Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. In patients with adult respiratory distress syndrome, initial responders to inhaled nitric oxide did not show better outcome than nonresponders Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Subgroup analysis and other (mis)uses of baseline data in clinical trials Cost-effectiveness of inhaled nitric oxide in the treatment of neonatal respiratory failure in the United States. Dose-response characteristics during long-term inhalation of nitric oxide in patients with severe acute respiratory distress syndrome: a prospective, randomized, controlled study. Low-dose inhaled nitric oxide improves the oxygenation and ventilation of infants and children with acute, hypoxemic respiratory failure. Inhaled nitric oxide does not prevent pulmonary edema after lung transplantation measured by lung water content: a randomized clinical study. [Role of nitric oxide in treatment of acute lung injury after surgery with extracorporeal circulation]. Impact of inhaled nitric oxide on platelet aggregation and fibrinolysis in rats with endotoxic lung injury. Role of cyclic guanosine 5'-monophosphate. Association between inhaled nitric oxide treatment and long-term pulmonary function in survivors of acute respiratory distress syndrome Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS. Inhaled nitric oxide in acute respiratory distress syndrome: a pilot randomized controlled study. Inhalation of nitric oxide in acute lung injury: results of a European multicentre study A randomized, controlled study of the 1-hour and 24-hour effects of inhaled nitric oxide therapy in children with acute hypoxemic respiratory failure. Healthcare costs and long-term outcomes after acute respiratory distress syndrome: A phase III trial of inhaled nitric oxide* Inhaled nitric oxide for modulation of ischemia-reperfusion injury in lung transplantation. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. Interactive effects of high-frequency oscillatory ventilation and inhaled nitric oxide in acute hypoxemic respiratory failure in pediatrics Multicenter randomized controlled trial of the effects of inhaled nitric oxide therapy on gas exchange in children with acute hypoxemic respiratory failure. Effect of inhaled nitric oxide on key mediators of the inflammatory response in patients with acute lung injury Analysis of interleukin-6 and interleukin-8 in lung transplantation: correlation with nitric oxide administration. Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory distress syndrome
CONTEXT Inhaled nitric oxide has shown evidence of efficacy in mouse models of sickle cell disease ( SCD ) , case series of patients with acute chest syndrome , and 2 small placebo-controlled trials for treatment of vaso-occlusive pain crisis ( VOC ) . OBJECTIVE To determine whether inhaled nitric oxide gas reduces the duration of painful crisis in patients with SCD who present to the emergency department or hospital for care . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve , multicenter , double-blind , r and omized , placebo-controlled clinical trial for up to 72 hours of inhaled nitric oxide gas vs inhaled nitrogen placebo in 150 participants presenting with VOC of SCD at 11 centers between October 5 , 2004 , and December 22 , 2008 . Intervention Inhaled nitric oxide gas vs inhaled nitrogen placebo . MAIN OUTCOME MEASURES The primary end point was the time to resolution of painful crisis , defined by ( 1 ) freedom from parenteral opioid use for 5 hours ; ( 2 ) pain relief as assessed by visual analog pain scale scores of 6 cm or lower ( on 0 - 10 scale ) ; ( 3 ) ability to walk ; and ( 4 ) patient 's and family 's decision , with physician consensus , that the remaining pain could be managed at home . RESULTS There was no significant change in the primary end point between the nitric oxide and placebo groups , with a median time to resolution of crisis of 73.0 hours ( 95 % confidence interval [ CI ] , 46.0 - 91.0 ) and 65.5 hours ( 95 % CI , 48.1 - 84.0 ) , respectively ( P = .87 ) . There were no significant differences in secondary outcome measures , including length of hospitalization , visual analog pain scale scores , cumulative opioid usage , and rate of acute chest syndrome . Inhaled nitric oxide was well tolerated , with no increase in serious adverse events . Increases in venous methemoglobin concentration confirmed adherence and r and omization but did not exceed 5 % in any study participant . Significant increases in plasma nitrate occurred in the treatment group , but there were no observed increases in plasma or whole blood nitrite . CONCLUSION Among patients with SCD hospitalized with VOC , the use of inhaled nitric oxide compared with placebo did not improve time to crisis resolution . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00094887 We examined data from 29 patients fulfilling the American-European Consensus Conference definition of ARDS who underwent NO inhalation from 1997 to 2001 . The University Institutional Review Board approved this therapy for patients with ARDS . Written informed consent was obtained from each patient ’s family to examine their records . Patients with immunosuppression and advanced malignant disease were excluded . All patients required mechanical ventilation with a Siemens Servo 300 ventilator ( Siemens , Danvers , MA , USA ) , in a volume-controlled ventilation mode and with a positive end-expiratory pressure ( PEEP ) of 10–15cmH2O . We kept peak airway pressures below 50cmH2O and applied tidal volumes of 8–10 ml·kg 1 . The target oxygenation parameters were PaO2 above 60mmHg and arterial oxygen saturation ( SaO2 ) above 90 % . To achieve sufficient removal of carbon dioxide we adjusted the ventilatory rate to 40 breaths/min . If hypercapnia developed , we accepted levels of PaCO2 below 50mmHg . All patients were se date d with propofol infusions , and muscle relaxation was achieved with vecuronium when necessary . NO was delivered through the ventilator , using a bleed-in adapter placed in the