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(Chest. 2001;119:1166-1172.)
© 2001 American College of Chest Physicians

Evaluating the Validity of Responsiveness to Inhaled Nitric Oxide in Pediatric Patients With ARDS*

An Analytic Tool

Mary Baldauf, MD; Peter Silver, MD, FCCP and Mayer Sagy, MD, FCCP

* From the Division of Critical Care Medicine, Schneider Children’s Hospital, New Hyde Park, NY.

Correspondence to: Mary Baldauf, MD, Division of Critical Care Medicine, Schneider Children’s Hospital, 269-01 76th Ave, New Hyde Park, NY 11040


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objectives: To determine whether improved oxygenation indicates a valid response to inhaled nitric oxide (iNO) therapy in patients with pediatric ARDS, and to establish an analytic tool to differentiate the iNO effects from those of other interactive factors in pediatric patients with ARDS.

Design: Consecutive case series evaluated by post hoc analysis tool.

Patients and methods: Nineteen patients treated with iNO for ARDS or pulmonary hypertension were enrolled in our study. We evaluated the PaO2/fraction of inspired oxygen ratio (PF ratio), oxygenation index (OI), patient position (prone vs supine), PaCO2, pH, and vasoactive drug support, and classified patients’ responsiveness to iNO into three categories: (1) possible response, an increase in PF ratio, with no alteration of the aforementioned variables in a direction known to improve oxygenation; (2) nonspecific response, an increase in PF ratio with no increase in OI, and alteration of one or more of the other four criteria in a direction known to improve oxygenation; and (3) undetermined response, an increase in both the PF ratio and OI, indicating a deliberate augmentation in ventilator support.

Results: A total of 119 data points were evaluated. Fifty data points (42%) exhibited no response to iNO. Thirty-two data points (27%) were classified as having possible responses, 35 data points (29%) as nonspecific, and 2 data points (2%) as undetermined responses to the iNO treatment.

Conclusions: In ARDS, improved oxygenation amid iNO treatment is multifactorial. In only 27% of our evaluated data points could the increase in PF ratio be attributed to iNO. We suggest that when clinically utilizing iNO, the interactive factors described by us should be taken into account for data analysis.

Key Words: ARDS • criteria • pulmonary hypertension • nitric oxide • responsiveness


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled nitric oxide (iNO) has been used in patients with ARDS in an attempt to improve oxygenation. The physiologic basis of this effect is the selective pulmonary vasodilation that occurs with iNO, resulting in reduced pulmonary vascular resistance and better ventilation/perfusion (/) ratio.1 2 3 4 5 The improvement observed in the PaO2/fraction of inspired oxygen (FIO2) ratio (PF ratio) as a result of iNO, in severe ARDS, has often been described as very small and clinically unimpressive.6 7 Moreover, many other interactive factors coexist amid iNO treatment that affect oxygenation as well. In order to be able to determine whether or not iNO has a beneficial effect in the management of ARDS, either randomized, controlled studies with an enormous number of patients are required8 9 or these interactive factors should be well recognized and eliminated, so that the studied sample is more homogeneous and, therefore, can be reduced. Such factors include fluctuations in the degree of mechanical ventilatory support that patients experience amid iNO treatment. One method of evaluating these fluctuations is by repeated calculations of the oxygenation index (OI): OI = MAP x FIO2 x 100/PaO2, where MAP = mean airway pressure. Thus, the OI provides an indication of severity of respiratory failure associated with the ARDS.10 OI values > 40 are generally accepted as predictors of increased mortality (80 to 90% in some centers), and, as such, this index has also been widely used as a criterion for the application of extracorporeal membrane oxygenation.11 In addition, changes occurring in the patient’s PCO2 in blood and/or in the pH have also been known to cause pulmonary vascular reactivity, which may lead to changes in oxygenation.12 13 14 More recently, changes from a supine to a prone position in patients with ARDS have been shown to improve the overall / ratio and oxygenation.15 16 Administration of vasoactive drugs and increases in the patient’s volume status improve right ventricular function and enhance pulmonary blood flow and gas exchange.17 18 19 Thus, changes in the dosages of these drugs during iNO treatment might also have an impact on a patient’s oxygenation.

