PDA: As the Pendulum Swings. Cathy Hammerman Shaare Zedek Medical Center & Hebrew University Faculty of Medicine, Jerusalem, Israel

Transcription

1 PDA: As the Pendulum Swings Cathy Hammerman Shaare Zedek Medical Center & Hebrew University Faculty of Medicine, Jerusalem, Israel

2 Six Blind Neonatologists Approach PDA It s not physiologic - all must be closed Permissive tolerance PDA is an epiphenomenon of prematurity Prophylactic indomethacin Early treatment of hspda with ibuprofen Prophylactic surgical ligation Ibuprofen and then ligate if still patent

3 Physiology vs. Pathology In prematures, an open ductus is natural Naturally, the ductus should close within the first hrs of life. Permissive Tolerance Active Intervention

4 Prophylactic Closure Does Not Prevent PDA Associated Morbidity (Fowlie et al, Cochrane 2009) Nineteen eligible trials; 2872 infants. Prophylactic indomethacin trials showed NO effect But On these Necrotizing were all Enterocolitis IVH prophylaxis trials not designed to study PDA closure. Many infants without PDA s were included in the IVH prevention group, and many with PDA in the control group. On Bronchopulmonary Dysplasia On Mortality Open-label rescue treatment was given to 15% - 50% On death or severe neurodevelopmental disability of assessed patients 18 in - the 36 placebo months groups.

5 % Era 1: traditional management with INDO and LIGATE early to close all moderate and large PDAs in infants receiving any respiratory support. 60 Era 2: modest fluid restriction, watchful waiting and limited INDO and LIGATE only those infants P=0.10 p=0.04 * Era 1 Era 2 Era 1 Era 2 with large PDAs 0 Chronic Lung Disease CLD or Mortality Permissive Tolerance CLD / Mortality Kaempf et al. Journal of Perinatology (2012) 32,

6 The Pendulum Swings Back Non-Closure Mortality Retrospective. <29 wks; <1500 gm. (surgical ligations and death in 1 st week - excluded) Persistent PDA - failed closure (spontaneous or pharmacologic) Survival Adjusted for Perinatal Factors Ductus Closed 11% Mortality Ductus Patent 71% Mortality

7 Morbidity and mortality in preterm neonates with patent ductus arteriosus on day 3. Sellmer et al. Arch Dis Child Fetal Neonatal Ed 2013;98:F505 F510 All preterm neonates, GA<28 wks, had echo on DOL 3. None of the PDA s treated yet. After day 3, all PDA s were treated according to clinical protocol. Those with PDA on DOL 3 had fourfold in severe morbidity or mortality compared with neonates without a PDA. Suggests that the hemodynamic impact of a PDA is significant and that the foundations may already be set by DOL 3.

8 % Survivors PDA Associated Long Term Morbidities by DOL 3 Echocardiogram Category 60 Ductus Closed hispda hspda * * CLD Severe NEC Severe IVH Severe ROP Hammerman 2017

9 Era 1 ( ): traditional management with pharmacologic closure/ligation. Era 2 ( ): PDAs not treated prophylactically. Echocardiography was performed in VLBW infants only when non-pda cardiovascular conditions were suspected. Survival until hospital discharge without CLD did not change Treat vs. No-Treat groups % vs 83.9% Non treatment of PDA is not associated with respectively. increased morbidities in VLBW infants Mohamed et al. Journal of Perinatology 2017

10 Flawed studies? Flawed patient selection? Wrong entry criteria? Wrong treatment? No placebo gp not treated large rescue treatment crossovers [in one study, 51% of infants initially randomized to placebo received ibuprofen or ligation] Effects may already be determined by DOL 3 Prophylactic not echo directed; lots of non-pdas treated and lots of PDAs not treated PDA as dichotomous parameter Recent studies show that BPD is associated with persistent moderate-to-large PDAs but not with small, insignificant PDAs NSAIDS may have side effects that counter positive hemodynamic effects of ductal closure PDA is an innocent bystander

11 Inhibition of platelet adhesiveness Interference with bilirubin albumin binding (ibuprofen) Might Harmful Side Effects of COX Inhibitors be Masking Benefits of PDA Closure??

