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Background Hyperventilation resulting in hypocapnic alkalosis (HA) is frequently encountered in spontaneously breathing patients with acute cerebrovascular conditions. The underlying mechanisms of this respiratory response have not been fully elucidated. The present study describes, applying the physical–chemical approach, the acid-base characteristics of cerebrospinal fluid (CSF) and arterial plasma of spontaneously breathing patients with aneurismal subarachnoid hemorrhage (SAH) and compares these results with those of control patients. Moreover, it investigates the pathophysiologic mechanisms leading to HA in SAH. Methods Patients with SAH admitted to the neurological intensive care unit and patients (American Society of Anesthesiologists physical status of 1 and 2) undergoing elective surgery under spinal anesthesia were enrolled. CSF and arterial samples were collected simultaneously. Electrolytes, strong ion difference (SID), partial pressure of carbon dioxide (PCO2), weak noncarbonic acids (ATOT), and pH were measured in CSF and arterial blood samples. Results Twenty spontaneously breathing patients with SAH and 25 controls were enrolled. The CSF of patients with SAH, as compared with controls, was characterized by a lower SID (23.1 ± 2.3 vs. 26.5 ± 1.4 mmol/L, p 2 (40 ± 4 vs. 46 ± 3 mm Hg, p TOT (1.2 ± 0.5 vs. 1.2 ± 0.2 mmol/L, p = 0.95) and pH (7.34 ± 0.06 vs. 7.35 ± 0.02, p = 0.69) were observed. The reduced CSF SID was mainly caused by a higher lactate concentration (3.3 ± 1.3 vs. 1.4 ± 0.2 mmol/L, p r = 0.71, p 2. A higher proportion of patients with SAH were characterized by arterial HA, as compared with controls (40 vs. 4%, p = 0.003). A reduced CSF-to-plasma difference in PCO2 was observed in nonhyperventilating patients with SAH (0.4 ± 3.8 vs. 7.8 ± 3.7 mm Hg, p Conclusions Patients with SAH have a reduction of CSF SID due to an increased lactate concentration. The resulting localized acidifying effect is compensated by CSF hypocapnia, yielding normal CSF pH values and resulting in a higher incidence of arterial HA.

BACKGROUND: Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a high risk of postoperative acute kidney injury (AKI). Due to limitations of current diagnostic strategies, we sought to determine whether free hemoglobin (fHb) ratio (ie, levels of fHb at the end of CPB divided by baseline fHb) could predict AKI after on-pump cardiac surgery. METHODS: This is a secondary analysis of a randomized controlled trial comparing the effect of nitric oxide (intervention) versus nitrogen (control) on AKI after cardiac surgery (NCT01802619). A total of 110 adult patients in the control arm were included. First, we determined whether fHb ratio was associated with AKI via multivariable analysis. Second, we verified whether fHb ratio could predict AKI and incorporation of fHb ratio could improve predictive performance at an early stage, compared with prediction using urinary biomarkers alone. We conducted restricted cubic spline in logistic regression for model development. We determined the predictive performance, including area under the receiver-operating-characteristics curve (AUC) and calibration (calibration plot and accuracy, ie, number of correct predictions divided by total number of predictions). We also used AUC test, likelihood ratio test, and net reclassification index (NRI) to compare the predictive performance between competing models (ie, fHb ratio versus neutrophil gelatinase-associated lipocalin [NGAL], N-acetyl-β-d-glucosaminidase [NAG], and kidney injury molecule-1 [KIM-1], respectively, and incorporation of fHb ratio with NGAL, NAG, and KIM-1 versus urinary biomarkers alone), if applicable. RESULTS: Data stratified by median fHb ratio showed that subjects with an fHb ratio >2.23 presented higher incidence of AKI (80.0% vs 49.1%; P =.001), more need of renal replacement therapy (10.9% vs 0%; P =.036), and higher in-hospital mortality (10.9% vs 0%; P =.036) than subjects with an fHb ratio ≤2.23. fHb ratio was associated with AKI after adjustment for preestablished factors. fHb ratio outperformed urinary biomarkers with the highest AUC of 0.704 (95% confidence interval [CI], 0.592-0.804) and accuracy of 0.714 (95% CI, 0.579-0.804). Incorporation of fHb ratio achieved better discrimination (AUC test, P =.012), calibration (likelihood ratio test, P