inspiratory limb of the circuit , just distal to the humidifier . NO was supplied from tanks containing 812ppm , with the remaining gas being nitrogen ( Taiyo-Toyo , Kanagawa , Japan ) . The NO and NO2 concentrations were continuously monitored using an NO/NO2 Gas Monitor ( TMS-100R ; Taiyo-Toyo ) . Gas sample s were withdrawn a short distance proximal to the patient ’s endotracheal tube , ensuring that a length of 100 cm was maintained between the central NO instillation and the withdrawal of gas for analysis . The analyzers were regularly calibrated at 0 and 10ppm NO and 0 and 4 ppm NO2 . The exhaled gas was scavenged with an NO nitric oxide scavenger system OBJECTIVES To evaluate the safety and physiologic response of inhaled nitric oxide ( NO ) in patients with acute respiratory distress syndrome ( ARDS ) . In addition , the effect of various doses of inhaled NO on clinical outcome parameters was assessed . DESIGN Prospect i ve , multicenter , r and omized , double-blind , placebo-controlled study . SETTING Intensive care units of 30 academic , teaching , and community hospitals in the United States . PATIENTS Patients with ARDS , as defined by the American-European Consensus Conference , were enrolled into the study if the onset of disease was within 72 hrs of r and omization . INTERVENTIONS Patients were r and omized to receive placebo ( nitrogen gas ) or inhaled NO at concentrations of 1.25 , 5 , 20 , 40 , or 80 ppm . MEASUREMENTS AND MAIN RESULTS Acute increases in PaO2 , decreases in mean pulmonary arterial pressure , intensity of mechanical ventilation , and oxygenation index were examined . Clinical outcomes examined were the dose effects of inhaled NO on mortality , the number of days alive and off mechanical ventilation , and the number of days alive after meeting oxygenation criteria for extubation . A total of 177 patients were enrolled over a 14-month period . An acute response to treatment gas , defined as a PaO2 increase > or = 20 % , was seen in 60 % of the patients receiving inhaled NO with no significant differences between dose groups . Twenty-four percent of placebo patients also had an acute response to treatment gas during the first 4 hrs . The initial increase in oxygenation translated into a reduction in the FIO2 over the first day and in the intensity of mechanical ventilation over the first 4 days of treatment , as measured by the oxygenation index . There were no differences among the pooled inhaled NO groups and placebo with respect to mortality rate , the number of days alive and off mechanical ventilation , or the number of days alive after meeting oxygenation criteria for extubation . However , patients receiving 5 ppm inhaled NO showed an improvement in these parameters . In this dose group , the percentage of patients alive and off mechanical ventilation at day 28 ( a post hoc analysis ) was higher ( 62 % vs. 44 % ) than the placebo group . There was no apparent difference in the number or type of adverse events reported among those patients receiving inhaled NO compared with placebo . Four patients had methemoglobin concentrations > 5 % . The mean inspired nitrogen dioxide concentration in inhaled NO patients was 1.5 ppm . CONCLUSIONS From this placebo-controlled study , inhaled NO appears to be well tolerated in the population of ARDS patients studied . With mechanical ventilation held constant , inhaled NO is associated with a significant improvement in oxygenation compared with placebo over the first 4 hrs of treatment . An improvement in oxygenation index was observed over the first 4 days . Larger phase III studies are needed to ascertain if these acute physiologic improvements can lead to altered clinical outcome BACKGROUND Baseline data collected on each patient at r and omisation in controlled clinical trials can be used to describe the population of patients , to assess comparability of treatment groups , to achieve balanced r and omisation , to adjust treatment comparisons for prognostic factors , and to undertake subgroup analyses . We assessed the extent and quality of such practice s in major clinical trial reports . METHODS A sample of 50 consecutive clinical -trial reports was obtained from four major medical journals during July to September , 1997 . We tabulated the detailed information on uses of baseline data by use of a st and ard form . FINDINGS Most trials presented baseline comparability in a table . These tables were often unduly large , and about half the trials inappropriately used significance tests for baseline comparison . Methods of r and omisation , including possible stratification , were often poorly described . There was little consistency over whether to use covariate adjustment and the criteria for selecting baseline factors for which to adjust were often unclear . Most trials emphasised the simple unadjusted results and covariate adjustment usually made negligible difference . Two-thirds of the reports presented subgroup findings , but mostly without appropriate statistical tests for interaction . Many reports put too much emphasis on subgroup analyses that commonly lacked statistical power . INTERPRETATION Clinical trials need a predefined statistical analysis plan for uses of baseline data , especially covariate-adjusted analyses and subgroup analyses . Investigators and journals need to adopt improved st and ards of statistical reporting , and exercise caution when drawing conclusions from subgroup findings OBJECTIVE Two recent r and omized controlled trials ( RCTs ) reported that inhaled nitric oxide ( iNO ) decreased the incidence of extracorporeal membrane oxygenation ( ECMO ) or death in term and near-term newborns with hypoxic respiratory failure . Our objective was to estimate the cost-effectiveness ratio of iNO in this population . METHODS We studied 1000 simulation cohorts ( n = 483 for each cohort ) of term/near-term newborns with hypoxemic respiratory failure . We conducted our study following US Public Health Service Panel on Cost-Effectiveness in Health and Medicine guidelines , adopting the US societal perspective . We constructed a decision tree reflecting iNO use , subsequent  ECMO  use , death , and long-term neurologic and respiratory morbidity in survivors , as determined from the combined outcomes of the 2 RCTs ( n = 483 ) . We estimated costs on the basis of length-of-stay data for the initial episode of care from 1 of the RCTs , unit costs from administrative data sets , and current pricing for iNO . We ran a Monte Carlo simulation to generate estimates of differences in costs and effects at 1 year , along with the stochastic uncertainty around these estimates . We expressed effects as quality -adjusted survival , assuming quality of life = 1 with no comorbidity , 0.7 with 1 comorbidity , and 0.49 ( 0.7 x 0.7 ) with 2 comorbidities . We constructed a base case , in which iNO was initiated at tertiary care ECMO centers ( mimicking the RCTs ) and a Public Health Service Panel on Cost-effectiveness in Health and Medicine reference case , in which iNO was initiated at the local hospital before transfer ( mimicking real-world practice ) . We exposed our assumptions to a sensitivity analysis . RESULTS Direct application of the trial results ( base case ) suggested that iNO was both more effective and cheaper ( cost savings of 1880 dollars per case despite acquisition costs of 5150 dollars , predominantly as a result of decreased need for ECMO ) , with 84.6 % probability that the cost-effectiveness ratio was better than 100,000 dollars per quality -adjusted life-year . Under the reference case , iNO was also more effective ( though slightly less so ) and was even cheaper ( cost savings of 4400 dollars per case ) , with 71.6 % probability that iNO was cheaper and more effective and 91.6 % probability that the cost effectiveness ratio was better than 100,000 dollars per quality -adjusted life-year . Sensitivity analyses showed these estimates to be sensitive to patient selection and the price of iNO but insensitive to assumptions regarding quality of life . CONCLUSIONS From a US societal perspective , iNO has a favorable cost-effectiveness profile when initiated either at ECMO centers or at local hospitals in term/near-term neonates with hypoxemic respiratory failure Inhaled nitric oxide ( NO ) improves systemic oxygenation ( PaO2/FIO2 ) in adult patients with acute respiratory distress syndrome ( ARDS ) . However , individual response varies , and previous trials demonstrated no outcome benefit . This prospect i ve , r and omized study in 40 ARDS patients analyzed dose-response ( DR ) characteristics  during long-term inhaled NO .  Patients were r and omized for conventional therapy ( control ) or continuous treatment with 10 parts per million ( ppm ) inhaled NO until weaning was initiated . We measured DR curves of PaO2/FIO2 versus the inhaled NO dose at regular intervals . Before treatment ( Day 0 ) , peak improvement in PaO2/FIO2 was achieved at 10 ppm for both control and NO-treated patients . After 4 days , the DR curve of the NO-treated patients was left shifted with a peak response at 1 ppm . At higher doses ( 10 and 100 ppm ) , oxygenation deteriorated , and the response to inhaled NO disappeared in several patients . This effect was not observed in the control group . There was no effect of inhaled NO on duration of mechanical ventilation or stay at the intensive care unit . In conclusion , long-term inhaled NO with constant doses of 10 ppm leads to enhanced sensitivity after several days and does do not allow reduction of ventilation parameters . Hence , previous trials on therapy with inhaled NO in ARDS should be carefully interpreted , as they used constant NO concentrations , which may have become overdoses leading to deterioration of oxygenation after several days OBJECTIVE To describe the effects of inhaled nitric oxide on oxygenation and ventilation in patients with acute , hypoxic respiratory failure and to characterize those who respond to low doses with a significant improvement in PaO2 . DESIGN Prospect i ve dose response trial of inhaled nitric oxide .  Patients who demonstrated a > or = 15 % improvement in PaO2 were r and omized to receive conventional  mechanical ventilation  with or without prolonged inhaled nitric oxide . SETTING Pediatric intensive care unit of a tertiary care children 's hospital serving as a regional referral center for respiratory failure . PATIENTS Pediatric patients with an acute parenchymal lung disease requiring mechanical ventilation , an F(IO2 ) of > or = 0.5 , a positive end-expiratory pressure of > or = 7 cm H2O , and whose PaO2/FIO2 ratio was < or = 160 . INTERVENTIONS PaO2 , PaCO2 , pH , heart rate , blood pressure , and methemoglobin were recorded at baseline and after inhaling 1 , 5 , 10 , and 20 ppm of nitric oxide .  Peak expiratory flow rate and mean airway resistance were measured while subjects received 0 and 20 ppm of inhaled nitric oxide . Patients were followed up until extubation or death . MEASUREMENTS AND MAIN RESULTS Twenty-six patients ( median age , 2.6 yrs [ range , 1 mo-18.2 yrs ] ) were enrolled in the study .  PaO2 increased ( p < .001 ) and Pa(CO2 ) fell ( p < .0001 ) from baseline with the administration of inhaled nitric oxide . There was no statistical difference among 1 , 5 , 10 , and 20 ppm with regard to effects on oxygenation . Sixteen patients ( 62 % ) responded to inhaled nitric oxide with a > or = 15 % improvement in PaO2 ; 14 of these responses occurred at a dose of 1 or 5 ppm . Response to inhaled nitric oxide was not associated with age , length of intubation , presence of primary lung disease , chest radiograph , or illness severity . Among patients weighing < or = 20 kg , responders showed a greater fall in mean airway resistance ( p < .05 ) than nonresponders . Mortality was not influenced by prolonged inhaled nitric oxide when analyzed by intention to treat . Patients receiving prolonged inhaled nitric oxide at doses of < or = 20 ppm maintained methemoglobin levels of < 3.0 % and circuit concentrations of NO2 of < 1 ppm . CONCLUSIONS Inhaled