Original Article
Nitric Oxide in Cardiac Surgery: A Meta-Analysis
of Randomized Controlled Trials
Salvatore Sardo, MD
n, Eduardo Atsushi Osawa, MD, PhD
†,
Gabriele Finco, MD
n,
Filomena Regina Barbosa Gomes Galas, MD, PhD
‡,
Juliano Pinheiro de Almeida, MD, PhD
‡,
Salvatore Lucio Cutuli, MD
§, Claudia Frassanito, MD
¶,
Giovanni Landoni, MD
¶,‖,1, Ludhmila Abrahao Hajjar, MD, PhD
‡nDepartment of Medical Sciences and Public Health, University of Cagliari, Monserrato, Italy †Intensive Care Unit, Instituto do Cancer, Hospital das Clinicas da Faculdade de Medicina da Universidade de
Sao Paulo, Sao Paulo, Brazil
‡Heart Institute, University of Sao Paulo, Sao Paulo, Brazil
§Department of Anesthesiology and Intensive Care, Università Cattolica del Sacro Cuore, Rome, Italy ¶IRCCS San Raffaele Scientific Institute, Milan, Italy
‖Vita-Salute San Raffaele University of Milan, Milan, Italy
Objectives: To investigate the efficacy and safety of perioperative administration of nitric oxide in cardiac surgery. Design: Meta-analysis of randomized controlled trials (RCTs).
Participants: Cardiac surgery patients.
Interventions: A search of Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and MEDLINE for RCTs that compared nitric oxide with placebo or other comparators.
Measurements and Main Results: The primary outcome was intensive care unit (ICU) stay, and secondary outcomes were mortality, duration of mechanical ventilation, and reduction of mean pulmonary artery pressure. The study included 18 RCTs comprising 958 patients. The authors calculated the pooled odds ratio (OR) and the mean difference (MD) with random-effects model. Quantitative synthesis of data demonstrated a clinically negligible reduction in the length of ICU stay (MD –0.38 days, confidence interval CI [–0.65 to –0.11]; p ¼ 0.005) and mechanical ventilation duration (MD –4.81 hours, CI [–7.79 to –1.83]; p ¼ 0.002) compared with all control interventions with no benefit on mortality. Conclusions: Perioperative delivery of inhaled nitric oxide resulted to be of no or minimal benefit in patients with pulmonary hypertension undergoing cardiac surgery. Large, randomized trials are needed to further assess its effect on major clinical outcomes and its cost-effectiveness. &2018 Elsevier Inc. All rights reserved.
Key Words: nitric oxide; cardiac; pulmonary hypertension; meta-analysis; vasodilator; cardiopulmonary bypass
PULMONARY HYPERTENSION (PH) is defined by a mean pulmonary artery pressure Z25 mmHg at rest,
measured through right heart catheterization.1,2 PH is a
recognized risk factor for increased morbidity and mortality after cardiac surgery.3,4It is classified according to
pathophy-siologic mechanisms into the following 5 groups: pulmonary arterial hypertension (PAH, group 1), PH due to left heart disease (group 2), PH due to chronic lung disease and/or
Contents lists available atScienceDirect
journal homepage: www.jcvaonline.com
Journal of Cardiothoracic and Vascular Anesthesia
https://doi.org/10.1053/j.jvca.2018.02.003
1053-0770/& 2018 Elsevier Inc. All rights reserved.
1Address reprint requests to Giovanni Landoni, MD, IRCCS San Raffaele
Scientific Institute, Via Olgettina 60, Milan 20132, Italy. E-mail address:[email protected](G. Landoni).
hypoxemia (group 3), PH due to chronic thromboembolic pulmonary hypertension (group 4), and PH due to unclear multifactorial mechanism (group 5).5
The perioperative care of these patients is challenging, and selective pulmonary vasodilators are frequently administered to prevent or reverse right ventricular failure and cardiogenic shock. Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator whose potential benefits include pulmonary pres-sure reduction without systemic arterial hypotension, vasodila-tion in the adequately ventilated areas of the lungs, rapid onset and offset, a very low incidence of adverse effects in the usual range of dosage, and replacement of endogenous nitric oxide depletion due to cardiopulmonary bypass.6–12
The aim of this systematic review and meta-analysis was to assess and quantify the effect of intraoperative and/or post-operative delivery of iNO in a clinical population of cardiac surgery patients with known PH related to congenital heart disease or left heart disease.
