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Importance: In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation).Objective: To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease.Design, Setting, and Participants: Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021.Interventions: Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685).Main Outcomes and Measures: The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels.Results: Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of -0.01 days (95% CI, -0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups.Conclusions and Relevance: In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery.Trial Registration: anzctr.org.au Identifier: ACTRN12617000821392. [ABSTRACT FROM AUTHOR]

Rationale: Acute changes in cardiopulmonary hemodynamics that include tricuspid regurgitant jet velocity (TRV) elevation measured by Doppler echocardiography are often encountered during sickle cell vasoocclusive pain and acute chest syndrome (ACS). Arginine and nitric oxide depletion develop in patients with these complications. Arginine administration may therefore improve nitric oxide bioavailability and potentiate pulmonary vasodilatation. Objectives: To evaluate effects of l-arginine supplementation on Doppler indices of cardiopulmonary hemodynamics in children with sickle cell anemia experiencing pain. Methods: This was a prospective, double-blinded, randomized placebo-controlled trial of oral arginine in children with sickle cell anemia age 5-17 years hospitalized with severe pain and/or ACS. Measurements and Main Results: Blood biomarkers and Doppler echocardiographic indices of cardiopulmonary hemodynamics were measured before and after supplementation. The mean change in TRV, pulmonary artery systolic pressure, mean pulmonary artery pressure, and other indices of cardiopulmonary hemodynamics were tested with paired Student's t test and correlated with markers of arginine bioavailability using Pearson correlation. Sixty-six children were randomized into arginine versus placebo groups. An elevated TRV ⩾ 2.5 m/s was seen in 40 (61%) patients. A Day 5 Doppler echocardiogram was performed in 47 patients who remained hospitalized. A greater reduction in median TRV occurred in the arginine group than placebo (22.2%, n = 22 vs. 3.8%, n = 25; p < 0.01). A larger percentage increase in global arginine bioavailability was associated with a lower TRV after 5 days of supplementation (r = -0.533; P = 0.001). Significant differences in multiple indices of cardiopulmonary hemodynamics and mean N-terminal pro B-type brain natriuretic peptide were also noted after arginine therapy. Conclusions: Oral arginine supplementation improves cardiopulmonary hemodynamics during sickle cell disease vasoocclusive pain and ACS.Clinical trial registered with Pan African Clinical Trial Registry https://pactr.samrc.ac.za/Search.aspx (PACTR201611001864290). [ABSTRACT FROM AUTHOR]

The article highlights the role of home nitric oxide therapy for COVID-19. It also mentions about infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes a range of cardiopulmonary and vascular complications, ranging from upper respiratory tract symptoms to severe acute respiratory distress syndrome (ARDS), as well as shock, acute kidney injury, and thromboembolic complications.

Aim: Pulmonary hypertension (PH) frequently complicates neonatal hypoxaemic respiratory failure, but is inconsistently defined. We aimed to describe the variation among randomised controlled trials (RCTs) of inhaled nitric oxide (iNO), in relation to the definition of PH and/or hypoxaemic respiratory failure used to select patients for trial inclusion.Methods: PubMed, Cochrane Library and ClinicalTrials.gov were systematically searched for RCTs of iNO in neonates. Included studies were assessed for clinical and/or echocardiography criteria used to define PH/hypoxaemic respiratory failure.Results: Thirty-two trials were included in this review, of which 23 enrolled infants ≥34 weeks' gestation. Echocardiographic diagnosis was used in 21 studies, but there was considerable variation in the echocardiographic parameters used to diagnose PH. The most commonly used indices included markers of tricuspid regurgitation and extrapulmonary shunt.Conclusion: There is wide variation in the definition of PH used to select infants for inclusion into RCTs of iNO therapy in neonates. We recommend that an international consensus be reached on which parameters should be used and the thresholds defining severity of disease. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to determine whether neonatal intensive care therapies increase the risk of carcinogenesis in childhood.Methods: This study used population-based data on 1 072 957 infants born in New South Wales, Australia, between 2000 and 2011 and multivariate logistic regression to examine any associations between therapies used in the neonatal intensive care unit and diagnoses of cancer until mid 2012.Results: A total of 1126 of 1 072 957 (0.1%) children were diagnosed with cancer. Cancer risk was significantly increased by preterm birth (gestation <37 weeks; adjusted odds ratio (aOR) 1.3 (95% confidence interval: 1.0-1.6), birth weight ≥4 kg (aOR 1.4, 1.2-1.6) and caesarean delivery (aOR 1.2, 1.1-1.4). Extremely preterm (<28 weeks of gestation) infants were more likely to develop hepatic tumours (aOR 12.7, 3.3-48.3) than term infants. The only therapy used in the neonatal intensive care that was independently associated with an increased risk of cancer was nitric oxide (aOR 8.6, 4.3-17.4). Eight of the 790 (1%) infants treated with nitric oxide developed cancer (gestation range 30-41 weeks, age of cancer diagnosis: four months-five years).Conclusion: Treatment with nitric oxide was associated with a higher risk of childhood cancer. These findings require further research. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between inhaled nitric oxide treatment and ICU mortality and 28-day ventilator-free days in pediatric acute respiratory distress syndrome.Design: Retrospective cohort study. A propensity score for inhaled nitric oxide treatment was developed and used in the analysis.Setting: Two quaternary care PICUs.Patients: Children with pediatric acute respiratory distress syndrome.Interventions: None.Measurements and Main Results: There were 499 children enrolled in this study with 143 (28.7%) receiving inhaled nitric oxide treatment. Children treated with inhaled nitric oxide were more likely to have a primary diagnosis of pneumonia (72% vs 54.8%; p < 0.001), had a higher initial oxygenation index (median 16.9 [interquartile range, 10.1-27.3] vs 8.5 [interquartile range, 5.8-12.2]; p < 0.001), and had a higher 72-hour maximal Vasoactive-Inotrope Score (median 15 [interquartile range, 6-25] vs 8 [interquartile range, 0-17.8]; p < 0.001) than those not receiving inhaled nitric oxide. Mortality was higher in the inhaled nitric oxide treatment group (25.2% vs 16.3%; p = 0.02), and children in this group had fewer 28-day ventilator-free days (10 d [interquartile range, 0-18 d] vs 17 d (interquartile range 5.5-22 d]; p < 0.0001). We matched 176 children based on propensity score for inhaled nitric oxide treatment. In the matched cohort, inhaled nitric oxide treatment was not associated with mortality (odds ratio, 1.3 [95% CI, 0.56-3.0]) or 28-day ventilator-free days (incidence rate ratio, 0.91 [95% CI, 0.80-1.04]). These results remained consistent in the entire study cohort when the propensity score for inhaled nitric oxide treatment was used for either inverse probability weighting or stratification in regression modeling with the exception that subjects treated with inhaled nitric oxide were more likely to have 0 ventilator-free days (p ≤ 0.02). In secondary analysis stratified by oxygenation response, inhaled nitric oxide treatment was not associated with mortality or 28-day ventilator-free days in children with a positive oxygenation response (all p > 0.2) CONCLUSIONS:: Treatment with inhaled nitric oxide in pediatric acute respiratory distress syndrome is not associated with improvement in either mortality or ventilator-free days and may be associated with harm. Further prospective trials are required to define the role of inhaled nitric oxide treatment in pediatric acute respiratory distress syndrome. [ABSTRACT FROM AUTHOR]

Background: Congenital diaphragmatic hernia (CDH) is associated with lung hypoplasia, cardiac dysfunction and pulmonary hypertension. Inhaled nitric oxide (iNO) and milrinone are commonly used pulmonary vasodilators in CDH. We studied the hemodynamic effects of iNO and milrinone in infants with CDH.Methods: A retrospective chart review was performed of all CDH infants admitted to two regional perinatal centers and infants classified into three groups: No-iNO group; iNO-responders and iNO-nonresponders. Oxygenation and hemodynamic effects of iNO and milrinone were assessed by blood gases and echocardiography.Results: Fifty-four percent (39/72) of infants with CDH received iNO and 31% of these infants (12/39) had complete oxygenation response to iNO. Oxygenation response to iNO was not associated with a decrease in right ventricular pressures (RVP) or ECMO use. Four infants (33%) in the iNO-responder group and eight infants (30%) in the iNO-nonresponder group received milrinone. Milrinone lowered RVP and improved ejection fraction (EF). Response to iNO was associated with improved oxygenation to milrinone and increased survival following ECMO (67 vs. 20% among nonresponders).Conclusions: Response to inhaled nitric oxide in combination with milrinone may be associated with improved oxygenation and better survival after ECMO in infants with CDH. [ABSTRACT FROM AUTHOR]