nitric oxide at doses of < or = 5 ppm improves the oxygenation and ( to a lesser extent ) ventilation of most children with acute , hypoxic respiratory failure . The unpredictable response of patients necessitates individualized dosing of inhaled nitric oxide , starting at concentrations of < or = 1 ppm . Inhaled nitric oxide at < or = 20 ppm may exert a small salutary effect on bronchial tone . The benefits of prolonged inhaled nitric oxide remain unknown STUDY OBJECTIVE In order to assess the effects of inhaled nitric oxide ( iNO ) in preventing early-onset lung edema from occurring after lung transplantation , we measured extravascular lung water ( EVLW ) in a group of lung transplant recipients who were at high risk for developing ischemia-reperfusion-induced lung injury . DESIGN Prospect i ve , r and omized study . SETTING S Surgical ICU in a teaching hospital . PATIENTS Thirty double-lung transplant recipients . INTERVENTIONS Patients were r and omized to receive or not receive 20 ppm iNO at the time of reperfusion ( ie , before any occurrence of lung edema ) . In the NO group , iNO was then administered for a 12-h period . A double-dilution technique was used for the serial assessment of EVLW , intrathoracic blood volume , and cardiac index . St and ard hemodynamic and pulmonary parameters were also recorded during the first 3 postoperative days . MEASUREMENTS AND RESULTS Patients who received iNO did not have a different lung water content compared to control subjects ( p = 0.61 [ by analysis of variance ( ANOVA ) ] ) . Blood oxygenation ( ie , Pao(2)/fraction of inspired oxygen [ Fio(2 ) ] ratio ) did not differ between the two groups ( p = 0.61 [ by ANOVA ] ) . In both groups , EVLW and Pao(2)/Fio(2 ) ratio dropped significantly over time , regardless of the use of iNO ( p < 0.01 [ by ANOVA ] ) . CONCLUSIONS In the population studied , prophylactic iNO that was administered at 20 ppm had no effect on pulmonary edema formation and resolution following lung transplantation Postoperative acute lung injury ( ALI ) compromises oxygen transfer across alveolar-capillary membrane with consecutive hypoxia , one of its indicators being reduction of oxygenation index PaO2/FiO2 below 40 kPa ( 300 mm Hg ) . Management of ALI includes different procedures like mechanical lung ventilation ( MLV ) , drugs and others . One of the new possibilities for treatment of ALI is nitric oxide ( NO ) inhalation . The aim of this prospect i ve study was to examine the role of NO inhalation in treatment of ALI . 14 patients with ALI developed immediately after operation with extracorporeal circulation ( ECC ) were included in the study . Group A ( n = 8) inhaled NO and group B ( n = 6 ) did not inhale NO during treatment of ALI . All other therapeutic measures were the same in both groups . The groups were similar in relation to demographic data , type of surgery and duration of ECC . PaO2/FiO2 was calculated before operation ( T1 ) , immediately after surgery ( T2 ) and after lung recovery , when the need for MLV stopped ( T3 ) . The duration of MLV was also registered . PaO2/FiO2 ( kPa ) in referent times was in group A 54.9 + /- 1.6 , 33.8 + /- 1.2 and 46.2 + /- 0.8 and in group B 52.2 + /- 1.1 , 33.5 + /- 1.5 and 47.3 + /- 0.9 , respectively . There was a statistically significant decrease of PaO2/FiO2 in T2 and T3 vs T1 in both groups ( p < 0.05 ) , while the difference between the groups was not statistically significant . The duration of MLV ( h ) in group B ( 28.5 + /- 1.6 ) was statistically significantly shorter than in group A ( 63.1 + /- 8.7 ) ( p < 0.01 ) . According to the results of this study we conclude that NO inhalation during ALI after surgery with ECC significantly reduces the duration of MVL and improves pulmonary recovery As inhaled nitric oxide ( iNO ) may differently increase bleeding time ( BT ) and inhibit platelet aggregation in normal and lung-injured patients or experimental models , we studied the effects of iNO on hemostasis in presence and absence of an endotoxic lung injury in the rat . Eight hours after intratracheal administration of endotoxin ( lipopolysaccharide [ LPS ] ) or its solvent ( phosphate-buffered solution [ PBS ] ) , four groups of rats were r and omized according to the presence or absence of 15 ppm iNO added for an additional 10 h. We measured BT , ex vivo platelet aggregation , plasma fibrinogen , euglobulin clot lysis time ( ECLT ) , and platelet and aortic cyclic guanosine 5'-monophosphate ( cGMP ) contents . Acute lung inflammation did not influence BT , but increased platelet aggregability , fibrinogen levels , and platelet and aortic cGMP . In control and endotoxic rats , iNO increased BT , reduced platelet aggregability , and increased platelet cGMP .  iNO increased aortic cGMP only in healthy rats .  ECLT was increased by LPS and unchanged with iNO . These results suggest that the extrapulmonary " systemic " effects induced by iNO on hemostasis were not strictly similar in healthy and LPS rats , inflammation inducing proper changes in coagulation parameters . However , iNO attenuated the procoagulant activity induced by acute lung inflammation , suggesting a potentially beneficial effect of this therapy Introduction Assessment of treatments for acute respiratory distress syndrome ( ARDS ) has focused on short-term outcomes ( for example , mortality ) ; little information exists regarding long-term effects of ARDS treatment . Survivors of ARDS episodes may have long-term obstructive/restrictive pulmonary abnormalities and pulmonary gas exchange impairment . A 2004 prospect i ve r and omized placebo-controlled trial assessed the efficacy and safety of inhaled nitric oxide ( iNO ) in patients with non-septic ARDS ; the primary endpoint was days alive and off assisted breathing . This analysis examined potential effects of iNO or placebo on pulmonary function six months post-treatment in ARDS survivors from that original study . Methods ARDS survivors ( N = 92 ) from a large-scale r and omized , placebo-controlled study