Materials and Methods Study Type and Registration
The authors conducted a systematic review of randomized, controlled, parallel-group trials in accordance with a pre-viously registered protocol (International Prospective Register of Systematic Reviews, registration No. PROSPERO 2016: CRD42016032702) based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.13
Identification of Relevant Studies
Two trained investigators independently searched pertinent studies in the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and MEDLINE (updated up to January 25, 2018). They employed backward snowballing (ie, scanning of references of retrieved articles and pertinent reviews) and contacted international experts for retrieving additional studies. No language restriction was enforced, and non–English-language articles were translated before further analysis in order to include any indexed, peer-reviewed relevant publica-tion and consequently prevent a “language bias.” Detailed search strings and reference lists are given in theSupplemental Material. Two investigators independently examined the title and abstract of the references obtained from database and literature searches with divergences resolved by consensus and, if potentially pertinent, retrieved complete articles. Eligibility Criteria
The authors included randomized, controlled, parallel-group trials with all the following criteria: cardiac surgery setting (adult or pediatric); patients receiving iNO versus any com-parator such as placebo, no intervention, other inhalation therapies (eg, prostacyclin), or intravenous medications (eg,
milrinone, nitroglycerin, sodium nitroprusside); and reporting at least one relevant outcome among length of stay in the intensive care unit ([ICU] primary endpoint), duration of mechanical ventilation, mortality at longest follow-up, and reduction of mean pulmonary artery pressure.
Trial Selection and Data Extraction
Two authors independently extracted data, with disagree-ments resolved by discussion and, if needed, via a third author, who acted as an adjudicator. An attempt was made twice to contact authors to request any missing outcome data.
Risk of Bias Assessment and Strength of Evidence
Two authors independently examined the reported metho-dology for each article and assessed the risk of bias of included trials using the Cochrane Collaboration tool. The following domains were evaluated individually and graded as “low risk,” “high risk,” or “unclear risk”: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias. The item “selec-tive outcome reporting” was assessed as “unclear” risk if the study protocol was not published or registered previously. Data Synthesis
The authors used Review Manager (The Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark) for performing the statistical analysis and drawing the related plots.14 They computed standard deviations from standard
error of the mean according to the Cochrane Handbook for Systematic Reviews of Interventions.15 If continuous variables were expressed as median and interquartile range, the median was entered as mean and standard deviation was computed as the difference between third- and first-quartile values.16
When nitric oxide was compared with multiple control interventions, the authors managed continuous variables com-bining groups to create a single pair-wise comparison accord-ing to the Cochrane Handbook for Systematic Reviews of Interventions recommended formulae.17
They calculated the pooled odds ratio and 95% confidence interval (CI) for binary outcomes using the Mantel-Haenszel method with random-effects model, and estimated the mean difference (MD) and 95% CI for continuous outcomes using the inverse variance method with random-effects model.
