise in plasma albumin and plasma volume at a virtual steady-state for almost 2 hours. The rate constant for urinary excretion (k10 ) was slightly reduced by the preceding surgery, by a marked rise in plasma albumin, and by a high preinfusion urinary concentration of creatinine. The arterial pressure, body weight, and plasma concentrations of C-reactive protein and shedding products of the endothelial glycocalyx layer (syndecan-1, heparan sulfate, and hyaluronic acid) did not serve as statistically significant covariates. CONCLUSIONS: There were no clinically relevant differences in the kinetics of 20% albumin between postoperative patients and volunteers.

Long Intravascular Persistence of 20% Albumin in Postoperative Patients.

BACKGROUND: Albumin may persist intravascularly for a shorter time in patients after major surgery than in healthy volunteers due to a surgery-induced breakdown (shedding) of the endothelial glycocalyx layer. METHODS: In this nonrandomized clinical trial, an IV infusion of 3 mL/kg of 20% albumin was given at a constant rate during 30 minutes to 15 patients on the first day after major open abdominal surgery (mean operating time 5.9 h) and to 15 conscious volunteers. Blood samples and urine were collected during 5 h and mass balance calculations used to estimate the half-lives of the administered albumin molecules and the induced plasma volume expansion, based on measurements of hemodilution and the plasma albumin concentration. RESULTS: At the end of the infusions, albumin had diluted the plasma volume by 13.3% ± 4.9% (mean ± SD) in the postoperative patients and by 14.2% ± 4.8% in the volunteers (mean difference -0.9, 95% CI, -4.7 to 2.9; 1-way ANOVA P = .61), which amounted to twice the infused volume. The intravascular half-life of the infused albumin molecules was 9.1 (5.7-11.2) h in the surgical patients and 6.0 (5.1-9.0) h in the volunteers (Mann-Whitney U test, P = .26; geometric mean difference 1.2, 95% CI, 0.8-2.0). The half-life of the plasma volume expansion was 10.3 (5.3-17.6; median and interquartile range) h in the surgical patients and 7.6 (3.5-9.0) h in the volunteers (P = .10; geometric mean difference 1.5, 95% CI, 0.8-2.8). All of these parameters correlated positively with the body mass index (correlation coefficients being 0.42-0.47) while age and sex did not affect the results. CONCLUSIONS: Twenty percent albumin caused a long-lasting plasma volume expansion of similar magnitude in postoperative patients and volunteers.

Performance of a capnodynamic method estimating effective pulmonary blood flow during transient and sustained hypercapnia.

The capnodynamic method is a minimally invasive method continuously calculating effective pulmonary blood flow (COEPBF), equivalent to cardiac output when intra pulmonary shunt flow is low. The capnodynamic equation joined with a ventilator pattern containing cyclic reoccurring expiratory holds, provides breath to breath hemodynamic monitoring in the anesthetized patient. Its performance however, might be affected by changes in the mixed venous content of carbon dioxide (CvCO2). The aim of the current study was to evaluate COEPBF during rapid measurable changes in mixed venous carbon dioxide partial pressure (PvCO2) following ischemia-reperfusion and during sustained hypercapnia in a porcine model. Sixteen pigs were submitted to either ischemia-reperfusion (n = 8) after the release of an aortic balloon inflated during 30 min or to prolonged hypercapnia (n = 8) induced by adding an instrumental dead space. Reference cardiac output (CO) was measured by an ultrasonic flow probe placed around the pulmonary artery trunk (COTS). Hemodynamic measurements were obtained at baseline, end of ischemia and during the first 5 min of reperfusion as well as during prolonged hypercapnia at high and low CO states. Ischemia-reperfusion resulted in large changes in PvCO2, hemodynamics and lactate. Bias (limits of agreement) was 0.7 (-0.4 to 1.8) L/min with a mean error of 28% at baseline. COEPBF was impaired during reperfusion but agreement was restored within 5 min. During prolonged hypercapnia, agreement remained good during changes in CO. The mean polar angle was -4.19° (-8.8° to 0.42°). Capnodynamic COEPBF is affected but recovers rapidly after transient large changes in PvCO2 and preserves good agreement and trending ability during states of prolonged hypercapnia at different levels of CO.

A modified breathing pattern improves the performance of a continuous capnodynamic method for estimation of effective pulmonary blood flow.