evaluating mortality after either 5 ppm iNO or placebo for up to 28 days were assessed six months post-treatment . Pulmonary function testing across seven parameters was conducted . Results At 6 months post-treatment , results indicated significantly better absolute values for iNO versus placebo for mean ± SD total lung capacity ( TLC , 5.54 ± 1.42 vs. 4.81 ± 1.00 ; P = 0.026 ) . There were also significantly better values for mean ± SD percent predicted values for a ) forced expiratory volume in 1 second ( FEV1 , 80.23 ± 21.21 vs. 69.51 ± 28.97 ; P = 0.042 ) , b ) forced vital capacity ( FVC , 83.78 ± 19.37 vs. 69.84 ± 27.40 ; P = 0.019 ) , c ) FEV1/FVC ( 96.14 ± 13.79 vs. 87.92 ± 19.77 ; P = 0.033 ) , and d ) TLC ( 93.33 ± 18.21 vs. 76.10 ± 21.84 ; P < 0.001 ) . Nonsignificant differences were found in absolute FEV1 , FEV1/FVC , FVC , forced expiratory flow from 25 % to 75 % of FVC , functional residual capacity , and CO diffusion . Conclusions ARDS patients surviving after treatment with low-dose iNO had significantly better values for select pulmonary function tests at six months post-treatment than placebo-treated patients . Further trials are warranted to determine the effects of iNO on chronic lung function in ARDS survivors , a factor in long-term morbidity and quality of life in this population .Trial Registration A Double-blind , R and omized , Placebo-controlled , Dose-response Study of Inhaled Nitric Oxide in the Treatment of  Acute Respiratory Distress Syndrome .  NCT number : IS RCT A r and omized , controlled clinical trial was performed with patients with acute respiratory distress syndrome ( ARDS ) to compare the effect of conventional therapy or inhaled nitric oxide ( iNO ) on oxygenation .  Patients were r and omized to either conventional therapy or conventional therapy plus iNO for 72 h. We tested the following hypotheses : ( 1 ) that iNO would improve oxygenation during the 72 h after r and omization , as compared with conventional therapy ; and ( 2 ) that iNO would increase the likelihood that patients would improve to the extent that the FI(O2 ) could be decreased by > or = 0.15 within 72 h after r and omization . There were two major findings . First , That iNO as compared with conventional therapy increased Pa(O2)/FI(O2 ) at 1 h , 12 h , and possibly 24 h. Beyond 24 h , the two groups had an equivalent improvement in Pa(O2)/FI(O2 ) . Second , that patients treated with iNO therapy were no more likely to improve so that they could be managed with a persistent decrease in FI(O2 ) > or = 0.15 during the 72 h following r and omization ( 11 of 20 patients with iNO versus 9 of 20 patients with conventional therapy , p = 0.55 ) . In patients with severe ARDS , our results indicate that iNO does not lead to a sustained improvement in oxygenation as compared with conventional therapy This pilot r and omized controlled clinical trial of patients with ARDS was implemented to study the impact of inhaled nitric oxide ( inhNO ) on lung function , morbidity , and mortality .  Thirty patients with ARDS were r and omly allocated to usual care or usual care plus inhNO . The optimal dose of inhNO was determined to be between 0.5 and 40 parts-per-million daily . All therapeutic interventions were st and ardized . ARDS result ed mainly from sepsis ( 25 of the 30 ) . During the first 24 h , the hypoxia score increased greatly in patients treated with inhNO + 70.4 mm Hg ( + 59 % ) versus + 14.2 mm Hg ( + 9.3 % ) for the control group ( p = 0.02 ) , venous admixture decreased from 25.7 to 15.2 % in the inhNO group , and from only 19.4 to 14.9 % in the control group ( p = 0.05 ) . After the first day of therapy no further beneficial effect of inhNO was detected . Forty percent of the patients treated with inhNO were alive and weaned from mechanical ventilation within 30 d after r and omization compared with 33.3 % in the control group ( p = 0.83 ) . The 30-d mortality rate was similar in the two groups ; most deaths ( 11 of 17 ) were due to multiple organ dysfunction syndrome . This study shows that inhNO , in this population , may improve gas exchange but does not affect mortality Objective : To determine whether inhalation of nitric oxide ( INO ) can increase the frequency of reversal of acute lung injury ( ALI ) in nitric oxide ( NO ) responders . Design : Prospect i ve , open , r and omised , multicentre , parallel group phase III trial . Setting : General ICUs in 43 university and regional hospitals in Europe . Patients : Two hundred and sixty-eight adult patients with early ALI . Interventions : NO responders were patients whose PaO2 increased by more than 20 % when receiving 0 , 2 , 10 and 40 ppm of INO for 10 min within 96 h of study entry . Responders were r and omly allocated to conventional treatment with or without INO . INO , 1–40 ppm , was given at the lowest effective dose for up to 30 days or until an end point was reached . The primary end point was reversal of ALI . Clinical outcome parameters and safety were assessed in all patients . Results : Two hundred and sixty-eight patients were recruited , of which 180 were r and omised NO responders .  Frequency of reversal of ALI was no different in INO patients ( 61 % ) and controls ( 54 % ; p > 0.2 ) . Development of severe respiratory failure was lower in the INO ( 2.2 % ) than controls ( 10.3 % ; p < 0.05 ) . The mortality at 30 days was 44 % for INO patients , 40 % for control patients ( p > 0.2 vs INO ) and 45 % in non-responders . Conclusions : Improvement of oxygenation by INO did not increase the frequency of reversal of ALI . Use of inhaled NO in early ALI did not alter mortality although it did reduce the frequency of severe respiratory failure in patients developing severe hypoxaemia STUDY OBJECTIVE To determine whether 24 h of inhaled nitric oxide improves oxygenation greater than conventional therapy alone in children with acute hypoxemic respiratory failure . DESIGN Prospect i ve , r and omized , controlled study . SETTING Twenty-six-bed pediatric ICU in a tertiary children 's hospital . PATIENTS Twenty-four patients with acute bilateral lung disease requiring a positive-end expiratory pressure > 6 cm H2O and a fraction of inspired oxygen > 0.5 for > 12 h. INTERVENTIONS Twelve patients were treated with 10 ppm inhaled nitric oxide from the onset of r and omization and 12 control patients were initially maintained on a regimen of conventional therapy alone . After a period of 24 h , control patients were also treated with 10 ppm inhaled nitric oxide .  