Cost-Effectiveness of Inhaled Nitric Oxide in the Treatment of Neonatal Respiratory Failure in the United States
* Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Laboratory, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
Health Process Management, LLC, Doylestown, Pennsylvania
Pediatrix Medical Group, Inc, Sunrise, Florida
|| Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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Objective. Two recent randomized 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 per case despite acquisition costs of $5150, predominantly as a result of decreased need for ECMO), with 84.6% probability that the cost-effectiveness ratio was better than $100 000 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 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 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.
Key Words: newborn • nitric oxide • respiratory failure • cost-effectiveness • ECMO
Abbreviations: ECMO, extracorporeal membrane oxygenation • iNO, inhaled nitric oxide • RCT, randomized controlled trial • NINOS, Neonatal Inhaled Nitric Oxide Study • CINRGI, Clinical Inhaled Nitric Oxide Research Group Initiative • PCEHM, Panel on Cost-effectiveness in Health and Medicine • ICU, intensive care unit; CI, confidence interval • QALY, quality-adjusted life-year
Traditional management of severe neonatal hypoxemic respiratory failure includes mechanical ventilation and high concentrations of inspired oxygen. Newer therapies include high-frequency oscillatory ventilation and surfactant therapy. Newborns who fail to respond to conventional therapy can be placed on extracorporeal membrane oxygenation (ECMO). ECMO improves survival1 but is expensive, labor intensive, and still associated with high mortality and morbidity.2–4 Recently, several studies suggested that inhaled nitric oxide (iNO) improves hypoxia and reduces the need for ECMO.5–7 In a randomized controlled trial (RCT) of 235 term and near-term newborns with severe hypoxic respiratory failure, the Neonatal Inhaled Nitric Oxide Study (NINOS) group found that ECMO use fell from 54% in the placebo arm to 39% in the iNO arm (P = .014). Mortality was also lower in newborns who were treated with iNO (14% vs 17%), although this finding was not statistically significant.6 A second randomized study, the Clinical Inhaled Nitric Oxide Research Group Initiative (CINRGI), reported similar results (ECMO use 64% in placebo vs 38% in iNO arm, P = .001; mortality 13% placebo vs 10% iNO, P = .8).7
These data prompted the US Food and Drug Administration to approve iNO as a treatment for severe hypoxic respiratory failure in term and near-term neonates in December 1999, and iNO is being adopted rapidly into clinical practice. However, iNO therapy is expensive, the consequences of avoiding ECMO are unclear, and the cost-effectiveness of iNO therapy is unknown, raising debate over the value of iNO. In an effort to assess formally the balance of costs and effects of iNO, we conducted a cost-effectiveness analysis of iNO therapy for the treatment of severe hypoxemic respiratory failure in term and near-term neonates.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Framework and Decision Model
We conducted our analysis following the recommendations of the US Public Health Service Panel on Cost-effectiveness in Health and Medicine (PCEHM)8 and the American Thoracic Society Panel on Understanding Costs and Cost-Effectiveness in Critical Care.9 We adopted the societal perspective for all analyses and generated both a "data-driven" base case (a direct extension of trial results with as few assumptions as possible)9 and a PCEHM reference case (an estimate of the likely costs and effects in the real world).8,9 We constructed a standard decision model for mechanically ventilated newborns with hypoxic respiratory failure that described key management decisions and a set of potential outcomes (Fig 1). Outcomes included alive and healthy, alive with major neurologic disability, alive with major respiratory disease, alive with both disabilities, and dead. The model incorporated costs and outcomes up to 1 year from birth.
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We populated the model with data from several sources and a set of assumptions. The model compared 2 identical cohorts: 1 cohort that received iNO (iNO arm) and 1 cohort that did not receive iNO (no-iNO arm). Because most newborns in the United States are born at hospitals that do not perform ECMO, seriously ill newborns with hypoxic respiratory failure are often transferred from non-ECMO hospitals (local hospitals) to ECMO centers for additional care. We therefore incorporated decisions about which newborns were transferred and where iNO was started (at the local hospital or at the ECMO center). We calculated cost per 1-year survivor and per quality-adjusted 1-year survivor but did not extend beyond 1 year because of a lack of information regarding duration of clinical and economic effects after 1 year.
