We all wish that every patient who goes into cardiac surgery would be a straight-forward fast track case. Unfortunately, the issues that lead most patients to need cardiac surgery also put them at risk for complications. Some patients present with pulmonary hypertension that is discovered in the operating room once the pulmonary artery catheter is floated in the pulmonary artery (PA). Some have right ventricular (RV) dysfunction to start off the case. During the case, there are different factors that could irritate the PA and RV. These include left heart failure, acidosis, hypercapnia, hypoxia and being on bypass within itself. A mitral valve replacement just illicits a response in me to where I wonder what the PA pressures are going to be when they arrive to the CVICU. Do we start inhaled nitric oxide or Epoprostenol in these patients?
Regardless of the etiology (and group) of the pulmonary hypertension, everyone involved in the care prepares for a potential rollercoaster. We need to keep the RV stroke volume happy. We need to make sure that there’s not too much afterload for the RV to contend against. How we will battle this pulmonary vascular resistance (PVR)? In our heads we ask: will this patient need either nitric oxide or Epoprostenol during or after their surgery? After all, the mortality rate ranges between 37-90% when the right heart gets knocked out. We need to do something.
What makes this tough is the lack of robust prospective randomized controlled trials looking at nitric oxide or Epoprostenol in cardiac surgery. Well, this is my expert opinion of the data as of 07.23.22.
What is the mPAP that defines Pulmonary Hypertension?
I will provide the non-pulmonologist definition. Pulmonary Arterial Hypertension is defined as a mean pulmonary arterial pressure greater than or equal to 20. Patients also need a pulmonary vascular resistance (PVR) of greater than or equal to 3 woods units. Some papers do not act unless the mPAP is > 25mmHg. I will not provide the discussion of the different groups as it is beyond the scope of this quick review. If patients develop pulmonary hypertension in the OR, it makes them challenging to get off pump and could lead them to go into full RV failure.
Nitric Oxide
Nitric oxide is naturally occurring in our bodies. Per UpToDate, it “diffuses into adjacent vascular smooth muscle and decreases vascular tone in the systemic and pulmonary circulation”. In addition, it causes “suppression of both smooth muscle proliferation and platelet aggregation”. When it is inhaled, it focuses that action in the ventilated areas of the lungs. The mechanism of action gets complicated to explain and could be found via a quick Google search. The half-life is just 15-30 seconds.
Many of us have experience with nitric from taking care of severe ARDS patients, especially during the recent pandemic, as well as cardiac surgery.
Nitric Oxide in Cardiac Surgery
Nitric oxide is used in cardiac surgery for either patients whose pulmonary artery pressures make us a bit uncomfortable, or for a type of acute right heart syndrome. In the latter, our cardiac anesthesia colleagues watch the deterioration of the RV via TEE and choose to remove some afterload from the RV with a pulmonary vasodilator. Nonami published the first review article on nitric oxide I could find in cardiac surgery back in 1997 when the papers he cited were merely trying to tease out the dosing. More recently, Deshpande et al. calls nitric oxide the “tried and tested” selective pulmonary vasodilator. There was a trend, because the trial was very small with just 30 patients, that those with PVR’s > 3 were better responders to nitric oxide per Solina et al.
A more recent meta-analysis of RCT’s in cardiac surgery patients looked at 18 studies to see if there was a benefit to using iNO. The difference in length of stay was statistically significant, but trivial considering the cost at a mean of 0.4 days less if receiving iNO. The time on mechanical ventilation was also shortened but this was by a mean of 4.8 hours. There was no difference in mPAP nor survival. The lack of difference in mPAP really catches my eye because that is what it is supposed to do. It is not what I have seen in practice. This caught the eyes of the authors as well but I guess that’s what happens in a combination of numerous small trials.
Possible Renal Protection of Nitric Oxide in Cardiac Surgery
If one has to find other benefits of using inhaled nitric oxide in cardiac surgery, they can check out a study by Lei et al. looking at AKI in this patient population. They were very specific of the patient population looked at here which makes generalizability questionable. They were patients with multiple valve surgery and underlying renal dysfunction. Mostly rheumatic valve disease. They got nitric while on pump and up to 24 hours after. Post-op AKI decreased from 64% to 50% in the nitric group versus the nitrogen (control) group. That’s a NNT of 7.1. There were another number of positive kidney secondary outcomes as well.