Heterogeneity was managed using the random-effects model and by performing subanalysis for age groups (ie, adult and pediatric patients). The hypothesis of statistical heterogeneity was tested using the Cochran Q test, with statistical signifi-cance set at the two-tailed 0.10 level, whereas extent of statistical consistency was measured with I2, defined as
100% " (Q – df)/Q, where Q is Cochran’s heterogeneity statistic and df the degrees of freedom.18Inconsistency across
significant at I2 440%. Publication bias was evaluated by
visualization of funnel plots. Results
After excluding nonpertinent or noneligible studies (major exclusions listed in the Supplemental Material) the authors identified 18 studies (Table 1) randomizing 958 patients (Fig 1).12,19–35
When the pooled data of all comparators were analyzed, iNO minimally decreased the length of ICU stay (MD –0.38 days, CI [–0.65 to –0.11], I2 ¼ 11%, z ¼ 2.79, p ¼ 0.005, with 9 studies reporting these data and 560 patients included) with no small publication bias (Figs 2and3). Nitric oxide also marginally reduced mechanical ventilation duration (MD – 4.81 hours, CI [–7.79 to –1.83], I2 ¼ 31%, z ¼ 3.17, p ¼ 0.002, with 11 studies and 596 patients included Fig 4) compared with all the studied control interventions.
Nitric oxide did not significantly reduce mean pulmonary artery pressure (MD –1.37, CI [–4.40 to 1.67], I2 ¼ 74%, z ¼ 0.88, p ¼ 0.38, with 8 studies and 303 patients included) compared with all interventions (Fig 5).
No difference in survival was noted (absolute number of events 10/272 [3.67%] in the iNO group v 10/297 [3.37%] in the control group, OR 1.33, CI [0.52-3.39], I2 ¼ 0%, z ¼ 0.6, p ¼ 0.55, with 8 studies and 569 patients included
Fig 6).
Compared with iloprost, prostacyclin, or prostaglandin E1, no differences between nitric oxide and comparators were found (Supplemental Figs 12-15). Compared with standard care or placebo, a significant reduction in mechanical ventilation duration in the nitric oxide group was found
(MD –7.9 hours, CI [–11.22 to –4.58], I2
¼ 0%, z ¼ 4.67, p o 0.00001,Supplemental Fig 18).
Adult Patients
The authors performed a subanalysis for adult patients, mostly undergoing valve repair or valve replacement surgery (see Table 1), to compare nitric oxide with all comparators. The subanalyses confirmed a small reduction of ICU stay (MD –0.31 days, CI [–0.61 to –0.01], I2
¼ 19%, z ¼ 2.01, p ¼ 0.04 [Fig 3 and Supplemental Fig 21]) and mechanical ventilation (MD –5.76 hours, CI [–8.53 to –2.99], I2
¼ 11%, z ¼ 4.07, p o 0.0001 v MD –3.19 hours, CI [–9.3 to 2.92], I2
¼ 34%, z ¼ 1.02, p ¼ 0.31 [see Fig 4andSupplemental
Fig 22]) in the iNO group, with a nonsignificant trend versus higher mortality in the intervention group (see Fig 6 and
Supplemental Fig 21). Pediatric Patients
The subanalysis on congenital heart disease pediatric patients showed a slightly inferior ICU stay in the nitric oxide treatment group (MD –1.00 days, CI [–1.76 to –0.25], I2
¼ 0%, z ¼ 2.6, p ¼ 0.009 [seeFig 3 andSupplemental
Fig 23]). No significant differences were found in mechanical ventilation duration and mortality between nitric oxide and all comparators (Figs 4 and6; Supplemental Figs 24 and 25). Risk of Bias
Most studies were unblinded, and the full Cochrane risk of bias analysis is illustrated inSupplemental Figures 26 and 27
and Supplemental Table 1. The small study publication bias
Table 1
Characteristics of Included Studies
Study Comparator Population Surgery Nitric Oxide Dose Nitric Oxide Initiation Setting
Cai et al19 Milrinone Pediatric CHD Fontan-type o20 ppm Intensive care unit
Checchia et al20 Placebo Pediatric CHD (Fallot repair) 20 ppm Operating room
Chung et al21 Iloprost Adult CABG 20 ppm Operating room
Fattouch et al22 1-PGE1 Adult MVR 7 TVr 20 ppm Intensive care unit
2-Nitroprusside
Fattouch et al23 1-PGI2 Epoprostenol Adult MVR or MVr Unclear Operating room
2-intravenous vasodilators
Fernandes et al24 Oxygen Adult MVR or MVr 10 ppm Operating room
Gianetti et al12 Standard care Adult
AVR þ CABG 20 ppm Operating room
James et al25 Standard care Pediatric CHD repair 20 ppm Operating room