Background: Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(-)-ketamine isomers, or esketamine, containing just the S(+)-isomer.Methods: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 μg kg-1 min-1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point.Results: Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P=0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion.Conclusions: These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(-)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms.Clinical Trial Registration: NTR 5359. [ABSTRACT FROM AUTHOR]

The aim of this multicenter, prospective, observer‐blinded, parallel group, randomized controlled trial was to assess the safety and efficacy of EDX110, a nitric oxide generating medical device, in the treatment of diabetic foot ulcers in a patient group reflecting "real world" clinical practice compared against optimal standard care. Participants were recruited from ten hospital sites in multidisciplinary foot ulcer clinics. The ulcers were full thickness, with an area of 25–2,500 mm2 and either a palpable pedal pulse or ankle brachial pressure index > 0.5. Infected ulcers were included. Treatment lasted 12 weeks, or until healed, with a 12‐week follow‐up period. Both arms were given optimal debridement, offloading and antimicrobial treatment, the only difference being the fixed used of EDX110 as the wound dressing in the EDX110 group. 135 participants were recruited with 148 ulcers (EDX110—75; Control—73), 30% of which were clinically infected at baseline. EDX110 achieved its primary endpoint by attaining a median Percentage Area Reduction of 88.6% compared to 46.9% for the control group (p = 0.016) at 12 weeks in the intention‐to‐treat population. There was no significant difference between wound size reduction achieved by EDX110 after 4 weeks and the wound size reduction achieved in the control group after 12 weeks. EDX110 was well tolerated. Thirty serious adverse events were reported (12 in the EDX110 group, of which 4 were related to the ulcer; 18 in the control group, of which 10 were related and 1 possibly related to the ulcer), with significant reduction in serious adverse events related to the ulcer in EDX group. There was no significant difference in adverse events. This study, in a real world clinical foot ulcer population, demonstrates the ability of EDX110 to improve healing, as measured by significantly reducing the ulcer area, compared to current best clinical practice. [ABSTRACT FROM AUTHOR]

Background: Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. Here, we seek to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on risk for cardiovascular diseases, thus informing the potential utility of pharmacological stimulation of the nitric oxide pathway as a therapeutic strategy.Methods: We analyzed the association of common and rare genetic variants in 2 genes that mediate nitric oxide signaling (Nitric Oxide Synthase 3 [NOS3] and Guanylate Cyclase 1, Soluble, Alpha 3 [GUCY1A3]) with a range of human phenotypes. We selected 2 common variants (rs3918226 in NOS3 and rs7692387 in GUCY1A3) known to associate with increased NOS3 and GUCY1A3 expression and reduced mean arterial pressure, combined them into a genetic score, and standardized this exposure to a 5 mm Hg reduction in mean arterial pressure. Using individual-level data from 335 464 participants in the UK Biobank and summary association results from 7 large-scale genome-wide association studies, we examined the effect of this nitric oxide signaling score on cardiometabolic and other diseases. We also examined whether rare loss-of-function mutations in NOS3 and GUCY1A3 were associated with coronary heart disease using gene sequencing data from the Myocardial Infarction Genetics Consortium (n=27 815).Results: A genetic predisposition to enhanced nitric oxide signaling was associated with reduced risks of coronary heart disease (odds ratio, 0.37; 95% confidence interval [CI], 0.31-0.45; P=5.5*10-26], peripheral arterial disease (odds ratio 0.42; 95% CI, 0.26-0.68; P=0.0005), and stroke (odds ratio, 0.53; 95% CI, 0.37-0.76; P=0.0006). In a mediation analysis, the effect of the genetic score on decreased coronary heart disease risk extended beyond its effect on blood pressure. Conversely, rare variants that inactivate the NOS3 or GUCY1A3 genes were associated with a 23 mm Hg higher systolic blood pressure (95% CI, 12-34; P=5.6*10-5) and a 3-fold higher risk of coronary heart disease (odds ratio, 3.03; 95% CI, 1.29-7.12; P=0.01).Conclusions: A genetic predisposition to enhanced nitric oxide signaling is associated with reduced risks of coronary heart disease, peripheral arterial disease, and stroke. Pharmacological stimulation of nitric oxide signaling may prove useful in the prevention or treatment of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Purpose: Cardiopulmonary bypass induces an ischaemia-reperfusion injury and systemic inflammatory response, which contributes to low cardiac output syndrome following cardiac surgery. Exogenous nitric oxide during cardiopulmonary bypass has shown potential to ameliorate such injury. We undertook a large randomised controlled trial to investigate the clinical effects of administering nitric oxide to the cardiopulmonary bypass circuit in children.Methods: After written informed consent, children were randomised to receive 20 ppm nitric oxide to the gas inflow of the cardiopulmonary bypass oxygenator, or standard conduct of bypass.Results: 101 children received nitric oxide and developed low cardiac output syndrome less frequently (15 vs. 31 %, p = 0.007) than the 97 children who did not receive nitric oxide. This effect was most marked in children aged less than 6 weeks of age (20 vs. 52 %, p = 0.012) and in those aged 6 weeks to 2 years (6 vs. 24 %, p = 0.026), who also had significantly reduced ICU length of stay (43 vs. 84 h, p = 0.031). Low cardiac output syndrome was less frequent following more complex surgeries if nitric oxide was administered (17 vs. 48 %, p = 0.018). ECMO was used less often in the nitric oxide group (1 vs. 8 %, p = 0.014).Conclusions: Delivery of nitric oxide to the oxygenator gas flow during paediatric cardiopulmonary bypass reduced the incidence of low cardiac output syndrome by varying degrees, according to age group and surgery complexity.Clinical Trial Registration: ACTRN12615001376538. [ABSTRACT FROM AUTHOR]

Treatment of children and adults with pulmonary hypertension (PH) with or without cardiac dysfunction has improved in the last two decades. The so-called pulmonary arterial hypertension (PAH)-specific medications currently approved for therapy of adults with PAH target three major pathways (endothelin, nitric oxide, prostacyclin). Moreover, some PH centres may use off-label drugs for compassionate use. Pulmonary hypertensive vascular disease (PHVD) in children is complex, and selection of appropriate therapies remains difficult. In addition, paediatric PAH/PHVD therapy is vastly based on experience and trial data from adult rather than paediatric studies; however, the first randomised paediatric PAH trials have been conducted recently. We present consensus recommendations for the treatment of children with PH. Class of recommendation and level of evidence were assigned based on paediatric data only or on adult studies that included >10% children. After a systematic literature search and analysis of the published data, we developed treatment strategies and algorithms that can guide goal-oriented PH therapy. We discuss early combination therapy (double, triple) in patients with PAH in functional class II-IV and in those with inadequate response to the initial pharmacotherapy. In those children with progressive, severe PAH and inadequate response, advances in drug development, and interventional and surgical approaches provide promising new strategies to avoid, reverse or ameliorate right heart failure and left ventricular compression. In particular, first follow-up data indicate that Potts shunt (left pulmonary artery to descending aorta anastomosis) may be an alternative destination therapy, or bridge to bilateral lung transplantation, in end-stage paediatric PAH. [ABSTRACT FROM AUTHOR]

Acute pulmonary hypertension (PH) complicates the course of several cardiovascular, pulmonary and other systemic diseases in children. An acute rise of RV afterload, either as exacerbating chronic PH of different aetiologies (eg, idiopathic pulmonary arterial hypertension (PAH), chronic lung or congenital heart disease), or pulmonary hypertensive crisis after corrective surgery for congenital heart disease, may lead to severe circulatory compromise. Only few clinical studies provide evidence on how to best treat children with acute severe PH and decompensated RV function, that is, acute RV failure. The specific treatment in the intensive care unit should be based on the underlying pathophysiology and not only be focused on so-called 'specific' or 'tailored' drug therapy to lower RV afterload. In addition therapeutic efforts should aim to optimise RV preload, and to achieve adequate myocardial perfusion, and cardiac output. Early recognition of patients at high risk and timely initiation of appropriate therapeutic measures may prevent the development of severe cardiac dysfunction and low cardiac output. In patients not responding adequately to pharmacotherapy, (1) novel surgical and interventional techniques, temporary mechanical circulatory support with extracorporeal membrane oxygenation, (2) pumpless lung assist devices (3) and/or lung or heart-lung transplantation should be timely considered. The invasive therapeutic measures can be applied in a bridge-to-recovery or bridge-to-lung transplant strategy. This consensus statement focuses on the management of acute severe PH in the paediatric intensive care unit and provides an according treatment algorithm for clinical practice. [ABSTRACT FROM AUTHOR]

