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PEDIATRIC ANESTHESIA: Review Article

Inhaled Nitric Oxide for Acute Hypoxic Respiratory Failure in Children and Adults: A Meta-analysis

Sokol, Jennifer FRACP, FJFICM*†,; Jacobs, Susan Elizabeth FRACP; Bohn, Desmond FRCPC*

Author Information
doi: 10.1213/01.ANE.0000078819.48523.26
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Abstract

Acute respiratory distress syndrome (ARDS) may result from primary lung disease or may be secondary to a number of systemic disease processes. It is associated with considerable morbidity in both children and adults, regardless of age. In addition, mortality from ARDS continues to be significant despite decreasing over the past decade from >60% to between 30% and 50%(1–5). Mortality is often due to the primary disease or multifactorial processes rather than respiratory failure per se(3,6–9). Systemic inflammatory responses and immunosuppression are also thought to play a role in the pathogenesis of ARDS (7,10–13); the severity contributes to morbidity and mortality. Therefore, treatments aimed at modifying lung disease, such as inhaled nitric oxide (INO), may not affect the ultimate outcome.

NO was first identified as “vascular endothelial-derived relaxing factor”(14,15), which, through relaxation of vascular smooth muscle, was noted to cause vasodilatation (16). When it is inhaled, it is thought to reverse the ventilation/perfusion (V̇/𝑄̇) mismatch seen in ARDS by selectively mediating pulmonary vasomotor tone in well ventilated lung units and subsequently reducing increased pulmonary vascular resistance and pulmonary hypertension. Earlier noncontrolled studies of INO in ARDS demonstrated transient improvement in oxygenation (17–21). Other modalities of treatment for ARDS have been examined, such as prone positioning (22–28), the use of high positive end-expiratory pressure (PEEP) (29,30), and reverse inspiratory to expiratory ratio (I:E) (31), but none has been shown to significantly affect morbidity or mortality. This review aims to assess whether INO improves the outcome of children and adults with hypoxic respiratory failure by systematically analyzing the most accurate evidence available.

Methods

This systematic review followed the Cochrane methodology (32). A more detailed review has been published in the Cochrane Database of Systematic Reviews (33).

In this review, acute hypoxic respiratory failure (AHRF) encompasses ARDS, acute lung injury (ALI), and/or hypoxemic respiratory failure. ARDS was defined by any adult or child (older than 1 mo) with acute onset of noncardiac pulmonary disease associated with diffuse, bilateral pulmonary infiltrates on chest radiograph, a pulmonary wedge pressure <18 mm Hg or absent left atrial enlargement, and hypoxemia defined by a hypoxia score (Pao2/fraction of inspired oxygen [Fio2]) <200 mm Hg, regardless of PEEP. ALI was defined by a hypoxia score between 200 and 300 mm Hg (in addition to the other ARDS criteria) (3). Hypoxemic respiratory failure was used for patients classified with respiratory failure, but where the ARDS or ALI definition was not used or where different outcome variables were examined, such as an oxygenation index (OI), rather than the hypoxia score.

Randomized controlled trials (RCTs) examining the use of INO in AHRF were identified from MEDLINE (from 1966) by using the Medical Subject Headings “nitric oxide,” “endothelial-derived relaxing factor,” and “respiratory distress syndrome/adult” and the text words “acute lung injury,” “sepsis syndrome,” “ARDS,” and “shock lung.” Other databases, including EMBASE and CINAHL (from 1980 and 1982, respectively), were searched by using a similar strategy. The Cochrane Controlled Trials Register (Issue 2, 2002) (32) and bibliographies of published trials and conference proceedings were reviewed, and authors published in the field were contacted for knowledge of unpublished or current trials. No language restrictions were applied.