Kirbas et al26 Iloprost Pediatric CHD repair 20 ppm Operating room
Knothe et al27 Standard care Adult Cardiac surgery 30 ppm Operating room
Miller et al28 Placebo Pediatric CHD repair 10 ppm Intensive care unit
Prendergast et al29 Standard care Adult CABG 10-40 ppm Intensive care unit
Rajek et al30 PGE1 Adult Heart transplantation 4-24 ppm Operating room
Solina et al31 Milrinone Adult Cardiac surgery 20/40 ppm Operating room
Solina et al32 Milrinone Adult Cardiac surgery 10/20/30/40 ppm Operating room
Wagner et al33 Nitroglycerine Adult Valve replacement 40 ppm Operating room
Winterhalter et al34 Iloprost Adult Cardiac surgery 20 ppm Operating room
Zhang et al35 Standard care Adult Valve replacement 20 ppm Operating room
Abbreviations: AVR, aortic valve replacement; CABG, coronary artery bypass grafting; CHD, congenital heart disease; MVR, mitral valve replacement; MVr, mitral valve repair; ppm, parts per million; TVr, tricuspid valve repair.
was absent, as depicted in the funnel plots (see Fig 2 and
Supplemental Figs 1-11). Discussion
The authors conducted a systematic review of 18 rando-mized controlled trials (RCTs) in cardiac surgery patients to evaluate the effect of perioperative delivery of nitric oxide on
clinical outcomes. Most studies had a high or unclear risk of bias, and studies were highly heterogenous regarding the dosage, initiation, and duration of iNO delivery; the compara-tors; and the underlying cardiac defect or pathology. Con-sidering these limitations, the quantitative synthesis showed that the perioperative use of nitric oxide minimally reduced the duration of length of ICU stay (MD –0.38 days, CI [–0.65 to –0.11]) and mechanical ventilation (MD –4.81 hours, CI [–7.79 to –1.83]), with no benefit on mortality rate compared with all comparators (including other vasodilator therapies). The small effect on mechanical ventilation is confirmed in the analysis of nitric oxide versus standard care or placebo (MD –7.90, CI [–11.22 to –4.58]). Surprisingly, no significant reduction of pulmonary artery pressure was found. Although the authors recognize the “statistical strength” of these results, they should be interpreted with caution. Despite a significant association between iNO and a decrease in mechan-ical ventilation and ICU stay duration, the effect size seems small and clinically negligible. Furthermore, if those effects are real, they do not seem to relate with the degree of pulmonary artery pressure relief, so other mechanisms should be sought.
No previous reviews addressing the effects of iNO on major clinical outcomes in patients undergoing cardiothoracic pro-cedures were found. One systematic review involved RCTs
Fig 2. Funnel plot of intensive care unit stay outcome for comparison of nitric oxide versus all comparators. MD, mean difference; SE, standard error.
comparing the efficacy of the use of inhaled aerosolized vasodilators in the treatment of PH during cardiac surgery.36
That review found that aerosolized agents were associated with longer ICU stay compared with placebo, with no differences in hemodynamic profile and mortality. However, most of the studies had a moderate to high risk of bias, and the effect size for length of ICU stay outcome was pooled from 3 studies. Moreover, different drugs with variable pulmonary vasodila-tory potency and distinct systemic vasodilation effects were included in the intervention group.
Some systematic reviews with greater data robustness evaluated the role of iNO in other intensive care settings. A Cochrane review of 14 trials in patients with hypoxemic respiratory failure demonstrated improvement in the oxygena-tion index but no benefit in survival.37 Nevertheless, cardiac
surgical patients with underlying PH face additional issues other than hypoxemia, including right ventricular failure and increased pulmonary vascular resistance on the background of surgical stress injury. In this context, some components of cardiopulmonary bypass inflammatory activation such as
metabolic acidosis and systemic hypotension may act as contributors for PH exacerbation.