Objectives To test the feasibility, safety, and efficacy of intratracheal delivery of nitric oxide (NO) generated from air by pulsed electrical discharge via a Scoop catheter. Study design We studied healthy 3- to 4-month-old lambs weighing 34 ± 4 kg (mean ± SD, n = 6). A transtracheal Scoop catheter was inserted through a cuffed tracheostomy tube. U46619 was infused to increase mean pulmonary arterial pressure (mPAP) from 16 ± 1 to 32 ± 3 mmHg (mean ± SD). Electrically generated NO was delivered via the Scoop catheter to awake lambs. A sampling line, to monitor NO and nitrogen dioxide (NO2) levels, was placed in the distal trachea of the lambs. The effect of varying doses of electrically generated NO, produced continuously, on pulmonary hypertension was assessed. Results In awake lambs with acute pulmonary hypertension, NO was continuously delivered via the Scoop catheter at 400 ml/min. NO induced pulmonary vasodilation. NO2 levels, measured in the trachea, were below 0.5 ppm at intratracheal NO doses of 10–80 ppm. No changes were detected in the levels of methemoglobin in blood samples before and after 5 min of NO breathing. Conclusions Continuously delivering electrically generated NO through a Scoop catheter produces vasodilation of the pulmonary vasculature of awake lambs with pulmonary hypertension. Transtracheal NO delivery may provide a long-term treatment for patients with chronic pulmonary hypertension as an outpatient without requiring a mask or tracheal intubation.

Background: Acid–base status in full-term pregnant women is characterised by hypocapnic alkalosis. Whether this respiratory alkalosis is primary or consequent to changes in CSF electrolytes is not clear. Methods: We enrolled third-trimester pregnant women (pregnant group) and healthy, non-pregnant women of childbearing age (controls) undergoing spinal anaesthesia for Caesarean delivery and elective surgery, respectively. Electrolytes, strong ion difference (SID), partial pressure of carbon dioxide (PaCO), and pH were measured in simultaneously collected CSF and arterial blood samples. Results: All pregnant women (20) were hypocapnic, whilst only four (30%) of the controls (13) had an arterial PaCO

BACKGROUND: When helmet CPAP is performed using a Venturi system, filters are frequently interposed in the respiratory circuit to reduce noise within the helmet. The effect of the interposition of these filters on delivered fresh gas flow and the resulting FIO2 is currently unknown. METHODS: In a bench study, 2 different Venturi systems (WhisperFlow and Harol) were used to generate 3 different gas flow/FIO2 combinations (80 L/min-FIO2 0.6, 100 L/min-FIO2 0.5, 120 L/min-FIO2 0.4). Different combinations of filters were applied at the flow generator input line and/or at the helmet inlet port. Two types of filters were used for this purpose: a heat and moisture exchanger filter and an electrostatic filter. The setup without filters was used as baseline. Gas flow and FIO2 were measured for each setup. RESULTS: Compared to baseline, the interposition of filters reduced the gas flow between 1–13% (P < .001). The application of a filter at the Venturi system or at the helmet generated a comparable flow reduction (-3 ± 2% vs-4 ± 2%, P = .12), whereas a greater flow reduction (-7 ± 4%) was observed when filters were applied at both sites (P < .001). An increase in FIO2 up to 5% was observed with filters applied. A strong inverse linear relationship (P < .001) was observed between the resulting gas flow and FIO2. CONCLUSIONS: The use of filters during helmet CPAP reduced the flow delivered to the helmet and, consequently, modified FIO2. If filters are applied, an adequate gas flow should be administered to guarantee a constant CPAP during the entire respiratory cycle and avoid rebreathing. Moreover, it might be important to measure the effective FIO2 delivered to the patient to guarantee a precise assessment of oxygenation.