Base Case
Under the base case, we assumed that iNO was administered to newborns who were similar to newborns who were enrolled in the NINOS and CINRGI trials and was initiated only after transfer to an ECMO center. This case is the closest to that of the 2 trials (>90% of all patients enrolled in the trials had already been transferred to an ECMO center before starting iNO) and likely represents the cost-efficacy of iNO (the ratio obtained when iNO is used under controlled conditions most closely reflecting clinical trial conditions).
PCEHM Reference Case
Under the PCEHM reference case, we assumed that iNO was administered to newborns who were similar to those in the base case but that it was initiated at the local hospital, not at the ECMO center. This case incorporated 2 decisions: the decision to transfer the infant to an ECMO center after the initiation of iNO and, if the infant was transferred, the decision to start ECMO therapy. This case is a closer reflection of actual practice patterns.
Transition Probabilities and Outcomes
We summarize the transition probabilities and outcomes and their sources and underlying assumptions in Table 1. The transition probabilities for each branch decision were derived from the pooled results of NINOS and CINRGI, the 2 RCTs of iNO.6,7 We assumed that all newborns who were alive at hospital discharge survived to 1 year of age (based on NINOS long-term follow-up10 and analysis of all ventilated newborns in the Pennsylvania Medicaid claims data from September 1989 to June 199511). To account for the effects of chronic respiratory and neurologic disability, we assigned a utility to newborns with these conditions. Because there is no established way to assign utilities to newborns and young children, investigators have used utilities for comparable adult conditions.12 We assigned a utility of 0.7 (70% of perfect health) to infants with either chronic respiratory or chronic neurologic morbidity. These utilities were based on the average utility of adult patients living with chronic illness in the Beaver Dam general population cohort (range for respiratory conditions: 0.67–0.68; range for neurologic conditions: 0.65–0.68).13 We assigned a utility of 0.49 (or 0.7 x 0.7) to infants with both disabilities. Although the relationship between the 2 conditions when both are present may not be multiplicative, this approach has been used by other investigators.14 Furthermore, we subsequently subjected these estimates to a conservative sensitivity analysis, ranging utilities for each condition from 0.5 to 0.9 (and thus a combined range of 0.25–0.81). These estimates are in keeping with other evaluations of quality of life in infants and children.15
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Costs
We summarize the costs and their sources and underlying assumptions in Table 2. To generate hospital costs at ECMO centers, we multiplied the number of different types of hospital days (ECMO intensive care unit [ICU] days; non-ECMO, ventilated ICU days; non-ECMO, nonventilated ICU days; and ward days) of patients in the CINRGI trial by estimates of the daily costs for such days. Because we did not have direct cost information from the RCTs, we obtained daily cost estimates from the detailed bills of a separate cohort of infants (detailed cost cohort).
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The detailed cost cohort consisted of 260 term or near-term newborns who were referred to 1 of 4 ECMO centers (Denver Children’s Hospital, Denver, CO; the Children’s Hospital of Pittsburgh, Pittsburgh, PA; Vanderbilt Children’s Hospital, Nashville, TN; and the Packard Children’s Hospital, Palo Alto, CA) for possible ECMO therapy. We multiplied all individual charges in these detailed billing records by hospital- and department-specific Centers for Medicare and Medicaid Services cost-to-charge ratios and summed all costs incurred each day to generate daily costs. Because the initial day of invasive therapy is more expensive than subsequent days, we generated separate cost estimates for the first day on ECMO and the first day on mechanical ventilation.
From CINRGI, we generated length-of-stay streams for 4 outcome groups: survivors without ECMO, survivors with ECMO, nonsurvivors without ECMO, and nonsurvivors with ECMO. The probability of being in a particular group differed between the iNO and no-iNO arms (see Table 1), but the numbers of different types of days within an outcome group did not. For example, mean duration of ECMO for ECMO survivors was the same in both treatment arms.