In a previous study a new capnodynamic method for estimation of effective pulmonary blood flow (COEPBF) presented a good trending ability but a poor agreement with a reference cardiac output (CO) measurement at high levels of PEEP. In this study we aimed at evaluating the agreement and trending ability of a modified COEPBF algorithm that uses expiratory instead of inspiratory holds during CO and ventilatory manipulations. COEPBF was evaluated in a porcine model at different PEEP levels, tidal volumes and CO manipulations (N = 8). An ultrasonic flow probe placed around the pulmonary trunk was used for CO measurement. We tested the COEPBF algorithm using a modified breathing pattern that introduces cyclic end-expiratory time pauses. The subsequent changes in mean alveolar fraction of carbon dioxide were integrated into a capnodynamic equation and effective pulmonary blood flow, i.e. non-shunted CO, was calculated continuously breath by breath. The overall agreement between COEPBF and the reference method during all interventions was good with bias (limits of agreement) 0.05 (-1.1 to 1.2) L/min and percentage error of 36 %. The overall trending ability as assessed by the four-quadrant and the polar plot methodology was high with a concordance rate of 93 and 94 % respectively. The mean polar angle was 0.4 (95 % CI -3.7 to 4.5)°. A ventilatory pattern recurrently introducing end-expiratory pauses maintains a good agreement between COEPBF and the reference CO method while preserving its trending ability during CO and ventilatory alterations.

Capnodynamic assessment of effective lung volume during cardiac output manipulations in a porcine model.

A capnodynamic calculation of effective pulmonary blood flow includes a lung volume factor (ELV) that has to be estimated to solve the mathematical equation. In previous studies ELV correlated to reference methods for functional residual capacity (FRC). The aim was to evaluate the stability of ELV during significant manipulations of cardiac output (CO) and assess the agreement for absolute values and trending capacity during PEEP changes at different lung conditions. Ten pigs were included. Alterations of alveolar carbon dioxide were induced by cyclic reoccurring inspiratory holds. The Sulphur hexafluoride technique for FRC measurements was used as reference. Cardiac output was altered by preload reduction and inotropic stimulation at PEEP 5 and 12 cmH2O both in normal lung conditions and after repeated lung lavages. ELV at baseline PEEP 5 was [mean (SD)], 810 (163) mL and decreased to 400 (42) mL after lavage. ELV was not significantly affected by CO alterations within the same PEEP level. In relation to FRC the overall bias (limits of agreement) was -35 (-271 to 201) mL, and percentage error 36 %. A small difference between ELV and FRC was seen at PEEP 5 cmH2O before lavage and at PEEP 12 cmH2O after lavage. ELV trending capability between PEEP steps, showed a concordance rate of 100 %. ELV was closely related to FRC and remained stable during significant changes in CO. The trending capability was excellent both before and after surfactant depletion.

Biomarkers of endothelial injury in plasma are dependent on kidney function.

BACKGROUND: Injury (shedding) of the endothelial glycocalyx layer, which alters local blood flow and microvascular permeability, is assessed by measuring components of this layer in circulating blood. The influence of renal function on their concentrations is unknown. METHODS: Plasma and urine concentrations of three shedding products (syndecan-1, hyaluronic acid, and heparan sulfate) and creatinine were measured over 5 hours in 15 healthy volunteers and 15 postoperative patients; this guaranteed a spread of kidney functions. Renal clearances were calculated. RESULTS: Low renal clearances of syndecan-1 (mean 3.5 mL/min) and hyaluronic acid (0.8 mL/min) correlated inversely with the 6-fold variability in the plasma concentrations of these substances (r = - 0.45 and- 0.49). Low creatinine clearance correlated inversely (r = - 0.60) and plasma creatinine directly (r = 0.52) with the two-fold variability in heparan sulfate, which was the only shedding substance that also correlated with C-reactive protein (r = 0.51) and, therefore, showed higher concentrations after surgery. CONCLUSIONS: The present explorative study suggests that a 6-fold variability in the plasma concentrations of three commonly measured endothelial shedding products can be understood by the kidney's ability to excrete them. This finding has implications when interpreting results of studies where shedding is assessed.

Protection from nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers by dietary nitrate.

