Paracetamol in treatment of PDA A collection of Pharmacothrapies and relevant review of Literature and recent article reveiw

2. PDA
 It is the persistent vascular connection between the
pulmonary artery and the aorta.
 Functionally, the closure of ductus arteriosus occurs soon
after birth.
 Term Neonate : 12-24 hrs
 Pre Term : 3-5 days
 When ductus remains patent after birth, the blood flows
from the aorta to the pulmonary artery; due to higher
pressure
Wednesday, November 2, 2016

3.  Patent Ductus Arteriosus (PDA) is major comorbidity
seen in premature infants
 Incidence is inversely related to gestational age
 VLBW, 32- 36 wks : 15-40%
 <28 wks, <1000 gms : 50-65%
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4. NORMAL POSTNATAL CLOSURE
 Closure of the ductus arteriosus is effected in two phases
 Immediately after birth, contraction and cellular
migration of the medial smooth muscles in the wall of
the ductus resulting in functional closure.
 Permanent closure by
 infolding of the endothelium,
 disruption and fragmentation of the internal elastic
lamina,
 replacement of muscle fibers with fibrosis;
 permanent sealing of the lumen to produce the
ligamentum arteriosum

5.  Spontaneous ductal closure is evident in many VLBW
infants
 Hemodynamically significant PDA is associated with
severe morbidity.

6. Wednesday, November 2, 2016

7. PHARMACOLOGICAL CLOSURE
 The mainstay of treatment if conservative measures
fails.
 MOA: Use of Non Selective COX inhibitors which
inhibits PG synthesis and causes ductal constriction.
 Indomethacin and ibuprofen have been extensively
studied.
 Paracetamol is an emerging moiety.

8.  Previous trials of prophylactic indomethacin and
ibuprofen:
 decreased the risk of PDA
 pulmonary hemorrhage
 severe intra-ventricular hemorrhage.
 Optimal time of ductal closure / need for medical closure
of the ductus remains controversial.

9. MECHANISM OF ACTION
 Paracetamol (acetaminophen) inhibits the peroxidase
moiety of the prostaglandin synthase enzyme,
decreasing prostaglandin synthesis.
 Present paracetamol trial: based on the previous use of
intravenous paracetamol to limit the use of opiates and
their adverse effects during respiratory therapy after
very preterm birth.

10. OBJECTIVE:
 To study the biologic effect of paracetamol, on early
closure of ductus arteriosus, and to evaluate possible
adverse effects associated with the drug.

11. METHODS
 Present trial is a phase I-II study with the aim of
establishing a new paracetamol indication in high-risk
preterm infants.
 Study in accordance : Good Clinical Practice guidelines.

12. STUDY POPULATION
 All VLGA neonates with hsPDA admitted to the NICU
 Duration of gestation was defined by ultrasound at 16
weeks POG

13. HEMODYNAMICALLY SIGNIFICANT PDA
Clinical criteria of cardiopulmonary distress
 Increased need for respiratory support,
 Decreased systolic or mean blood pressure, increased
pulse pressure
 Pulmonary congestion, cardiomegaly, hepatomegaly, a
murmur, hyperdynamic precordium, or bounding pulses
 Unexplained O2 Requirement(FiO2>30%) or rising O2
requirement on respiratory support
Echocardiography criteria:
 LA/Ao >1.4
 PDA diameter >50%wider than left pulmonary artery,
 the flow patterns showing a large volume left-to-right
ductal shunt

14. EXCLUSION CRITERIA
 Septic shock,
 Major malformation,
 Chromosomal abnormality.

15. METHODOLOGY
 VLGA (<32 weeks) infants requiring intensive care :
randomly assigned to intravenous paracetamol or placebo
(0.45% NaCl).
 The investigators had no influence on the drug choice.
 Computed randomization was performed using a 4-block
design
 To decrease the risk of significant heterogeneity between
cases and controls, individual treatment strata were defined
by sex and gestational age.