Persistent pulmonary hypertension of the newborn (PPHN) is the most common neonatal form and mostly reversible after a few days with improvement of the underlying pulmonary condition. When pulmonary hypertension (PH) persists despite adequate treatment, the severity of parenchymal lung disease should be assessed by chest CT. Pulmonary vein stenosis may need to be ruled out by cardiac catheterisation and lung biopsy, and genetic workup is necessary when alveolar capillary dysplasia is suspected. In PPHN, optimisation of the cardiopulmonary situation including surfactant therapy should aim for preductal SpO2between 91% and 95% and severe cases without post-tricuspid-unrestrictive shunt may receive prostaglandin E1 to maintain ductal patency in right heart failure. Inhaled nitric oxide is indicated in mechanically ventilated infants to reduce the need for extracorporal membrane oxygenation (ECMO), and sildenafil can be considered when this therapy is not available. ECMO may be indicated according to the ELSO guidelines. In older preterm infant, where PH is mainly associated with bronchopulmonary dysplasia (BPD) or in term infants with developmental lung anomalies such as congenital diaphragmatic hernia or cardiac anomalies, left ventricular diastolic dysfunction/left atrial hypertension or pulmonary vein stenosis, can add to the complexity of the disease. Here, oral or intravenous sildenafil should be considered for PH treatment in BPD, the latter for critically ill patients. Furthermore, prostanoids, mineralcorticoid receptor antagonists, and diuretics can be beneficial. Infants with proven or suspected PH should receive close follow-up, including preductal/postductal SpO2measurements, echocardiography and laboratory work-up including NT-proBNP, guided by clinical improvement or lack thereof. [ABSTRACT FROM AUTHOR]

Aim: Use of inhaled nitric oxide (iNO) in preterm infants is not supported by current evidence. In 2013, in Australia and New Zealand, 14% infants' ≤25 weeks of gestations were administered iNO. Within the cohort administered iNO, we aimed to identify subgroups where it may be more efficacious and compared characteristics before and after the set-up of the functional echocardiography (fEcho) programme.Methods: A retrospective audit for the period 2000-2013 involving preterm infants administered iNO in the first four weeks of life was performed. Comparisons were made between the two time epochs: up to 2007 and post-2007.Results: Eighty-five infants fulfilled the inclusion criteria; 62 (73%) were ≤28 weeks of gestation; 51 (60%) survived. Amongst survivors, gestation and birthweight were higher and oxygenation index (OI) was lower. Fourteen (16.5%) infants weighed small for gestation age; survival was lower in this subgroup (6/14, 43%, p = 0.0005). The fEcho programme increased prenitric assessments for a definitive diagnosis and monitoring; iNO was started earlier, at a lower OI with a trend towards reduced usage (hours).Conclusion: Characteristics of subgroups (within the cohort of infants ≤34 weeks of gestation) more likely to benefit from iNO therapy were identified. Use of fEcho could rationalise usage. [ABSTRACT FROM AUTHOR]

Purpose: Previous clinical trials suggested that inhaled nitric oxide (iNO) could have beneficial effects in sickle cell disease (SCD) patients with acute chest syndrome (ACS).Methods: To determine whether iNO reduces treatment failure rate in adult patients with ACS, we conducted a prospective, double-blind, randomized, placebo-controlled clinical trial. iNO (80 ppm, N = 50) gas or inhaled nitrogen placebo (N = 50) was delivered for 3 days. The primary end point was the number of patients with treatment failure at day 3, defined as any one of the following: (1) death from any cause, (2) need for endotracheal intubation, (3) decrease of PaO2/FiO2 ≥ 15 mmHg between days 1 and 3, (4) augmented therapy defined as new transfusion or phlebotomy.Results: The two groups did not differ in age, gender, genotype, or baseline characteristics and biological parameters. iNO was well tolerated, although a transient decrease in nitric oxide concentration was mandated in one patient. There was no significant difference in the primary end point between the iNO and placebo groups [23 (46 %) and 29 (58 %); odds ratio (OR), 0.8; 95 % CI, 0.54-1.16; p = 0.23]. A post hoc analysis of the 45 patients with hypoxemia showed that those in the iNO group were less likely to experience treatment failure at day 3 [7 (33.3 %) vs 18 (72 %); OR = 0.19; 95 % CI, 0.06-0.68; p = 0.009].Conclusions: iNO did not reduce the rate of treatment failure in adult SCD patients with mild to moderate ACS. Future trials should target more severely ill ACS patients with hypoxemia.Clinical Trial Registration: NCT00748423. [ABSTRACT FROM AUTHOR]

Objective:The purpose of this study was to evaluate the demographic characteristics and outcomes of neonates who were admitted to a neonatal intensive care unit and treated with inhaled nitric oxide (iNO) during the years 2000-08. The goal of studying this group of neonates was to evaluate how iNO use has evolved in infants and to estimate the frequency of off-label use of this drug in this population.Study Design:Retrospective review of the Pediatrix Clinical Data Warehouse de-identified data set. Pediatrix Medical Group provides intensive care services in 244 hospitals in 32 states and Puerto Rico. Nine (3.7%) centers provide extracorporeal membrane oxygenation.Result:There were 494 255 neonates in the data set; 4316 (0.9%) were treated with iNO. The use of iNO increased from 154 of 32 967 patients in 2000 to 921 of 75 911 patients in 2008; a 2.6-fold increase (0.47 to 1.23%). There were 155 872 infants <34 weeks estimated gestational age discharged between 1 January 2000 and 31 December 2008; 1656 (1.1%) were treated with iNO. Since approval in 2000, the reported use of iNO in neonates <34 weeks increased from 0.3 to 1.8% in 2008; a sixfold increase in the reported use of iNO. The biggest increase occurred in infants between 23 and 26 weeks' gestational age (0.8 to 6.6%). In contrast, the increase in iNO use among neonates born 34 weeks has only increased from 0.5 to 1%.Conclusion:The use of iNO has increased and the greatest increase has been the off-label use among preterm neonates. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To compare the effectiveness, safety, and affordability of isosorbide mononitrate with alendronate for postmenopausal osteoporosis. Methods: A randomized controlled trial of 60 postmenopausal women with osteoporosis. Participants were randomly assigned to receive either 20 mg daily of isosorbide mononitrate or 70 mg weekly of alendronate for 12 months. Bone mineral density (BMD) was measured using dual X-ray absorptiometry (DXA) at baseline and after 12 months. Results: Both groups showed significant improvement in BMD. Isosorbide mononitrate yielded a comparable effect to alendronate for BMD and T-score at the end of the follow-up period. For BMD and T score the mean differences between the 2 groups were –0.005 (95% CI, –0.02 to 0.03) and 0.31 (95% CI, –0.03 to 0.64), respectively. A 10.8% and 12.1% change in BMD after 12 months was seen for isosorbide mononitrate and alendronate, respectively. Conclusion: Isosorbide mononitrate is comparable to alendronate. Nitric oxide donors may be an effective and affordable therapy to improve bone mineral density. [Copyright &y& Elsevier]

Objective: Pneumonia is a frequent cause of acute respiratory distress syndrome (ARDS), and Pseudomonas aeruginosa is a leading pathogen in nosocomial pneumonia. The management of ARDS remains a major problem, and only a limited number of options can improve the oxygenation. Inhaled nitric oxide (iNO) has been widely used, although this molecule is a free radical potentially harmful through the generation of toxic radical derivatives. The goal of our study was to assess the consequences of iNO (10 ppm) in a rat model of P. aeruginosa-induced lung injury.Design: The animals were exposed for 24 h to iNO after instillation of the pathogen. Distal alveolar fluid clearance (DAFC) and epithelial and endothelial permeability were measured with a double flux of radio-labeled albumin.Results: DAFC and epithelial permeability were increased in pneumonia but not influenced by iNO. In contrast, endothelial permeability was statistically significantly higher in the pneumonic animals exposed to iNO than in the pneumonic group without iNO (0.24+/-0.03 vs 0.47+/-0.1, p<0.05). This increase was not related to the production of nitrate/nitrite, nor to the increase of the inflammatory response evaluated by cytokine levels in the bronchoalveolar lavage fluid (TNF-alpha, IL-6, IL-10). The alveolar recruitment of polymorphonuclear neutrophils was comparable in the pneumonic group exposed to iNO and the pneumonic group without iNO.Conclusion: iNO increases the endothelial permeability in P. aeruginosa pneumonia. The mechanism is not related to the production of nitrate/nitrite or to a greater inflammatory response. [ABSTRACT FROM AUTHOR]

