manas jc pcm in preterms

Monday, May 1, 2023

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

Monday, May 1, 2023

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%

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

Spontaneous ductal closure is evident in many VLBW infants

Hemodynamically significant PDA is associated with severe morbidity.

Monday, May 1, 2023

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.

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.

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.

OBJECTIVE:

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

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.

STUDY POPULATION

All VLGA neonates with hsPDA admitted to the NICU

Duration of gestation was defined by ultrasound at 16 weeks POG

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

EXCLUSION CRITERIA

Septic shock,

Major malformation,

Chromosomal abnormality.

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.

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.

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.

OUTCOMESPrimary : 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

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

RESULTS

RESULTSParacetamol 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 weeksMean postnatal age

80hours 322hours

GA < 27 weeks Not detected(P=0.63)

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)

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.

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

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

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

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

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