Ann Thorac Surg 2006;82:2161-2169
© 2006 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Clinical Indication for Use and Outcomes After Inhaled Nitric Oxide Therapy
Isaac George, MDa,*,
Steve Xydas, MDa,
Veli K. Topkara, MDa,
Corrina Ferdinando, MDa,
Eileen C. Barnwell, MS, RRTb,
Larissa Gablemana,
Robert N. Sladen, MDc,
Yoshifumi Naka, MD, PhDa,
Mehmet C. Oz, MDa
a Department of Surgery, Division of Cardiothoracic Surgery, Columbia University College of Physicians and Surgeons, New York, New York
b Department of Respiratory Therapy, Columbia-Presbyterian Medical Center, New York, New York
c Department of Anesthesia and Critical Care, Columbia-Presbyterian Medical Center, New York, New York
Accepted for publication June 28, 2006.
Abbreviations and Acronyms ARDS = adult respiratory distress syndrome; iNO = inhaled nitric oxide; OHT = orthotopic heart transplantation; OLT = orthotopic lung transplantation; PAP = pulmonary artery pressure; PVR = pulmonary vascular resistance; ROC = receiver operating curve; RV = right ventricular; VAD = ventricular assist device
* Address correspondence to Dr George, Department of Surgery, Columbia University College of Physicians and Surgeons, 630 W 168th St, P&S Bldg 17-415, New York, NY 10032 (Email: isaacgeorge{at}hotmail.com).
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Abstract
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BACKGROUND: Inhaled nitric oxide (iNO) use is widespread, but the long-term outcomes after therapy in adult patients remain unknown.
METHODS: All 376 patients receiving perioperative iNO (excluding pediatric and interventional cardiology procedures) at Columbia University Medical Center were prospectively followed from 2000 to 2003. Survival data were collected from chart review.
RESULTS: Inhaled nitric oxide was used to treat pulmonary and right ventricular failure in patients undergoing orthotopic heart transplantation (OHT, n = 67), orthotopic lung transplantation (n = 45), cardiac surgery (n = 105), and ventricular assist device placement (n = 66), and for hypoxemia in other surgery (n = 34) and medical patients (n = 59). Average follow-up was 2.9 ± 1.0 years. Overall mortality was lowest when iNO was used after OHT (25.4%) and orthotopic lung transplantation (37.8%), intermediately after cardiac surgery (61%), ventricular assist device (62%), and other surgery patients (75%), and highest among medical patients (90%; all p < 0.005). The cost of iNO therapy was lower in transplantation versus medical patients, with a trend toward shorter duration of use. In multivariate analysis, respiratory failure and use in non-OHT were independent predictors of mortality (both p = 0.001). A risk score greater than 1 (score = non-OHT use 1, plus right ventricular failure 1) predicted a mortality of 76.5% versus 37.2% (p < 0.001).
CONCLUSIONS: Use of iNO for pulmonary hypertension in patients undergoing OHT and orthotopic lung transplantation was associated with a significantly lower overall mortality rate compared with its use after cardiac surgery or for hypoxemia in medical patients. Inhaled nitric oxide does not appear to be cost effective when treating hypoxemia in medical patients with high-risk scores and irreversible disease.
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Introduction
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Despite limited data on its benefit on patient outcomes, inhaled nitric oxide (iNO) is an established pulmonary vasodilator in adult and pediatric critical care settings [1]. It selectively vasodilates pulmonary vessels through cyclic guanosine monophosphate production in pulmonary smooth muscle cells [2], and its adsorption by hemoglobin prevents the induction of systemic hypotension. Its ability to rapidly decrease pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR) and improve gas exchange has led to its use in primary pulmonary hypertension [3, 4], chronic obstructive pulmonary disease [5], adult respiratory distress syndrome (ARDS) [6], sickle cell anemia [7], and after orthotopic heart transplantation (OHT) and orthotopic lung transplantation (OLT) [8–10]. Inhaled nitric oxide is also the diagnostic agent of choice for assessing pulmonary vasculature response to oral vasodilators in patients with primary pulmonary hypertension [11]. It is utilized after OHT, OLT, and congenital and adult cardiac surgery for right ventricular (RV) afterload reduction [12–14], reduction of ischemia-reperfusion injury [10], and improvement of allograft function [8–10]. Pulmonary vasodilators that act through cyclic adenosine monophosphate, such as prostacyclin, produce similar effects on pulmonary vasculature, but also induce systemic vasodilatation [15].