Nitrate is abundant in our diet with particularly high levels in many vegetables. Ingested nitrate is concentrated in saliva and reduced to nitrite by bacteria in the oral cavity. We recently reported that application of nitrite-containing saliva to the gastric mucosa increases superficial blood flow and mucus generation via acid-catalyzed formation of bioactive nitrogen oxides including nitric oxide. Here we studied if dietary supplementation with nitrate would protect against gastric damage caused by a nonsteroidal anti-inflammatory drug. Rats received sodium nitrate in the drinking water for 1 week in daily doses of 0.1 or 1 mmol kg(-1). Control rats received 1 mmol kg(-1) sodium chloride. Diclofenac (30 mg kg(-1)) was then given orally and the animals were examined 4 h later. In separate experiments we studied the effects of dietary nitrate on intragastric NO levels and mucus formation. Luminal levels of NO gas were greatly increased in nitrate-fed animals. The thickness of the mucus layer increased after nitrate supplementation and gene expression of MUC6 was upregulated in the gastric mucosa. Nitrate pretreatment dose dependently and potently reduced diclofenac-induced gastric lesions. Inflammatory activity was reduced in the rats receiving nitrate as indicated by lower mucosal myeloperoxidase activity and expression of inducible NO synthase. We conclude that dietary nitrate protects against diclofenac-induced gastric ulcers likely via enhanced nitrite-dependent intragastric NO formation and concomitant stimulation of mucus formation. Future studies will reveal if a diet rich in nitrate can offer an additional nutritional approach to preventing and treating peptic ulcer disease.

Sex differences and effects of oestrogen in rat gastric mucosal defence.

AIM: To evaluate sex differences and the effects of oestrogen administration in rat gastric mucosal defence. METHODS: Sex differences in gastric mucus thickness and accumulation rate, absolute gastric mucosal blood flow using microspheres, the integrity of the gastric mucosal epithelium in response to a chemical irritant and the effects of oestrogen administration on relative gastric mucosal blood flow in an acute setting was assessed in an in vivo rat experimental model. Subsequently, sex differences in the distribution of oestrogen receptors and calcitonin gene related peptide in the gastric mucosa of animals exposed to oestrogen in the above experiments was evaluated using immunohistochemistry. RESULTS: The absolute blood flow in the GI-tract was generally higher in males, but only significantly different in the corpus part of the stomach (1.12 ± 0.12 mL/min•g in males and 0.51 ± 0.03 mL/min•g in females) (P = 0.002). After removal of the loosely adherent mucus layer the thickness of the firmly adherent mucus layer in males and females was 79 ± 1 µm and 80 ± 3 µm respectively. After 60 min the mucus thickness increased to 113 ± 3 µm in males and 121 ± 3 µm in females with no statistically significant difference seen between the sexes. Following oestrogen administration (0.1 followed by 1 µg/kg•min), mean blood flow in the gastric mucosa decreased by 31% [68 ± 13 perfusion units (PFU)] in males which was significantly different compared to baseline (P = 0.02). In females however, mean blood flow remained largely unchanged with a 4% (5 ± 33 PFU) reduction. The permeability of the gastric mucosa increased to a higher level in females than in males (P = 0.01) after taurocholate challenge. However, the calculated mean clearance increase did not significantly differ between the sexes [0.1 ± 0.04 to 1.1 ± 0.1 mL/min•100 g in males and 0.4 ± 0.3 to 2.1 ± 0.3 mL/min•100 g in females (P = 0.065)]. There were no significant differences between 17ß-Estradiol treated males (mean ratio of positive staining ± SEM) (0.06 ± 0.07) and females (0.11 ± 0.11) in the staining of ERα (P = 0.24). Also, there were no significant differences between 17ß-Estradiol treated males (0.18 ± 0.21) and females (0.06 ± 0.12) in the staining of ERß (P = 0.11). Finally, there were no significant differences between 17ß-Estradiol treated males (0.04 ± 0.05) and females (0.11 ± 0.10) in the staining of CGRP (P = 0.14). CONCLUSION: Gastric mucosal blood flow is higher in male than in female rats and is reduced in male rats by oestrogen administration.

Intragastric generation of antimicrobial nitrogen oxides from saliva--physiological and therapeutic considerations.