Under the reference case, some newborns whose hypoxemia improves with iNO at a local hospital may avoid transfer to an ECMO center. We assumed that their hospital costs were a fraction of the costs that would have been incurred at an ECMO center for similar services. We estimated this fraction to be 0.8 (from our analysis of administrative discharge abstracts of newborns who required mechanical ventilation for hypoxic respiratory failure in 1994 in California16). The cost of iNO therapy was based on current pricing in the US market ($125/hour with a maximum of $12 000) from INO Therapeutics, Inc (Clinton, NJ). The duration of therapy was based on patient-level observations from the CINRGI trial.7 We assumed physician fees during the initial hospitalization to be 17% of hospital costs, based on a previous study of sick newborns.17 We estimated postdischarge costs from analysis of the postdischarge costs of newborns who underwent mechanical ventilation or ECMO in the 1989–1995 Pennsylvania Medicaid claims database.18 We did not include nonmedical costs as per PCEHM recommendations but valued lost wages from 1 parent while neonates were hospitalized (time of hospitalization) or attended follow-up visits (one half-day per visit), as well as transportation costs for these visits.8 We expressed all costs as 2002 US dollars.
Cost-Effectiveness
Cost-effectiveness is the ratio of the difference in costs to the difference in effects between treatment arms. For both the base case and the reference case, we used a Monte Carlo simulation to generate 1000 cohorts consisting of 483 simulated cases (the size of the pooled cohorts from both RCTs). In the simulation, all observed rates were ranged across their stochastic error distributions, and all observed costs were ranged across their observed length of stay and cost distributions.19 For each cohort, we calculated mean costs, mean effects, and cost-effectiveness ratios. We generated the point (or "best") estimates of the cost-effectiveness ratios for the 2 cases from the grand means (the average of the means) of the simulations. We generated 95% confidence ellipses around point estimates using the method described by Mullahy and Manning.20
Sensitivity Analysis
We conducted sensitivity analyses on the reference case. We varied our assumptions regarding clinical effects, health care costs, and the population treated (Table 3). For the population treated, we explored inclusion of 2 additional types of patients: 1) patients who did not meet the entry criteria for the clinical trials and 2) patients who would have met entry criteria but never had access to ECMO centers (eg, because of remote location16). We assumed that the first type of patients are neither helped nor harmed by iNO (ie, they simply incur the added acquisition costs for iNO). We calculated outcomes for the second type of patients as follows: if (s)he would have received ECMO in the clinical trial (see base case, Table 1) but now does not because (s)he could not be transferred, then her/his mortality is multiplied by the penalty of being denied ECMO care. We estimate this penalty as an increased risk of 1.8, determined from the UK ECMO collaborative trial.1 As per PCEHM guidelines, we conducted both 1-way and 2-way analyses.8
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Data Manipulation and Analyses
The CINRGI trial, California State discharge, and hospital detailed cost data were manipulated in FoxPro (Microsoft Corp, Redwood, WA) and Datadesk (Data Description, Inc, Ithaca, NY). The decision tree and Monte Carlo simulations were built and conducted in Data Professional (TreeAge Software, Inc, Williamstown, MA).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Patient Characteristics
We present the probability of clinical outcomes used in the decision model in Table 1. iNO use decreased ECMO use in both studies (n = 483) by an average absolute difference of 21%. Mortality rates were 10.8% and 13.8% in the iNO (n = 243) and no-iNO (n = 240) cohorts, respectively (P = .35). In the iNO cohort, mortality was higher in those who received ECMO (17.4% vs 6.8%; P = .01). In the no-iNO cohort, there was no difference in mortality between those who did and did not receive ECMO (13.9% vs 13.1%; P = .87). Data sources for the rates of long-term outcomes are provided in Table 1.