Inhaled nitric oxide is approved by the Food and Drug Administration (FDA) for only one indication: persistent pulmonary hypertension of the newborn. Although iNO therapy has not been demonstrated to decrease overall mortality, it improves oxygenation in this population and decreases the duration of mechanical ventilation, as well as the need for extracorporeal membrane oxygenation [16–18]. In adults with ARDS, iNO improves oxygenation and ventilation-perfusion mismatch but does not improve survival at 30 days [19, 20]. In fact, use of iNO has not been shown to improve survival at any timepoint in any patient population [16, 17, 21, 22], while lengthy periods of iNO treatment substantially increase intensive care costs [23]. Studies addressing the long-term survival of specific adult populations who may benefit from iNO therapy, such as OHT or OLT patients, do not exist and may help guide more judicious and cost-effective use. The objective of the present study was to evaluate long-term outcomes and acquisition costs associated with iNO therapy in adult cardiopulmonary transplantation, cardiac surgery, ventricular assist device (VAD) implantation, other surgery, and medical subgroups.
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Material and Methods
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Study Design
Data on all patients receiving iNO at Columbia University Medical Center from 2000 to 2003 were prospectively collected and retrospectively analyzed for the purposes of this study. Pediatric patients (<18 years) and patients receiving short-term iNO for diagnostic purposes in the cardiac catheterization laboratory were excluded. Institutional guidelines for iNO administration are listed in Table 1. Additional off-guideline utilization of iNO was allowed for the treatment of life-threatening hypoxemia after acute respiratory decompensation, as a potentially life-saving therapy. Use in this immediate setting required departmental approval, and approval was granted on a case-by-case basis.
Clinical data were obtained from chart review. Patients were separated into surgical and nonsurgical groups, and further categorized by the primary surgical procedure performed: OHT, OLT, cardiac surgery (including adult congenital cardiac surgery), VAD implantation, and other surgery (including nonthoracic organ transplantation). A patient was classified as a surgical patient if iNO was administered within the hospital admission of surgery. Subjects not undergoing surgery were classified as medical patients. The study was approved and informed consent waived by the Institutional Review Board; all procedures were in accordance with institutional guidelines.
Long-Term Mortality
Long-term mortality was evaluated by examination of hospital medical records, national death registries, and through telephone contact. In-hospital mortality was defined as expiration during the hospital admission of iNO treatment. Deaths occurring during subsequent hospitalizations without iNO treatment were not counted toward in-hospital mortality, and mortality was only attributed to one encounter and one patient when multiple iNO encounters were present. The mean patient follow-up period was 2.9 ± 1.0 years.
Clinical Variables
Data on clinical variables were collected and are listed in Table 2.
Acquisition Cost of iNO
Charges for each iNO therapy encounter were calculated based on the charging practice of INO Therapeutics (AGA Healthcare, Clinton, New Jersey) between 2000 and 2003, and recalculated using the current 2005 charging practice. For the years 2000 to 2003, the charge to hospitals was $3,000 per 24 hours of therapy, up to a maximum charge of $12,000 per month, independent of total hourly usage. Using the current 2005 charging practice, the charge for iNO was changed to an hourly rate of $125, with a maximum charge of $12,000 per month, independent of hourly usage. Indirect costs associated with iNO administration, including those for respiratory personnel, intensive care unit care, and daily monitoring were not included in this analysis.
Statistical Analysis and Risk Model Derivation
Continuous variables are expressed as mean ± SD and were compared using one-way analysis of variance tested using Bonferroni post-hoc analysis. Categorical variables were compared by 
2 tests. Kaplan-Meier analysis was used to calculate survival, and groups were compared using a two-sided log-rank test, at the p equals 0.05 significance level. Actuarial survival at 1, 2, 3, and 4 years after iNO use was calculated by constructing life tables. Independent predictors of mortality were identified using stepwise multivariate logistic regression models, and model fit was evaluated using the Hosmer and Lemeshow goodness-of-fit statistic. For all analyses, a p value of less than 0.05 was considered statistically significant. All data were analyzed utilizing SPSS 11.5 (SPSS, Chicago, Illinois).
A risk summation score was derived from a multivariate analysis of all patients who received iNO therapy. The score was developed with inclusion of all univariate clinical predictors of mortality after iNO therapy (p < 0.25). The score was then calculated by using the independent predictor variables selected in the multivariate logistic regression model, with weights assigned according to their univariate odds ratios. The probability of mortality was calculated for the sum of each score, as defined above. Model discrimination was assessed by using the area under the receiver operating characteristic (ROC) curve for each score.
