Prematurity and PDA diagnosis and closure

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Premature PDA Closure : Know all the details you want to know about PDA closure:
Role of Brufen Vs Indomethacin; ROle of prophylactic closure etc

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Prematurity and PDA diagnosis and closure

  1. 1. Patent Ductus Arteriosus:How to diagnose & when to treat Dr. Vikas Kohli MD FAAP FACC American Board Certified Pediatric CardiologistPediatric Cardiology & Cardiac Surgery Unit Indraprastha Apollo Hospital
  2. 2. Suspicion of Diagnosis
  3. 3. How many pts can one diagnose based on clinical signs ?• Murmur : – Continuous 30% – Systolic 59% – None 11%• Hyperactive precordium : 47%• Bounding pulses (∆PP>35) 50%• Tachycardia (>170) 11%• Tachypnea (>70) 15%• Hepatomegaly (>3cm) 5%
  4. 4. Clinical Scoring System• NO ADVANTAGE OF COMBINING CLINICAL SIGNS TOWARDS A HIGHER DIAGNOSIS• ATLEAST 20% PTS WOULD BE MISSED: Which clinical condition we would accept missing the diagnosis in 20% pts
  5. 5. CONFIRMING THE DIAGNOSIS
  6. 6. Is echo needed for confirmingPDA• Clinical suspicion is undeniable• Relaible clinical diagnosis is not possible• Reliably ruling out assoc cardiac anomalies is not possible• I do come across failed Indometh courses X2 after which echo is done and Cyanotic CHD is confirmed !!
  7. 7. Is echo needed for confirmingPDA• Lack of reliable bedside echo cannot justify bypassing this diagnostic modality and allow us to accept clinical criteria• Striving to continue seeking the best as has always resulted in progression
  8. 8. Echo Features confirmingdiagnosis of PDA• Parasternal Short Axis View• Branch PA’s noted AO MPA RPA LPA
  9. 9. Echo Features confirmingdiagnosis of PDA• Normal forward flow in PA is blue in color• Left to Right shunt noted as “red color flow”-diagnostic of PDA• Right to Left shunt is seen as “blue color flow” which is the same as the normal forward flow
  10. 10. TINY PDA
  11. 11. CLOSING PDA
  12. 12. HUGE PDA
  13. 13. HUGE PDA POST PHARMATHERAPY
  14. 14. Doppler Patterns• Measures velocity of flow• Flow this is calculated the difference in pressure• In PDA the difference is between AO and PA
  15. 15. Doppler Patterns• Left to Right Shunt: PA pressure less than AO in systole and diastole• Bidirectional Shunt: PA pressure less than AO only in one diastole• Right to Left Shunt: PA pressure above AO pressure in Systole and most of diastole
  16. 16. Doppler Patterns: gradient=36 mmHg
  17. 17. Doppler Patterns: Post Rx Gradient =90 mmHg
  18. 18. Bidirectional Shunt: Gradient = 3mmHg
  19. 19. Bidirectional Shunt: Gradient = 4mmHg
  20. 20. Echo Features to assess severityof PDA• Effects of PDA: – PDA steals from Aorta – PDA Overloads LA LV
  21. 21. Echo Features to assess severityof PDA: Steal from Aorta• How much is the steal ? – From Descending Aorta: Flow reversal – From Ascending Aorta: Reflected in SVC Flow – Is there end organ compromise: CNS, Gut, Kidney
  22. 22. Echo Features to assess severityof PDA• LA, LV Volume Overload – LA/Ao Ratio is one guide – LV Dilatation is another guide – Volume overload will depend on: • PDA Size • Pulmonary Vascular Resistance
  23. 23. Assesment of PDA size by echo• PDA is funnel shaped• PDA structurally is NOT seen on echo in entirety• Flow across PDA is best seen: cannot be used as a tool to assess size (30% variability)
  24. 24. Assesment of PDA size by echo• Why is it unreliable ? – Foreshortening – Variability of views – – Inability to standardize method of measurement