Objective: To determine the workplace concentrations of NO and NO(2) in and around a paediatric incubator during inhaled NO (iNO) treatment and during an accidental emptying of NO cylinders into room air.Design: We simulated iNO-nasal CPAP treatment in order to assess the impact on the occupational environment. Furthermore, two full NO cylinders for therapy, 1,000 ppm, 20 litres, 150 bar and 400 ppm, 10 litres, 150 bar, were emptied as rapidly as possible into an intensive care unit (ICU) room.Setting: University hospital ICU.Measurements and Results: To correctly gauge the contribution from iNO-CPAP we constructed a system measuring breathing zone and room ventilation inlet-outlet values during a 10-ppm iNO treatment of a simulated infant. Maximal breathing zone values were 17.9 +/- 7.0 (mean +/- 95% CI) ppb for NO and 25.2 +/- 4.8 ppb for NO(2). If room inlet values were subtracted, the contributions to breathing zone values emanating from iNO-CPAP were 14.8 +/- 4.6 ppb for NO and 14.6 +/- 4.6 ppb for NO(2). At the ventilation outlet the maximal contributions were 4.2 +/- 2.9 ppb NO and 9.6 +/- 4.3 ppb NO(2). During rapid total release of a gas cylinder in the ICU room, simulating an accident, we found transient NO levels comparable to the high therapeutic dosing range, but only low NO(2) levels.Conclusions: Neither 8-h time-weighted average (TWA) nor 15 min short-term exposure limits (STEL) were exceeded during normal operation or during a simulated accident. The contribution of nitrogen oxides from treatment to workplace air were minor compared to those from ambient air. [ABSTRACT FROM AUTHOR]

Background: Inhaled nitric oxide (iNO) has been used for treatment of acute respiratory failure and pulmonary hypertension since 1991 in adult patients in the perioperative setting and in critical care.Methods: This contribution assesses evidence for the use of iNO in this population as presented to a expert group jointly organised by the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists.Conclusions: Expert recommendations on the use of iNO in adults were agreed on following presentation of the evidence at the expert meeting held in June 2004. [ABSTRACT FROM AUTHOR]

Objective: To explore the acute effects of inhaled nitric oxide (iNO) on oxygenation, respiratory rate, and CO2 levels in spontaneously breathing preterm infants treated with nasal continuous positive airway pressure (nCPAP) for moderate respiratory distress syndrome (RDS).Design and Setting: Randomized, prospective, double-blind, cross-over study in the neonatal intensive care units of a university hospital.Patients: 15 infants treated for RDS, with a median gestational age of 32 weeks (27-36), birth weight 1940 g (1100-4125), and postnatal age at the beginning of study 23 h (3-91). nCPAP pressure was kept constant at 4.3 cmH2O (3.4-5.1).Interventions: We examined effects on gas exchange and vital signs during a 30-min exposure to 10 ppm iNO or placebo gas (nitrogen).Results: Before administering test gases the baseline arterial to alveolar oxygen tension ratio (aAPO2) was 0.19+/-0.06. aAPO2 remained unchanged during placebo but increased to 0.22+/-0.05 (+20%) during iNO exposure. Respiratory rate and arterial carbon dioxide tension remained unchanged, as did heart rate, blood pressure, and methemoglobin. Follow-up at 30 days of age showed no deaths, delayed morbidity, or need for supplemental oxygen.Conclusions: Adding 10 ppm nitric oxide to nasal CPAP treatment in preterm infants suffering from RDS results in a moderate but statistically significant improvement in oxygenation, with no effect on respiratory drive or systemic circulatory parameters. [ABSTRACT FROM AUTHOR]

Objective: To determine whether nitric oxide (NO) might modulate ventilator-induced lung injury.Design: Randomized prospective animal study.Setting: Animal research laboratory in a university hospital.Subjects: Isolated, perfused rabbit heart-lung preparation.Interventions: Thirty-six isolated, perfused rabbit lungs were randomized into six groups (n = 6) and ventilated using pressure-controlled ventilation for two consecutive periods (T1 and T2). Peak alveolar pressure during pressure-controlled ventilation was 20 cm H2O at T1 and was subsequently (T2) either reduced to 15 cm H2O in the three low-pressure control groups (Cx) or increased to 25 cm H2O in the three high-pressure groups (Px). In the control and high-pressure groups, NO concentration was increased to approximately equal to 20 ppm (inhaled NO groups: CNO, PNO), reduced by NO synthase inhibition (L-NAME groups: CL-Name, PL-Name), or not manipulated (groups CE, PE).Measurements and Main Results: Changes in ultrafiltration coefficients (deltaKf [vascular permeability index: g.min(-1).cm H2O(-1).100 g(-1)]), bronchoalveolar lavage fluid 8-isoprostane, and NOx (nitrate + nitrite) concentrations were the measures examined. Neither L-NAME nor inhaled NO altered lung permeability in the setting of low peak alveolar pressure (control groups). In contrast, L-NAME virtually abolished the change in permeability (deltaKf: PL-Name (0.10 +/- 0.03) vs. PNO [1.75 +/- 1.10] and PE [0.37 +/- 0.11; p <.05]) and the increase in bronchoalveolar lavage 8-isoprostane concentration induced by high-pressure ventilation. Although inhaled NO was associated with the largest change in permeability, no significant difference between the PE and PL-NAME groups was observed. The change in permeability (deltaKf) correlated with bronchoalveolar lavage NOx (r2 =.6; p <.001).Conclusions: L-NAME may attenuate ventilator-induced microvascular leak and lipid peroxidation and NO may contribute to the development of ventilator-induced lung injury. Measurement of NO metabolites in the bronchoalveolar lavage may afford a means to monitor lung injury induced by mechanical stress. [ABSTRACT FROM AUTHOR]

Inhaled nitric oxide (iNO) was first used in neonatal practice in 1992 and has subsequently been used extensively in the management of neonates and children with cardiorespiratory failure. This paper assesses evidence for the use of iNO in this population as presented to a consensus meeting jointly organised by the European Society of Paediatric and Neonatal Intensive Care, the European Society of Paediatric Research and the European Society of Neonatology. Consensus Guidelines on the Use of iNO in Neonates and Children were produced following discussion of the evidence at the consensus meeting. [ABSTRACT FROM AUTHOR]

Pulmonary hypertension is an uncommon, yet devastating, syndrome with a complex underlying pathobiology. Hypoxia, inflammation, and increased shear stress appear to be the primary pathogenic events; however, mechanisms by which these processes lead to pulmonary hypertension remain incompletely understood. The ultimate increase in pulmonary vascular resistance is attributed to remodelling of the walls of resistance vessels, which can lead to encroachment on and reduction of the vascular lumen. The number of blood vessels per unit of cross-sectional area in the hypertensive lung is also reduced, which can contribute to increased vascular resistance. Regardless of its etiology, endothelial dysfunction underlies pulmonary hypertension, one manifestation of which is the attenuated production of bioactive nitric oxide. Nitric oxide administration can exert beneficial effects at various stages of the disease. Here we review the known pathobiology of pulmonary hypertension, with a principal focus on endothelial nitric oxide, and also summarize the data on nitric oxide replacement therapy and other novel therapies that relate to nitric oxide as one approach to treatment. [ABSTRACT FROM AUTHOR]

Objective: To investigate the acute effects of intravenous sildenafil on haemodynamics and oxygenation, and its interaction with inhaled nitric oxide (iNO) in infants at risk of pulmonary hypertension early after cardiac surgery.Design: Prospective, randomised trial.Setting: Paediatric intensive care unit of a children's hospital.Patients and Participants: Sixteen ventilated infants early after closure of ventricular or atrioventricular septal defects, were randomly assigned to one of two groups. The study was completed in 15 infants.Interventions: Studies were commenced within 7 h of separation from bypass. Seven infants received iNO (20 ppm) first, with the addition of intravenous sildenafil (0.35 mg/kg over 20 min) after 20 min. Eight infants received sildenafil first, iNO was added after 20 min. Vascular pressures, cardiac output and a blood gas were recorded at 0, 20 and 40 min.Measurements and Results: In infants receiving iNO first, iNO lowered the pulmonary vascular resistance index (PVRI) from 3.45 to 2.95 units (p=0.01); sildenafil further reduced PVRI to 2.45 units p<0.05). In those receiving sildenafil first, PVRI was reduced from 2.84 to 2.35 units (p<0.05) with sildenafil, and fell to 2.15 units (p=0.01) with the addition of iNO. In both groups, sildenafil reduced the systemic blood pressure and systemic vascular resistance (p<0.01) and worsened arterial oxygenation and the alveolar-arterial gradient (p<0.05).Conclusion: Intravenous sildenafil augmented the pulmonary vasodilator effects of iNO in infants early after cardiac surgery. However, sildenafil produced systemic hypotension and impaired oxygenation, which was not improved by iNO. [ABSTRACT FROM AUTHOR]