In infants born at or near term, a review demonstrated that iNO reduced the incidence of the combined endpoint of death and use of extracorporeal membrane oxygenation (ECMO).38
Due to favorable outcomes and the high quality of trials, neonates currently are the only population for which iNO holds Food and Drug Administration approval. In this analysis, the evidence of PH did not seem to affect the response to nitric oxide. In contrast to cardiac surgery patients, neonatal hypoxemia may result from a degree of pulmonary shunting and parenchymal lung disease.39 Similarly to the systematic
review presented here, the studies conducted in neonatal patients were heterogenous in regard to the implementation of adjunctive therapies, which may limit the internal validity and generalizability of the results.
In patients with PH, cardiac surgery may constitute the only therapeutic alternative to treat the causal underlying condition. After surgical trauma, a number of mechanisms take place and may spark a PH crisis, including ischemia-reperfusion injury,
Fig 4. Forest plot for mechanical ventilation duration mean difference (hours) between nitric oxide and all comparison interventions with subanalysis for age group. CI, confidence interval; IV inverse variance.
Fig 3. Forest plot for ICU stay mean difference (days) between nitric oxide and all comparison interventions with subanalysis for age group. CI, confidence interval; IV, inverse variance; SD, standard deviation.
endotoxemia, and cardiopulmonary bypass–induced contact activation.40 In such a proinflammatory milieu, perioperative
administration of iNO may provide support against pulmonary vasculature constriction. In the present systematic review, the timing of delivery was variable, with the majority of studies initiating the intervention in the operating room. The effect of a pre-emptive iNO delivery from anesthetic induction in carefully selected patients at risk of PH exacerbation might be an interesting topic of investigation.41,42
Nitric oxide delivery carries non-negligible risks and costs. iNO is inactivated rapidly in the circulation by hemoglobin iron oxidation, resulting in a dose-related methemoglobinemia. According to the published evidence, it seems that a clinically significant methemoglobinemia (45%) may develop not only in patients exposed to a high dose, but also in patients treated with conventional doses with specific risks. For example, a standard dose may cause this adverse event in patients affected by a methemoglobin reductase deficiency (ie, the enzyme involved in converting methemoglobin to hemoglobin) or in cases of technical mishaps (eg, pooling of nitric oxide in the breathing circuit or monitoring dysfunction).43–45Nitric oxide
may be oxidized further to nitrogen dioxide, which may cause airway inflammation, bronchospasm, and pulmonary edema.46
Unfortunately, most included studies did not report sufficient data to quantitatively assess iNO-related organ toxicity.
The administration of iNO also may increase the burden of tasks for medical and nursing staff due to cumbersome equipment and the need for more intensive monitoring. It also
poses a safety risk of environmental pollution. Moreover, the mean cost of iNO delivery is estimated to be significantly more compared with aerosolized prostacyclin ($3,000/d v $200/d, respectively).47 However, nitric oxide has been used
exten-sively worldwide over the last few decades as an off-label treatment in cardiac surgery. Nevertheless, the real cost-effectiveness of iNO therapy in cardiac surgical patients can be answered only by large, multicenter, randomized and adequately powered RCTs.
This systematic review was conducted to provide a quali-tative and quantiquali-tative synthesis of the published literature regarding the use of iNO in cardiac surgery. The study question and rationale seem to be relevant because this therapy is available in many centers, despite its off-label use. The authors believe that the chosen outcomes are more relevant than instrumental indices of organ function because they relate better to the quality and costs of health care. Methodologic guidelines were strictly followed, the protocol was registered, and a comprehensive and inclusive search strategy was performed. To the authors’ knowledge, this is the first systematic review addressing the isolated effect of iNO in cardiac surgery. Any study on the combination of nitric oxide with other selective pulmonary vasodilator was carefully excluded, so its effect as add-on therapy cannot be assessed. Other aerosolized vasodilators were not considered in the inclusion criteria because they may have distinct pulmonary vasodilatory potency, pharmacokinetic properties, and variable safety profile.