16.  The treatment allocation codes were sealed in
sequentially labeled opaque envelopes
 All nurses and doctors involved in the treatment and study
of the infants were blinded to the study medication
 Loading dose: 20 mg/kg given within 24 hours of birth,
followed by 7.5 mg/kg every 6 hours for 4 days.

19. EVALUATION
 First ECHO before the study drug
 Then, once a day until 1 day after the study medication
period.
 Thereafter, infants with an open ductus were examined
1-2 times per week,
 All participants were studied for patency of the ductus at
discharge from NICU.

20. OUTCOMES
Primary :
Decrease in and closure of the ductus during the
intervention as function of postnatal age
Secondary :
 Left atrium to aorta ratio
 Age of permanent closure of the ductus, ductus
therapies,
 Side effects of paracetamol,
 Neonatal and long-term morbidity and mortality

21. ADR ASSESSMENT
 By monitoring:
oxygenation, blood pressures, and inotrope use and
laboratory values (eg, platelets, serum sodium, and
bilirubin).
o Renal function was monitored by measurements of
diuresis (mL/kg/h).
o The symptoms of pain and discomfort were assessed
using pain scales

22. RESULTS

23. RESULTS
Paracetamol group Control group
Ductal caliber before
giving medication
Mean SD 1.57 (0.66)
mm
1.39 (0.76)mm
Closure rate HR 0.49, 95% CI
0.25-0.97, P = .016
Time for closure
Mean Postnatal age
Median 41 hours
(IQR, 33-85 hours)
177 hrs
Median 78 hours
(IQR, 50-375 hours)
336 hrs
GA>27 weeks
Mean postnatal age
80hours 322hours
GA < 27 weeks Not detected
(P=0.63)

24. RESULTS
 Extremely preterm infants (born at <27 weeks gestation,
n = 8), an acute paracetamol effect on the contraction of
ductus arteriosus was not detected (P = .63),
 Four (50%) required PDA treatment (paracetamol n =
3, placebo n = 1)
 Paracetamol apparently increased closure of ductus in
boys (HR 0.31, 95% CI 0.12-0.85, P = .023) and not in
girls (HR 0.72, 95% CI 0.27-1.96, P = .52)

26. SECONDARY OUTCOME:
 No significant accumulation of paracetamol in serum
was evident and the concentrations decreased as a
function of time. { 87 serum samples: mean= 25.2 mg/L;
Accidental poisoining= 117-180mg/L}
 No difference noted in gestational age or sex difference
in secondary outcomes.

28. ADVERSE EVENTS AND NEONATAL OUTCOMES.
 No differences in adverse events were detected between the
infants treated with paracetamol or placebo.
 groups had similar diuresis rates
 frequency of hypernatremic serum sodium values
 No evidence of paracetamol-induced hypotension
because the requirement of inotropes was similar
 No signs of hepatotoxicity were observed.
 One extreme preterm baby developed pulmonary
hypertension but extreme prematuriy could be the cause and
paracetamol canbe an add on factor

29. DISCUSSION
 Intravenous paracetamol potentiated the early closure of
the ductus arteriosus after very preterm birth within 3
days.
 Complications of surgery and COX inhibitors (renal
insufficiency, gastrointestinal perforation, intraventricular
hemorrhage, and pulmonary hypertension) avoided.
 The effect of intravenous paracetamol on the contraction
of the ductus was limited to the male sex and to those
born after 27 weeks of gestation

30. LIMITATIONS OF THE STUDY
 Being an ITT, In the placebo group, details of babies
treated for hsPDA have not been mentioned.
 S/E of PCM have not been defined.
 Included mostly larger infants for whom treatment
strategies for PDA are less uncertain.
 Dose requirements for infants born extremely preterm
need to be investigated further

32. CONCLUSION
 Prophylactic intravenous paracetamol compared with
placebo, accelerated closure of the ductus arteriosus
in VLGA infants without detectable adverse effects,
providing evidence for its biologic effect and safety.
 Paracetamol may serve additionally as a non-sedative
analgesic, it could be an alternative drug for opiates and
COX inhibitors
 Large randomized trials, are required to define the clinical
potential and limitations of paracetamol for premature infants

33. THANK YOU…