Background: Pulmonary hypertension is a frequent complication of severe chronic obstructive pulmonary disease (COPD) and a major cause of morbidity and mortality in this condition. Based on the improved survival of these patients due to long term oxygen therapy and the potent and selective pulmonary vasodilation by inhaled nitric oxide, the safety and effectiveness of the combined inhalation of these two gases over a 3 month period was assessed.Methods: Forty patients with secondary pulmonary hypertension due to COPD were randomly assigned to receive either oxygen alone or "pulsed" inhalation of nitric oxide with oxygen over a period of 3 months. "Pulsed" inhalation of nitric oxide was used to reduce pulmonary ventilation-perfusion mismatch and formation of toxic reaction products of nitric oxide and oxygen.Results: Compared with oxygen alone, the combined inhalation of nitric oxide and oxygen caused a significant decrease in mean (SE) pulmonary artery pressure (from 27.6 (4.4) mm Hg to 20.6 (4.9) mm Hg, p<0.001) and pulmonary vascular resistance index (from 569.7 (208.1) to 351.3 (159.9) dyne x s(-1) x cm(-5) x m(-2), p<0.001) without decreasing arterial oxygenation. Cardiac output increased by 0.5 litres (from 5.6 (1.3) l/min to 6.1 (1.0) l/min, p=0.025). Systemic haemodynamics and left heart function remained unchanged during this period and no increase in toxic reaction products of nitric oxide was observed.Conclusions: This is the first controlled trial indicating that the "pulsed" inhalation of nitric oxide together with oxygen may be safely and effectively used for the long term treatment of severe COPD. [ABSTRACT FROM AUTHOR]

Objective. Inhaled nitric oxide (NO) is used as a therapy of pulmonary hypertension in children after cardiac surgery. Hemoglobin binds to NO with great affinity and forms methemoglobin by oxidation in the erythrocyte. Once produced, methemoglobin is unable to transport and unload oxygen in the tissues. The amount of available hemoglobin in the body for oxygen transport is thereby reduced. Anemia, acidosis, respiratory compromise and cardiac disease may render patients more susceptible than expected for a given methemoglobin level. The goal of the present study was to review the cumulative effect of inhaled NO on methemoglobin formation in critically ill children. We therefore looked for methemoglobin levels in children with congenital heart disease after cardiac surgery who were treated with inhaled NO in a range of 5–40 ppm. Methods. We retrospectively reviewed the medical charts of 38 children with congenital heart disease after cardiac surgery. We extracted demographic data and physiological measurements at the following time points: (1) T0 = before starting inhaled NO therapy, (2) T1 = 24 h after the beginning of inhaled NO therapy, (3) T2 = half-time therapy, (4) T3 = end of therapy, (5) T4 = 24 h after finishing inhaled NO therapy. Results. The median duration of inhaled NO therapy was 5.5 days (interquartile range 6, range 2–29), NO concentrations at T1 and T2 were 16 ppm (10, 5–40) and 12.5 ppm (12.3, 2–40), respectively. The median cumulative dose of inhaled NO was 1699 ppm (2313, 193–7018). Methemoglobin levels increased moderately, but significantly, during therapy ( T0 vs T1 p<0.05 and T0 vs T2 p<0.001). The highest methemoglobin level measured was 3.9%. Methemoglobin levels correlated positively with the inhaled NO doses applied at T1 (r2=0.8376; p<0.01) and at T2 (r2=0.8945; p<0.01). At T1 the methemoglobin level correlated negatively with the T1 blood pH value. The overall mortality rate was 13.2% (5 of 38 study patients died). There was no significant difference in methemoglobin levels between survivors and non-survivors. Conclusion. We conclude from our data that the use of inhaled NO therapy for children with congenital heart disease after cardiac surgery in the described range of 5–40 ppm, resulting in a maximum of 4% methemoglobin blood level, is feasible and safe. However, we recommend the use of the minimal effective dose of inhaled NO and continuous monitoring of methemoglobin levels, especially in cases of anemia or sepsis in critically ill children. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of inhaled nitric oxide (iNO) and partial liquid ventilation (PLV) on oxygenation and pulmonary haemodynamics in acute lung injury (ALI), and to assess their effects on lung function, systemic haemodynamics and lung injury.Methods: Using saline lung lavage, ALI was induced in 18 piglets. A control group was ventilated with conventional mechanical ventilation (CMV) for 2 h. An iNO-first group received iNO for the first hour and then iNO with PLV. A PLV-first group received PLV for the first hour and then PLV with iNO. Variables were measured at baseline, 5 min postlavage, and at 1 h and 2 h postlavage.Results: During the first hour, both treatment groups showed improvement in oxygenation index (OI). At 2 h, the dif-ferences in OI were statistically significant (P = 0.037), with a mean +/- SD of 23.8 +/- 20.7 in the control group, 4.4 +/- 0.9 in the PLV-first group and 6.5 +/- 3.1 in the iNO-first group. The OI was similar in both treatment groups (P = 0.178). At 2 h, the pulmonary artery pressure (PAP) was significantly different (P = 0.04) between groups, with a mean +/- SD PAP of 36.3 +/- 7.2 mmHg in the control group, 27.4 +/- 4.0 mmHg in the PLV-first group and 30.0 +/- 4.1 mmHg in the iNO-first group. The PAP was similar in both treatment groups (P = 0.319).Conclusion: In ALI, oxygenation and pulmonary hypertension are improved with PLV and iNO given together, regardless of the order in which they are commenced. [ABSTRACT FROM AUTHOR]

Coronary artery reperfusion is widely used to restore blood flow in acute myocardial infarction and limit its progression. However, reperfusion of ischemic myocardium results in reperfusion injury and persistent ventricular dysfunction even when achieved after brief periods of ischemia. Normally, small amounts of nitric oxide (NO) generated by endothelial NO synthase (eNOS) regulates vascular tone. Ischemia-reperfusion triggers the release of oxygen free radicals (OFRs) and a cascade involving endothelial dysfunction, decreased eNOS and NO, neutrophil activation, increased cytokines and more OFRs, increased inducible NO synthase (iNOS) and marked increase in NO, excess peroxynitrite formation, and myocardial injury. Low doses of NO appear to be beneficial and high doses harmful in ischemia-reperfusion. eNOS knock-out mice confirm that eNOS-derived NO is cardioprotective in ischemia-reperfusion. iNOS overexpression increases peroxynitrite but did not cause severe dysfunction. Increased angiotensin II (AngII) after ischemia-reperfusion inactivates NO, forms peroxynitrite and produces cardiotoxic effects. Beneficial effects of angiotensin-converting-enzyme inhibition and AngII type 1 (AT(1)) receptor blockade after ischemia-reperfusion are partly mediated through AngII type 2 (AT(2)) receptor stimulation, increased bradykinin and NO. Interventions that enhance NO availability by increasing eNOS might be beneficial after ischemia-reperfusion. [ABSTRACT FROM AUTHOR]

Mitral stenosis (MS) is associated with elevated left atrial pressure, increased pulmonary vascular resistance (PVR), and pulmonary hypertension (PH). The hemodynamic effects of inhaled nitric oxide (NO) in adults with MS are unknown. We sought to determine the acute hemodynamic effects of inhaled NO in adults with MS and PH. Eighteen consecutive women (mean age 58 +/- 15 years) with MS and PH underwent heart catheterization. Hemodynamic measurements were recorded at baseline, after NO inhalation at 80 ppm, and after percutaneous balloon valvuloplasty (n = 10). NO reduced pulmonary artery systolic pressure (62 +/- 14 mm Hg [baseline] vs 54 +/- 15 mm Hg [NO]; p <0.001) and PVR (3.7 +/- 2.5 Wood U [baseline] vs 2.2 +/- 1.4 Wood U [NO]; p <0.001). NO had no effect on mean aortic pressure, left ventricular end-diastolic pressure, left atrial pressure, cardiac output, or systemic vascular resistance. Mitral valve area increased after valvuloplasty (0.9 +/- 0.2 cm2 [baseline] vs 1.6 +/- 0.3 cm2 [postvalvuloplasty]; p <0.001). A decrease in left atrial pressure (25 +/- 4 mm Hg [baseline] vs 17 +/- 4 mm Hg [after valvuloplasty]; p <0.001) and pulmonary artery systolic pressure (58 +/- 12 mm Hg [baseline] vs 45 +/- 8 mm Hg [after valvuloplasty]; p <0.001) was observed after valvuloplasty. No change in cardiac output or PVR was observed. Thus inhaled NO, but not balloon valvuloplasty, acutely reduced PVR in women with MS and PH. This suggests that a reversible, endothelium-dependent regulatory abnormality of vascular tone is an important mechanism of elevated PVR in MS. [ABSTRACT FROM AUTHOR]

