Management of Infants with BPD: Evidence-Based or Eminence-Based?

Transcription

1 Management of Infants with BPD: Evidence-Based or Eminence-Based? Steven M. Donn, MD, FAAP Professor of Pediatrics Division of Neonatal-Perinatal Medicine C.S. Mott Children s Hospital University of Michigan Health System

2 Disclosures I have no disclosures or conflicts of interest related to the content of this presentation. I will only warn you about the off label use of some pharmaceuticals.

3 Content Pulmonary Injury Sequence Ventilator Management Pharmacotherapy

4 Bronchopulmonary Dysplasia Northway (1967) 13 infants surviving RDS g weeks GA Northway W, et al. New Engl J Med 1967; 276:

5 Old BPD Term or late preterm infants High Pressure, High FiO 2 Overinflation, cystic emphysema, fibrosis Interstitial and alveolar edema, small airway disease, extensive inflammation, and fibrosis

6

7

8 New BPD VLBW infants Modest ventilator, oxygen needs Diffuse haziness fine, lacy pattern Decreased alveolarization, minimal small airway disease, less inflammation, fibrosis Jobe AH. Curr Opin Pediatr 2011; 23:167-72

9

10

11 The Myths

12 Myth #1 In the era of antenatal corticosteroids, surfactant replacement therapy, and sophisticated mechanical ventilation, the incidence of BPD is decreasing.

13 Reality #1 As more and more extremely preterm infants survive, the incidence of BPD has remained relatively constant, but the absolute number is continuing to rise.

14 Incidence of BPD g 52% g 34% g 15% g 7% Vermont-Oxford Network Data

15 Death and Oxygen Use (36 wks PMA) St. John and Carlo, Semin Perinatol, 2003 Disturbing trend: Proportion of week survivors with BPD has increased over last 6 years of observation

16 Neonatal BPD: Health Significance Important cause of morbidity and mortality Prolonged and recurrent hospitalizations Higher rates of other serious complications of prematurity 7-10,000 new cases each year in the US Increasing prevalence as more ELBW infants survive

17 Neonatal BPD: Health Significance Long-term follow-up Life-long alterations in lung function Small airway damage, hyperinflation even at age 8-10 Airway obstruction in adult life Risk of cor pulmonale Increased susceptibility to RSV (and other viruses) Increased incidence of CP and neurodevelopmental delays

18 Why?

19 Pulmonary Injury Sequence Attar MA, Donn SM: Semin Neonatol 2002;7:357 Elsevier, Ltd., with permission.

20 Myth #2 Ventilator management of babies with BPD should be strategized to achieve normal gas exchange as evidenced by physiologic blood gas values and ph.

21 Reality #2 Ventilated babies with BPD are physiologically unable to achieve normal gas exchange because they lack adequate pulmonary surface area. Attempts to achieve normal gas exchange only inflicts further VILI and makes the situation worse.

22 Normal Lungs Stage IV BPD Lungs Normal gas exchange. Normal gas exchange?

23 Severe inspiratory flow restriction

24 Ventilation and BPD Oxygen is toxic to tissues. Hyperventilation may be injurious. Regional overdistention (stretch, not pressure per se) promotes lung injury. Recruitment/de-recruitment causes lung injury. Lung injury promotes a cycle of inflammation. Less (ventilation) is more.

25 Ventilator Strategy and BPD Each ventilatory change has a consequence Defining lung protective strategies requires a compromise between gas exchange goals and potential toxicities associated with overdistention, recruitment/derecruitment and exposure to high oxygen concentrations.

26 Non-Invasive Ventilation? Primary strategies using CPAP or its derivatives have not demonstrated any meaningful reduction in the incidence of BPD.

27 COIN Trial Nasal CPAP or Intubation and ventilation for very preterm infants at birth Infants 25+0 to 28+6 weeks Breathing at 5 min and needing respiratory support Randomized to nasal CPAP at 8 cm H 2 O or mechanical ventilation 610 infants (307 CPAP, 303 ventilation)

28 COIN Trial At 28 days the OR (95% CI) for death or oxygen treatment for the CPAP group was 0.63 (0.46 to 0.87, p=0.006). However, at 36 weeks it was 0.80 (0.58 to 1.12, p=0.21) Babies in the CPAP group - Intubation rate in first 5 days - 46% Death or CLD at 28 days lower - OR (95% CI), 0.63 ( , p=0.006) No difference in complications of prematurity Surfactant use halved Increase in pneumothorax, 9% vs. 3%, P<0.003 Morley CJ, et al, N Engl J Med 2008, 358:700-8.

29 SUPPORT Trial Early CPAP 48 % Surfactant 51% BPD Carlo, et al: N Engl J Med. 2010;362:1970.

30 Ventilator Strategy and BPD The most important issue is not the specific ventilator mode or modality, but matching ventilation strategy to the underlying pathophysiology Early lung injury can alter future lung growth and development

31 Myth #3 Pharmacotherapy, including diuretics, bronchodilators, and postnatal corticosteroids, play an integral role in the management of babies with bronchopulmonary dysplasia.

32 Reality #3 There is an alarming lack of evidence to support the use of any pharmacologic agent in the routine management of infants with BPD, with the exception of vitamin A and perhaps caffeine.

