Therapy Scenario

Thick meconium is passed during the delivery of a term infant. Immediately after birth, the trachea is intubated and suctioned for copious amounts of meconium. Despite intensive therapy which includes mechanical ventilation with pure oxygen and exogenous surfactant, the infant remains hypoxemic. Echocardiography confirms the presence of an anatomically normal heart and is consistent with the clinical diagnosis of Persistent Pulmonary Hypertension of the Newborn (PPHN). The resident asks whether to refer the patient to the Extracorporeal Membrane Oxygenation (ECMO) team in your tertiary care centre. You recently read about the benefits of inhaled nitric oxide and wonder whether this should be tried first.

You formulate the question, “In a term infant with hypoxic respiratory failure, does the use of inhaled nitric oxide decrease the need for ECMO?”

You start with Best Evidence. You enter the search term ‘inhaled nitric oxide’ and you find the abstract for the multi-centre trial of the Neonatal Inhaled Nitric Oxide Study Group. You review the abstract from Evidence Based Medicine (EBM) together with the original article N Engl J Med 1997; 336: 597-604.

Read the article and decide:

  • Is the evidence from this randomised trial valid?
  • If valid, is this evidence important?
  • If valid and important, can you apply this evidence in caring for your patient?

Completed Therapy Worksheet for Evidence-Based Neonatal Medicine

Citation

The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997; 336: 597-604.

Are the results of this single preventive or therapeutic trial valid?

Was the assignment of patients to treatments randomised?
And was the randomisation list concealed?
Yes. Central telephone randomisation was used.
Were all patients who entered the trial accounted for at its conclusion?
And were they analysed in the groups to which they were randomised?
Yes to both questions.
Were patients and clinicians kept “blind” to which treatment was being received?
Yes. Designated individuals who were not involved in the clinical care adjusted and monitored the study gases.
Aside from the experimental treatment, were the groups treated equally?
Yes.
Were the groups similar at the start of the trial?
Yes.

Are the valid results of this randomised trial important?

Your calculations:
Event rate for primary outcome (death by 120 days of age or initiation of ECMO) Relative Risk Reduction
RRR		 Absolute Risk Reduction
ARR		 Number Needed to Treat
NNT
CER EER (CER – EER)/CER CER – EER 1/ARR
64% 46% 28% 18% 6

Further analyses demonstrated that inhaled nitric oxide reduced the need for ECMO but did not decrease mortality: CER 55%, EER 39%, RRR 29%, ARR 16%, NNT 7 (95% CI 4 to 31).

Can you apply this valid, important evidence about a treatment in caring for your patient?

Do these results apply to your patient?
Is your patient so different from those in the trial that its results can’t help you?
No.
How great would the potential benefit of therapy actually be for your individual patient?
Method I: f

$$text{Risk of the need for ECMO in your patient, relative to patients in the trial. Expressed as a decimal: 1}\\
\\
mathit{NNT}/mathit{f} \\
= 7 / 1 \\
= 7 \\
text{($NNT$ for patients like yours)}$$

Method II:

$$ text{1 / ($PEER$ x $RRR$) Your patient’s expected event rate if they received the control treatment: $PEER$:______}\\
\\
1 / (mathit{PEER} times mathit{RRR})\\
= 1/underline{qquad qquad}\\
= underline{qquad qquad}\\
text{($NNT$ for patients like yours)}$$

Are your patient’s values and preferences satisfied by the regimen and its consequences?
Do your patient and you have a clear assessment of their values and preferences?
This needs to be discussed with the parents of the patient; however, since inhaled nitric oxide is far less invasive than ECMO, chances are that parent would accept a recommendation to try inhaled nitric oxide first.
Are they met by this regimen and its consequences?
Likely.

Additional Notes

See commentary with the abstract in Evidence Based Medicine Sept/Oct. 1997 page 153

Hypoxic Respiratory Failure in Term Infants: Inhaled nitric oxide reduces the need for ECMO.

Clinical Bottom Line

Use of inhaled nitric oxide in term infants with hypoxic respiratory failure will reduce need for ECMO (NNT = 7).

Citation

The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med 1997; 336: 597-604.

Clinical Question

In a term infant with hypoxic respiratory failure, does the use of inhaled nitric oxide decrease the need for ECMO?

Search Terms

Best Evidence: nitric oxide.

The Study

  • Double-blinded concealed randomised controlled trial with intention-to-treat.
  • The Study Patients: Infants born at 34 gestational age or greater who were 14 days of age or less. Infants required ventilation for hypoxic respiratory failure with oxygenation index greater than 25 on two consecutive measurements.
  • Control group (N = 121; 121 analysed): Treatment with 100% oxygen.
  • Experimental group (N = 114; 114 analysed): Standard care plus nitric oxide 20 ppm with a maximal increase to 80 ppm if only partial response (PaO2 increase by 20 or less) to 20 ppm nitric oxide.

The Evidence

Outcome Time to Outcome CER EER RRR ARR NNT
Death by 120 days of age or need for ECMO. 0.636 0.456 28% 0.180 6
95% Confidence Intervals 9% to 48% 0.055 to 0.305 4 to 19
Death by 120 days of age. 0.165 0.165 15% 0.025 40
95% Confidence Intervals: -40% to 71% -0.067 to 0.117 NNT = 9 to INF;
NNH = 15 to INF
Need for ECMO. 0.545 0.386 29% 0.159 7
95% Confidence Intervals: 6% to 52% 0.033 to 0.285 4 to 31
Particular to my patient:
Outcome f NNT
Death by 120 days of age or need for ECMO. 1 6
Death by 120 days of age. 1 40
Need for ECMO. 1 7

Comments

  • Study stopped early due to proven efficacy a scheduled interim analysis.
  • Although inhaled nitric oxide reduced the need for ECMO, it did not decrease mortality.

Appraised By

Aaron Chiu