12 Potential adverse effects of COX inhibitors may confound beneficial hemodynamic effects of ductal closure Many babies with contraindications to COX inhibitors Logistic/financial difficulties in obtaining drugs

13 Ductal Closure with Paracetamol: A Surprising New Approach to Patent Ductus Arteriosus Treatment Hammerman C, Bin-Nun A, Markovitch E, Schimmel MS, Kaplan M, Fink D. Pediatrics. 2011;128:e AGE WHEN PARA- CETAMOL BEGUN (DAYS) INTERNAL DUCTAL DIAME- TER LA/Ao RATIO PRESSURE GRADIENT ACROSS PDA [MMHG] REVERSE DIASTOLIC FLOW Baby B no 0.5 RATIO DUCTUS DIAMETER TO AORTA PREVIOUS IBUPROFEN TREATMENT AND RESPONSE 2 courses Ibuprofen no response Baby O Yes 0 97 None Baby C yes courses Ibuprofen no response Baby W Yes 1 00 None Baby L yes 0 51 None CONTRAINDI- CATIONS TO IBUPROFEN? Severe thrombo cytopenia Severe thrombo cytopenia Severe Hyperbilirubinemia Thrombo cytopenia

14 86 references in Medline for paracetamol and ductus arteriosus Uses - Acetaminophen Closure of patent ductus arteriosus (PDA): NSAIDs (indomethacin and ibuprofen) are the standard drugs for closure of PDA. However, there are risks to NSAIDs and there is a high rate of spontaneous closure; therefore, treatment should be limited to select preterm newborns with symptomatic PDA. Acetaminophen may be an alternative to an NSAID. Fever reduction and treatment of mild to moderate pain

15 Appeal of Paracetamol Biologic plausibility Similar efficacy to COX inhibitors Absence of GI perforations and/or peripheral vasoconstrictive effects Potential to treat those with contraindications to COX inhibitors Logistic / financial difficulties in procuring indomethacin

16 Phospholipase A2 Inhibited by Indomethacin And Ibuprofen Arachidonic Acid COX PGHS Complex Lipoxygenase POX Others Leukotrienes Inhibited by Paracetamol Prostaglandins Thromboxanes Isoprostanes Cyt. P450 products

17 20 observational studies; N=261; overall ductal closure rate of 77% Acetaminophen Ibuprofen Indomethacin Placebo IV vs. Enteral Acetaminophen Pre-Ligation 5 RCTs; N=781 Similar efficacy 2 RCTs; N=377 Similar efficacy 2 studies; N=238 PDA; BPD 30% vs.40% NS 1 study; n=18 Closure 88% vs 70% enteral vs IV (NS) 3 studies; N=69 Complete closure 25% Constriction 46% Ligation 20%; Deferred 9%

18 Observational Study Observations 100 % Successful Ductal Closure * * 0 First line drug Enteral vs. IV 88% vs. 47%; p<0.001 Yes No 94% vs. 68% p=0.01

19 What is the correct dose? No known recommendations for PDA dosing Limited data regarding the pharmacokinetics and toxicity. Only 2 of the perhaps observational the doses we have studies been using measured are too high? paracetamol concentrations [nl range mcg/ml in children] Oncel et al. measured serum levels on days 1, 2 and 3 of IV paracetamol treatment [7.3, 15.5 and 14.7 mcg/ml respectively]; Yurttutan et al. evaluated serum paracetamol levels 24 hours after the first dose of enteral paracetamol [5 to 18 mcg/ml].