Objective: High-frequency ventilation (HFV) and/or inhaled nitric oxide (iNO) has reduced ECMO in neonates. But, frequently, improvement with HFV/iNO is temporary and only prolongs lung injury without preventing ECMO. We tried to identify a threshold oxygenation index (OI) that predicts temporary or persistent improvement with HFV/iNO in neonatal ECMO candidates as early as possible.Design: Cohort study of all neonates with OI > 40 during intermittent positive pressure ventilation between 1992 and 1997. The first treatment was HFV; at an OI > 40 during HFV, iNO was added; at an OI > 40 during HFV+iNO, ECMO was initiated. Temporary improvement was defined as secondary need for ECMO or fatal chronic lung disease without ECMO.Setting: University hospital level III neonatal intensive care unit.Main Results: Ten of the 34 neonates studied rapidly required ECMO despite HFV/iNO. Eleven neonates temporarily improved for 1-10 days before the OI was again > 40. Nine received ECMO, two were denied ECMO after mechanical ventilation > 14 days and died of chronic lung disease. Thirteen neonates persistently improved with HFV/iNO without ECMO. The OI before, at 24 h or 48 h of HFV/iNO did not predict temporary or persistent improvement. However, after 72 h of HFV/iNO, neonates with persistent improvement had lower OIs than those with temporary improvement [median OI 16 (4-24) vs 31 (20-40); P = 0.0004]. In all neonates with an OI > or = 25 after 72 h, HFV/iNO eventually failed (positive predictive value 100%, sensitivity 91 %, specificity 100%, positive likelihood ratio 91).Conclusion: For neonates pretreated with HFV/iNO, an OI > 40 is an inadequate ECMO indication. Based on our data we hypothesize that an OI > or = 25 after 72 h of HFV/ iNO is a better ECMO indication that avoids prolonged barotrauma. [ABSTRACT FROM AUTHOR]

Recent studies suggest that nitric oxide (NO) plays an important role in nitrate-induced headache and in spontaneous migraine attacks. Organic nitrates act as prodrugs for NO and headache is a predominant adverse effect of nitrates but often disappears during continuous treatment. Insight into tolerance to headache could lead to insight into vascular headache mechanisms in general. The specific aim of the present study was therefore to characterize the headache and accompanying symptoms during continuous nitrate administration until a state of tolerance to headache had developed. 5-isosorbide-mononitrate (5-ISMN) 30 mg three times daily was administered orally for 7 days in 11 healthy subjects in a double-blind, randomized placebo controlled cross-over design. Wash-out between periods was 14 days or more. Haemodynamic data from the present study were compared to the observed changes of headache over time. Headache during 5-ISMN was longer lasting and more severe compared to placebo (P<0.004). In 10 subjects the headache fulfilled the pain sub-criteria for migraine and in five subjects all diagnostic criteria for migraine without aura were fulfilled. Conversely, 20 min of intravenous infusion of glyceryl trinitrate caused a milder headache and no migraine. The present results therefore suggest that NO may elicit a migraine attack in many healthy subjects if a high enough dose is given for several hours. A close temporal association between the disappearance of headache and the attenuation of the 5-ISMN induced dilatation of the superficial temporal artery was observed. In contrast, tolerance in the middle cerebral artery already appeared after 24 h, which was earlier than the development of tolerance to headache. If vasodilatation is the cause of headache the results point to extracerebral arteries. However, cytotoxic and pain modulating central nervous system effects of NO, the time courses of which are unknown, may also play a role, involving both intra- and extracranial arteries. [ABSTRACT FROM AUTHOR]

Unlabelled: The aims of the present study were to investigate whether induction of nitrate tolerance is a useful treatment in cluster headache and to correlate any changes in attack frequency of cluster headache and nitrate-induced headache to the vascular adaptation during continuous nitrate administration. The results were compared to results obtained from studies of nitrate tolerance in healthy subjects. Materials and Methods: 5-isosorbide-mononitrate (5-ISMN) 30 mg was administered orally three times daily for 4 weeks in nine sufferers of chronic cluster headache in a double-blind, randomized placebo-controlled cross-over design. Blood velocity in the middle cerebral artery was measured with transcranial Doppler and the diameters of the temporal and radial arteries were measured with high frequency ultrasound. The haemodynamic data were compared to changes in the frequency of cluster headache attacks and interval headaches over time. Results: Tolerance was complete within 24 h in the middle cerebral arteries and after 7 days in the symptomatic temporal artery, while tolerance of the radial artery was not observed within this period. The time profiles of tolerance were almost identical to the time profiles observed in healthy subjects. A close temporal association between the disappearance of nitrate-induced headache and tolerance of the temporal artery was observed but tolerance had no effect on cluster headache attack frequency. Conclusions: Induction of tolerance to nitrates cannot be used to treat cluster headache. If pain is related to arterial dilatation the results point to extracerebral rather than cerebral arteries as the site of nociception. However, other peripheral and central pain-modulating effects of nitric oxide, the time courses of which are unknown, should also be taken into consideration. [ABSTRACT FROM AUTHOR]

The necessity for postoperative inhaled nitric oxide (NO) therapy and predictive factors for that need were retrospectively analysed in 457 paediatric patients at risk of pulmonary hypertensive events following open-heart surgery for congenital heart disease. Inhaled NO was given postoperatively to 46% of the study group and to 23% of all patients undergoing open-heart surgery during the study period. Factors associated with increased need for postoperative NO were age <1 year, Down's syndrome, preoperative pulmonary hypertension and increased pulmonary vascular resistance. Using a multivariate model based on these factors, 73% of the patients who were given NO were identified. Thus, in a setting with unrestricted access to NO therapy, almost half of the patients with cardiac lesions that commonly give rise to postoperative pulmonary hypertension were given postoperative NO. Seventy-three percent of postoperative NO treatment was associated with a relatively small number of pre- and perioperative patient-related risk factors. [ABSTRACT FROM AUTHOR]

Background: Inhaled nitric oxide (iNO) is a potential therapeutic agent for the management of acute respiratory distress syndrome (ARDS). Concerns remain, however, regarding the potential toxicity from iNO and/or its oxidative derivatives and methaemoglobinaemia.Aims: To determine the risk of toxicity from iNO, which includes worsening of lung injury, a prospective study evaluating the acute effects of three concentrations of iNO on gas exchange and haemodynamics in 12 children with ARDS was performed in a tertiary paediatric intensive care unit.Intervention: iNO was administered for one hour at three concentrations (1, 10, and 20 parts per million (ppm)) in a random order of possible dosing schedules to avoid dose accumulation bias. Arterial blood gas, methaemoglobin concentrations, and haemodynamic parameters were obtained at baseline before commencement of iNO, at the end of each study hour, and after iNO was discontinued. Nitric oxide and nitrogen dioxide concentrations were continuously monitored during the study.Results: iNO significantly improved the oxygenation ratio (Pao2/Fio2) from a mean (SEM) baseline of 11.9 (1.7) kPa to 20 (3.9) kPa, 24 (4.5) kPa, and 21.6 (3.9) kPa at 1, 10, and 20 ppm iNO, respectively. There was no significant difference in the improvement in oxygenation achieved between the three concentrations. Correspondingly, there was a significant improvement in oxygenation index (pre-iNO 28.3 (5) v post-iNO 18 (3) (1 ppm), 15 (3) (10 ppm), 16 (3) (20 ppm)). No toxicity from methaemoglobinaemia or nitrogen dioxide was seen during iNO administration.Conclusion: The results show that a low concentration of iNO (1 ppm) is as effective as higher concentrations (10 and 20 ppm) in improving oxygenation in children with ARDS and may be important in minimising toxicity during iNO use. [ABSTRACT FROM AUTHOR]

