Download - Lessons Learned from a Career in Neonatal Research...Lessons Learned from a Career in Neonatal Research Richard J. Martin, M.D. Drusinsky-Fanaroff Chair in Neonatology Rainbow Babies

Lessons Learned from a Career in Neonatal Research

Richard J. Martin, M.D.Drusinsky-Fanaroff Chair in Neonatology

Rainbow Babies and Children’s Hospital

Professor of Pediatrics

Case Western Reserve University

Cleveland, Ohio

Seize opportunities and energetic mentorship

Hang in there and formulate the next question

Lessons learned from animal models

Take opportunities to engage in clinical trials

Lessons Learned…

Maureen Hack, M.D., Marshall H. Klaus, M.D., Avroy A. Fanaroff, M.D.

ABSTRACT

“…Continuous monitoring of respiration in small infants is now clinically feasible.”

Pediatrics 1969

Kattwinkel 1975

BEFORE

CPAP

DURING

CPAP

(p<0.02)A

PN

EIC

EP

ISO

DE

S /

12

HO

UR

S

60

50

40

30

20

10

0

Effect of CPAP on Incidence of Apnea

Effect of CPAP on Respiratory Timing

Martin et al: J Appl Physiol 1978





Lessons Learned…

HEART

RATE

(BPM)

CHEST

WALL

MOVEMENT

TIDAL

VOLUME

(cc)

180

120

60

15

0

15

10 sec.

Mixed Apnea

Physiologic Data From Upper Airway Dilator Muscles During Development

Alae nasi (AN)

Genioglossus (GG)

Sternohyoid (SH)

Posterior Cricoarytenoid

(PCA)

Nasal CPAP for Neonatal Apnea

Decrease in upper airway resistance

Increase in FRC

Improvement in oxygenation





Lessons Learned…

Mexico[undated]

Bedside to Bench to Bedside

CO2 Threshold of Respiratory Muscles

Carlo: J Appl Physiol 1988

DIA

GG

m±SE

control 30 60 90 120

100

80

60

40

20

0

CO2

Time (sec)

Min

ute

EM

G (

% m

ax)

Respiratory Control andLES Pressure

Kiatchoosakun, Pediatr Res 2002

25

0

PLES(mmHg)

30 s

DIA EMG

(AU)

Hypoxia-induced apnea

LES Pressure Associatedwith Apnea Onset

Time Relative to Apnea Onset (sec)

mm

Hg

0 4 8 12 16 20-20 -16 -12 -8 -40

10

20

30

ApneaLES Pressure

Omari, J Pediatr 2009





Lessons Learned…

Lessons from ClinicalTrial Opportunities

HIFI Study, NEJM 1989

CHIME Study, JAMA 2001

NO CLD, NEJM 2006

PreVent, 2016-

HFOV to Prevent BPD

CVHFOV

BP

D I

NC

IDE

NC

E (

%) 50

40

30

20

10

0

HIFI Study Group, 1989




NO CLD, NEJM 2006

PreVent, 2016-

33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 560

5

10

15

20

25

30

35

40

45

50

55

60Preterm SympPreterm AsympHealthy Term

PCA (weeks) at beginning of 4-week observation period

No. of

infa

nts

CHIME Study: JAMA 2001

Infants with ≥ One Extreme Event per 20,000 Monitor Hours




NO CLD, NEJM 2006

PreVent, 2016-

Proposed Effects of Nitric Oxide on the Development of the Respiratory System

Martin RJ: N Engl J Med 2005

NIH Consensus Development Conference: Inhaled Nitric Oxide for Premature Infants

“Available evidence does not support use of iNO in

routine care of premature infants who require

respiratory support”.

“Future research should seek to understand the gap

between benefits on lung development and function

suggested by basic research and animal studies, and

the results of clinical trials to date”.

Pediatrics 2011




NO CLD, NEJM 2006

PreVent, 2016-

Prematurity-related VentilatoryControl [PreVent] 2016-

An NHLBI sponsored multicenter observational study to investigate mechanisms of ventilatory control that contribute to the risk of respiratory morbidity in preterm infants

Case Western • Northwestern • UABUniv Miami • Washington Univ • UVA

So….Does Apnea of Prematurity Still Matter?

Serves as a biologic link between the lung and brain

May contribute to pulmonary morbidity via need for increased respiratory support

May contribute to neurodevelopmental morbidity via intermittent hypoxic episodes

Prolongs hospitalization and cost