20 Less Hepatotoxicity in Neonates?? Prematures: Lower levels of CYP2E1 reduced production of toxic NAPQI glutathione levels, leading to effective destruction of any NAPQI that is generated

21 Echocardiographic severity scores Postnatal Physiologic Environment Metabolic hypoxia, ph Elevated PVR Sepsis Tissue perfusion [Doppler] Tissue oxygenation [NIRS] Shifting the Diagnostic Paradigm

22 Individualized treatments Multi-Drug Cocktails Transcatheter PDA closure EP Receptor Antagonists Genetic therapies Shifting the Therapeutic Paradigm

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24 No reports of permanent liver damage in the newborn 2 o to paracetamol overdose Clinical Details of Overdose 436 mg/kg Porta et al IV 136 mg/kg Isbister oral et al paracetamol 146 mg/kg Nevin et al paracetamol IV during anesthesia Brener P 266 mg/kg in et al three doses GA (wk) AGE (days) Trea ted Peak paracetamol concentration NAC 180 mcg/ml Char -coal 121 mcg/ml No 28 7 wks NAC 117 mcg/ml 27 9 NAC 480 mcg/ml Outcome No hepatotoxicity hepatotoxicity No hepatotoxicity No hepatotoxicity. Campbell 75 mg/kg acetaminophe n IV mo 78 mcg/ml No hepatotoxicity

25 Clinical Details of Overdose GA (wk) AGE (days) Treated Peak Measured paracetamol concentration Outcome Porta et al 436 mg/kg IV NAC 180 mcg/ml No hepatotoxicity Isbister et al Nevin et al Brener P et al Walls L et al De la Pintière et al Campbell 136 mg/kg oral Charcoal paracetamol 121 mcg/ml No hepatotoxicity 146 mg/kg paracetamol IV during 28 7 wks NAC 117 mcg/ml No hepatotoxicity anesthesia 266 mg/kg in three doses 27 9 NAC 480 mcg/ml No hepatotoxicity. 26 mg/kg q4 h for the first 24 h (156 AST 718 mg/l on mg/kg/day), after admission. circumcision; then NAC mcg/ml Improved over mg q4 h for the next 2 several days. No days (78 mg/kg/day). residual effects Total dose=468 mg/kg Two IV doses of 900 First mg propacetamol ( days NAC mg/kg/dose) mg/kg IV of life at 6 hour intervals 168 mcg/ml No hepatotoxicity 2.3 kg. given 75 mg/kg acetaminophen IV mo 78 mg/l No hepatotoxicity

26 27 wk, 750 gm neonate received three doses of paracetamol in attempt to treat her PDA. She was accidentally given 266 mg/kg. Plasma paracetamol level was 480 µg/ml. When the error was noted, she was given acetylcysteine. There was no elevation of liver function.

27 New Problems from Old Drugs? Viber et al (2014) paracetamol during pregnancy affects cognitive function in adult male mice. Liew et al (2014) paracetamol during pregnancy was associated with more ADHD-like behaviors. Maternal reporting is retrospective and inaccurate, with little to no data regarding dose, duration and time of gestational exposure. Maternal psychiatric illness, fever, infection, etc. may adversely affect pregnancy outcome, including contributing to ADHD not factored. Paracetamol (acetaminophen) remains the first line for the treatment of pain and fever during pregnancy, and is generally considered safe by obstetricians.

28 Sordillo et al: childhood asthma after infant acetaminophen. But, when controlled for respiratory tract infections (NS). Amberbir et al: Retrospective questionnaire on paracetamol use (at ages 1, 3 and 5). High exposure was associated with 3-fold increased risk of new onset wheeze compared to never users. Lowe: prospectively studied 620 children with family histories of allergy. Children who took paracetamol for nonrespiratory illnesses had no increased risk of asthma. Potentially confounded by - Indication-many didn t control for respiratory infections Maternal Recall bias asked to remember acetaminophen usage after 1-3 years is more likely to remember if child remains sick. Correlations weaker during early infancy compared with prenatal exposure. Effects also mediated by NAPQI

29 Rcvd. Proph Indo Neurosensory impairment Surgery (n=84) No Surgery (n=245) 35% 31% NS Significance 53% 34% 1.98 ( ) p = Cognitive Delay 45% 18% 1.96 ( ) p = Cerebral Palsy 19% 14% 1.22 ( ) p = 0.55 BPD 67% 51% 1.81 ( ) p = Severe ROP 27% 13% 2.20 ( ) p = Neurosensory Impairment after Surgical Closure of Patent Ductus Arteriosus in Extremely Low Birth Weight Infants: Results from the TIPP Kabra et al (J Pediatr 2007;150:229-34)