Nick Evans, DM, MRCPCH Royal Prince Alfred Hospital Sydney, Australia

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Nick Evans, DM, MRCPCH Royal Prince Alfred Hospital Sydney, Australia

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1. Nick Evans, DM, MRCPCH Royal Prince Alfred Hospital Sydney, Australia

2. Too many preterm babies survive with disability. Cerebal Palsy rates, RPA Hospital, Sydney

3. The starting point: The preterm brain.

4. The Injury: Ultrasound

5. The Injury: MRI

6. What’s going wrong with the preterm circulation? Is it low blood pressure? Is it loss of cerebral autoregulation? Is it low blood flow? Is it all of the above?

7. Evidence for Blood Pressure Early evidence based entirely on blood pressure. Easy to measure and continuously monitor Studies associating early low MBP with ultrasound brain injury. Miall-Allen 1987. Watkins 1989. Bada 1990.

8. Systemic Circulation Pressure vs Flow? This proposed relationship between CBF and MBP is often used to support a pressure based therapeutic rationale. This hypothesised point when autoregulation fails ís used to rationalise keeping the BP above a certain number by whatever means. Now basic principles would dictate that there must be a blood pressure below which cerebral blood flow will fall but I’ve never seen convincing data to show what that number is or that the number is the same in all babies. The result is magic numbers which are mainly based on guestimates and from that magic number medicine where any intervention that pushes that parameter above that number must be good and anything that leaves it below must be bad. What data there is about this relationship in human preterms is actually quite conflicting. This proposed relationship between CBF and MBP is often used to support a pressure based therapeutic rationale. This hypothesised point when autoregulation fails ís used to rationalise keeping the BP above a certain number by whatever means. Now basic principles would dictate that there must be a blood pressure below which cerebral blood flow will fall but I’ve never seen convincing data to show what that number is or that the number is the same in all babies. The result is magic numbers which are mainly based on guestimates and from that magic number medicine where any intervention that pushes that parameter above that number must be good and anything that leaves it below must be bad. What data there is about this relationship in human preterms is actually quite conflicting.

10. Recent evidence for impaired autoregulation Du Plessis et al and Wong et al.

11. HbD:MAP coherence and IVH: Tsuji 2000 and O’Leary 2009. More coherence associated with IVH but… First head US day 5-7 so cause or effect? HbD:MAP coherence and death: Wong et al 2008. More coherence associated with death but not IVH (n = small) Recent evidence for impaired autoregulation.

12. Longitudinal study of pressure passivity. Soul et al, 2007 Babies <1500g studied over first 5 days, pressure passivity assessed in serial 10 minute epochs. 97% (87/90) had periods of pressure passivity and it varied within individuals with time. No correlation with IVH. Recent evidence for impaired autoregulation.

13. Preliminary Data: Coherence between Cerebral TOI and MBP Eight babies born before 30 weeks. Monitoring of TOI and MBP for 3 to 4 hour period: First period starting within the first 6 hours Second period between 24 and 48 hrs. Also had echocardiograms but numbers currently insufficient for analysis.

14. Coherence between Cerebral TOI and MBP

17. Pressure vs Flow: Is it as simple as this? This proposed relationship between CBF and MBP is often used to support a pressure based therapeutic rationale. This hypothesised point when autoregulation fails ís used to rationalise keeping the BP above a certain number by whatever means. Now basic principles would dictate that there must be a blood pressure below which cerebral blood flow will fall but I’ve never seen convincing data to show what that number is or that the number is the same in all babies. The result is magic numbers which are mainly based on guestimates and from that magic number medicine where any intervention that pushes that parameter above that number must be good and anything that leaves it below must be bad. What data there is about this relationship in human preterms is actually quite conflicting. This proposed relationship between CBF and MBP is often used to support a pressure based therapeutic rationale. This hypothesised point when autoregulation fails ís used to rationalise keeping the BP above a certain number by whatever means. Now basic principles would dictate that there must be a blood pressure below which cerebral blood flow will fall but I’ve never seen convincing data to show what that number is or that the number is the same in all babies. The result is magic numbers which are mainly based on guestimates and from that magic number medicine where any intervention that pushes that parameter above that number must be good and anything that leaves it below must be bad. What data there is about this relationship in human preterms is actually quite conflicting.

18. Anecdote 1: 25 weeks, 8 hours old and MBP 30-35mmHg

19. Anecdote 2: 27 weeks, 7 days old, septic, MBP 18 mmHg on full support

20. Systemic Blood Flow

21. Myth 1:Early ductal shunting is not significant!

26. Average SVC flow over 24 hrs significantly related to: Death Abnormal DQ Abnormal motor development Average MBP (12 hrs or 24 hrs) No significant relationship with death and/or disability Flow, Pressure and 3 Yr Outcome J Pediatr 2004; Pediatrics 2006

27. Possible Causative Factors for Low SVC Flow Gestation:

28. Weak Relationship between SVC Flow and Blood Pressure at 5 Hrs

30. Is this an Afterload Problem? Consistent animal and human data suggest immature newborn myocardium has limited ability to respond to an increase in afterload. (Hawkins 1989, Takahashi 1997, Osborn 2002) Transitional Circulation:

31. That was during the first 24 hours. What about after that time?

32. Circulatory Compromise after 24 Hours Hypotension in sepsis usually associated with normal or high systemic blood flow (De Waal & Evans, J Pediatr 2010)

33. Pathophysiology and possible Treatments of Low Systemic Blood Flow Intravascular volume Treatment options: Delayed cord clamping or routine volume expansion? Positive intrathoracic pressure from ventilation Treatment options: Manipulation of ventilation? Failure to adapt to higher extrauterine resistance Treatment option: Afterload reduction? Large shunts out of systemic circulation Treatment Option: Early treatment of large ducts?

