A propensity-matched analysis of inhaled nitric oxide for Congenital Diaphragmatic Hernia
Robert Baird, Kartik Pandya, Pramod Puligandla
Background:
The use of inhaled nitric oxide (iNO) as a pulmonary vasodilator in the context of
congenital diaphragmatic hernia (CDH) remains controversial. Evidence supporting its beneficial
effects are scarce and dated; three underpowered trials as well as case series have failed to
demonstrate a significant imporvement in outcomes. (1-4) A meta-analysis of this data also
could not clarify the utility of iNO; all of these studies were published >15 years ago. (5)
Despite the paucity of evidence and associated cost of iNO administration, it continues
to be used routinely. Indeed, an audit of recent CAPSNet data demonstrates that nearly 33% of
neonates with CDH receive iNO during the course of their intensive care stay. A recent PHIS
data query evaluating over 1700 patients demonstrated that 57% of patients were administered
iNO, and that extreme variability existed between centers. In addition, iNO usage is increasing
over time. (6) Finally, the use of inhaled nitric oxide has been previously described as
‘exorbitant’. (7)
In general, the classical evaluation of post hoc treatment effects are marred by
‘counfounding by indication’ – that patients receiving a treatment are inherently higher risk than
those not receiving the treatment. By creating a propensity score (a predicted probability of
receving iNO), patients can be reasonably matched and key outcomes (mortality, ECMO use)
can be compared. The objective of this research project is to investigate which covariates
influence the clinical decision making to begin iNO treatment and to determine whether the
administration of iNO influences patient outcomes using a propensity matched analysis. A
rudimentary (indirect) cost analysis will also be performed. The possible demonstration of no
effect coupled with the associated cost of iNO has a greater likelihood of influencing practice
change.
Research question:
What determinants predict the use of iNO?
Does the use of iNO improve outcomes for patient with CDH?
Proposed Research and Statisitical Methodology:
The latest iteration of the CAPSNet dataset will be queried. The data analysis will proceed as
follows:
1. An unadjusted comparison of cases (patients receiving iNO) and controls (patients not
receiving iNO) will be performed with conventional inferential statisics used to evaluate
differences in outcomes between the two groups. Outcomes to be evaluated include:
a. Mortality
i. Without surviving to surgery
ii. Surviving to surgery
b. ECMO use
c. An aggregate of a. and b.
d. Oxygen use at discharge
2. A multivariate logistic regression model will then be used to create a propensity score
which reflects the predicted probability of each neonate receiving iNO. Covariates to be
evaluated are stratified as follows:
a. Prenatal (e.g. prenatal diagnosis Lung-head ratio, Liver position)
b. At birth (e.g. Apgar, Gestational Age, Birthweight, Gender, defect sidedness,
inborn, concomittant diagnosis)
c. Postnatal (e.g. Prognostic scores [SNAP, CDHSG score, Santa Rosa score],
Ventilatory mode [CMV, HFOV], Ventilatory pressures [PIP, PEEP, MAP],
Ventilatory efficacy [PO2, PCO2, OI], Other [vasopressor and inotrope use,
corticosteroids, surfactant, urine output, pH <7.25…]
d. Systemic (e.g. hospital Volume, ECMO capabilities, year of treatment)
3. An adjusted comparison of the aformentioned outcomes after matching cases and
controls 1:1 based on the propensity score of receving iNO. If 1:1 matching is not
possible due to unequal numbers, an alternative matching plan may be considered in
conjunction with a biostatician
4. A cost/day of iNO will be generated based on current costing. The additional overall
cost/patient of iNO will then be calculated
Time frame:
All available years of CAPSNet data will be queried
Inclusion/Exclusion:
Inclusion:
1. Entered into the CDH database as having had CDH
2. Treated at a CAPSNet center
3. Closed file (in-hospital outcome complete)
Exclusion:
1. In utero fetal demise (never treated post-natal)
Expected Outcome and Mock Tables:
1. Unadjusted analysis
Outcome
Case (iNO), n=
Mortality
ECMO use
Mortality and ECMO
(combined outcome)
Post-op vent days
Length of Stay
Ventilation mode at
72 hours
Oxygen
use
at
discharge
Control (no iNO), n=
P=
P=
P=
P=
P=
2. Covariate analysis
Covariate
Prenatal
LHR
o/e LHR
TFLV
o/e TFLV
Liver position
Associated anolamies
At birth
APGAR (5 min)
Birthweight
Gender
Gestational age
Outborn
Postnatal
SNAP score
Ventilatory mode
Pre-op ECHO (and degree of PHN)
Pulmonary Vasodilators
Inotropes
4 hour SAT
4 hour post-ductal PaO2
24 hour SAT
24 hour post-ductal PaO2
Pre-op SAT
Pre-op post-ductal PaO2
Pre-op ECHO
Size of defect (As per CAPSNet def)
Patch (yes/no)
Institutional
Case (iNO), n=
Control (no iNO), n=
P=
P=
P=
P=
Year of treatment (before and after 2010)
ECMO center (Y/N)
Hospital Volume (Low, Medium, High), use
CAPSNet defintion
Hospital Geography (West, Central, East)
Time of ICU admission (night vs not), use
publiication definition
1. Adjusted analysis
Outcome
Case
(iNO), n=
Control (no iNO), n=
Odds Ratio
95% CI
Mortality
ECMO use
Mort and ECMO
(combined)
Post-op
Vent
days
Length of stay
Ventilation mode
at 72 hours
Oxygen use at
discharge
Problem of missing data:
For variables with missing data, the mean of the variable will be inserted for continuous
variables. Dichotomous variables will be dropped (and the ‘n’ adjusted accordingly). A sensitivity
analysis will also be performed using a ‘complete case analysis’ in order to ascertain whether a
significant difference exists in the result of complete versus ‘incomplete’ cases.