Prospective RCTs comparing INO with “inhaled placebo gas” or “no treatment” and maximal conventional ventilator therapy in AHRF were included. In addition, studies must have examined adults and/or children (excluding neonates in the first month of life) treated in intensive care units for AHRF from any cause. Those with structural or ischemic heart disease were excluded from the trials by all authors. Studies were excluded if they did not report outcome data during and after the administration of the treatment gas for the entire duration of the illness, if they administered INO for a short predetermined period of time to examine only acute changes in oxygenation, if they contained multiple crossover arms, or if they were published abstracts.

Outcome variables included 1) changes in oxygenation (at 24-h intervals up to 1 wk) as measured by OI [(mean airway pressure × fractional concentration of oxygen × 100)/Pao2] and the hypoxia score (Pao2/Fio2); 2) ventilator-free days over a 30-day period; 3) duration of stay in the intensive care unit; 4) duration of stay in the hospital; 5) mortality (both early and late, defined as less than and more than 30 days, respectively); and 6) adverse effects.

Data were extracted, and the analyses were performed independently by two reviewers (JS and SEJ). Metaanalyses were performed by using the Cochrane statistical package MetaView 4.1 (Update Software, Oxford, England). For categorical outcomes, estimators of treatment effect included relative risk and risk difference. For continuous variables, estimators of treatment effects were expressed as the weighted mean difference. In all cases, 95% confidence intervals were used. Studies allowing crossover of treatment failure were excluded from mortality analyses. The fixed effects model was used unless there was significant between-study heterogeneity (1 df, χ2 > 3.841; 2 df, χ2 > 5.991; 3 df, χ2 > 7.815). The quality of trials was evaluated by the descriptive process described by Schulz (34).

Results

Five studies met entry criteria (35–39). The objectives and size of the studies varied. Eligibility criteria were strict: patients with cardiac anomalies were excluded from each trial. Two groups (35,36) used the European-American consensus statement (on ARDS) definition (3) for entry criteria. Troncy et al. (37) used the entry criteria of ARDS (Murray Lung Injury Score of >2.5) (40) without further definition. Dobyns et al. (38) used AHRF as defined by OI criteria, and Lundin et al. (39) used the criteria for ALI with a modified definition from the consensus statement. Only Lundin et al. (39) examined some degree of long-term outcome (at 90 days postenrollment).

Dellinger et al. (35) studied 177 nonpregnant adults from 30 centers over 14 months in a prospective, Phase II, double-blinded RCT. Those with severe burns, immunocompromise, sepsis, persistent hypotension, or multiorgan failure were excluded. Randomization was to placebo (n = 57) or INO doses of 1.25, 5, 20, 40, or 80 ppm for 28 days or until tracheal extubation. The ventilation strategy and weaning of INO was standardized, and there was no crossover of treatment failures. The primary outcome was duration of mechanical ventilation. Secondary outcomes included changes in oxygenation (Pao2, Pao2/Fio2, and OI) and pulmonary artery pressure (PAP), percentage responders, the number of patients alive and not ventilated at 28 days, and the degree of mechanical ventilation, each at 4 h and then daily for 7 days.

The quality of the study was good, with concealment of treatment allocation, a block design allocation sequence (method not stated), and intent to treat. Of note, the 80-ppm dosing strategy was eliminated midway through the study. Treatment was stopped before reaching the oxygenation threshold in 56 patients, and the analysis of ventilator-free days was post hoc. The study was not stratified for etiology, and the sample size derivation was not described (although it was hypothesis generating and therefore not powered to demonstrate statistically significant outcomes).

Michael et al. (36) studied 40 adults and children in a prospective, multicenter RCT as a pilot study over 30 months. Those with terminal illness, heart failure, or left atrial hypertension were excluded. Randomization was to no treatment (n = 20) or to increasing doses of INO (5, 10, 15, and 20 ppm) every 6 h (n = 20) for 72 h. The mode of ventilation remained unchanged throughout the study, and crossover of treatment failures (for predefined criteria) was allowed. The primary outcome examined changes in oxygenation within the 72 h and then a correlation between changes in Pao2/Fio2 acutely after 72 h. Secondary outcomes included changes in Pao2, respiratory compliance, pulmonary artery and central venous pressure, and pulmonary and systemic vascular resistance.