The contribution of different types of days to the hospitalization and the costs of each type of day are detailed in Table 2. The first day of treatment was more expensive than subsequent days, both for newborns who did require ECMO ($6360) and those who did not require ECMO ($5150). The marginal cost of an ECMO day over a day on mechanical ventilation was $1320. The marginal cost of a day on mechanical ventilation over a nonventilated ICU day was $1700. Nonsurvivors received ECMO and mechanical ventilation for much longer than survivors (Table 2). The mean and median duration and acquisition costs for iNO were 41 and 33 hours and $5150 and $4060, respectively.
Base Case: iNO Initiated at ECMO Centers
The mean per-patient costs in the first year were $73 200 (95% confidence interval [CI]: $69 140–$77 390) in the iNO arm and $75 080 (95% CI: $70 950–$79 240) in the no-iNO arm. This cost saving of $1880 (95% CI: $7420 cheaper to $3550 more expensive) was attributable primarily to reduced ECMO use. The mean per-patient quality-adjusted survival in the first year was 0.77 quality-adjusted life-years (QALYs; 95% CI: 0.72–0.82) in the iNO arm and 0.74 QALYs (95% CI: 0.68–0.79) in the no-iNO arm. This yields an additional 0.030 QALY in the first year of life (95% CI: 0.034 QALY lost to 0.096 QALY gained) per treated infant.
In other words, iNO therapy reduced health care costs and improved quality-adjusted survival (treating 100 infants yielded cost savings of $188 000 and effects gained of 3.0 QALYs in the first year). There was considerable uncertainty around these means, with only 60.3% probability that iNO was dominant (cost saving and better outcomes). However, there was 84.6% probability that iNO was better than $100 000 per QALY and only 6.3% probability that iNO was dominated (higher costs and worse outcomes).
Reference Case: iNO Initiated at Local Hospitals
The mean per-patient costs in the first year were $75 800 (95% CI: $70 100–$80 800) in the iNO arm and $80 200 (95% CI: $76 200–$85 000) in the no-iNO arm. This incremental cost saving of $4400 (95% CI: $11 040 cheaper to $2410 more expensive) per treated patient is larger than that observed in the base case as a result of the additional savings incurred by decreased transfers to ECMO centers. The mean per-patient quality-adjusted survival in the first year was 0.77 QALYs (95% CI: 0.71–0.82) in the iNO arm and 0.74 QALYs (95% CI: 0.68–0.79) in the no-iNO arm. This yields an additional 0.03 QALY (95% CI: 0.037 QALY lost to 0.100 QALY gained) at 1 year per treated infant.
In other words, initiating iNO at local hospitals also reduced health care costs and improved quality-adjusted survival (treating 100 infants yielded cost savings of $440 000 and effects gained of 3.0 QALYs in the first year). The uncertainties around these means are demonstrated graphically in Fig 2. There was 71.6% probability that iNO was dominant, 91.6% probability that it was better than $100 000 per QALY, and only 2.6% probability that it was dominated.
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One-Way Sensitivity Analyses on the Reference Case
The effects on the reference case of varying our assumptions in 1-way sensitivity analyses are displayed in Table 3. The ratio was insensitive to assumptions regarding the incidence of complications and their impact on quality of life. It was also insensitive to assumptions regarding differences in cost between local and ECMO hospitals and the impact of ECMO on mortality. It was moderately sensitive to the survival benefit of iNO over placebo in newborns who did not receive ECMO. It was also moderately sensitive to including patients who would not benefit from iNO. Cost-effectiveness was also sensitive to price of drug with the ratio exceeding $100 000 per QALY once average acquisition costs exceeded $11 900. iNO would also become much less cost-effective if it were to prolong hospital length of stay by >2 days.
