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PREVIOUS ISSUES - JANUARY 2004
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January 2004 |
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COURSE DIRECTORS |
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Edward E. Lawson, M.D.
Professor
Department of Pediatrics - Neonatology
The Johns Hopkins University School of Medicine |
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Christoph U. Lehmann, M.D.
Assistant Professor
Department of Pediatrics - Neonatology
The Johns Hopkins University School of Medicine |
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Lawrence M. Nogee, M.D.
Associate Professor
Department of Pediatrics - Neonatology
The Johns Hopkins University School of Medicine |
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Lorraine A. Harbold, R.N., M.S.
The Johns Hopkins Hospital;
NICU Education Coordinator |
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In this issue... Volume
1, Number 5 |
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Our focus this month is on Congenital Diaphragmatic Hernia (CDH).
Despite generalized improvements in neonatal mortality over the last
decade, the mortality of infants with CDH has remained frustratingly
consistent (1). The primary limitation to survival is the degree of
pulmonary hypoplasia that is associated with the diaphragmatic defect.
Are outcomes predetermined in patients with congenital diaphragmatic
hernia? This month we review investigations into the three main areas
of research in this field: - measures that predict outcome
- therapeutic interventions to alter outcome, and
- efforts to understand the mechanisms of the defect.
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Guest Editors of the Month
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Tami Hutton Garmany, M.D.
Newborn Medicine Fellow
Division of Newborn Medicine
Washington University
St. Louis Children's Hospital |
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Aaron Hamvas, M.D.
Professor of Pediatrics
Division of Newborn Medicine
Washington University
St. Louis Children's Hospital |
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Guest Faculty Disclosures
Tami Hutton Garmany, MD
Faculty Disclosure: Dr. Garmany receives support from the National Institutes of Health.
Aaron Hamvas, M.D.
Faculty Disclosure: Dr Hamvas receives grant and research support from the National Institutes of Health.
Unlabelled/Unapproved Uses
No faculty member has indicated that their presentation will include information on off label products.
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COMMENTARY |
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The ability to quantify the extent of the hypoplasia and predict the
outcomes has remained elusive, whether by ultrasonographic measurements
or indices of gas exchange. While these indices may permit some
stratification for clinical research purposes, they fail to be either
sensitive or specific enough to permit directed care.
Two interventions have received significant attention. "Permissive
hypercapnea" challenges the dogma of treating the associated pulmonary
hypertension with hyperventilation and attempts to minimize ventilator
induced lung injury. While survival rates of 70-80% provide optimism
and indicate that this strategy is probably not harmful, we need to
interpret these studies cautiously. First, they have been primarily
retrospective and focus on the changes in respiratory management over
time, often neglecting parallel improvements in newborn care, such as
aggressive nutritional intervention. Second, 60-70% of the mortality
occurs within the first 24-48 hours after birth, a timeframe in which
ventilator-induced lung injury is unlikely to be the operative
explanation for improved survival. Fetal intervention, while showing
promise in animals with experimentally induced CDH, has been
disappointing in human trials. Attempts to repair the diaphragmatic
defect or occlude the trachea to improve lung growth have been
successful from a technical standpoint, but have resulted in premature
birth, which masks the effectiveness of the interventions (2).
These trials illustrate some important points. First, the factors that
determine pulmonary outcome of CDH apparently play a role much earlier
in gestation than can be addressed by intervention at 22 weeks
gestation or beyond. Second, these observations suggest that the animal
models, while simulating the mechanical features of CDH, do not
adequately recapitulate the basic embryologic defect(s). Jesudason, et
al, through their series of studies examining the roles of growth
factors in lung development, raise the critical question: which comes
first, a disruption of lung development with subsequent disruption of
diaphragm development, or vice-versa? (3) It is likely that these
disparate mechanisms are responsible for the disparate pulmonary
outcomes of these infants.
Continuing collaboration between the basic, surgical, neonatal, and
nursing sciences will be necessary to understand the genetic,
developmental, and environmental factors that cause CDH, and to improve
the care and outcomes of these infants.
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INVESTIGATING THE PATHOPHYSIOLOGY OF CDH
Jesudason,
EC. Challenging embryological theories on congenital diaphragmatic
hernia: future therapeutic implications for paediatric surgery. Ann R
Coll Surg Engl 2002;84: 252-259.
A
series of animal experiments challenges the theory that lung hypoplasia
results from extrinsic compression in diaphragmatic hernia.
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These
experiments used the pesticide nitrofen to induce CDH and lung
hypoplasia in rats. At the equivalent of 4.5 weeks human gestation and
prior to diaphragmatic herniation, nitrofen-exposed lung primordia
already had fewer terminal buds than normal lungs.
In
subsequent experiments, terminal bud counts were recorded daily and
lung epithelia were evaluated. Both normal and nitrofen-exposed lungs
increased in size and branching, but the nitrofen-exposed lungs had
reduced lung area, lung perimeter and terminal bud count. There were
morphological differences between the two groups as well.
The third and fourth experiments involved the impact of growth factors
on lung development. FGF1 binds FGFR2IIIb while FGF2 essentially does
not. Binding of the FGFR2IIIb receptor is essential for lung branching
morphogenesis. Heparin modulates FGF kinetics. Normal lungs responded
to FGF1+heparin with increased terminal bud counts, lung epithelial
area and lung perimeter while nitrofen-exposed lungs did not. FGF2
alone had minor effects on normal lungs and FGF2+heparin was
inhibitory. Nitrofen-exposed lungs with FGF2 alone had increases in
lung area and reductions in terminal bud count while FGF2+heparin
transiently and modestly altered lung morphogenesis.