Fig 6. Forest plot for mortality odds ratio between nitric oxide and all comparison interventions. CI, confidence interval; M-H Mantel-Haenszel method. Fig 5. Forest plot for change of mean pulmonary artery difference between nitric oxide and all comparison interventions. CI, confidence interval; IV, inverse variance; SD, standard deviation.
This systematic review has limitations. First, the number of studies included was limited, and most of them were small and single-centered. Second, most studies included had a high or unclear risk of bias. Blinding of personnel and outcome assessment were highly biased in the majority of trials, so a spurious inflation of intervention effects cannot be excluded. Third, a large variability of dose, timing of the initiation, duration of the intervention, and comparators was found (see
Table 1). Fourth, the authors acknowledge the complexity of PH syndrome and its multiple pathophysiologic mechanisms in cardiac surgery patients undergoing different surgical procedures. Despite this, the authors considered that even in the setting of postcapillary PH, such as mitral stenosis, endothelium-dependent dysregulation of vascular tone still could affect both pulmonary vascular resistance and right ventricle afterload.48
These expected differences in treatment responses were addressed using a statistical model of random effects and performing subgroup analysis, but the scarcity of RCTs limited the efficacy of the latter strategy. Fifth, the authors cannot account for all undisclosed confounding factors, such as different mechanical ventilation strategies (eg, ventilator set-tings, inspired fraction of oxygen, weaning and extubation criteria) or vasopressor therapy, but believe that center- and study-related differences may be balanced.
This systematic review showed that perioperative delivery of iNO exerted minimal or null effects on major outcomes; therefore, new recommendations for practicing anesthesiolo-gists and intensivists who face the challenging management of PH in cardiac surgery patients cannot be provided. Given the heterogeneity and limitations of the studies included, and the ongoing widespread use of iNO in this setting, the authors support the conduct of well-designed, adequately powered, multicenter randomized trials to investigate the appropriate-ness of iNO in this surgical population.
Acknowledgements
The authors thank Dr. Paul Checchia, who kindly provided in-hospital mortality data, and Drs. Robert Wagner, Maria Rajek, and Jacopo Gianetti, who kindly answered the authors’ questions. The authors also thank Drs. Ryo Ueno (Kameda Medical Center, Japan), Diego Carter Borges (University of Sao Paulo, Brazil), Fang Mingxing (Hebei Medical University, China) and Sofia Beatrice Pellegrini (San Raffaele Scientific Institute, Italy) for their valuable collaboration.
Appendix A. Supporting Material
Supplementary data associated with this article can be found in the online version athttps://doi.org/10.1053/j.jvca.2018.02. 003.
References
1 Hoeper MM, Bogaard HJ, Condliffe R, et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013;62:D42–50.
2 Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67–119.
3 Nashef SA, Roques F, Michel P, et al. European system for cardiac operative risk evaluation (EuroSCORE). Eur J Cardiothorac Surg 1999;16: 9–13.
4 Tuman KJ, McCarthy RJ, March RJ, et al. Morbidity and duration of ICU stay after cardiac surgery. A model for preoperative risk assessment. Chest 1992;102:36–44.
5 Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62:D34–41. 6 Frostell CG, Blomqvist H, Hedenstierna G, et al. Inhaled nitric oxide
selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation. Anesthesiology 1993;78:427–35. 7 Pepke-Zaba J, Higenbottam TW, Dinh-Xuan AT, et al. Inhaled nitric oxide
as a cause of selective pulmonary vasodilatation in pulmonary hyperten-sion. Lancet 1991;338:1173–4.
8 Girard C, Lehot JJ, Pannetier JC, et al. Inhaled nitric oxide after mitral valve replacement in patients with chronic pulmonary artery hypertension. Anesthesiology 1992;77:880–3.