Hemodynamic and blood gas measurements were performed at baseline , at 1 h after r and omization , and at 24-h intervals for 2 days . MEASUREMENTS AND RESULTS Inhaled nitric oxide decreased the ratio of pulmonary to systemic vascular resistance and improved oxygenation indexes during the initial hour following r and omization . However , 24 h after r and omization , the oxygenation indexes of 11 surviving treated patients were not improved in comparison to baseline or the oxygenation indexes of 10 surviving control patients . Oxygenation indexes acutely improved in control patients when inhaled nitric oxide was started after 24 h of conventional therapy .  Oxygenation indexes remained improved in the initial control patients after 24 h of inhaled nitric oxide . CONCLUSIONS Pulmonary vascular resistance and systemic oxygenation are acutely improved by 10 ppm inhaled nitric oxide in some children with severe lung disease . However , a sustained improvement in oxygenation may not occur during prolonged therapy . Thus , inhaled nitric oxide may have a limited therapeutic role in children with acute hypoxemic respiratory failure Objective : To determine the costs and long-term outcomes of acute respiratory distress syndrome ( ARDS ) in previously healthy adults . To determine whether treatment with inhaled nitric oxide affects these costs and outcomes . Design : One-year follow-up of a r and omized trial of inhaled nitric oxide . Hospital bills were collected , and follow-up was performed at hospital discharge , 6 months , and 1 year . Setting : Forty-six U.S. centers . Patients : Three hundred and eighty-five previously healthy adults with ARDS . Interventions : Subjects were r and omized to 5 ppm inhaled nitric oxide or placebo gas . Measurements and Main Results : One-year survival was 67.8 % , with no difference by treatment arm ( 67.3 % vs. 68.3 % for inhaled nitric oxide vs. placebo , p = .71 ) . Hospital costs from enrollment to discharge were high and similar in the inhaled nitric oxide and placebo arms ( $ 48,500 vs. $ 47,800 , p = 0.8 ) . There were also no differences in length of stay or Therapeutic Intervention Scoring System points . Almost half ( 43.4 % ) of subjects were discharged to another healthcare facility or to home with professional help , and 24.1 % were readmitted in 6 months , with no differences between groups . At 1 year , survivors reported low quality of life with no differences by treatment arm ( Quality of Well-Being score [ range 0–1 ] , 0.61 vs. 0.64 for inhaled nitric oxide vs. placebo , p = .11 ) and poor function with no differences by treatment arm ( 32.5 % returned to ≤5 points of baseline Activities of Daily Living [ range 0–100 ] , 63.3 % returned to ≤10 points , and the remaining 36.7 % suffered a mean decrement of 27 points ) . Conclusions : ARDS , even in previously healthy adults , not only is followed by poor survival , quality of life , and function but also is associated with high costs of care and postdischarge re source use .  Inhaled nitric oxide at 5 ppm had no effect on these outcomes BACKGROUND The prophylactic administration of inhaled nitric oxide ( NO ) during reperfusion after lung transplantation has been shown to reduce neutrophil-induced injury in animal models . There remain questions regarding efficacy in the clinical setting and concerns regarding increased free radical injury . We sought to assess the efficacy of NO in reducing neutrophil infiltration and associated injury if administered from the very onset of reperfusion in clinical lung transplantation . METHODS Twenty bilateral sequential lung transplant recipients were r and omized to receive 20-ppm inhaled NO ( NO group ) or a st and ard anesthetic gas mixture ( control group ) from the onset of ventilation . Bronchoalveolar lavage was performed immediately prior to implantation and after 30 minutes of reperfusion and analyzed for inflammatory cytokine levels and free radical surrogates . Primary graft dysfunction ( PGD ) scoring was performed prospect ively for 72 hours post-transplant . RESULTS The prophylactic administration of NO during the first 30 minutes of reperfusion had no statistically significant effect on the development of Grade II to III PGD ( 5 of 10 in NO group and 7 of 10 in control group , p = 0.36 ) or gas exchange ( area under the curve : 429 + /- 296 vs 336 + /- 306 ; p = 0.64 ) in the NO and control groups , respectively . Pulmonary neutrophil sequestration , as measured by the transpulmonary arteriovenous neutrophil difference , was not influenced by the administration of NO . Prophylactic NO did not significantly alter the concentration of interleukin-8 , myeloperoxidase or nitrotyrosine during transplantation . CONCLUSIONS This study could not demonstrate a significant effect of inhaled NO during the first 30 minutes of reperfusion in the prevention of neutrophil injury and primary graft dysfunction after lung transplantation CONTEXT Inhaled nitric oxide has been shown to improve oxygenation in acute lung injury . OBJECTIVE To evaluate the clinical efficacy of low-dose ( 5-ppm ) inhaled nitric oxide in patients with acute lung injury . DESIGN AND SETTING Multicenter , r and omized , placebo-controlled study , with blinding of patients , caregivers , data collectors , assessors of outcomes , and data analysts ( triple blind ) , conducted in the intensive care units of 46 hospitals in the United States . Patients were enrolled between March 1996 and September 1999 . PATIENTS Patients ( n = 385 ) with moderately severe acute lung injury , a modification of the