The quality of this study was of concern. Although the allocation sequence was described and it was powered to detect a 35%–40% difference in oxygenation, only 32 patients completed the study. In addition, neither concealment of treatment allocation nor intent-to-treat was stated. Results were given in graphical form for 72 h, preventing inclusion in the metaanalysis.

Troncy et al. (37) studied 30 adults in a prospective single-center pilot RCT over 10 mo. Those with severe immunocompromise or pulmonary wedge pressure >18 mm Hg were excluded. Randomization was to no treatment (n = 15) or INO (n = 15) at increasing doses: 2.5, 5, 10, 20, 30, and 40 ppm. The ventilation and weaning of INO were standardized. The primary outcomes included death before 30 days, continued ventilation after 30 days, and the efficacy of INO on lung function. Secondary outcomes included lung compliance, PAP, Pao2, Paco2, pH, dead-space volume, tidal volume, cardiac output, and the arterial-alveolar oxygenation gradient. There was no crossover of treatment failures.

Concealment of treatment allocation, sample size derivation, and the generation of randomization allocation were not obvious in the published article, although it was analyzed by intent to treat. The effect on oxygenation was stated as the difference between two measurements; no individual values were noted, which prevented inclusion into the metaanalysis. In addition, initial patient characteristics were different in that, on the basis of the Pao2 and Acute Physiology and Chronic Health Evaluation (APACHE) II score, the INO group was more unwell than the control group.

Dobyns et al. (38) studied 108 children in a prospective, multicenter, placebo-controlled RCT. Inclusion (OI ≥ 15 twice, 6 h apart) and exclusion criteria (congenital heart disease or cardiac surgery within 2 wk) were clearly stated, although the study duration was not noted. Randomization was to placebo gas (n = 55) or INO (n = 53) at 10 ppm for a minimum of 3 days to a maximum of 7 days after entry. The ventilation strategy and weaning of gas were standardized, and crossover of treatment failures was allowed. The primary outcomes were acute effect on OI and Pao2/Fio2, and the secondary outcomes included rate of decline in oxygenation, PEEP, and mean airway pressure at 30 min and 6 h and then every 12 h throughout the study.

The quality of this study was good, with concealment of the treatment allocation and generation of randomization (randomization cards) stated. Of note, there was no stratification for etiology, but a post hoc analysis was performed for immunocompromised patients. The sample size derivation was not described, nor was intent to treat stated. The INO group had a nonsignificant but higher OI than the control group at baseline.

Lundin et al. (39) studied 268 adults in a prospective, multicenter, open-labeled RCT over 28 mo. Inclusion criteria required a response to INO with confirmed ALI, adequate PEEP (>5 cm H2O), and mean airway pressure >10 cm H2O. Patients were excluded if they had a malignancy or severe heart failure, were immunocompromised, or had chronic renal or liver failure or pulmonary disease. Randomization occurred after the INO test response was established (Pao2 increase by 25%). Randomization was to INO (n = 93) or no treatment (n = 87) until improvement, until 30 days, or until death. Ventilation strategy and weaning of INO were according to standard care at each hospital. The primary outcome was reversal of ALI, with secondary outcomes examining mortality, intensive care, hospitalization status at 30 and 90 days, and reduction in days of ALI, severe respiratory failure, or both.

The main concern with this study was that despite being powered for 600 patients, it was stopped early because of slow recruitment. In addition, there were protocol amendments after 140 patients were randomized: Patients were considered eligible for randomization if the Pao2 improved by 20% rather than 25% after INO, and stratification occurred by the hypoxia score, rather than by study center and the APACHE II score. Concealment of treatment allocation was stated, as was intent to treat, but analysis of the reversal of ALI was post hoc. Although a block design was used for generation of allocation sequence, the method was not stated.