Although in some experimental settings, hypercapnia and acidosis have been shown to improve / matching,20 it is widely accepted that hypocapnia and metabolic alkalosis cause pulmonary vasodilation and enhance pulmonary perfusion. In order to be able to attribute improvement in a patient’s oxygenation to iNO during mechanical ventilation in severe ARDS, the aforementioned factors should stay unchanged or change in a direction deemed irrelevant to the observed improvement in oxygenation. Namely, the OI should remain unchanged or decrease, the patient’s position should not be changed from supine to prone, the PaCO2 should stay unchanged or increase, the pH should stay unchanged or decrease, and the dosages of vasoactive drugs should stay unchanged or decrease. Under these circumstances, a determination as to whether or not a response to iNO has occurred is easier to make. By contrast, significant fluctuations in contributory factors known to improve oxygenation may lead to an inability to determine whether or not a response to iNO has indeed occurred, or at best to a conclusion that the response is nonspecific. To better analyze the validity of improved oxygenation as an indicator of responsiveness to iNO, we developed a post hoc analysis tool for patients who were enrolled in our prospective US Food and Drug Administration (FDA)-approved iNO study and who had severe courses of ARDS.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
A prospective FDA and institutional review board-approved study to investigate the responsiveness of ARDS or pulmonary hypertension to iNO was conducted for 36 months, and an interim data analysis was performed, as per FDA regulations. Informed consent was obtained from a parent of each patient. Patients were considered for our iNO protocol if a diagnosis of ARDS was made based on our admission criteria (bilateral infiltrates on chest radiograph, no evidence of left ventricular dysfunction, PF ratio < 200, and OI > 12). The delivery systems used (Pulmonox II, 245RC; Pulmonox Medical; Tofield, Alberta, Canada; and INOvent; Datex-ohmeda; Madison, WI) utilize an amperometric electrochemical cell for continuous monitoring of the concentration of the delivered nitric oxide and the generated nitrogen dioxide. Doses of iNO were as follows: 5 ppm for 30 min, followed by 10 ppm for 30 min, followed by 25 ppm for an additional 30 min. The patients continued to receive the dose that was believed to be associated with the largest improvement in PF ratio, but not to be > 25 ppm. Every 24 h, an attempt to wean the iNO dose by 20% was made, with a goal to discontinue iNO no later than 120 h, if clinically feasible. To minimize adverse effects of iNO, guidelines were established and posted at the bedside of these patients that mandated the termination of the iNO treatment if nitrogen dioxide concentration was > 5 ppm or if methemoglobin levels in the patients’ blood were > 10%.

A post hoc table of criteria was established in order to identify data points of improved oxygenation that could be due to iNO, and to distinguish them from other responses that may either be nonspecific or undetermined (Fig 1 ). Previous iNO studies have utilized an increase in PF ratio by at least 20% or an absolute increase of at least 10 mm Hg as a marker of improved oxygenation.6 7 21 22 23 24 Based on the PF ratios of each patient prior to iNO treatment, an absolute increase of at least 10 mm Hg corresponded to a 5 to 23% increase in the PF ratio. As per our criteria, a possible response to iNO required a mandatory increase in the PF ratio by at least 15% while the OI had to remain stable. Any increase (a decrease was allowed) in the OI amid iNO treatment due to a deliberate increase in the MAP or the FIO2 would have automatically rendered the response to iNO undetermined. In addition, the patient should not have been placed in the prone position (a change to a supine position was allowed), his or her PaCO2 should not have decreased by > 5 mm Hg (an increase was permitted), the pH should not have increased by > 0.05 (a decrease was permitted), and the patient’s dosage of vasoactive drugs should not have been increased (a decrease was allowed). If one or more of the aforementioned criteria were not met, the response to iNO was defined as nonspecific, despite the improvement observed in oxygenation. Data points demonstrating an improvement in the PF ratio < 15% represented a possible nonresponse to nitric oxide and were not evaluated.



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  		Figure 1. A post hoc analysis tool used to determine responsiveness of ARDS patients to iNO. The direction of the arrows represents no change, a decrease, or an increase in the analyzed parameters (see "Materials and Methods" section for details). A possible response to iNO requires all six criteria to be met. A nonspecific response requires the PF ratio to be increased by at least 15%, while the OI did not increase, and one or more of the other four criteria did not alter in a direction known to improve oxygenation. An undetermined response requires the PF ratio to be increased by at least 15%, yet the OI is also increased by a deliberate increase in the MAP and/or the FIO2.