34. Optimising Intravascular Volume

35. Intravascular Volume Routine early volume expansion? No difference in outcomes. NNNI trial. Eur J Paed 1996 Delayed cord clamping: Rabe et al, Neonatology 2008 Better haematocrit and circulating volume Less hypotension and less IVH Better measures of systemic blood flow. Sommer et al, PAS 2011. Significantly better SVC flow and RV Output through 48h. Better motor outcomes at 7 months. Mercer et al, J Perinatol 2010 Australian Placental Transfusion Study (APTS) Nested Echo sub-study

36. Manipulation of Ventilation

37. Effect of Changing PEEP (De Waal et al. Arch Dis Child 2007;92:F444-F448)

38. Afterload Reduction

39. Hypothesis: In preterm infants with low systemic blood flow: Dobutamine (reduces afterload) will result in greater improvements in systemic blood flow than dopamine (increases afterload)

40. At highest dose: Dobutamine produced significantly better increases in SVC flows than dopamine

41. RCT Milrinone vs Placebo to prevent low SBF (Paradisis et al. J Pediatrics, 2009) Randomised to: Milrinone (0.75?g/kg/min for 3 h then maintain on 0.2?g/kg/min until 18 h of age) OR Placebo (5% dextrose) Identical syringes Co-interventions: Normal saline 15ml/kg over 1 h Indomethacin for PDA closure Volume and dopamine for hypotension If a baby was randomised to Milrinone, needed to ensure adequate intravascular volume as Mil is a vasodilator Pragmatic trial: Further haemodynamic support was provided on the basis of low BP and did not include flow based criteria -> reflecting standard care in most NICU around the world. Most NICU can’t provide echocardiographic monitoring. Dopamine is still probably the most widely used first line inotrope and it is most appropriate in this study because milrinone is a vasodilator DA used as first line at 4 micrograms/kg/min titrating the dose up to achieve a minimally acceptable blood pressure. If a baby was randomised to Milrinone, needed to ensure adequate intravascular volume as Mil is a vasodilator Pragmatic trial: Further haemodynamic support was provided on the basis of low BP and did not include flow based criteria -> reflecting standard care in most NICU around the world. Most NICU can’t provide echocardiographic monitoring. Dopamine is still probably the most widely used first line inotrope and it is most appropriate in this study because milrinone is a vasodilator DA used as first line at 4 micrograms/kg/min titrating the dose up to achieve a minimally acceptable blood pressure.

42. Haemodynamic Results: No Differences The mean time to starting inotrope was 9 hours (range: 3 – 20 hours) The mean dose was 8 mcg/kg/min (range: 4 – 15 mcg/kg/min) The mean time to starting inotrope was 9 hours (range: 3 – 20 hours) The mean dose was 8 mcg/kg/min (range: 4 – 15 mcg/kg/min)

43. Heart Rate: Increased with Milrinone

44. Ductal Constriction: Reduced with Milrinone

45. Why Didn’t Milrinone Work? Is there limited efficacy in an immature myocardium? Consistent with data in immature dogs Did we start it too late? Mean start time = 4.5 hrs Did we have the correct dose? Is our hypothesis in relation to low flow and afterload compromise correct?

46. Outcome Based Research in Circulatory Support Few circulatory support interventions tested against placebo! We know more about the effect of milrinone on clinical outcomes than almost any other interventions that we use. “More Research Needed.” But how?

47. Complexity of the preterm circulation? Haemodynamics are heterogenous

48. What should we do while we wait for the evidence?

49. Systemic Blood Flow

50. Point of Care Ultrasound Neonatologist.

51. Screening for Low Systemic Blood Flow: MPA Velocity

52. Early Scenario Low Flow Any Pressure Suggested Regimen 10 ml/kg N-Saline Dobutamine 10 ?g/kg/min increasing to 20 ?g/kg/min if needed. If pressure still too low? Start Dopamine at 5?g/kg/min and titrate to a minimal acceptable pressure.

53. Conclusions Low systemic blood flow occurs in first 12 hours, uncommon thereafter. Causes and relationship to blood pressure are complex. Correct approach to treatment remains unclear. Potential of targeting therapy with measure of blood flow and blood pressure.

54. Is Outcome-Based Research Possible in Circulatory Support? Is “one size fits all” treatment possible? Is the way forward better haemodynamic diagnosis and then test targeted treatment? How do we diagnose haemodynamic compromise? Then how do we design studies to show that we improve outcomes?

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