Two-Way Sensitivity Analyses Exploring the Consequences of iNO Use at Local Hospitals
Figure 3 shows the results of 2 illustrative 2-way analyses. In Fig 3A, we vary the proportion of infants who have severe respiratory failure and have the option to be transferred to an ECMO center (x axis) and simultaneously vary the consequence of being denied transfer (ie, the increased odds of dying if ECMO is not an option; y axis). When the odds of dying are set to 1 (the lowest point on the y axis), there is no increased mortality in infants who are denied access to an ECMO center (ie, transfer to an ECMO center does not decrease mortality). Under this assumption, the introduction of iNO at local hospitals is cheaper than $100 000 per QALY, as long as the percentage of children who are denied access to an ECMO center is less than approximately 70%. When the percentage is more than approximately 70%, there are fewer ECMO runs to be avoided (because fewer infants can get to ECMO centers), minimizing the cost savings of iNO and making iNO cost-ineffective.
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If, however, lack of access to an ECMO center does increase mortality (y axis >1), then iNO helps offset that risk of death (because iNO keeps some infants from needing ECMO). As the risk of death rises, iNO becomes more cost-effective (as a result of a larger gain in effects). This is seen by the $100 000 per QALY line curving toward the right (creating a wider "cost-effective" range) as the risk of mortality from lack of access to an ECMO center rises.
In Fig 3B, the x axis remains the same but the y axis is now the proportion of infants who are treated and gain no benefit from iNO. Fig 3B therefore shows the effects of simultaneously diluting the "RCT" population with both additional types of infants: those who look like those in the RCT but have no access to an ECMO center (x axis) and those who gain no benefit (y axis). As might be expected, iNOs cost-effectiveness deteriorates as we add either infants who gain no benefit (climbing the y axis), because the costs per "benefiting" infant rise, or infants who have no access to an ECMO center (moving right on the x axis), because, as explained above, fewer ECMO runs (which are very expensive) can be avoided as the number of infants who have access to an ECMO center drops. Depending on the type of infant treated, the original "RCT" population can be diluted by approximately 55% to 85% and iNO will still fall below $100 000 per QALY.
Two-way analyses are particularly relevant when both variables studied are potentially modifiable. The $100 000/QALY line represents the trade-off between the 2 variables that maintains this cost-effectiveness ratio. In the situation presented, as a greater proportion of neonates are denied access to an ECMO center, cost-effectiveness is maintained only when recipients of iNO therapy are chosen more judiciously.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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We found that, despite its high acquisition costs, iNO has a favorable cost-effectiveness profile for treatment of hypoxic respiratory failure in term/near-term newborns. Our best estimates were that iNO both reduces costs and improves outcomes, regardless of whether it is initiated at a local hospital before transfer or on arrival at an ECMO center. Our estimates were sensitive to patient selection, the availability of ECMO as a rescue therapy, and the cost of iNO therapy. The relatively small sample sizes of the 2 RCTs led to considerable uncertainty around our point estimates. However, the Monte Carlo simulation demonstrated that iNO seems favorable from a societal perspective under a large proportion of scenarios for this patient population and therefore would compare very advantageously with competing treatment strategies.21
We restricted the time horizon to the first year of life. This conservatively assumed that all costs and effects of iNO have disappeared at 1 year. Although there is ample evidence that sequelae of severe neonatal illness extend well into later childhood and adolescence,22 whether iNO differentially affects those sequelae awaits additional research. If the reduction in pulmonary complications with iNO is sustained, then there may be a gain in quality-adjusted survival well beyond the first year, which in turn would yield a better cost-effectiveness profile. However, chronic pulmonary disease was assessed only by a crude and somewhat controversial23 proxy, persistent need for oxygen at 30 days, and the persistence of any protective effect of iNO is unknown. The CINRGI trial included 31 neonates with congenital diaphragmatic hernia, a condition that typically is less responsive to iNO, carries a higher mortality, and is associated with longer ECMO runs. We believe that iNO would be used routinely in those newborns and therefore also included them in our analysis. Their exclusion would likely have produced an even more favorable cost-effectiveness profile.
Quality of life of infants and young children is difficult to evaluate, and standardized approaches are lacking.22,24 However, our conclusions are robust to varying the quality of life attributed to infants with pulmonary or neurologic morbidity. We did not ascribe any ongoing health care costs of managing specific pulmonary or neurologic morbidities. We also did not attempt to quantify the considerable intangible costs to parents associated with the care of a sick newborn,25 although we did include the indirect costs of lost wages. If the beneficial effects of iNO also minimize subsequent health care costs and family burden, then the cost-effectiveness would improve further.