American-European Consensus Conference definition of acute respiratory distress syndrome ( ARDS ) using a ratio of PaO2 to FiO2 of < or = 250 , were enrolled if the onset was within 72 hours of r and omization , sepsis was not the cause of the lung injury , and the patient had no significant nonpulmonary organ system dysfunction at r and omization . INTERVENTIONS Patients were r and omly assigned to placebo ( nitrogen gas ) or inhaled nitric oxide at 5 ppm until 28 days , discontinuation of assisted breathing , or death . MAIN OUTCOME MEASURES The primary end point was days alive and off assisted breathing . Secondary outcomes included mortality , days alive and meeting oxygenation criteria for extubation , and days patients were alive following a successful unassisted ventilation test . RESULTS An intent-to-treat analysis revealed that inhaled nitric oxide at 5 ppm did not increase the number of days patients were alive and off assisted breathing ( mean [ SD ] , 10.6 [ 9.8 ] days in the placebo group and 10.7 [ 9.7 ] days in the inhaled nitric oxide group ; P = .97 ; difference , -0.1 day [ 95 % confidence interval , -2.0 to 1.9 days ] ) . This lack of effect on clinical outcomes was seen despite a statistically significant increase in PaO2 that resolved by 48 hours . Mortality was similar between groups ( 20 % placebo vs 23 % nitric oxide ; P = .54 ) . Days patients were alive following a successful 2-hour unassisted ventilation trial were a mean ( SD ) of 11.9 ( 9.9 ) for placebo and 11.4 ( 9.8 ) for nitric oxide patients ( P = .54 ) . Days alive and meeting criteria for extubation were also similar : 17.0 placebo vs 16.7 nitric oxide ( P = .89 ) . CONCLUSION Inhaled nitric oxide at a dose of 5 ppm in patients with acute lung injury not due to sepsis and without evidence of nonpulmonary organ system dysfunction results in short-term oxygenation improvements but has no substantial impact on the duration of ventilatory support or mortality Objective High-frequency oscillatory ventilation ( HFOV ) and inhaled nitric oxide ( iNO ) have been reported to improve oxygenation in children with acute hypoxemic respiratory failure ( AHRF ) , but their roles in the treatment of AHRF remains unknown . The use of HFOV improves oxygenation by increasing lung recruitment . iNO can improve oxygenation in AHRF , but it may have limited efficacy in patients with poor lung inflation . Based on these findings , we hypothesized that the combined treatment of HFOV and inhalation of low-dose NO would improve oxygenation and survival in children with severe AHRF compared with children treated with conventional mechanical ventilation ( CMV ) or either treatment alone . Setting Tertiary pediatric intensive care units at seven academic centers . Design Post hoc analysis of data from children enrolled in a multicenter , r and omized , masked study of the use of iNO in the treatment of AHRF . Patients A total of 108 pediatric patients with AHRF defined as an oxygenation index of > 15 twice within 6 hrs . Mode of  ventilation ( HFOV or CMV ) was determined by the patient ’s physician based on guidelines to maximize oxygenation . The patient was then r and omized to treatment with or without iNO . Comparisons were made between patients who were treated with HFOV plus iNO ( n = 14 ) , HFOV alone ( n = 12 ) , CMV plus iNO ( n = 35 ) , and CMV alone ( n = 38 ) . Interventions Ventilation with CMV or HFOV with or without iNO . Measurements and Main Results We found that the change in Pao2/Fio2 ratio was greatest in the HFOV plus iNO group compared with the other treatment groups at 4 hrs ( p = .02 ) and 12 hrs ( p = .01 ) . After 24 hrs of treatment , both HFOV plus iNO and HFOV alone result ed in greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO ( p = .005 ) . After 72 hrs , treatment with HFOV alone result ed in a greater improvement in Pao2/Fio2 ratio than either CMV alone or CMV plus iNO ( p = .03 ) . There was no difference in predefined treatment failures between treatment groups . Conclusions We conclude that the combination of HFOV with iNO causes a greater improvement in oxygenation than either treatment strategy alone in children with severe AHRF . We speculate that the enhanced lung recruitment by HFOV enhances the effects of low dose iNO on gas exchange OBJECTIVES AND BACKGROUND To determine whether inhaled nitric oxide ( iNO ) therapy can attenuate the progression of lung disease in acute hypoxemic respiratory failure , we performed a multicenter , r and omized , masked , controlled study of the effects of prolonged iNO therapy on oxygenation . We hypothesized that iNO therapy would improve oxygenation in an acute manner , slow the rate of decline in gas exchange , and decrease the number of patients who meet pre-established oxygenation failure criteria . STUDY DESIGN A total of 108 children ( median age 2.5 years ) with severe acute hypoxemic respiratory failure from 7 centers were enrolled . After consent was obtained , patients were r and omized to treatment with iNO ( 10 ppm ) or mechanical ventilation alone for at least 72 hours . Patients with an oxygenation index > /=40 for 3 hours or > /=25 for 6 hours were considered treatment failures and exited the study . RESULTS Patient age , primary diagnosis , pediatric risk of mortality score , mode of ventilation , and median oxygenation index ( 35 + /- 22 vs 30 + /- 15 ; iNO vs control ; mean + /- SEM ) were not different between groups at study entry . Comparisons of oxygenation indexes during the first 12 hours demonstrated an acute improvement in oxygenation in the iNO group at 4 hours ( -10.2 vs -2.7 , mean values ; P < .014 ) and at 12 hours ( -9.2 vs -2.8 ; P < .007 ) . At 12 hours 36 % of the control group met failure criteria in contrast with 16 % in the iNO group ( P < .05 ) . During prolonged therapy the failure rate was reduced in the iNO group in patients whose entry oxygenation index was > /=25 ( P < .04 ) and in immunocompromised patients ( P < .03 ) . CONCLUSIONS We conclude that iNO causes an acute improvement