Eight studies were excluded on the basis of exclusion criteria (41–48). Another two studies were identified in abstract form and were excluded until further results are available (49,50).

Because between-study heterogeneity was not demonstrated, the fixed-effect method was applied to the analyses. Subgroup analyses to assess the effect of varied primary etiologies were not performed because insufficient data were provided. Subgroup analyses assessing the effect of different INO dosages were assessed in one trial (35). Authors were contacted for missing data. All responded but have not as yet provided additional information other than that originally published.

Each author described a nonsustained improvement in oxygenation, although analyses were hindered because different measures of oxygenation and measurement intervals were used. Only Dellinger et al. (35) published this outcome at the specified intervals, and this is discussed below. No particular dose of INO effected a greater change of oxygenation.

The OI was equal in both groups at the commencement of treatment (OI, 17; sd, 7) but decreased significantly in the treatment group each 24 h for 96 h, after which time there was no improvement. (This was a marginally statistically significant but not clinically significant difference.) After 96 h, the mean difference between groups became nonsignificant and the mean OI increased (Fig. 1A).

F1-14
Figure 1:
A, The effect of inhaled nitric oxide on the oxygenation index (OI) at 24-h intervals as assessed by Dellinger et al. (35). B, The effect of inhaled nitric oxide on the hypoxia score at 24-h intervals as assessed by Dellinger et al. (35). WMD = weighted mean difference; CI = confidence interval.

Regarding the Pao2/Fio2 ratio, the hypoxia score was similar in both the treatment (127; sd, 39) and control (129; sd, 38) groups at the commencement of treatment. There was a significant increase for 24 h with INO, after which time there was no difference (Fig. 1B).

Two studies—Dellinger et al. (35) and Lundin et al. (39) —reported ventilator-free days (alive and extubated at 30 days) from different perspectives. Dellinger et al. (35) reviewed the number of ventilator-free days (alive and extubated at 28 days). There was no significant difference in the weighted mean difference between any dose of INO and the placebo group (pooled data; not published) (Fig. 2), although the authors reported a significant difference in ventilator-free days between a treatment group (receiving 5 ppm) and placebo (P < 0.05) on post hoc analysis. Lundin et al. (39) reported the percentage of patients alive and extubated at 30 days. Data were displayed as a survival curve, preventing inclusion into the meta-analysis. A post hoc analysis demonstrated a significantly increased proportion of patients in the no-treatment group to be alive and extubated at 30 days (P <0.01).

F2-14
Figure 2:
Effect of inhaled nitric oxide on ventilator-free days (alive and extubated at 30 days) as assessed by Dellinger et al. (35). WMD = weighted mean difference; CI = confidence interval.

Only Lundin et al. (39) reported the duration of stay in the intensive care unit and hospital. There was no significant difference in the number of survivors between the treatment and no-treatment groups at either 30 or 90 days in duration of stay in either the intensive care unit or the hospital overall (Fig. 3).

F3-14
Figure 3:
Relative risk (RR) for the number of patients in the intensive care unit or hospital at 30 and 90 days as assessed by Lundin et al. (39). CI = confidence interval.

Mortality was reported in each study, although it was not assessed as a primary outcome. Overall, none of the studies described showed any significant difference in mortality between the treatment and placebo or no-treatment groups. Subgroup analyses assessing the effect of varied doses of INO were examined only by Dellinger et al. (35). No particular dose of INO was significantly more effective (Fig. 4). Of the studies not allowing crossover (of treatment failures) (35,37), there was no significant difference in mortality (Fig. 5). Three studies allowed crossover of treatment failures (36,38,39). Lundin et al. (39) allowed crossover but reported no significant difference in mortality at either 30 or 90 days (Fig. 6). A 60-day survival curve demonstrated no significant difference between the treatment and control groups (0.2 <P < 0.5). Most patients died in the first 30 days, with little change in survival probability after that time.