Objective: To assess the different effect of filters’ application during helmet-CPAP delivered with three different flow generators on the delivered fresh gas flow, FiO2, and the noise level inside and outside the helmet. Methods: In a bench study, three flow generators (air-oxygen blender, turbine ventilator and Venturi system) were used to generate two different gas flows (60 L/min and 80 L/min), with a fixed FiO2 at 0.6, to perform a helmet-CPAP on a manikin. Three different fixed PEEP valves (7.5, 10, and 12.5 cmH2O) were applied at the expiratory port. Gas flow, FiO2 and noise were recorded for each Flow-generator/Flow/PEEP combination, first without filter interposition and then after positioning a heat and moister exchanger filter (HMEF) at the helmet inlet port. Results: The application of the HMEF lead to a significant difference in the flow variation among the three flow generators (p < 0.001). Compared to baseline, the highest flow reduction was observed with the VENTURI (−13.4 ± 1.2 %, p < 0.001), a slight increase with the BLENDER (1.2 ± 0.5 %, p < 0.001), whereas no difference was recorded with the TURBINE (0.1 ± 0.6 %, p = 0.12). After HMEF was interposed, a significant FiO2 variation was observed only with VENTURI (11.3 ± 1.8 %, p < 0.001). As for the noise, the TURBINE was the least noisy system, both with and without the filter interposition. Conclusions: Flow generators used to deliver helmet-CPAP have different characteristics and responses to HMEF interposition. Users should be aware of the effects on FiO2 and flow of the different devices in order to make a precise setup of the circuit.

Patients with sepsis are poorly protected against acute respiratory acid-base derangements due to a lower noncarbonic buffer power, which is caused both by a reduction in the major noncarbonic buffers, i.e. hemoglobin and albumin, and by a reduced buffering capacity of albumin. Electrolyte shifts from and to the red blood cells determining acute variations in strong ion difference are the major buffering mechanism during acute respiratory acid-base disorders.

Rationale: Acidemia is a severe condition among critically ill patients. Despite lack of evidence, sodium bicarbonate is frequently used to correct pH; however, its administration is burdened by several side effects. We hypothesized that the reduction of plasma chloride concentration could be an alternative strategy to correct acidemia.Objectives: To evaluate feasibility, safety, and effectiveness of a novel strategy to correct acidemia through extracorporeal chloride removal by electrodialysis.Methods: Ten swine (six treated and four control animals) were sedated, mechanically ventilated and connected to an extracorporeal electrodialysis device capable of selectively removing chloride. In random order, an arterial pH of 7.15 was induced either through reduction of ventilation (respiratory acidosis) or through lactic acid infusion (metabolic acidosis). Acidosis was subsequently sustained for 12-14 hours. In treatment pigs, soon after reaching target acidemia, electrodialysis was started to restore pH.Measurements and Main Results: During respiratory acidosis, electrodialysis reduced plasma chloride concentration by 26 ± 5 mEq/L within 6 hours (final pH = 7.36 ± 0.04). Control animals exhibited incomplete and slower compensatory response to respiratory acidosis (final pH = 7.29 ± 0.03; P

Background The effect of nitric oxide (NO) on renal function is controversial in critical illness. We performed a systematic meta-analysis and trial sequential analysis to determine the effect of NO gas on renal function and other clinical outcomes in patients requiring cardiopulmonary bypass (CPB). The primary outcome was the relative risk (RR) of acute kidney injury (AKI), irrespective of the AKI stage. The secondary outcome was the mean difference (MD) in the length of ICU and hospital stay, the RR of postoperative hemorrhage, and the MD in levels of methemoglobin. Trial sequential analysis (TSA) was performed for the primary outcome. Results 54 trials were assessed for eligibility and 5 studies (579 patients) were eligible for meta-analysis. NO was associated with reduced risk of AKI (RR 0.76, 95% confidential interval [CI], 0.62 to 0.93, I2 = 0%). In the subgroup analysis by NO initiation timing, NO did not decrease the risk of AKI when started at the end of CPB (RR 1.20, 95% CI 0.52–2.78, I2 = 0%). However, NO did significantly reduce the risk of AKI when started from the beginning of CPB (RR 0.71, 95% CI 0.54–0.94, I2 = 10%). We conducted TSA based on three trials (400 patients) using KDIGO criteria and with low risk of bias. TSA indicated a CI of 0.50–1.02 and an optimal information size of 589 patients, suggesting a lack of definitive conclusion. Furthermore, NO does not affect the length of ICU and hospital stay or the risk of postoperative hemorrhage. NO slightly increased the level of methemoglobin at the end of CPB (MD 0.52%, 95% CI 0.27–0.78%, I2 = 90%), but it was clinically negligible. Conclusions NO appeared to reduce the risk of postoperative AKI in patients undergoing CPB. Additional studies are required to ascertain the finding and further determine the dosage, timing and duration of NO administration.