in oxygenation in children with severe AHRF . Two subgroups ( immunocompromised and an entry oxygen index > /=25 ) appear to have a more sustained improvement in oxygenation , and we speculate that these subgroups may benefit from prolonged therapy Objective Inhaled nitric oxide is used to treat hypoxia associated with acute lung injury . Endogenous nitric oxide regulates inflammatory responses , but the effect of inhaled nitric oxide therapy is unknown . We hypothesized that inhaled nitric oxide may alter inflammatory responses and endogenous nitric oxide synthase activity . Design A r and omized , prospect i ve interventional study . Setting A university hospital ’s general intensive care unit . Patients Thirty-two patients with acute lung injury . Interventions Patients who responded to test doses of nitric oxide were r and omized to ventilator therapy with and without inhaled nitric oxide . The inhaled concentration of nitric oxide was determined by dose titration at 0 , 2 , 10 , and 40 ppm and the minimum concentration used , which result ed in an increase in the Pao2/Fio2 ratio of at least 25 % . Measurements and Main Results Patients were followed up for 30 days or until death , and bronchoalveolar lavage ( BAL ) was performed at 0 , 24 , and 72 hrs . Nitric oxide synthase activity was measured spectrophotometrically , and myeloperoxidase , elastase , interleukin-8 , and leukotrienes were measured in BAL fluid by enzyme immunoassay . Total nitrite and lipid peroxides in serum were measured colorimetrically . Nitric oxide synthase activity decreased ( p = .01 ) and total nitrite increased ( p = .02 ) in patients receiving inhaled nitric oxide . Other markers of inflammation in BAL fluid did not change . Lipid peroxide concentrations also did not alter . Conclusions The decrease in activity of nitric oxide synthase in patients receiving nitric oxide is likely to be the result of feedback inhibition of the enzyme . This study shows that inhaled nitric oxide has no effect on several markers of the inflammatory response system and does not lead to increased oxidant stress INTRODUCTION AND OBJECTIVES Primary graft dysfunction ( PGD ) following lung transplantation ( LT ) is associated with an activation of the inflammatory cascade and release of cytokines . Inhaled nitric oxide ( iNO ) provides specific pulmonary vasodilatation and improves oxygenation . Our objective was to verify whether administering iNO to LT patients modified the blood and bronchoalveolar lavage ( BAL ) interleukin (IL)-6 and -8 levels in the event of PGD . MATERIAL S AND METHODS Thirty-two LT patients were r and omized to the  iNO treatment or the  control group .  Patients in the first group were given 10 ppm of iNO from the start of LT until 48 hours afterward . BAL and peripheral arterial blood sample s were taken preimplantation as well as 12 , 24 , as and 48 hours postreperfusion . RESULTS The iNO treatment group showed a lower incidence of PGD ( 29 % ) in comparison with the control group ( 40 % ) . Significant differences ( P < .05 ) were observed in the iNO group , with lower IL-6 levels at 12 hours in blood and BAL . A lower percentage of IL-8 was also detected in the iNO group at 24 hours in BAL and at 12 hours in blood and BAL . CONCLUSIONS Lung transplant recipients develop an inflammatory response following implantation with systemic elevation of IL-6 and significant local elevation of IL-8 within the first few hours , especially in the event of PGD . In our series , iNO appeared to modulate the inflammatory response by reducing IL concentrations found immediately after reimplantation , and this reduction was related to a lower incidence of PGD Purpose Pulmonary vascular dysfunction is common during acute respiratory distress syndrome ( ARDS ) , but there is controversy concerning prevalence and prognosis of cor pulmonale during protective ventilation for ARDS . Methods This was a prospect i ve observational study in an academic medical intensive care unit in France . Two hundred and twenty-six consecutive patients with moderate to severe ARDS ( Berlin definition ) ventilated with plateau pressure limited at 30 cmH2O ( mean PEEP of 8.8 ± 3.6 cmH2O ) underwent transesophageal echocardiography ( TEE ) within the first 3 days after the diagnosis of ARDS . Cor pulmonale was defined as a dilated right ventricle associated with septal dyskinesia . Results Cor pulmonale was detected in 49 patients ( prevalence of 22 % ; 95 % confidence interval , 16–27 % ) . Multivariate logistic regression identified infectious causes of lung injury and higher driving pressures as independent factors associated with cor pulmonale . Patients with cor pulmonale exhibited a higher incidence of shock ( need for vasoactive drug ) at the time of TEE and were more often managed with prone positioning and /or nitric oxide as adjunctive therapy for severe hypoxemia during ARDS course . The 28-day mortality rate was significantly higher in the group with cor pulmonale ( 60 vs. 36 % , p < 0.01 ) . Multivariate logistic regression identified McCabe and Jackson class , lung injury not related to pneumonia , aspiration , or sepsis , lactic acidosis , driving pressure , and cor pulmonale as independent risk factors for 28-day mortality . Conclusion Cor pulmonale occurrence is not negligible in ARDS patients ventilated with airway pressure limitation . Cor pulmonale was associated with sepsis and higher values of driving pressure and was an independent risk factor for 28-day mortality in our series
OBJECTIVE Treatment with inhaled nitric oxide improves oxygenation but not survival in mechanically ventilated patients with acute respiratory distress syndrome , but the effect may depend on the severity of hypoxemia .
Our objective was to determine whether nitric oxide  reduces hospital mortality in patients with severe acute respiratory distress syndrome ( PaO2/FIO2 ≤ 100 mm Hg ) but not in patients with mild-moderate acute respiratory distress syndrome ( 100 < PaO2/FIO2 ≤ 300 mm Hg ) at the time of r and omization .