  25. 25. Echo Features to assess severityof PDA• LA, LV Volume Overload – LA/Ao Ratio is one guide – LV Dilatation is another guide – Volume overload will depend on: • PDA Size • Pulmonary Vascular Resistance
  26. 26. Pulmonary vascular resistance• Pulmonary Vascular resistance is affected by degree musculature in the Pulmonary vessles• 28-32 weeks is when the Pulmonary Media gets muscle• Co-mobidity affects PVR significantly• Ventilation can alter the resistance to flow into lungs
  27. 27. Pulmonary vascular resistance• Pre 28 weeker Premie – Very Low PVR – High shunt situation – LA LV volume overload early – Therefore the question of prophylactic closure
  28. 28. Pulmonary vascular resistance• Post 32 weeker Premie – High PVR – Low shunt across PDA – LA LV volume overload does not happen – Symptoms come late – And are milder
  29. 29. MANAGEMENT• MEDICAL• INDOMETHACIN• IBUPROFEN• PROPHYLACTIC• SURGICAL LIGATION
  30. 30. MANAGEMENT ISSUES MEDICAL MANAGEMENT
  31. 31. Management of PDA • Medical management – Fluid restriction ( ensure 10% wt loss ) – Diuretics ( Furosemide 1-2mg/kg/dose ) – Correction of anemia ( Keep Hct >45%) – Adequate oxygenation ( Po2 50-80 mmHg ) – Indomethacin ( 3 doses q 12h ) • Surgical Management - ligation
  32. 32. Medical management of PDA• How effective ? – 48 hours of usual medical management • without indomethacin: 28% PDA closure • with indomethacin: 79% closure 1. – Back-up Rx required (Ligation) • without indomethacin : 65% • with indomethacin : 21% 1. 1: National Collaborative study on Patent Ductus Arteriosus in Premature Infants. J Pediatr 102: 895, 1983.
  33. 33. Medical management of PDA • Indmcin + Frusemide vs Indmcin alone ? – No change in PDA closure rate – May decrease effect of Indocin on Kidney (small trial with low power) • There is not enough evidence to support the administration of furosemide to premature infants treated with indomethacin for symptomatic patent ductus arteriosus.
  34. 34. MANAGEMENT ISSUES INDOMETHACIN
  35. 35. Indmcin: Short Vs Prolonged • Between1988 and 2000 • Included a total of 431 preterm and low birth weight infants • Indomethacin was given IV : 4 trials • Orally: 1 trial • total amounts of 0.6 to 1.6 mg/kg prolonged course (six to eight doses) • 0.3 to 0.6 mg/kg for the short course (two to three doses).
  36. 36. Indmcin: Short Vs Prolonged • No significant benefit of prolonged indomethacin on failure of the PDA to close (4 studies, 361 infants). • Prolonged Vs Short course did not reduce the – Rate of PDA re-opening (3 studies, 322 infants) – rate of PDA re-treatment (5 studies, 431infants) – Ligation rate (four studies, 310 infants). • Prolonged course assoc with dec incidence of renal function impairment • Prolonged course increased risk of NEC • The number of deaths was no different.
  37. 37. Dopamine to prevent renal side-effects• Dopamine has not been shown to prevent adverse effects of indomethacin on the kidneys of preterm babies
  38. 38. Indomethacin- efficacyPredictors of indo failure:• n=60 <1750g – Mean PDA size (2.2mm vs 1.4mm) – Mean LA:Ao ratio (2.0 vs 1.5) – Mean birth weight (1027g vs 1125g) – Mean platelet count (1.37 vs1.83) Sing Med J 2006; 47(9) : 763
  39. 39. MANAGEMENT ISSUES IBUPROFEN
  40. 40. Ibuprofen: Cochrane database• 11 studies 620 pts compared ibuprofen to indomethacin• Failure of duct closure: no difference• No statistical difference for : mortality, surgical duct ligation, duration of ventilator support, IVH, PVL, NEC, time to full enteral feeds, ROP, sepsis, duration of hospital stay or gastrointestinal bleed