Possible impact of results:
Propensity matching affords the unique opportunity of identifying the determinants that
predict iNO use for neonates with CDH. Once controlled for, a meaningful adjusted comparison
of treated versus untreated patients is then possible. The results of this analysis should heavily
influence the future use/disuse of iNO for patients with CDH both within and outside Canada.
Given the popularity of the treatment, associated costs and the current lack of evidence
supporting its use, the potential impact of this analysis is large; publication in a journal with
wide readership is expected
Specific Variables requested:
Prenatal:
Associated anomalies
Cardiac anomalies
Side of defect
Herniated Liver
Stomach position
LHR
o/e LHR
TFLV (fetal MRI)
o/e TFLV (fetal MRI)
Demographic:
Live birth (all variables, including delivery room intubation and labs)
Gender
Gestational age
Weight
Birth hospital:
APGAR:
Postnatal:
Outborn
Prenatal Diagnosis
Transfusion
Intubation
Chest tube
Inotropes
Pulmonary vasodilators
**Nitric Oxide (NO) – this variable is not expressly listed but is required
All Ventilation modes
Vent mode prior to surgery
Surgery start/end time
Location
Surgeon
Hernia
Sac present
Ipsilateral liver lobe
Surgical Approach
Materials for patch
Abdo fascia closure
Size of defect
ECMO required
Pre-op Echo (and degree of pulmonary hypertension)
Post-op Echo (and degree of pulmonary hypertension)
4 hour, 24 hour , pre-op
pH
pre-ductal pO2
post-ductal pO2
Lactate
HcO3
pre-ductal saturation
post-ductal sturation
FiO2
MAP
BP
Institutional
Year of treatment
ECMO center
Hospital Volume
Hospital Geography
Time of ICU Admission
Outcomes:
ECMO use
Post op vent days
Mortality
Length of Stay
72 hour vent mode
Oxygen use at discharge
Timeline:
This study is expected to yield results with a high probability of shaping future practice
patterns. It will be submitted to the AAP meeting (deadline spring 2015).
References:
1. Inhaled nitric oxide and hypoxic repsiratoy failure in infants with congenital
diaphragmastic hernia. The Neonatal Inhaled Nitric Oxide Group (NINOS). Pediatrics.
1997;99(6):838-45.
2. Karamanoukian HL, Glick PL, Zayek M, et al. Inhaled nitric oxide in the congenital
hypoplasia of the lungs due to diaphragmtic hernmia or oligohydramnios. Pediatric
1994;94(5):715-8
3. Kinsella JP, Truog WE, Walsh WF, et al. (1997) Randomized, multicenter trial of
inhaled nitric oxide and high-frequency oscillatory ventilation in severe, persistent
pulmonary hypertension of the newborn. The Journal of pediatrics, 131(1), 55-62.
4. N Shah, T Jacob, R Exler, et al. Inhaled nitric oxide in congenital diaphragmatic
hernia. J. Pediatr Surg 1994;29:8):1010-4.
5. Finer NN, Barrington KJ Nitric oxide in repiratory failure in the newborn infant. Semin
Perinatol., 1997 21(5) 426-40.
6. Campbell BT, Herbs KW, Briden KE, et al. Inhaled nitric oxide use in neonates with
congenital diaphragmatic hernia. Pediatrics 2014;134(2):e420-6.
7. C M Pierce, M J Peters, G Cohen et al. Cost of nitric oxide is exorbitant BMJ. Aug 10,
2002; 325(7359): 336.