 
Data were collected and analyzed during the first 72 h of treatment at the following time points: 0 min, 30 min (iNO = 5 ppm), 60 min (iNO = 10 ppm), 90 min (iNO = 25 ppm), 12 h (iNO = 19.5 ± 6.2 ppm), 24 h (iNO = 18.2 ± 7.2 ppm), 48 h (iNO = 15.7 ± 6.3 ppm), and 72 h (iNO = 13.6 ± 5.9 ppm). The PF ratio was calculated for each time point, and the percent change from baseline was calculated and plotted. For PF ratio data points >=15% increase from baseline, a note was added next to that point to indicate whether or not this was a possible response to iNO, an undetermined response, or a nonspecific improvement in oxygenation (examples given in Fig 2 ). The calculated PF ratio and the measured mean pulmonary arterial pressure (mPAP) were also plotted against time for the initial 90 min, and the statistical significance of the changes observed was calculated by one-way analysis of variance (ANOVA) for repeated measures. Data are presented as mean ± SD.



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  		Figure 2. The percent change of PF ratio from baseline at various time points of iNO. An increase in the PF ratio of >= 15% (dotted line) was analyzed by our tool (Fig 1) . Possible response (R), nonspecific response (NS), and undetermined response (UD) were indicated. The numbers in parentheses indicate which of the criteria as described in our analysis tool (Fig 1) was not met. Top: patient 3, showing three possible responses to iNO during the first 90 min followed by a possible nonresponse at 12 h and nonspecific responses thereafter, as the patient’s position was changed to prone (3), the PaCO2 decreased (4), the pH increased (5), and the dosage of vasoactive drugs increased (6). Middle: patient 4, showing one possible response during the first 90 min of iNO and one undetermined response thereafter, indicating a deliberate increase in the OI (2). The pH in this patient also rose significantly (5). Bottom: patient 7, showing one nonspecific response during 72 h of treatment in which the PaCO2 decreased (4), the pH increased (5), and the vasoactive drug dose increased (6), amid the iNO treatment.

 

   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Nineteen patients met our enrollment criteria. No adverse effects of iNO were encountered. Twelve patients survived, and 7 died (Table 1 ). The patients received iNO for 175 ± 106 h (range, 32 to 424 h). Twelve patients were treated with conventional mechanical ventilation, and 7 patients with high-frequency oscillatory ventilation (HFOV). In six patients, a thermodilution cardiac output pulmonary artery catheter was inserted. The PF ratio prior to initiation of iNO was 94 ± 34 (range, 43 to 189), and the OI was 28 ± 10 (range, 13 to 52).


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  		Table 1. Patient Data

 
A total of 119 data points were evaluated within a 72-h period of initiation of iNO treatment in the 19 patients (Table 2 ). Fifty data points (42%) failed to show a PF ratio that was >= 15% of the pre-iNO baseline value, indicating a possible nonresponse to iNO. We performed no further evaluation on these points. In 32 data points (27%), the increased PF ratio could possibly be attributed to the iNO treatment, as no other contributory factors were identified. In two data points (2%), the observed improvement in oxygenation could not be attributed to iNO (undetermined), as an increase in the OI was also documented. In 35 data points (29%), the observed responses were nonspecific since other interactive factors were identified, as per our table of criteria (Fig 1) , which could have caused or contributed to the observed increase in the PF ratio. The changes in the mPAP and the PF ratio during the initial 90 min of the dose-response period (Fig 3 ) did show a trend of improvement in both parameters. The trend in mPAP was marginally significant (p = 0.05 by ANOVA).


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  		Table 2. No. of Data Points per Each Definition Category During 72 h of iNO Treatment*

 


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  		Figure 3. Changes in the mPAP and PF ratio during the first 90 min of iNO. Top: mPAP vs iNO dose (ppm). The trend in mPAP was marginally significant (p = 0.05), as determined by ANOVA. Bottom, PF ratio vs iNO dose (ppm). The trend in the PF ratio was not statistically significant.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Nitric oxide is an endogenous endothelial-derived mediator that causes smooth muscle relaxation.25 26 In animal models of various lung diseases, iNO has been shown to have a selective pulmonary vasodilatory effect.1 27 This pulmonary vasodilation is believed to result in an increased blood flow to well-ventilated areas of the lungs and in the diversion of blood away from poorly ventilated areas. The clinical experience with iNO in patients with ARDS,3 28 29 primary pulmonary hypertension of the newborn, 30 31 32 33 34 and cardiac diseases35 36 37 has led to an overall clinical impression that iNO does increase oxygenation and decrease pulmonary arterial pressure. However, the improvement observed in oxygenation in patients with ARDS has been described as trivial and short lived.6 7 A few editorials referred to iNO in their titles as "cosmetic therapy,"38 treatment that we should say "no to,"39 and treatment that "works, but can we prove it?"40