This was further covered by Jacob et al. in a paper looking at strategies for post-op AKI in the cardiac surgery population. A systematic review and meta-analysis including 5 trials by Hu et al. noted a decreased risk of AKI but that was only when it was started at the beginning of bypass. No benefit when for AKI when started at the end of bypass. Data is definitely limited as the dosing, timing, and duration is still in question. That being said, there’s an ongoing RCT looking to “prevent postoperative acute kidney injury by administering nitric oxide gas“.
Epoprostenol
Epoprostenol, more common called Flolan as it is much easier to say, is another medical commonly used for pulmonary hypertension. The only labeled indication is for the treatment of pulmonary arterial hypertension. I have personally used it off-label for refractory ARDS, post-cardiac surgery with pulmonary hypertension and/or RV dysfunction. It is a prostacyclin and PGI2.
Epoprostenol in Cardiac Surgery
Buckley et al. published a summary of 11 studies of epoprostenol in the critically ill. 6 of those were in the cardiac surgery population. This was published back in 2010 so the trials were small with the largest being of 126 patients and the smallest being of just 9. The common criteria for utilization was a mPAP > 25mmHg, a PVR > 200, or a sPAP of > 30mmHg.
Comparing Nitric Oxide vs. Epoprostenol in Cardiac Surgery
McGinn and Reichert, the latter of whom I worked with during my fellowship and is a great guy, published a single-center, retrospective, observational, cohort study comparing nitric oxide versus epoprostenol in cardiac surgery. After including 49 patients into each group, there was no difference in the reduction of the mPAP nor in adverse events. The big difference was in the cost. The median cost per patient on nitric oxide was $2562.50. The media cost per patient on Epoprostenol was $363.53. This was published in 2016 so costs will most like have increased.
Can we come to a conclusion based on these limited data?
Rao et al. attempted to do just that. Basically, the struggle is the cost with inhaled nitric oxide compared to Epoprostenol in cardiac surgery. Their paper published in 2018 states that it costs over $200 an hour for nitric in a 70kg person versus up to $10 an hour for Epoprostenol. The most important part is that they conclude that “the existing evidence indicates that the physiologic actions of these 2 agents were equivalent”. We need more comparison trials, but who is going to pay for it? To learn how I recover hearts in the CVICU, CLICK HERE.
Citations of Nitric Oxide in Cardiac Surgery
Sardo S, Osawa EA, Finco G, Gomes Galas FRB, de Almeida JP, Cutuli SL, Frassanito C, Landoni G, Hajjar LA. Nitric Oxide in Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials. J Cardiothorac Vasc Anesth. 2018 Dec;32(6):2512-2519. doi: 10.1053/j.jvca.2018.02.003. Epub 2018 Apr 25. PMID: 29703580.
Link to (NOT FREE) Article
Solina AR, Ginsberg SH, Papp D, Pantin EJ, Denny J, Ghandivel I, Krause TJ. Response to nitric oxide during adult cardiac surgery. J Invest Surg. 2002 Jan-Feb;15(1):5-14. doi: 10.1080/08941930252807732. PMID: 11931495.
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Lei C, Berra L, Rezoagli E, Yu B, Dong H, Yu S, Hou L, Chen M, Chen W, Wang H, Zheng Q, Shen J, Jin Z, Chen T, Zhao R, Christie E, Sabbisetti VS, Nordio F, Bonventre JV, Xiong L, Zapol WM. Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery. Am J Respir Crit Care Med. 2018 Nov 15;198(10):1279-1287. doi: 10.1164/rccm.201710-2150OC. PMID: 29932345; PMCID: PMC6290943.
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Jacob KA, Leaf DE. Prevention of Cardiac Surgery-Associated Acute Kidney Injury: A Review of Current Strategies. Anesthesiol Clin. 2019 Dec;37(4):729-749. doi: 10.1016/j.anclin.2019.08.007. Epub 2019 Sep 21. PMID: 31677688; PMCID: PMC7644277.
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Nonami Y. The role of nitric oxide in cardiac surgery. Surg Today. 1997;27(7):583-92. doi: 10.1007/BF02388212. PMID: 9306558.
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Hu J, Spina S, Zadek F, Kamenshchikov NO, Bittner EA, Pedemonte J, Berra L. Effect of nitric oxide on postoperative acute kidney injury in patients who underwent cardiopulmonary bypass: a systematic review and meta-analysis with trial sequential analysis. Ann Intensive Care. 2019 Nov 21;9(1):129. doi: 10.1186/s13613-019-0605-9. PMID: 31754841; PMCID: PMC6872705.