Objective: Although unlicensed, inhaled nitric oxide (NO) therapy is now widely used in the United Kingdom. Our aim was to produce guidelines for the clinical application of inhaled NO in adult intensive care practice, based upon the current level of published information.Methods: The published data regarding the use of inhaled NO in the acute respiratory distress syndrome and right-sided cardiac failure was presented, analysed and discussed. Recommendations based on these data as well as on current experience in the United Kingdom were formulated.Design: An expert group comprising intensive care specialists from within the United Kingdom, representatives from the European Society of Intensive Care Medicine and the Society of Critical Care Medicine and individuals from the Departments of Health and Industry related to the field was assembled.Results: United Kingdom guidelines for the indications, contraindications, dose, delivery, monitoring and scavenging of inhaled NO therapy were produced.Conclusions: The need for additional quality research to establish evidence of efficacy and safety was emphasized. The guidelines are designed to act within the context of current practice and knowledge and should be revised as further data emerge. [ABSTRACT FROM AUTHOR]

Objective: Inhalation of nitric oxide (NO) can improve oxygenation and decrease mean pulmonary artery pressure (MPAP) in patients with the acute respiratory distress syndrome (ARDS). It is not known whether inhaled NO exerts a similar effect in hypoxemic patients with chronic obstructive pulmonary disease (COPD). Design: Prospective clinical study. Setting: General intensive care unit in Sabadell, Spain. Patients: Nine mechanically ventilated COPD patients (mean age 72±2 years; forced expiratory volume in 1 s 0.91±0.11 l) and nine ARDS patients (mean age 57±6 years; mean lung injury score 2.8±0.1) Measurements and results: We measured hemodynamic and gas exchange parameters before NO inhalation (basal 1), during inhalation of 10 ppm NO (NO-10), and 20 min after NO was discontinued (in basal 2) in the ARDS group. In the COPD group, these parameters were measured before NO inhalation (basal 1), during different doses of inhaled NO (10, 20, and 30 ppm), and 20 min after NO was discontinued (basal 2). A positive response to NO was defined as a 20% increment in basal arterial partial pressure of oxygen (PaO2). MPAP and pulmonary vascular resistance (PVR) decreased significantly, while other hemodynamic parameters remained unchanged after NO-10 in both groups. Basal oxygenation was higher in the COPD group (PaO2/FIO2 (fractional inspired oxygen) 190±18 mmHg) than in the ARDS group (PaO2/FIO2 98±12 mmHg), ( p<0.01). After NO-10, PaO2/FIO2 increased (to 141±17 mmHg, p<0.01) and Qva/Qt decreased (39±3 to 34±3%, p<0.01) in the ARDS group. There were no changes in PaO2/FIO2 and Qva/Qt when the NO concentration was increased to 30 ppm in the COPD group. In both groups, a correlation was found between basal MPAP and basal PVR, and between the NO-induced decrease in MPAP and in PVR. The NO-induced increase in PaO2/FIO2 was not correlated with basal PaO2/FIO2. In the ARDS group, six of the nine patients (66%) responded to NO and in the COPD group, two of nine (22%) ( p=0.05). Conclusions: NO inhalation had similar effects on hemodynamics but not on gas exchange in ARDS and COPD patients, and this response probably depends on the underlying disease. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy of nitric oxide (NO) inhalation against endotoxin-induced lung injury.Design: Randomized prospective short-term study.Setting: University school of Medicine Laboratory.Interventions: Animal experiment (using 16 Japanese white rabbits). The animals inhaled NO at a concentration of 10 ppm.Measurements and Results: The rabbits were randomly divided into the NO inhaling group (n = 7) and the control group (n = 9). Both groups received continuous infusion of 1200 mcg lipopolysaccharide (LPS) and the NO group inhaled 10 ppm NO during the LPS administration. In the control group, severe right ventricular (RV) failure was observed at 30-90 min of LPS infusion, and 4 of 9 animals died within 90 min of LPS infusion. In the NO group, none of the animals died and the early phase hemodynamic deterioration was milder than in the control group. But pulmonary gas exchange was not significantly different between the two groups throughout the study. At the end of the study there were no significant differences in any parameters of the surviving animals between the two groups.Conclusion: Although an improvement of pulmonary gas exchange was not demonstrated, NO inhalation (10 ppm) improved the outcome of severe RV failure caused by LPS infusion. [ABSTRACT FROM AUTHOR]

Objectives: To compare the effects of inhaled nitric oxide and aerosolized prostacyclin (PGI2) on hemodynamics and gas exchange as well as on the indocyanine-green plasma disappearance rate and gastric intramucosal pH in patients with septic shock.Design: Prospective, randomized, interventional clinical study.Setting: Intensive care unit in a university hospital.Patients: Sixteen patients with pulmonary hypertension and septic shock according to the criteria of the ACCP/SCCM consensus conference all requiring norepinephrine and/or epinephrine to maintain mean arterial blood pressure above 65 mmHg.Methods and Interventions: Patients were randomly assigned to receive either nitric oxide or aerosolized prostacyclin. Nitric oxide was inhaled using a commercially available delivery system, prostacyclin was administered with a modified ultrasound nebulizer. Both nitric oxide and prostacyclin were incrementally adjusted to obtain a 15% decrease of mean pulmonary artery pressure. Hemodynamics and gas exchange as well as indocyanine-green plasma disappearance rate and gastric intramucosal pH were determined at baseline after 90 min in steady state, after 90 min of nitric oxide inhalation or prostacyclin aerosol administration had elapsed in stable conditions, and after 90 min in stable conditions after nitric oxide or prostacyclin withdrawal.Results: Both inhaled nitric oxide and aerosolized prostacyclin selectively reduced the mean pulmonary artery pressure from 35 +/- 4, 30 +/- 4 mmHg (p < 0.05) and 34 +/- 4 to 30 +/- 3 mmHg (p < 0.05) respectively; after removal of nitric oxide and prostacyclin, the mean pulmonary artery pressure returned to the baseline values. Systemic hemodynamics remained unaltered during the vasodilator treatment. While the mean PaO2 was not significantly influenced, it increased in 4/8 of the NO- and 3/8 of the PGI2-treated patients. Neither of the drugs influenced indocyanine-green plasma disappearance rate, but prostacyclin--unlike nitric oxide--significantly increased gastric intramucosal pH (from 7.26 +/- 0.07 to 7.30 +/- 0.05, p < 0.05) which remained elevated in four of these patients after prostacyclin removal, and decreased the arterial-gastric mucosal pressure of carbon dioxide gap from 19 +/- 6 to 15 +/- 4 mmHg (p < 0.05).Conclusions: Our data suggest that aerosolized prostacyclin--unlike nitric oxide--has similar beneficial effects on splanchnic perfusion and oxygenation as intravenous prostacyclin without detrimental effects on systemic hemodynamics. The different effects of prostacyclin and nitric oxide might be explained by the longer half-life of prostacyclin associated with a certain spillover into the systemic circulation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the dose response of inhaled nitric oxide (NO) on gas exchange and central haemodynamics in patients with early acute lung injury (ALI).Design: Prospective, multicentre clinical study.Setting: General ICUs in university and regional hospitals.Patients: 18 Patients with early ALI according to specified criteria.Interventions: During controlled ventilation an inhalation system was used to deliver NO (1000 ppm in N2) and O2/air to the low pressure fresh gas inlet of a Siemens 900C ventilator. Haemodynamics and pulmonary gas exchange variables were measured at baseline and at stepwise increased inspiratory NO concentrations of 0.1, 0.3, 1, 3, 10, 30 and 100 ppm, each dose being maintained for 15 min. Dose testing was repeated the next day, and the response to prolonged (2 h) NO inhalation at 1 and 10 ppm was also tested.Measurements and Results: Inhalation of NO produced a significant increase in PaO2 (P < 0.0025). The degree of response, as well as the optimal NO dose varied in individual patients and between different days. Venous admixture (QVA/QT) was reduced (P < 0.02) from 38% (31-46%) to 33% (26-41%). In our patients with early acute lung injury and only a moderate elevation in pulmonary arterial pressure NO inhalation did not reduce mean pulmonary artery pressure significantly, being 27.0 (21-30) mmHg at baseline and 26.0 (21-30) mm Hg at 100 ppm.Conclusions: This study shows that improvements in arterial oxygenation in response to inhaled NO may show great inter- as well as intraindividual variability, and that improvements in arterial oxygenation occur without any measurable lowering of the pulmonary artery pressure. [ABSTRACT FROM AUTHOR]

