manas jc pcm in preterms
TRANSCRIPT
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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
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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%
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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
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Spontaneous ductal closure is evident in many VLBW infants
Hemodynamically significant PDA is associated with severe morbidity.
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Monday, May 1, 2023
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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.
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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.
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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.
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OBJECTIVE:
To study the biologic effect of paracetamol, on early closure of ductus arteriosus, and to evaluate possible adverse effects associated with the drug.
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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.
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STUDY POPULATION
All VLGA neonates with hsPDA admitted to the NICU
Duration of gestation was defined by ultrasound at 16 weeks POG
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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
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EXCLUSION CRITERIA
Septic shock,
Major malformation,
Chromosomal abnormality.
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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.
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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.
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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.
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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
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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
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RESULTS
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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)
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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)
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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.
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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
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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
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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
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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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