33 Life Cycle of the Neonatologist Use of drugs Skepticism Age

34 A Real Patient 5 month old, former 25 week female Transferred at 144 days of age Severe BPD with ventilator dependence requiring 55% oxygen Wt kg

35 Medications Hydrodiuril 4 mg Q12h Aldactone 5.2 mg Q24h Lasix 3.6 mg Q12h NaCl 2 meq Q12h KCl 1 meq Q8h Reglan 0.18 mg PO Q8h Prevacid 2.6 mg PO Q24h Dexamethasone 0.14 mg Q12h Versed 0.18 mg Q2-4h Atrovent Q6h Fluticasone Q12h

36 Pulmonary Consultant Given that she has cystic BPD, diuretics are an important part of her plan of care. The determination of whether to use Lasix or chlorothiazide and aldactone can be made based on her potassium level given that fluid overload may further compromise her respiratory status.

37 Are Diuretics An Important Part of BPD Management?

38 Historical Perspective Infants with BPD tolerate excessive fluid intake poorly and tend to accumulate lung water Water and salt intake must be limited to the minimum necessary to provide adequate calories to support metabolic needs and growth

39 Deductive Reasoning So, if I give diuretics, I can give more fluid and more calories and get the baby to grow better.

40 Can Diuretics Prevent BPD? Two Cochrane reviews included small studies of single dose or short-term therapy and only short-term outcomes (extubation rates, change in compliance or FiO 2 ). Evidence does not support preventative use of diuretics. Laughon, et al. Sem Fetal Neonatal Med 2009; 14:

41 Can Diuretics Treat BPD? Systematic reviews of diuretic therapy indicate some short-term improvement in pulmonary function, but this does not translate to any substantial reduction in ventilator support or duration. No long-term benefits (mortality, duration of PPV or oxygen use, LOS) have been shown. Wiswell et al. Clin Perinatol 2007; 34:

42 The Physiology

43 Fluid Retention Salt and Water Loss Diuretics Salt and Fluid Repletion Na, K and Cl Alkalosis, Calciuria

44 Slaughter JL et al. Pediatrics 2013; doi: /peds

45 We have no idea what we are doing! Slaughter JL et al. Pediatrics 2013; doi: /peds

46 Bronchodilators Evidence of the efficacy or safety of bronchodilators to treat BPD is lacking, yet their use is commonplace There is a paucity of evidence about benefits and toxicity of chronically administered common bronchodilators

47 Postnatal Steroids Large and small trials of postnatal steroids have claimed great attention and utilized resources.

48 Postnatal Steroids

49 Postnatal Steroids: The Good Immediate beneficial shortterm effects Reduced oxygen need Weaning of ventilatory support Earlier extubation

50 Postnatal Steroids- The Bad Adverse short-term effects Hypertension Hyperglycemia Osteopenia Immunosuppression

51 Postnatal Steroids- The Ugly Long-term morbidities Adverse neurologic outcomes Cerebral palsy

52 Postnatal Steroids Is timing everything? Early administration (days 1-4) facilitates extubation, reduces the risk of BPD, but is associated with GI bleeding, GI perforation, and adverse neurodevelopmental outcomes, including CP

53 Postnatal Steroids Is timing is everything? Later administration (days 7-14) reduces death or BPD at 28 d and 36 wk without documented effect on neurologic outcomes, but follow-up data are very limited, raising caution.

54 Postnatal Steroids Is timing is everything? Delayed administration (after 3 weeks) reduces death or BPD at 36 weeks; the trend toward more CP is offset by fewer pulmonary deaths and reduced mortality overall Combined outcome of death or CP did not differ

55 Postnatal Steroids Increasing BPD trend coincides temporally with marked reduction in postnatal steroid use since Unknown whether trend towards more BPD is related to the reduction in postnatal steroid use. Prudent to reserve use of steroids to ventilator-dependent infants; minimize the dose and duration of treatment.

56 Postnatal Steroids

57 What About Reflux? Is it really a disease (or does spit happen )? Most reflux is not acid reflux If so, could the treatments be worse than the disease?

58 Back to the Patient Nephrolithiasis Nephrocalcinosis Severe osteopenia, multiple pathologic fractures Hyponatremia, hypokalemia, hypochloremia Hypertrophic cardiomyopathy Hypertension

59 Summary Current neonatal practices related to management of infants with BPD are shrouded in myths. Commonly used therapies are not supported by the evidence

60 The Hopes

61 Respiratory Management Earlier tracheostomy? Heliox? Inhaled nitric oxide/surfactant? Servo-controlled ventilation? Tidal volume Minute ventilation Rate Oxygen delivery

62 Pharmacotherapies Treatment of pulmonary hypertension Milrinone Epoprostenol Sildenafil Diuretics?

63 Pharmacotherapies Treatment of pulmonary hypertension Milrinone Epoprostenol Sildenafil Diuretics? WARNING:

64 Pharmacotherapies Anti-inflammatories Nitric oxide Surfactant repletion Azithromycin and Clarithromycin Nutrition

65 BPD is a Multifactorial Disease

66 BPD is a Multifactorial Disease There is no silver bullet!

67 Summary Improvements in survival free of major morbidity will require: Cooperation among centers Funding and participation in well designed, multi-center clinical trials Educational commitment to the principals of evidence-based practice Maintenance of equipoise as new treatments evolve until the evidence dictates their acceptance or rejection

68 Conclusion It s time for us to change our approach to infants with BPD. We need to move from EMINENCE-BASED to EVIDENCE-BASED medicine. Our patients deserve no less.

69 Their Fate is in Our Hands Tracheotomy, FiO 2 0.5, mechanical ventilation Room Air