human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    