9 Germann P, Braschi A, Della Rocca G, et al. Inhaled nitric oxide therapy in adults: European expert recommendations. Intensive Care Med 2005;31: 1029–41.
10 Dickstein ML. Con: Inhaled prostaglandin as a pulmonary vasodilator instead of nitric oxide. J Cardiothorac Vasc Anesth 2005;19:403–5. 11 Morita K, Ihnken K, Buckberg GD, et al. Pulmonary vasoconstriction due
to impaired nitric oxide production after cardiopulmonary bypass. Ann Thorac Surg 1996;61:1775–80.
12 Gianetti J, Del Sarto P, Bevilacqua S, et al. Supplemental nitric oxide and its effect on myocardial injury and function in patients undergoing cardiac surgery with extracorporeal circulation. J Thorac Cardiovasc Surg 2004;127:44–50.
13 Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. BMJ 2009;339:b2535.
14 The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan 5). Available at:http://community.cochrane.org/tools/ review-production-tools/revman-5. Accessed January 29, 2018.
15 Higgins JPT, Green S. Obtaining standard deviations from standard errors, confidence intervals, t values and P values for differences in means. In Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions, Vol Version 5.1.0. Available at:http://handbook.cochrane. org. Accessed January 29, 2018.
16 Greco T, Biondi-Zoccai G, Gemma M, et al. How to impute study-specific standard deviations in meta-analyses of skewed continuous endpoints? World J Meta-Anal 2015;3:215–24.
17 Higgins JPT, Green S. Table 7.7.a: Formulae for combining groups. In Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of interventions, Vol Version 5.1.0. Available at:http://handbook.cochrane. org. Accessed January 29, 2018.
18 Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002;21:1539–58.
19 Cai J, Su Z, Shi Z, et al. Nitric oxide and milrinone: Combined effect on pulmonary circulation after Fontan-type procedure: A prospective, rando-mized study. Ann Thorac Surg 2008;86:882–8.
20 Checchia PA, Bronicki RA, Muenzer JT, et al. Nitric oxide delivery during cardiopulmonary bypass reduces postoperative morbidity in children—a randomized trial. J Thorac Cardiovasc Surg 2013;146:530–6.
21 Chung A, Wildhirt SM, Wang S, et al. Combined administration of nitric oxide gas and iloprost during cardiopulmonary bypass reduces platelet dysfunction: A pilot clinical study. J Thorac Cardiovasc Surg 2005;129:782–90. 22 Fattouch K, Sbraga F, Bianco G, et al. Inhaled prostacyclin, nitric oxide,
and nitroprusside in pulmonary hypertension after mitral valve replace-ment. J Card Surg 2005;20:171–6.
23 Fattouch K, Sbraga F, Sampognaro R, et al. Treatment of pulmonary hypertension in patients undergoing cardiac surgery with cardiopulmonary bypass: A randomized, prospective, double-blind study. J Cardiovasc Med (Hagerstown) 2006;7:119–23.
24 Fernandes JL, Sampaio RO, Brandão CM, et al. Comparison of inhaled nitric oxide versus oxygen on hemodynamics in patients with mitral stenosis and severe pulmonary hypertension after mitral valve surgery. Am J Cardiol 2011;107:1040–5.
25 James C, Millar J, Horton S, et al. Nitric oxide administration during paediatric cardiopulmonary bypass: A randomised controlled trial. Inten-sive Care Med 2016;42:1744–52.
26 Kirbas A, Yalcin Y, Tanrikulu N, et al. Comparison of inhaled nitric oxide and aerosolized iloprost in pulmonary hypertension in children with congenital heart surgery. Cardiol J 2012;19:387–94.
27 Knothe C, Scholz S, Zickmann B, et al. [NO inhalation in heart surgery procedures: Relevance for right heart function?]. Anaesthesist 1996;45: 240–8.
28 Miller OI, Tang SF, Keech A, et al. Inhaled nitric oxide and prevention of pulmonary hypertension after congenital heart surgery: A randomised double-blind study. Lancet 2000;356:1464–9.