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Results
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Patient Demographics and Clinical Characteristics
Between 2000 and 2003, there were 419 uses of iNO in 376 patients (Table 3 and 4).
The mean patient age was 58.7 ± 16.2 years. Inhaled nitric oxide was administered for an average of 105 ± 186 hours. Pulmonary hypertension was the indication for therapy in all OHT and OLT patients, while the majority (84.7%) of the medical patients received iNO for life-threatening hypoxemia (Fig 1A).
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Fig 1. (A) Indication for inhaled nitric oxide (iNO) use (black bar = orthotopic heart transplantation [OHT] with pulmonary hypertension; blue bar = precapillary pulmonary hypertension; pink bar = coronary surgery with right ventricular failure; green bar = congenital cardiac disease; red bar = hypoxemia). (OLT = orthotopic lung transplantation; VAD = ventricular assist device.) All orthotopic heart transplant (OHT) and orthotopic lung transplant (OLT) patients received iNO for treatment of pulmonary hypertension, whereas right ventricular failure was the most common indication for patients undergoing cardiac surgery and ventricular assist device (VAD) implantation. (B) Average duration of iNO use per patient. Other surgical and medical patients received iNO predominantly for hypoxemia use. A trend toward a lower average duration of iNO use was seen after OHT (n = 67) and OLT (n = 45) versus cardiac surgery (n = 105), VAD (n = 66), other surgery (n = 34), and medical patients (n = 59; p = 0.09).
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The clinical characteristics of all patients receiving iNO are summarized in Table 3. Patients receiving iNO therapy after OLT were significantly younger than patients in the medical, cardiac surgery, and other surgery groups (all p < 0.05). Medical patients had the highest rate of respiratory failure (80%) compared with other groups (all p < 0.05), and had higher rates of renal insufficiency (39%), leukocytosis (36%), pneumonia (27%), and other infections (31%) compared with transplant and cardiac surgery groups (all p < 0.05).
A trend toward a lower average duration of iNO use was seen after OHT and OLT versus cardiac surgery, VAD, other surgery, and medical patients (p = 0.09; Fig 1B).
Long-Term Mortality
The cumulative mortality for all patients after iNO therapy was 58.2% (n = 219) at a mean of 2.9 ± 1.0 years of follow-up. Mortality in OHT (25.4%) and OLT (37.8%) patients was significantly less than the other groups (all p < 0.05; Fig 2A). Mortality classified by indication of iNO use yielded similar findings. Patients with pulmonary hypertension after OHT had a lower mortality (23.8%) than all other groups (p < 0.05; Fig 2B). Medical patients treated for life-threatening hypoxemia had the highest observed mortality rate (89.5%).
Figure 3
shows the Kaplan-Meier survival curves for iNO therapy over the 4-year follow-up period by patient group and the indication for iNO use. Actuarial survival for OHT and OLT patients treated for pulmonary hypertension was far greater than survival in medical patients treated for life-threatening hypoxemia (p < 0.001).
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Fig 3. (A, B) Kaplan-Meier survival curves after inhaled nitric oxide (iNO) therapy. (OHT = orthotopic heart transplantation; OLT = orthotopic lung transplantation; PHTN = pulmonary hypertension; Pre-Cap = precapillary; RVF = right ventricular failure; VAD = ventricular assist device.)
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Predictive Clinical Variables and Risk Model
Using a stepwise multivariate logistic regression model, respiratory failure and a non–heart transplant diagnosis conferred a significant risk of mortality after iNO therapy (odds ratio 3.173, p < 0.001; odds ratio 3.89, p = 0.001, respectively; Table 5).
Table 5 shows the independent risk factors and scoring weight used to devise the risk summation score from multivariate analysis. The final risk score for each patient was calculated as: risk score = non-OHT use + respiratory failure.
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Table 5. Independent Predictors of Mortality After Inhaled Nitric Oxide Therapy by Multivariate Logistic Regression Analysis
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Figure 4
demonstrates the mortality associated with iNO treatment with the risk score in all patients and the ROC curve associated with the risk scoring model. Increasing mortality was seen with higher risk scores; a risk score greater than 1 resulted in a mortality of 76.5% (sensitivity 60%, specificity 79%), versus 37.2% with scores less than 1 (p < 0.001). The model demonstrated adequate statistical precision to predict mortality after iNO therapy, with an area under ROC of 0.731.