IntroductionPostoperative acute kidney injury (AKI) is a common complication in cardiac surgery. Levels of intravascular haemolysis are strongly associated with postoperative AKI and with prolonged (>90 min) use of cardiopulmonary bypass (CPB). Ferrous plasma haemoglobin released into the circulation acts as a scavenger of nitric oxide (NO) produced by endothelial cells. Consequently, the vascular bioavailability of NO is reduced, leading to vasoconstriction and impaired renal function. In patients with cardiovascular risk factors, the endothelium is dysfunctional and cannot replenish the NO deficit. A previous clinical study in young cardiac surgical patients with rheumatic fever, without evidence of endothelial dysfunction, showed that supplementation of NO gas decreases AKI by converting ferrous plasma haemoglobin to ferric methaemoglobin, thus preserving vascular NO. In this current trial, we hypothesised that 24 hours administration of NO gas will reduce AKI following CPB in patients with endothelial dysfunction.MethodsThis is a single-centre, randomised (1:1) controlled, parallel-arm superiority trial that includes patients with endothelial dysfunction, stable kidney function and who are undergoing cardiac surgery procedures with an expected CPB duration >90 min. After randomisation, 80 parts per million (ppm) NO (intervention group) or 80 ppm nitrogen (N2, control group) are added to the gas mixture. Test gases (N2or NO) are delivered during CPB and for 24 hours after surgery. The primary study outcome is the occurrence of AKI among study groups. Key secondary outcomes include AKI severity, occurrence of renal replacement therapy, major adverse kidney events at 6 weeks after surgery and mortality. We are recruiting 250 patients, allowing detection of a 35% AKI relative risk reduction, assuming a two-sided error of 0.05.Ethics and disseminationThe Partners Human Research Committee approved this trial. Recruitment began in February 2017. Dissemination plans include presentations at scientific conferences, scientific publications and advertising flyers and posters at Massachusetts General Hospital.Trial registration numberNCT02836899.