F4-14
Figure 4:
Subgroup analysis for varied doses of inhaled nitric oxide on mortality as assessed by Dellinger et al. (35). RR = relative risk; CI = confidence interval; INOppm = inhaled nitric oxide dose in parts per million.
F5-14
Figure 5:
Mortality in trials without crossover of failures to treatment as assessed by Dellinger et al. (35) and Troncy et al. (37). RR = relative risk; CI = confidence interval.
F6-14
Figure 6:
Relative risk (RR) for mortality at 30 and 90 days after inhaled nitric oxide therapy as assessed by Lundin et al. (39). CI = confidence interval.

Because insufficient data about adverse effects were supplied to analyze systematically, descriptive comments follow. Methemoglobin levels >5% were reported in two groups: in one, methemoglobinemia was documented in three treatment cases, each of which had received at least 40 ppm INO, and also in one control case (35). Lundin et al. (39) also documented this in one each of the treated and control groups. Four of the five studies reported nitrogen dioxide formation (35–38), with increased levels reported in those receiving 80 ppm of INO (35). Two groups reported platelet effects (36,39). Michael et al. (36) monitored both bleeding and platelet effects, but the method was not stated. Two patients bled, but there was no evidence that INO was the primary cause. Lundin et al. (39) reported no significant difference in the number of patients with bleeding diathesis or platelet or clotting disorders between groups.

In addition, Dellinger et al. (35) and Lundin et al. (39) examined changes in blood pressure, renal function, and end-organ function, whereas Michael et al. (36) and Troncy et al. (37) examined cardiovascular and respiratory function measurements. No adverse short-term complications were noted by any author.

Discussion

This metaanalysis suggests that INO transiently results in improved oxygenation in AHRF, with no discrepancy between small or large doses, but that is has not demonstrated a significant effect on mortality. Given that many patients with AHRF die from causes such as sepsis and multiorgan failure rather than lung disease (6), this is not surprising. The transient improvement in oxygenation after the administration of INO may be explained by reduced V̇/𝑄̇ mismatch, hence the benefit for patients acutely decompensating from severe hypoxemia. Hypoxic pulmonary vasoconstriction, a protective phenomenon causing vasoconstriction of poorly ventilated lung units, is a normal response to V̇/𝑄̇ mismatch. NO could theoretically modify this normal response, resulting in vasodilatation of poorly ventilated areas, increased shunting through the lung, and worse oxygenation (51). In addition, surfactant inhibition, edematous changes, and continuing fibrosis as a result of volutrauma, barotrauma, oxygen toxicity, and toxic metabolites of INO may override any benefit that INO may have on resolving intrapulmonary V̇/𝑄̇ mismatch. Unlike neonates with persistent pulmonary hypertension of the newborn, who die from right heart failure due to suprasystemic PAPs (and therefore benefit from INO) (52), children and adults with AHRF have PAP half that of the systemic mean arterial pressure (documented in three of these five trials) (35,37,39). Consequently, death from right heart failure is less likely, and an effect from INO will be difficult, if not impossible, to show.

Concerns have arisen over the use of INO. NO is also known to mediate immune function by modifying the release of cytokines and other components of the inflammatory cascade from alveolar macrophages (53–55). It also causes inhibition of active adhesion molecules and the neutrophil oxidative burst involved in neutrophil migration (56). Attenuation of the inflammatory response, particularly in sepsis-induced lung injury, may therefore be an important factor in the success or failure of INO in the treatment of AHRF (16). NO is also a free radical that rapidly converts to active intermediates, including nitrogen dioxide, peroxynitrite, and nitrotyrosine, in the presence of superoxide (57). These substances may act synergistically with other free radicals to cause further lung tissue damage (15,58) or impair surfactant function (59,60). No clinically significant toxic side effects of nitric dioxide were documented, although significant methemoglobinemia occurred at doses of ≥40 ppm. INO exerts platelet inhibitory effects, such as blocking adenosine diphosphate- and collagen-induced aggregation and altering adhesion of platelets, resulting in prolonged bleeding time at both large and small doses (61–63). Clotting defects were inconsistently reported in the included trials and were descriptive only. No authors examined any long-term complication of oxidant formation or bleeding diathesis.

