Nitric oxide & Congenital Diaphragmatic Hernia; not so safe after all?

As a young resident I have a vivid memory of a baby with CDH having saturations of 60 – 65% despite HFOV, paralysis and alkalinization (yes we used to do that).  It was at that time that I pretty much threw my hands in the air and declared there was really nothing left that we could do.  One of my mentors, a very wise Neonatologist Dr. Henrique Rigatto looked at me and said “why don’t we try inhaled nitric oxide?”  Being the resident immersed in the burgeoning field of evidence based medicine I questioned him on this stating “But the evidence shows no benefit of iNO in CDH in any trials”.  He looked back at me and asked “Are you prepared to let this baby die without even trying it?”.  When put that way I answered shyly that I would order the iNO and… it worked.  Whether it was coincidence or not I cannot say but I felt he had a point which I have shared many times with students over the years.  A drug may not show a benefit in a clinical RCT so at a population level it should not be our ” go to” drug of choice but on an individual level as a last resort sometimes these medications for an individual patient may make a difference.  Looking at it from a different standpoint one might say it falls into the “can’t hurt but might help” category of therapy.

Or is it safe in CDH?

The Congenital Diaphragmatic Hernia Study Group (CDHSG) of which we are a contributing centre recently published a retrospective analysis of the registry (now including over 9000 patients!) in an attempt to answer whether iNO use in babies with CDH is indeed safe. Evaluation of Variability in Inhaled Nitric Oxide Use and Pulmonary Hypertension in Patients With Congenital Diaphragmatic Hernia.

The study looked at 2047 patients treated with iNO most of whom received 20 ppm of iNO.  Interestingly about 15% of the patients treated with iNO did not have pulonary hypertension on ECHO. figure The study found a positive association between centres using iNO and mortality. Moreover as the number of centres increased over time that used iNO so did the overall mortality in the study cohort.   Beyond just looking at the trend in mortality with increasing use the authors took this one step further and used the statistical technique of propensity scoring to determine the attributable risk to mortality of using iNO in patients with CDH.

Propensity scoring is an interesting technique that one can use to estimate risk when it is unlikely that a randomized controlled trial will be available and this is one of those cases.  The technique uses an approach which strives to balance the variables that determined why different patients received a treatment so when comparing the outcomes of the two groups you manage to isolate the effect to just the treatment that is being studied.  In this case the technique indicates that the estimate of harm is estimated to be 15% meaning that there is an estimated 15% increase in mortality for patients with CDH treated with iNO regardless of the indication.

So what to do with our next patient?

I can’t help but think back to the words of one of my mentors and ask myself what I would do if I was confronted with a patient who had CDH and was saturating poorly.  I think what this study adds perhaps is that one should tread carefully with iNO in the setting of CDH. Maybe the overall message is that one should not jump to use iNO early in treatment. Optimizing  ventilation, use of analgesics and sedation and even paralysis may be a better approach to controlling oxygenation than early iNO.  When all those have been tried though and the patient is still not responding I think those wise words from long ago carry a lot of weight. “Are you prepared to let this baby die without even trying it?”

When mortality is already a strong possibility I believe at least for me the answer will remain no.  I think it is important to keep iNO in your back pocket but to let a patient die without trying would leave me forever asking “what if”.  That is a question I am certainly not comfortable asking at all.



7 thoughts on “Nitric oxide & Congenital Diaphragmatic Hernia; not so safe after all?

  1. What if we have limited resources and we are trying to save it for MAS pt or other pt with oxygenation problem ? And can we use Sildenafil instead !


    1. Interesting comment. I think sildenafil offers a very good alternative and in the setting of limited resources I would agree with limiting the use of iNO to situations with proven efficacy


    2. The problem in sildenafil is the route of adminstration we are giving it orally in critically sick patient it can be given in combination with NO
      Alone i doubt its efficacy another alternative called PONSNTAN also same problem
      There is an association between long term use of sildenafil with lung collapse
      But as the mentor said try the available resorts
      Magnesium sulphate also we can use but bad side effects
      No one of these drugs is magic all are disappointing
      Sorry this is my experience


  2. I am always a little wary about data such as these unless we have an understanding of the other variables that may contribute – certainly at our centre I get the feeling that the threshold at which termination of pregnancy for CDH has changed over the years – partly because of the introduction of fetal interventional studies, but also because overall survival appeared to be increasing. This changes the population making historical comparison difficult. Another confounder may be improvement in antenatal diagnosis in general – outborn diaphragms that reach a tertiary centre tend to do better (as they have survived to make it to the tertiary centre). With better antenatal diagnosis more CDH babies are born in tertiary centres (and as a result are probably more likely to receive iNO due to availability as a ‘last resort’ before they die). It would be interesting to see the survival rates overall in both groups with the diagnosis of CDH both antenatally (at any stage) and postnatally used as the denominator to capture those babies that are not born alive. What is clear I agree, is that while there is certainly a degree of equipoise, due to the nature of presentation a randomised study seems unlikely. We are currently having the same debate about iNO in early preterm babies with respiratory failure…


  3. Thanks a lot really everyday you are embressing us with your nice topics and this one came on time as 3 weeks ago i have patients with CDH left side discharged home safely after being operated in D3 and he was on pip/peep 18/4
    And dopamine plus dobutamine 15 mic/kg / min
    Everything runs smoothly
    And this baby had another sibling who is 10 years old and post operative diaphragmatic hernia repair which put us in another challenge
    We know that survival depend on lung condition i think managing those babies targetting less SPO2 may help them i have bad experience with NO
    Thanks again for you and the wise mentor
    Really i enjoyed a lot.
    Tarek Kotb


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