Background Endogenous nitric oxide (NO) may contribute to ischemic and anesthetic preconditioning while exogenous NO protects against ischemia-reperfusion (I/R) injury in the heart and other organs. Why those beneficial effects observed in animal models do not always translate into clinical effectiveness remains unclear. To mitigate reperfusion damage a source of NO is required. NO inhalation is known to increase tissue NO metabolites, but little information exists about the lifetime of these species. We therefore sought to investigate the fate of major NO metabolite classes following NO inhalation in mice in vivo. Methods C57BL/6J mice were exposed to 80 ppm NO for 1 h. NO metabolites were measured in blood (plasma and erythrocytes) and tissues (heart, liver, lung, kidney and brain) immediately after NO exposure and up to 48 h thereafter. Concentrations of S-nitrosothiols, N-nitrosamines and NO-heme products as well as nitrite and nitrate were quantified by gas-phase chemiluminescence and ion chromatography. In separate experiments, mice breathed 80 ppm NO for 1 h prior to cardiac I/R injury (induced by coronary arterial ligation for 1 h, followed by recovery). After sacrifice, the size of the myocardial infarction (MI) and the area at risk (AAR) were measured. Results After NO inhalation, elevated nitroso/nitrosyl levels returned to baseline over the next 24 h, with distinct multi-phasic decay profiles in each compartment. S/N-nitroso compounds and NO-hemoglobin in blood decreased exponentially, but remained above baseline for up to 30min, whereas nitrate was elevated for up to 3hrs after discontinuing NO breathing. Hepatic S/N-nitroso species concentrations remained steady for 30min before dropping exponentially. Nitrate only rose in blood, liver and kidney; nitrite tended to be lower in all organs immediately after NO inhalation but fluctuated considerably in concentration thereafter. NO inhalation before myocardial ischemia decreased the ratio of MI/AAR by 30% vs controls (p = 0.002); only cardiac S-nitrosothiols and NO-hemes were elevated at time of reperfusion onset. Conclusions Metabolites in blood do not reflect NO metabolite status of any organ. Although NO is rapidly inactivated by hemoglobin-mediated oxidation in the circulation, long-lived tissue metabolites may account for the myocardial preconditioning effects of inhaled NO. NO inhalation may afford similar protection in other organs., Highlights • Breathing 80 ppm NO for 1 h increases NO metabolite concentrations, except nitrite, in murine blood/tissues. • After NO inhalation, elevated NO metabolites return to baseline in a compartment-specific manner. • Cardiac S-nitrosothiol and NO-heme levels remain elevated for ∼1 h after discontinuation of NO treatment. • Breathing 80 ppm NO for 1 h just before cardiac ischemia reduces reperfusion injury in mice.

Study objective: To assess the effect of different intraoperative blood pressure targets on the development of POCD and test the feasibility of a larger trial. Design: Randomized controlled pilot trial. Setting: Perioperative care in a tertiary care teaching hospital with outpatient follow-up. Patients: One hundred one patients aged >= 75 years with ASA physical status < 4, undergoing elective, non-cardiac surgery under general anesthesia and 33 age-matched healthy controls. Interventions: Randomization to a personalized intraoperative blood pressure target, mean arterial pressure (MAP) >= 90% of preoperative values (Target group), or to a more liberal intraoperative blood pressure management (No-Target group). Strategies to reach intraoperative blood pressure target were at discretion of anesthesiologists. Measurements: An experienced neuropsychologist performed a validated battery of neurocognitive tests preoperatively and 3 months after surgery. Incidence of POCD at three months and postoperative delirium were assessed. Intraoperative time spent with MAP >= 90% of preoperative values, recruitment and drop-out rate at 3 months were feasibility outcomes. Main results: The Target group spent a higher percentage of intraoperative time with MAP >= 90% of preoperative values (65 +/- 25% vs. 49 +/- 28%, p < 0.01). Incidence of POCD (11% vs. 7%, relative risk 1.52; 95% CI, 0.41 to 6.3; p = 0.56) and delirium (6% vs. 14%, relative risk, 0.44; 95% CI, 0.12 to 1.60; p = 0.21) did not differ between groups. No correlation was found between intraoperative hypotension and postoperative cognitive performance (p = 0.75) or delirium (p = 0.19). Recruitment rate was of 6 patients/month (95% confidential interval (CI), 5 to 7) and drop-out rate at 3 months was 24% (95% CI, 14 to 33%). Conclusions: Intraoperative hypotension did not correlate with postoperative cognitive dysfunction or delirium occurrence in elderly patients undergoing general anesthesia for non-cardiac surgery. A multicenter randomized controlled trial is needed in order to confirm the effect of intraoperative blood pressure on the development of POCD

Acidosis is a frequent disorder among critically ill patients. When patient compensatory responses fail to restore a normal pH, administration of sodium bicarbonate (NaHCO3) or renal replacement therapy may be required. Intravenous NaHCO3 increases plasma Strong Ion Difference ([SID] = [Na+] + [K+] - [Cl-]) and HCO3- concentration by raising Na+ concentration. Although effective, this treatment is not devoid of complications, such as hypernatremia, hyperosmolarity and fluid overloading[1]. Selective chloride (Cl-) removal, by increasing SID in an alternative way, may allow a rapid correction of acidosis without altering plasma osmolality and Na+ concentration.