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Fig 4. (A) Relationship between mortality after inhaled nitric oxide (iNO) therapy and risk score. The risk score was calculated using independent predictors of mortality from multivariate analysis (risk score = non–heart transplant diagnosis + respiratory failure). A risk score of greater than 1 is associated with high mortality after iNO therapy. (B) Non–heart transplant diagnosis and respiratory failure (independent risk factors on multivariate analysis) were used in a scoring system to generate an estimate of risk, validated by agreement measured by the area under the curve (AUC of the receiver operating characteristic curve).
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Estimated Cost of iNO Therapy
The cost for iNO therapy is summarized in Table 6
using the 2000 to 2003 charging practice and current 2005 charging practice, demonstrating a higher cost of therapy in VAD and medical patients. Under the current 2005 pricing, a significantly lower proportion of OHT and OLT patients reached the maximal charge versus medical patients (23% versus 51%, p < 0.001).
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Comment
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Inhaled nitric oxide therapy has been shown to lead to reductions in PAP and PVR and improvement in oxygenation in several populations, including neonates and adult patients with ARDS and RV dysfunction, and after OHT or OLT [3, 6, 9, 10, 14]. These effects may improve short-term outcomes, but a study of long-term outcomes, costs, and clinical use of iNO use in other populations has not been conducted to date. This study is the first to describe outcomes and cost of iNO therapy in an unselected population of critically ill adult patients in a tertiary care center. These study results demonstrate that (1) outcomes after iNO vary substantially based on clinical indication of use, (2) iNO may benefit transplant patients more than other patients, and (3) iNO does not appear to alter the natural history or long-term clinical course of hypoxemic respiratory failure. This study also identifies the medical patient population with respiratory failure as one with substantial morbidity whose high mortality after iNO precludes prolonged therapy.
In the present study, OHT and OLT patients had a 1-year survival rate four times greater than medical patients not undergoing surgery, as well as higher survival rates compared with patients undergoing other types of surgery. The large differences in mortality after iNO therapy may be attributed to differences in the underlying etiology of the cardiac or respiratory failure (pulmonary hypertension versus hypoxemia) and the reversibility of pulmonary hypertension versus respiratory failure. In OHT, acutely elevated PAP, which accounts for 19% of early deaths after heart transplantation [24], may be secondary to both increases in flow (increased backward transmission of elevated left ventricular pressure) and increases in resistance in the pulmonary bed. With iNO use, PVR and PAP are reduced [25], decreasing RV afterload, ameliorating the wean from cardiopulmonary bypass, and preventing RV failure without affecting systemic vascular resistance. By providing temporary support, iNO therapy after transplant allows for the stabilization of hemodynamics until PVR returns to normal levels, which is attained in 80% of patients 1 year after OHT [26], reinforcing its reversible nature after cardiac transplantation. Short-term use of iNO after OHT has been demonstrated to improve RV function, PVR, and mean PAP after 12 to 76 hours of iNO use in 16 OHT patients, although there were no statistically significant differences in survival [9]. In 23 OLT patients, iNO therapy has been shown to reduce reimplantation edema, increase PAO2/FIO2, decrease the need for mechanical ventilation, and reduce the 2-month mortality rate [10].
The observed improvement in pulmonary hypertension also predicts significant outcome benefits, as OHT patients with reversible preoperative PVR have a much lower mortality than do those with a fixed elevated PVR [27, 28]. Survival at 4 years after iNO therapy was 68% in the transplant cohort in the present study, comparing favorably to reported 5-year survival rates of 71% for OHT [29] and 63% for OLT [30]. This study confirms prior studies that have shown acute benefits with iNO therapy after transplantation and shows that long-term survival in OHT and OLT after iNO therapy is comparable to that of patients not requiring iNO. In addition, although mortality in the VAD group was not appreciably different than that in the cardiac surgery group, a likely benefit of iNO in these patients was the avoidance of right ventricular assist device placement, as evidenced by the low rate of left ventricular assist device patients requiring a right ventricular assist device (5 of 66, 7.6%).