  41. 41. Ibuprofen: Cochrane database• Decreased urine output (< 1cc/kg/hr) was lower in the ibuprofen (statistically significant)• CLD defined as oxygen requirement at 28 days post-natally was statistically significantly more likely to occur in the ibuprofen group• pulmonary hypertension has been observed in three infants with ibuprofen
  42. 42. Ibuprofen oral dosage DOSAGE 27-29 WEEKS <27 WEEKS (mg/kg) 10-5-5 77% 30·6% 15–7·5–7·5 88% 20-10-10 54·8% L. Desfrere J Clin Pharmac & Therapeutics 2005; 30: 121
  43. 43. DOSAGE• Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method• the currently recommended dose regimen (10- 5-5 mg/kg) of IBU is associated with a high closure rate (80%)• Journal of Clinical Pharmacy & Therapeutics Volume 30 Issue 2 Page 121 - April 2005
  44. 44. ORAL IBUPROFEN• Closure of Patent Ductus Arteriosus With Oral Ibuprofen Suspension in Premature Newborns: A Pilot Study• PEDIATRICS Vol. 112 No. 5 November 2003, pp. e354-e354• Oral ibuprofen suspension may be an effective and safe alternative for PDA closure in premature infants with PDA
  45. 45. MANAGEMENT ISSUES PROPHYLACTIC CLOSURE
  46. 46. PROPHYLACTIC INDOMETHACINTHERAPY• Prophylactic IV indomethacin within 24 hrs in preterm: 19 studies• Reduced incidence of symptomatic PDA• Reduced incidence of PDA ligation• Reduced all grades of IVH and Grade 3 and 4 IVH• No reduction in incidence of mortality• No decrease in incidence of morbidities like – Pnemothorax, duration of ventilation or supplemental o2, incidence of CLD, neurological out come, NEC, ROP• It was associated with increased risk of oliguria
  47. 47. PROPHYLACTIC INDOMETHACIN: NEUROSENSORYIMPAIRMENT• Schmidt et al ( TIPP study)• 1202 infants ( 500-999 gm)• Primary end point was death before 18 months or• CP, Cognitive delay, hearing loss, bilateral blindness• Though reduced incidence of PDA or PDA ligation• No reduction in mortality or other morbidities like CLD, neurological outcome
  48. 48. Conclusion• Indomethacin is superior to ibuprofen• Advantages of Prophylactic PDA closure in extreme premie: – Short term co-morbidities decreased – NO LONG TERM ADVANTAGE OF: • SURVIVAL • NEURODEV • CHR LUNG DSS
  49. 49. MANAGEMENTSURGICAL LIGATION
  50. 50. Surgical ligation• Collaborative trial: – Infants randomised to surgical ligation or indomethacin – Higher pneumothorax, ROP – No diff in other outcomes incl mortality• Early prophylactic ligation (<1000g) – Less NEC – No diff in other outcomes, incl CLD, mortalityNational collaborative trial. J Pediatr 1983;102:895-906N EJM 1989;320:1511-1516
  51. 51. Indications of Surgical Ligation• Failed Pharmacological Closure at end of course• Is there a role of terminating Pharmacologic course early and proceeding with PDA ligation ?• Rescue Surgical Ligation
  52. 52. APOLLO EXPERIENCE: 7 PTS Wt Gest Co-M Op-Findgsb/o DS 950 28 wk HMD, Pneumonia Bilobed Lt lung Failure to ext, Failed PDA>>AO drugsb/o Su 1000 31 wk Vent depend Congested Lungs Failed Drugsb/o si 980 29 wk HMD, Vent Dep, 3 mm PDA Failed Drugs, Renal Failure, IVH Ib/o shw 1800 32 wk FTT, No Vent, Drugs 3.5 mm, Sev PAH, failed Musc VSDb/o pa 1100 29 wk Fungal Sepsis, LA Hug PDA, clot, Pulm GI Hmge Echymotic lungsb/o g 1200 29 wk Pn, vent dep, Failed Large PDA drugsb/o S 900 28 wk Pulm Hmmg, Arrest, Massive PDA HMD, Vent Hi Freb/o dr. S 1100 31 wk Sclerema, NEC, Musc Large PDA VSD
  53. 53. Stopping Pharma therapy• During course of Pharma Rx: – Sev PAH: C/I to duct closure – New onset early complic: • OF PDA: – NEC – IVH – PULM HMMGE – RENAL FAILURE • OF DRUG – RENAL FAILURE – PULM HYPERTENSION – PLATELETS – GI BLEED