The management of ARDS continues to be a challenge for the critical-care specialist. In some patients, adequate mechanical ventilation in conjunction with specific treatments may be sufficient to result in their full recovery. However, for other patients, the course of illness may be extremely severe and unpredictable. These patients often require other nonspecific treatments as well as ventilatory manipulations in order to improve their oxygenation while minimizing the risk of barotrauma. This includes treatments such as iNO, permissive hypercapnia, vasoactive drugs, periodic changes of positions (from supine to prone and vice versa), and IV administration of sodium bicarbonate for buffering respiratory or metabolic acidemia.41 Our patients had severe ARDS. It is therefore not surprising that their management had been multifaceted and that fluctuations in various physiologic parameters had been encountered during their course of illness. Under these circumstances, it is also not surprising that obvious beneficial responses to iNO were harder to elucidate.

The etiology of pulmonary artery hypertension (PAH) in ARDS is multifactorial. Microthromboemboli and macrothromboemboli, hypoxia, and endogenous vasoactive mediators have all been implicated in its pathogenesis.42 43 44 When PAH in ARDS is pronounced, right ventricular contractility may be depressed, and its dilation may interfere with left ventricular function,45 which further aggravates gas exchange. Despite the fact that the overall role of PAH in the clinical outcome of ARDS is unclear, there is a general consensus that treatment of PAH in ARDS might be beneficial.3 46 Thus, important considerations in the management of pediatric and adult patients with PAH include anticoagulation, iNO, vasoactive drugs, frequent body position changes, and adequate intravascular volume status.44 The experiences with persistent pulmonary hypertension of the newborn as well as with congenital diaphragmatic hernia have shown that hypocarbia and alkalemia are also effective modalities for reducing pulmonary vascular resistance.47 48 In our patients, these multiple interactive factors and treatments coexisted with the iNO treatment. How can clinicians sort out the signal (iNO effects) from the noise (other factors affecting oxygenation)?

The analysis tool described in this study, although possibly not comprehensive, was found useful for our data analysis. This tool helped us demonstrate that improvement in oxygenation may be a dubious indicator of a true beneficial response to iNO. In 73% of our data points, either no improvement in oxygenation occurred or the observed increase in the PF ratio could not be attributed solely to iNO. Yet, it is possible that when responses to iNO were concluded as nonspecific, the relative contribution of iNO to the observed improvement in oxygenation may have been much greater than that of the other factors, or vice versa. Thus, a response defined as nonspecific may range from being no response to iNO to being a full response to it, but there is no way of knowing. Moreover, when a determination is made that no response to iNO has occurred, as the PF ratio did not significantly increase, the same interactive factors could have been responsible for that occurrence as well. For example, an increase in the PF ratio by 5% would be concluded as no response to iNO by our criteria, yet, this could be due to the influence of a concomitant rise in PaCO2. We did not use the described tool to determine whether definitions of nonresponse were also questionable by the same factors and same mechanisms, but clinicians and researchers have to be aware of both possibilities.

The management of severe ARDS will continue to require multiple therapeutic modalities and mechanical ventilatory maneuvers in order to improve oxygenation and reduce the risk of barotrauma. The administration of iNO might remain one such treatment. However, the judgment as to how much it affects oxygenation in specific disease categories can only be made after a careful evaluation of multiple physiologic factors that coexist and interact amid this treatment. Ideally, prospective and controlled studies using a large patient population should be conducted to eliminate the interactive factors described. These studies may yield credible results that will determine whether or not iNO is indeed beneficial in the management of ARDS. However, an accurate evaluation and presentation of individual patients regarding their response to iNO during a severe course of ARDS mandates the use of a tool such as the one described in this study. Saying that " . . . our patient had a dramatic response to iNO within 5 h of treatment," may be much less convincing than saying the same, but adding, " . . . as assessed by an analysis tool described by . . . ".

In summary, to our knowledge, this is the first description of an analysis tool for patients treated with iNO. This study does not necessarily advocate the use of the tool described. Rather, further studies should be conducted to validate its credibility; hopefully, similar, more comprehensive, and better tools will be developed.


   Footnotes
 
Abbreviations: ANOVA = analysis of variance; FDA = US Food and Drug Administration; FIO2 = fraction of inspired oxygen; HFOV = high-frequency oscillatory ventilation; iNO = inhaled nitric oxide; MAP = mean airway pressure; mPAP = mean pulmonary artery pressure; OI = oxygenation index; PAH = pulmonary artery hypertension; PF ratio = PaO2/fraction of inspired oxygen ratio; / = ventilation/perfusion

Received for publication December 7, 1999. Accepted for publication September 7, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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