Furthermore, iNO therapy has not been shown to lead to long-term benefits in the treatment of severe respiratory failure, which was present in 80% of the medical cohort in this study, or hypoxemia, which was the primary indication in 85% of the medical patients. No benefit beyond 1 day of therapy was seen in indices of lung function in a randomized controlled clinical trial of 30 medical patients with severe respiratory failure and ARDS, yielding a 30-day mortality rate of 60% in iNO-treated patients and 53% in nontreated patients (p = 0.71) [31]. More importantly, nonresponders had a 30-day mortality rate of 80%, whereas responders had a 50% mortality rate. The lack of short-term mortality benefit was confirmed by Michael and colleagues [32] in a randomized controlled trial of iNO in ARDS patients that showed transient improvements after 1 hour but no sustained improvements after 72 hours in PAO2, FIO2, and PAO2/FIO2. These two studies highlight important findings that iNO initially improves indices of lung function but does not produce lasting effects on oxygenation.
The inability to produce sustained effects on hypoxia and respiratory failure may explain the striking 1-year survival of only 17.3% and 4-year survival of 0% in our medical cohort, rates higher than the 90-day mortality rates of 40% to 50% that have been previously reported [33, 34]. Medical patients with severe cardiac or respiratory failure requiring iNO therapy represent a critically ill, challenging population with numerous comorbidities. Judicious use of iNO is warranted for such patients if the immediate mortality risk is estimated to be high. The risk-scoring model reported here allows stratification of patients based on clinical history and provides prognostic information on mortality outcomes. The model predicted a mortality of 76.5% versus 37.2% (p < 0.001) for a risk score greater than 1, with a sensitivity of 60%, specificity of 79%, and area under ROC of 0.731. For cases in which the benefit is likely to be limited with a risk score greater than 1 (namely, respiratory failure in any non-OHT patient), efforts should be made to determine whether a patient responds to iNO therapy before prolonged administration is undertaken.
As expected, hours of iNO use were highest in the medical group at 133 hours, and lowest after OHT and OLT at 71 and 57 hours, respectively. However, longer average duration of use did not produce higher iNO costs using the 2000 to 2003 charging practice, as many patients in all subgroups reached the maximal monthly charge after the first 4 days of therapy. This cap on iNO charges served to equalize costs in surgical and nonsurgical groups, and healthcare providers may continue iNO use in nonresponders as salvage therapy, given that it may not increase iNO-associated charges. However, the cost difference was more pronounced for OLT patients compared with medical and VAD patients using the current hourly charging practice, which was intended to reduce the overall cost of iNO therapy through more precise hourly billing. These findings confirm that prolonged iNO use is associated with higher cost and provides a financial rationale for limiting therapy for patients without expected survival benefit.
The study limitations include those inherent to an observational study. The lack of a randomized design and a control cohort not receiving iNO therapy precludes any definitive conclusions regarding the long-term clinical efficacy or cost effectiveness of iNO use, as long-term hemodynamics were unable to be measured and cost-effectiveness measurements were not calculated. The transient but clinically important appearance of RV dysfunction in the operating room may only be apparent on hemodynamic analysis rather than on echocardiography, and RV dysfunction may be underreported using our echocardiographic definition. The poor survival rates observed in the medical cohort may be attributed to late initiation of iNO therapy in this group; it cannot, therefore, be excluded that earlier iNO administration may have led to higher survival rates. Finally, the absence of indirect hospital costs is a major limiting factor in the description of iNO costs, which may be significant.
In conclusion, the present study reports comprehensive long-term survival data from a critically ill adult population receiving iNO therapy. Inhaled nitric oxide treatment is a valuable pharmacologic adjunct in OHT and OLT for short-term hemodynamic improvements, and long-term data from the present study suggest a translation into long-term survival benefits. Mortality outcomes after iNO are directly related to the clinical indication for use, and prolonged therapy for patients with irreversible systemic disease processes, such as hypoxemia or respiratory failure in medical patients, is not warranted. Poor outcomes and high cost for medical patients with respiratory failure and hypoxemia in this study require further investigation to determine the appropriate duration of iNO use based on clinical response and appropriate endpoints of treatment. A prospective clinical study controlling for severity of illness and addressing clinical efficacy in both surgical and medical populations is needed to definitively answer these questions, and may help reduce the burden of intensive care expenses.
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Acknowledgments
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This work was supported by National Institutes of Health Grant T32-HL07854 (Dr George).
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Abstract
Introduction
p < 0.05 versus precapillary PHTN, coronary surgery with right ventricular failure (RVF), hypoxemia; 
p < 0.05 versus hypoxemia).