29 Prendergast B, Scott DH, Mankad PS. Beneficial effects of inhaled nitric oxide in hypoxaemic patients after coronary artery bypass surgery. Eur J Cardiothorac Surg 1998;14:488–93.
30 Rajek A, Pernerstorfer T, Kastner J, et al. Inhaled nitric oxide reduces pulmonary vascular resistance more than prostaglandin E(1) during heart transplantation. Anesth Analg 2000;90:523–30.
31 Solina A, Papp D, Ginsberg S, et al. A comparison of inhaled nitric oxide and milrinone for the treatment of pulmonary hypertension in adult cardiac surgery patients. J Cardiothorac Vasc Anesth 2000;14:12–7.
32 Solina AR, Ginsberg SH, Papp D, et al. Dose response to nitric oxide in adult cardiac surgery patients. J Clin Anesth 2001;13:281–6.
33 Wagner R,Černý J, Piler P, et al. Effect of nitric oxide on early myocardial function in valvular surgery. Scripta Medica (Brno) 2003;76:357–62. 34 Winterhalter M, Simon A, Fischer S, et al. Comparison of inhaled iloprost
and nitric oxide in patients with pulmonary hypertension during weaning from cardiopulmonary bypass in cardiac surgery: A prospective rando-mized trial. J Cardiothorac Vasc Anesth 2008;22:406–13.
35 Zhang WX, Gong GF, Chen SX. [Protective effects of low dose nitric oxide inhalation on lung ischemia/reperfusion injury during cardio-pulmonary bypass surgery]. Hunan Yi Ke Xue Xue Bao 2000;25:483–6. 36 Elmi-Sarabi M, Deschamps A, Delisle S, et al. Aerosolized vasodilators for the treatment of pulmonary hypertension in cardiac surgical patients: A systematic review and meta-analysis. Anesth Analg 2017;125:393–402. 37 Gebistorf F, Karam O, Wetterslev J, et al. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev 2016:CD002787.
38 Barrington KJ, Finer N, Pennaforte T, et al. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev 2017;1: CD000399.
39 Macrae DJ, Field D, Mercier J-C, et al. Inhaled nitric oxide therapy in neonates and children: Reaching a European consensus. Intensive Care Med 2004;30:372–80.
40 Laffey JG, Boylan JF, Cheng DCH. The systemic inflammatory response to cardiac surgery: Implications for the anesthesiologist. Anesthesiology 2002;97:215–52.
41 Aya HD, Cecconi M, Hamilton M, et al. Goal-directed therapy in cardiac surgery: A systematic review and meta-analysis. Br J Anaesth 2013;110: 510–7.
42 Osawa EA, Rhodes A, Landoni G, et al. Effect of perioperative goal-directed hemodynamic resuscitation therapy on outcomes following cardiac surgery: A randomized clinical trial and systematic review. Crit Care Med 2016;44:724–33.
43 Taylor MB, Christian KG, Patel N, et al. Methemoglobinemia: Toxicity of inhaled nitric oxide therapy. Pediatr Crit Care Med 2001;2:99–101. 44 Weinberger B, Laskin DL, Heck DE, et al. The toxicology of inhaled nitric
oxide. Toxicol Sci 2001;59:5–16.
45 Sydow M, Bristow F, Zinserling J, et al. Variation of nitric oxide concentration during inspiration. Crit Care Med 1997;25:365.
46 Augoustides JG, Ochroch EA. Pro: Inhaled prostaglandin as a pulmonary vasodilator instead of nitric oxide. J Cardiothorac Vasc Anesth 2005;19:400–2. 47 Lowson SM. Alternatives to nitric oxide. Br Med Bull 2004;70:119–31. 48 Mahoney PD, Loh E, Blitz LR, et al. Hemodynamic effects of inhaled
nitric oxide in women with mitral stenosis and pulmonary hypertension. Am J Cardiol 2001;87:188–92.