Salivary nitrite is suggested to enhance the antimicrobial properties of gastric juice by conversion to nitric oxide (NO) and other reactive nitrogen intermediates in the stomach. Intubated patients exhibit extremely low gastric levels of NO, because they do not swallow their saliva. The present investigation was designed to examine the antibacterial effects of human saliva and gastric juice. Furthermore, we studied a new mode of NO delivery, involving formation from acidified nitrite, which could prevent bacterial growth in the gastric juice of intubated patients in intensive care units. The growth of Escherichia coli ATCC 25922 and the formation of NO and nitroso/nitrosyl species were determined after incubation of gastric juice with saliva from healthy volunteers that was rich (nitrate ingestion) or poor (overnight fasting) in nitrite. In a stomach model containing gastric juice from intubated patients, we inserted a catheter with a silicone retention cuff filled with ascorbic acid and nitrite and determined the resulting antibacterial effects on E. coli and Candida albicans. Saliva enhanced the bactericidal effect of gastric juice, especially saliva rich in nitrite. Formation of NO and nitroso/nitrosyl species by nitrite-rich saliva was 10-fold greater than that by saliva poor in nitrite. In our stomach model, E. coli and C. albicans were killed after exposure to ascorbic acid and nitrite. In conclusion, saliva rich in nitrite enhances the bactericidal effects of gastric juice, possibly through the generation of reactive nitrogen intermediates, including NO. Acidified nitrite inside a gas-permeable retention cuff may be useful for restoring gastric NO levels and host defense in critically ill patients.

Intestinal nitric oxide in the normal and endotoxemic pig.

The gut is considered a central organ in the pathogenesis of sepsis and multiple organ failure, where several mediators, including endothelin (ET) and nitric oxide (NO), are involved. The aim of the current study was to characterize, by direct measurements, the intestinal NO production in the anesthetized pig during normal and endotoxemic conditions. In pigs subjected to endotoxin infusion, there was a progressive decrease in jejunal luminal NO levels, as well as portal venous blood flow and blood pressure. The ET- blocker 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfonamide (bosentan) completely reversed the reduction in portal venous blood flow without affecting intestinal NO levels. In control pigs, the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester dose-dependently decreased intestinal NO levels and mesenteric blood flow--effects that were reversed by L-arginine. We conclude that intestinal NO is a product of mucosal NO synthase activity, and is profoundly decreased during endotoxemia in the pig.

Cardioprotective effects of vegetables: is nitrate the answer?

A diet rich in fruits and vegetables is associated with a lower risk of certain forms of cancer and cardiovascular disease, but the mechanisms behind this protection are not completely understood. Recent epidemiological studies suggest a cardioprotective action afforded specifically by green leafy vegetables. We here propose that these beneficial effects are related to the high content of inorganic nitrate, which in concert with symbiotic bacteria in the oral cavity is converted into nitrite, nitric oxide, and secondary reaction products with vasodilating and tissue-protective properties.

Intragastric nitric oxide is abolished in intubated patients and restored by nitrite.

OBJECTIVE: Nitrite in saliva is reduced to nitric oxide (NO) in the acidic stomach, and this NO may serve gastroprotective functions. We studied intragastric NO levels in healthy controls and in intubated intensive care unit patients before and after supplementation with nitrite. DESIGN: Prospective observational study involving patients and controls. SETTING: A mixed intensive care unit and a university laboratory. PATIENTS AND SUBJECTS: Eight healthy volunteers and ten intubated, mechanically ventilated intensive care unit patients. INTERVENTIONS: A tonometric catheter was first evaluated in vitro and then used for all NO measurements. In fasting controls, gastric NO levels were measured repeatedly during periods of saliva depletion and after an intragastric nitrite infusion. In patients, changes in levels of intragastric NO, nitrite in plasma and gastric juice, and S-nitrosothiols in gastric juice were measured in response to an intragastric nitrite infusion. MEASUREMENTS AND MAIN RESULTS: The tonometric catheter had a recovery of 80% with a high intraclass and interclass correlation. Median baseline NO levels in healthy volunteers were 21.6 ppm (interquartile range, 11.4-22.3 ppm) and decreased by 90% to 3.3 ppm (2.0-5.2 ppm) during 25-50 mins of saliva depletion. The NO level was restored by an intragastric nitrite infusion. Baseline NO levels in patients were almost abolished (0.1 ppm [0.07-0.4 ppm]) but increased rapidly to 124 ppm (range, 65-180 ppm) during intragastric nitrite infusion. Nitrite levels in plasma increased from 0.18 +/- 0.03 to 1.3 +/- 0.2 microM (p < .01), and levels of S-nitrosothiols in gastric juice increased from 0.12 +/- 0.09 to 6.7 +/- 1.8 microM. CONCLUSIONS: Intragastric generation of NO requires continuous delivery of nitrite-containing saliva and is almost abolished in critically ill, intubated patients. Enteral supplementation with nitrite could however fully restore gastric NO levels. Future studies will reveal if low NO levels contribute to stress ulcers and gastric overgrowth of bacteria often seen in these patients and in turn if restoring gastric NO with nitrite could be a useful therapeutic approach.