  54. 54. NOT OFFERING PHARMACLOSURE• C/I TO DRUG THERAPY• HUGE DUCTUS WITH – EARLY NEC – EARLY RENAL FAILURE – WEIGHT < 1000G – VERY LOW DIASTOLIC IN A EXTR PREMIE: LOW CORONARY PERFUSION
  55. 55. CONCLUDING REMARKS• Echo is essential for PDA mx• Indometh vs Brufen: not a major difference• Renal Issues: Brufen better (personal exp)• Prophylactic closure: No longterm survival benefit (personal exp Pulm Hmmge prevented)
  56. 56. CONCLUDING REMARKS• Surgical Ligation shold be considered early• Co-morbidities esp infection not a contra-ind• Excellent results of surgical ligation• Future: – BNP may be helpful – SVC Flow as a marker of PDA significance
  57. 57. THANK YOU
  58. 58. CLINICAL CASE SCENARIOS
  59. 59. MYTH 1• Diagnosis of PDA by murmur is good enough
  60. 60. MYTH 2• Size of PDA is important and best and most accurately measured on echocardiogram
  61. 61. MYTH 3• After the course the PDA need not be re assessed if the murmur is not heard
  62. 62. CASE SCENARIO 1• Premie with dec urine output HUGE pda• Echo:• Early Closure ? Pharmacological Vs Surgical
  63. 63. CASE SCENARIO 2• Small appearing PDA; mild symptoms; small baby-• To close or not to close ?
  64. 64. CASE SCENARIO 3• PDA in an extreme premie on DOL # 2• Prophylactic Closure or none ?• Issue related to Pulmonary Hemmorrhage
  65. 65. Management- Indomethacin• Dosage schedule (mg/kg) Age 1st dose 2nd dose 3rd dose <48h 0.2 0.1 0.1 2-7d 0.2 0.2 0.2 ≥ 8d 0.2 0.25 0.25 Gersony WM. National Colaborative Study, J Pediatr 1983;102:895
  66. 66. Oral ibuprofen PHARMACOKINETICSn=20 GA= 30.45 ± 0.33 weeks Birth weight 1262.5 ± 55.4Oral Ibuprofen: 10 mg/kg 4-72 h postnatallyBlood samples at 0, 1, 2, 4, 8, 12, and 24 hourst 1/2=15.72 ± 3.76 hArea under plasma concentration-time curve (AUC 0-α) (402.60± 79.67 µ g • h/mL)Wide variability in pharmacokinetics, unrelated to GA, B Wt, sexSharma et al J Clin Pharmacol, 2003; 43:968-973
  67. 67. Management- Indomethacin 5 studies, n=292 – Short course • 1-3 doses of 0.1-0.2 mg/kg 8-12 hourly • Transient closure – Long course • 0.1-0.15mg/kg OD x 5-7 days • Anatomical closure/Less renal toxicity – Conclusion: • The prolonged course regime may have a role in those with borderline impairment of renal function Arch Dis Child 2003;88:1132-1133
  68. 68. Oral ibuprofen• Oral ibuprofen vs IV Indo – Rate of ductal closure similar in the two regimes (J Thai Med Assn 2002;85:Suppl 4:S1252-8 )• Oral ibuprofen- a pilot study – Closure achieved in 95.5% babies (Pediatrics. 2003;e354)
  69. 69. Indo or Ibu?• 11 studies, n=620• Differences – Less oliguria in ibuprofen group – Higher incidence of CLD• No statistically significant difference in – Primary outcome (failure of ductal closure) [typical RR 0.96 (95% CI 0.74, 1.25)]. – Secondary outcome: • Mortality, Surgical duct ligation, Duration of ventilator support • IVH, PVL, NEC, Time to full enteral feeds, ROP • Sepsis, Duration of hospital stay, Gastrointestinal bleedOhlsson A, Walia R, Shah S Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infantsCochrane Database of Systematic Reviews The Cochrane Library, Issue 4, 2005
  70. 70. COCHRANE DATABASE• Eight studies including 509 patients• No statistically significant difference between ibuprofen and indomethacin for PDA closure rates• no statistically significant differences in mortality, surgical duct ligation, duration of ventilator support, IVH, PVL, NEC, time to full enteral feeds, ROP, sepsis, duration of hospital stay or gastrointestinal bleed

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