One should be cautious in interpreting the results of this review because all studies had some degree of flawed methodology. Treatment was not blinded in three of five studies (36,37,39). Authors were unable to send unpublished data, preventing adequate comparison of outcomes. The method of randomization and allocation concealment was inadequately described, as was the derivation of the sample size. A major limitation in two studies was the small number in each, allowing for Type II error (36,37). The total number of patients enrolled into these studies was 535, but only 3 studies could be included into any analyses, resulting in insufficient power to observe substantial differences in morbidity or mortality when so many factors influence these outcomes in AHRF. The hypoxia score and OI were required for this metaanalysis because the former indicates the degree of intrapulmonary oxygen exchange, whereas the latter incorporates a measure of the intensity of mechanical ventilation support given. However, effects on oxygenation were described differently, preventing adequate comparison of data. Outcomes such as early and late mortality, duration of stay in both the intensive care unit and the hospital, ventilator-free days, and early and late effects of INO on oxygenation were considered to be the most clinically relevant outcomes, but they were inconsistently reported. Long-term outcomes, in addition to acute changes in oxygenation, were considered important for this metaanalysis, but apart from Lundin et al.’s (39) review at 90 days, long-term follow-up of survivors exposed to INO has not been reported.

Conclusions

Despite the large number of trials examining the use of INO in AHRF, there is insufficient evidence to state the true effect on mortality or morbidity when INO is used for this condition. This systematic review suggests that INO may be useful as a rescue treatment to improve oxygenation for a short period of time in AHRF. Overall, there was a lack of methodological rigor and, in particular, a lack of data for most potentially clinically relevant end-points, preventing completion of the metaanalysis.

Whether any single modality used in the treatment of AHRF has a significant effect on mortality remains to be seen. The RCTs examining the effects of prone positioning (22), partial liquid ventilation (64,65), inverse I:E ratio (66), small tidal volumes (67,68), continuous noninvasive positive airway pressure (69), and IV medication such as ketoconazole (70) have not demonstrated a significant effect on mortality or morbidity in this condition. NO donors have been used to decrease pulmonary hypertension and have been put forward as a treatment in AHRF (71,72). However, their success may be constrained by similar limitations: respiratory failure is sometimes the end result of multifactorial processes, and one modality will not usually treat such a wide spectrum of disease pathology. In addition, pulmonary hypertension has not been a consistent finding in AHRF.

If any further trials proceed, they need to address appropriate questions: Does the etiology of AHRF determine any benefit for survivors? Which dose(s) of INO, if any, effect clinically relevant outcomes? Is there any less morbidity for survivors of AHRF treated with INO? The trials would need to be stratified for etiology of respiratory failure and incorporate other suggested modalities of treatment of AHRF, including use of a clearly defined small tidal volume ventilation strategy, prone positioning, high PEEP, and reverse I:E ratio, to answer whether a combined approach using many modalities in addition to INO will benefit certain patients with different antecedent pathology. In addition, assessment of clinically relevant outcomes, such as duration of stay in intensive care and in the hospital, ventilator-free days, long-term outcomes, and uniform evaluation of outcomes between treatment centers, should be included. With rapidly changing available treatment modalities, a study of this magnitude would clearly be strategically very difficult. Because of the lack of demonstrated benefit, INO is as yet unlicensed by the Food and Drug Administration for the treatment of hypoxic respiratory failure, ARDS, or ALI. While further studies are required to change this edict, to be fruitful they must address relevant questions and be methodologically sound if the full potential of INO in this setting is to be established.

The authors wish to thank the Injuries Review Group of the Cochrane Collaboration for their guidance in developing the protocol for the metaanalysis; the Anaesthesia Review Group and their editors, who provided advice for the manuscript; and Professor Arne Ohlsson, who provided a constructive critique for the planning of the metaanalysis.

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