Post on 28-Jan-2020
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
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…
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
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…
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
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…
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
Lessons from ClinicalTrial Opportunities
HIFI Study, NEJM 1989
CHIME Study, JAMA 2001
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
Lessons from ClinicalTrial Opportunities
HIFI Study, NEJM 1989
CHIME Study, JAMA 2001
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
Lessons from ClinicalTrial Opportunities
HIFI Study, NEJM 1989
CHIME Study, JAMA 2001
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