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Magoon R, Dey S, Walian A, Kashav R. Nitric Oxide: Renoprotective in Cardiac Surgery! Braz J Cardiovasc Surg. 2020 Aug 1;35(4):602-603. doi: 10.21470/1678-9741-2020-0080. PMID: 32864944; PMCID: PMC7454621.
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Citations of epoprostenol use in cardiac surgery
Deshpande SP, Mazzeffi MA, Strauss E, Hollis A, Tanaka KA. Prostacyclins in Cardiac Surgery: Coming of Age. Semin Cardiothorac Vasc Anesth. 2018 Sep;22(3):306-323. doi: 10.1177/1089253217749298. Epub 2017 Dec 25. PMID: 29277148.
Link to (NOT FREE) Article
McGinn K, Reichert M. A Comparison of Inhaled Nitric Oxide Versus Inhaled Epoprostenol for Acute Pulmonary Hypertension Following Cardiac Surgery. Ann Pharmacother. 2016 Jan;50(1):22-6. doi: 10.1177/1060028015608865. Epub 2015 Oct 5. PMID: 26438636.
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Guan Z, Shen X, Zhang YJ, Li XG, Gao YF, Tan J, Yuan H, Liu JJ. Use of epoprostenol to treat severe pulmonary vasoconstriction induced by protamine in cardiac surgery. Medicine (Baltimore). 2018 Jul;97(28):e10908. doi: 10.1097/MD.0000000000010908. PMID: 29995750; PMCID: PMC6076185.
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Haché M, Denault A, Bélisle S, Robitaille D, Couture P, Sheridan P, Pellerin M, Babin D, Noël N, Guertin MC, Martineau R, Dupuis J. Inhaled epoprostenol (prostacyclin) and pulmonary hypertension before cardiac surgery. J Thorac Cardiovasc Surg. 2003 Mar;125(3):642-9. doi: 10.1067/mtc.2003.107. PMID: 12658208.
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Henke VG. Inhaled Selective Pulmonary Vasodilator Use After Cardiac Surgery: Broader Insights From a Study Describing Significant Changes in Drug Utilization and Savings After Implementation of a Guideline Favoring Inhaled Epoprostenol. J Cardiothorac Vasc Anesth. 2022 May;36(5):1350-1353. doi: 10.1053/j.jvca.2022.01.024. Epub 2022 Jan 23. PMID: 35227574.
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Buckley MS, Feldman JP. Inhaled epoprostenol for the treatment of pulmonary arterial hypertension in critically ill adults. Pharmacotherapy. 2010 Jul;30(7):728-40. doi: 10.1592/phco.30.7.728. PMID: 20575636.
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Schraufnagel DP, Elgharably H, Siddiqi S, Hakim AH, Sale S, Mehta A, Skubas NJ, Gordon SM, Bakaeen F, Gillinov AM, Svensson LG, Navia JL. Value of perioperative inhaled epoprostenol with low tidal volume ventilation for complex endocarditis surgery. J Card Surg. 2019 Aug;34(8):676-683. doi: 10.1111/jocs.14095. Epub 2019 Jun 18. PMID: 31212385.
Link to (NOT FREE) Article
Rao V, Ghadimi K, Keeyapaj W, Parsons CA, Cheung AT. Inhaled Nitric Oxide (iNO) and Inhaled Epoprostenol (iPGI2) Use in Cardiothoracic Surgical Patients: Is there Sufficient Evidence for Evidence-Based Recommendations? J Cardiothorac Vasc Anesth. 2018 Jun;32(3):1452-1457. doi: 10.1053/j.jvca.2017.12.014. Epub 2017 Dec 13. PMID: 29336971.
Link to (NOT FREE) Article
Henke VG. Inhaled Selective Pulmonary Vasodilator Use After Cardiac Surgery: Broader Insights From a Study Describing Significant Changes in Drug Utilization and Savings After Implementation of a Guideline Favoring Inhaled Epoprostenol. J Cardiothorac Vasc Anesth. 2022 May;36(5):1350-1353. doi: 10.1053/j.jvca.2022.01.024. Epub 2022 Jan 23. PMID: 35227574.
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