Data on the decision making that leads to transfer of a newborn to an ECMO facility are lacking.15,26 Our model assumed that experienced clinicians at local hospitals typically can assess a newborn’s responsiveness to iNO and initiate transfer to an ECMO center appropriately. Additional information on the determinants of the decision to transfer would further elucidate the impact of initiating iNO in local hospitals. Another important factor to consider is that iNO may improve safety of transfer to an ECMO center, thereby improving outcome. Conversely, if iNO produces a temporary improvement in some infants who ultimately need ECMO, then its use may produce a detrimental delay in their transfer.
Evidence suggests that ECMO use and costs of care vary substantially between the United States and other countries.27 Therefore, the relevance of our findings to other countries is unclear. Given the sensitivity of the cost-effectiveness ratio to hospital costs and costs of therapy, small differences in the financing and organization of factors such as ECMO delivery could have a profound effect on the cost-effectiveness of iNO.28 For example, in analyses of 96 infants from the Canadian Inhaled Nitric Oxide Study, Jacobs et al29,30 found that infants who received iNO had nonsignificantly higher hospital costs but similar postdischarge costs when compared with infants who received placebo. However, the total costs were estimated to be less than one third of the costs that we found using cost estimates from the United States.
Our study offers some insight into the potential impact of iNO on neonatal respiratory failure nationwide. There are approximately 24 000 term ventilated neonates each year,16 and, before the introduction of iNO, there were approximately 1400 ECMO runs in term/near-term neonates per year.31 On the basis of the ECMO rate of 59% in the placebo arms of the 2 RCTs, there are approximately 2400 infants per year (1400/59%) who would meet the RCT entry criteria. Figure 3B suggests that iNO remains better than $100 000 per QALY with dilution of the RCT population by between 55% and 85% (depending on the types of infants who "dilute" the trial population). This translates into a national estimate of 5300 to 16 000 infants per year who can receive iNO with a cost-effectiveness profile nationwide of <$100 000 per QALY and a decrease in ECMO runs by one third to approximately 900. If the acquisition cost of iNO decreases significantly, then the number of neonates who could be administered iNO could increase in the same proportion without jeopardizing cost-effectiveness, assuming conservatively that none of the neonates in the expanded population benefits from iNO. Without more information regarding the benefits of iNO over a longer time horizon or in other patient populations, one would be concerned that iNO use in a larger population than this might be increasingly cost-ineffective.
In conclusion, iNO seems to offer a cost-effective alternative to traditional care paradigms in the treatment of term or near-term infants with hypoxic respiratory failure. As it is disseminated into the community, it can be used in a reasonably large proportion of all ventilated, term infants with confidence that it will be cost-effective. However, the cost-effectiveness will degenerate if use is too indiscriminate. Subsequent study to better understand the long-term effects of perinatal iNO use will be crucial if we are to understand fully the societal consequences of this therapy.
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ACKNOWLEDGMENTS |
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This study was supported in part by a grant from INO Therapeutics, Inc (Clinton, NJ).
We are indebted to Tony T. Dremsizov, MBA, for assistance with manuscript preparation. We gratefully acknowledge Ann Thompson, MD (Children’s Hospital of Pittsburgh), William Walsh, MD (Vanderbilt Children’s Hospital), Steven Abman, MD (Denver Children’s Hospital) and William Rhine, MD (Lucile Packard Children’s Hospital) for their help in obtaining the detailed billing records of the newborns in our detailed cost cohort.
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FOOTNOTES |
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Received for publication Apr 1, 2002; Accepted Mar 28, 2003.
Reprint requests to (D.C.A.) Rm 604 Scaife Hall, CRISMA Laboratory, Department of Critical Care Medicine, University of Pittsburgh School of Medicine, 3550 Terrace St, Pittsburgh, PA 15261. E-mail: angusdc{at}ccm.upmc.edu
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