Objectives: Inhalation of nitric oxide (NO) selectively dilates pulmonary vessels in well-ventilated regions. Prostaglandin F2 alpha (PGF2 alpha) is a vasoconstrictor and is reported to enhance hypoxic pulmonary vasoconstriction. The objective of this study was to examine whether the combination of intravenous PGF2 alpha and inhaled NO in ARDS lungs has a beneficial effect on oxygenation.Design: We investigated the effect of intravenous PGF2 alpha infusion (0.05-10.0 micrograms/kg per min) with and without NO inhalation (60 ppm) on the hemodynamics and gas exchange in an ovine ARDS model, examining the pulmonary artery pressure versus the flow plot by varying cardiac output.Measurements and Results: After lung lavage, NO inhalation reduced the mean pulmonary arterial pressure (MPAP) by decreasing the zero-flow pressure intercept from 10.6 +/- 3.8 (mean +/- SD) to 8.5 +/- 3.8 mmHg (p < 0.05) with no significant change in slope. NO inhalation improved PaO2 from 56 +/- 12 to 84 +/- 38 mmHg (p < 0.005) and reduced pulmonary shunt from 65 +/- 5 to 53 +/- 8% (Qs/Qt) (p < 0.001). The dose-dependent effects of PGF2 alpha infusion were: (1) increased MPAP attributed to an increased slope in pulmonary artery pressure-flow plot; (2) decreased cardiac index; (3) decreased Qs/Qt with unchanged PaO2. The dose-dependent decrease in Qs/Qt after PGF2 alpha infusion was attributed to the decreased cardiac output.Conclusions: It is suggested that inhalation of NO reduced the critical vascular pressure near alveoli without affecting upstream vessels, while infused PGF2 alpha constricted the larger upstream pulmonary artery vessels without appreciably affecting the critical pressure. Inhalation of NO into well-ventilated lung areas shifted perfusion to well-oxygenated areas, and there was no supplemental shift in blood flow by adding an infusion of PGF2 alpha. [ABSTRACT FROM AUTHOR]

Objective: To assess changes associated with nitric oxide (NO) discontinuation in neonates receiving inhalational NO therapy as a treatment for pulmonary hypertension of the neonate (PPHN).Design: Prospective study.Setting: A pediatric PICU in a university hospital.Patients and Methods: Ten neonates were included. NO discontinuation was attempted when the oxygenation index fell below 10. The mean NO concentration was 4.9 +/- 0.8 ppm. Each infant was studied over three successive 5-min periods and was assigned to either group 1 (NO1+, NO2+, NO-) or group 2 (NO1+, NO-, NO2+).Measurements and Results: Postductal transcutaneous PO2 (tcPO2), postductal oxygen saturation with pulse oxymetry (SpO2), systolic and diastolic blood pressure (BP), heart rate (HR), left ventricular shortening fraction (LVSF), cardiac output (CO), and ratio of pulmonary artery time to peak velocity and right ventricular ejection time (TPV/RVET) were similar during the two successive NO+ periods (group 1), thus demonstrating that the measurements were reproducible. NO removal (groups 1 and 2) did not modify systolic or diastolic BP, HR, CO, or LVSF but did induce a significant decline in SpO2, tcPO2 (- 25 +/- 5%) and TPV/RVET ratio (- 25 +/- 3%). No reinstitution reversed the effects of NO withdrawal on tcPO2, SpO2 and TPV/RVET ratio (group 2) without any changes in systemic hemodynamics.Conclusion: The shut-off of low-dose NO induced in each patient a decrease in oxygen delivery that may be due to increased pulmonary vascular resistances and/or redistribution of pulmonary blood flow with ventilation-perfusion mismatching. The optimum weaning-off procedure of inhalational NO remains to be determined. [ABSTRACT FROM AUTHOR]

Unlabelled: Inhaled nitric oxide (NO) is thought to provide a noninvasive therapeutic alternative to extracorporeal membrane oxygenation (ECMO) in the treatment of persistent pulmonary hypertension of the newborn (PPHN).Objective: Since January 1993, we have studied inhalation of NO in PPHN patients meeting the ECMO criteria of our institution. We focused on the questions of whether or not the need for ECMO could be obviated and whether differences could be found between NO responders and nonresponders.Design: NO gas was delivered via conventional IPPV ventilation in incrementally increasing concentrations from 20 to 80 ppm.Patients: NO therapy was attempted in ten ECMO candidates with clinical and echocardiographical evidence of PPHN (mean OI 51.9, SD 10.4).Results: At various NO levels (30-60 ppm), five patients showed a significant increase in mean PaO2 (range 32.9-85.9 mmHg). Improvement was transient in three patients (6-10 h) and prolonged in two others (54-80 h); in the latter cases, ECMO was avoided. Five patients did not respond at all to treatment. Responders and nonresponders differed in their mean respiratory tidal volume (8.9 vs 4.18 ml/kg, P <0.05).Conclusions: In our study, inhalation of NO obviated the necessity of ECMO therapy in only two out of ten PPHN patients. Thus, we would discourage any overoptimistic expectations about the effectiveness of NO therapy in PPHN until larger clinical trials have been performed. [ABSTRACT FROM AUTHOR]

Objective: To compare the effects of inhaled nitric oxide (NO) and an infusion of prostacyclin (PGI2) on right ventricular function in patients with severe acute respiratory distress syndrome (ARDS).Design: Randomized prospective short-term study.Setting: Post-surgical ICU in an university hospital.Patients: 10 patients with severe ARDS referred to our hospital for intensive care.Interventions: In random sequence the patients inhaled NO at a concentration of 18 parts per million (ppm) followed by 36 ppm, and received an intravenous infusion of PGI2 (4 ng.kg-1.min-1).Measurements and Results: Inhalation of 18 ppm NO reduced the mean (+/- SE) pulmonary artery pressure (PAP) from 33 +/- 2 to 28 +/- 1 mmHg (p = 0.008), increased right ventricular ejection fraction (RVEF), as assessed by thermodilution technique, from 28 +/- 2 to 32 +/- 2% (p = 0.005), decreased right ventricular end-diastolic volume index from 114 +/- 6 to 103 +/- 8 ml.m-2 (p = 0.005) and right ventricular end-systolic volume index from 82 +/- 4 to 70 +/- 5 ml.m-2 (p = 0.009). Mean arterial pressure (MAP) and cardiac index (CI) did not change significantly. The effects of 36 ppm NO were not different from the effects of 18 ppm NO. Infusion of PGI2 reduced PAP from 34 +/- 2 to 30 +/- 2 mmHg (p = 0.02), increased RVEF from 29 +/- 2 to 32 +/- 2% (p = 0.02). Right ventricular end-diastolic and end-systolic volume indices did not change significantly. MAP decreased from 80 +/- 4 to 70 +/- 5 mmHg (p = 0.03), and CI increased from 4.0 +/- 0.5 to 4.5 +/- 0.5 l.min-1.m-2 (p = 0.02).Conclusions: Using a new approach to selective pulmonary vasodilation by inhalation of NO, we demonstrate in this group of ARDS patients that an increase in RVEF is not necessarily associated with a rise in CI. The increase in CI during PGI2 infusion is probably related to the systemic effect of this substance. [ABSTRACT FROM AUTHOR]

Unlabelled: Our aim was to identify factors predictive of death in preterm infants in whom inhaled nitric oxide was administered in response to poor oxygenation (oxygenation index > or =15). Of the 23 (median gestational age 28 weeks, range 24-36) infants consecutively so treated, 15 died. Non-survival was commoner in infants with air leaks (12 of 12, P < 0.002) and/or a change in their oxygenation index of less than 30% in response to inhaled nitric oxide administration (P < 0.05).Conclusion: In preterm infants given inhaled nitric oxide because of poor oxygenation, a diagnosis of airleak and a lack of initial response are predictive of death. [ABSTRACT FROM AUTHOR]

The past decade has witnessed technological advancements which are unparalleled in neonatology. ECMO has been demonstrated to be a powerful rescue treatment, but has perhaps been overutilised and is not universally available. Alternative treatments have been shown to be both safe and efficacious in the management of infants with respiratory failure. Direct head to head clinical trials will probably be necessary to establish appropriate criteria and indications for use, given the wide diversity of pathophysiology these unique patients present. [ABSTRACT FROM PUBLISHER]

Highlights a study on meconium aspiration syndrome (MAS) in infants in Great Britain. Percentage of infants with MAS who require mechanical ventilation; Proportion of neonatal units that use prostacyclin; Purpose of amnioinfusion.

The article focuses on a study on the efficacy of glyceryl trinitrate (nitric oxide) in patients with acute stroke and high blood pressure (BP). Topics discussed include poor performance in activities of daily living (ADL) by continue antihypertensive medications, improving functional outcome by assigning glyceryl trinitrate, and association of increased risk for poor performance in ADL with allocation to continuing antihypertensive drugs.

Examines the relation between the oxygenation response to inhaled nitric oxide (iNO) and the ABO blood-group system. Incidences of respiratory distress syndrome; Examination made of the medical records of children who received iNO; Findings.