In the fourth experiment, epidermal growth factor (EGF) was cultured
with embryonic lung explants. In normal lungs, EGF produced minor
inhibitory changes in morphological development while in
nitrofen-exposed lungs, EGF yielded moderate morphological changes.
The author concluded that lung hypoplasia begins during embryogenesis
and prior to the diaphragmatic defect. A 36% incidence of stunted
nitrofen-exposed lungs correlates well with the 30-40% incidence of CDH
subsequently seen in these animals and supports the theory that lung
hypoplasia occured before the hernia. Secondly, nitrofen-exposed lungs
respond abnormally when cultured with heparin and/or certain FGFs.
Growth factor signaling may be perturbed in the hypoplastic lung.
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(For non-journal subscribers, an additional fee may apply for full text article)
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 view journal abstract |
 view full article |
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PREDICTING OUTCOMES
Lipshutz
GS, Albanese CT, Feldstein VA, Jennings RW, Housley HT, Beech R,
Farrell JA, Harrison MR. Prospective Analysis of Lung-to-Head Ratio
Predicts Survival for Patients With Prenatally Diagnosed Congenital
Diaphragmatic Hernia. J Ped Surg 1997; 32(11): 1634-1636.
Accurate
prediction of outcome for fetuses with CDH is difficult. This
prospective study measured lung-to head ratios (LHR) in fetuses with
left-sided diaphragmatic hernias and correlated these ratios to outcome. |
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Fifteen
patients with sonographically identified left-sided CDH were
prospectively referred to the UCSF Fetal Treatment Center for
evaluation. Sonography was repeated by one of four experienced
sonographers and fetal lung-to-head ratio (LHR) was determined between
24-26 weeks estimated gestational age. Postnatal care took place at
UCSF or another tertiary care facility.
The principal outcome
variable was survival at 60 days after optimal postnatal care,
including high frequency ventilation, inhaled nitric oxide, and ECMO if
necessary. Need for ECMO support was a secondary outcome. Overall
survival rate was 47% with pulmonary insufficiency responsible for all
mortality. Survivors had a LHR of 1.4 ± 0.33 and non-survivors had LHR
of 1.05 ± 0.3 (P < .05). All fetuses with a LHR of less than 1.0
died and all fetuses with a LHR greater than 1.4 survived. ECMO support
was needed for all patients with a LHR < 1.0, seventy-five percent
of patients with a LHR between 1.0 and 1.4, but only one of four
patients with LHR > 1.4.
The authors conclude that LHR can be a reliable measure used as an
adjunct in predicting postnatal survival with conventional therapy or
ECMO support, although it is dependent on sonographic technique and
gestational age.
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(For non-journal subscribers, an additional fee may apply for full text article)
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view journal abstract |
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TREATMENT: EARLY VERSUS LATE TERM DELIVERY
Stevens
TP, Chess PR, McConnochie KM, Sinkin RA, Guillet R, Maniscalco WM,
Fisher SG. Survival in Early- and Late-Term Infants With Congenital
Diaphragmatic Hernia Treated With Extracorporeal Membrane Oxygenation.
Pediatrics Sept 2002; 110 (3), Sept 2002: 590-596
The
optimal gestational age for delivery of infants with CDH is unknown.
This study compared outcomes in infants born early-term versus those
born late-term. |
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Data
from the Extracorporeal Life Support Organization Registry for infants
with CDH treated with ECMO were obtained retrospectively from four time
periods: Era 1: April 1976-1985; Era 2: 1986-1990; Era 3: 1991-1995;
and Era 4: 1996-June 2001. Within each era, infants born at early-term
(38 0/7 to 39 6/7 weeks) were compared to those born at late-term (40
0/7 to 41 6/7 weeks).
The relative survival rate for late-term
infants was almost 20% greater than for early-term infants. Early-term
infants who survived ECMO were on ECMO longer and had longer hospital
stays than late-term infants. Gestational age did not independently
predict survival but was correlated with birth weight, which was
associated with improved survival.
Patient data associated with survival was analyzed by era to identify
trends in characteristics of infants treated with ECMO over time. The
percentage of infants born early-term increased (40% in Era 1 to 57% in
Era 4) as did the percentage of prenatal diagnoses (4% to 51%). In Era
4, early-term infants were more likely to suffer a renal, neurologic,
and hemorrhagic complication than were late-term infants (50% vs 40%).
The respiratory severity parameters (PIP ≥ 40 and PaO2/FiO2 < 0.4)
at initiation of ECMO decreased over the 4 eras and there were no
significant differences in the incidences of low arterial pH (<7.2)
or elevated pCO2 (>50 torr) between the early- and late-term infants
over the 4 eras.
With greater birth weight having a protective effect against
complications on ECMO, the trend toward earlier delivery and at lower
birth weights may contribute to higher complication rates on ECMO. The
authors conclude that for the approximately 50% percent of infants with
CDH that are treated with ECMO, clinical outcomes may be improved by
delay of elective delivery until 40 weeks completed gestation.
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(For non-journal subscribers, an additional fee may apply for full text article)
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CHALLENGING CONVENTIONAL TREATMENT THEORY: THE FLORIDA EXPERIENCE
Kays
DW, Langham MR, Ledbetter DJ, Talbert JL. Detrimental Effects of
Standard Medical Therapy in Congenital Diaphragmatic Hernia Annals of
Surgery September 1999; 230 (3): 340-351
This
study, from the University of Florida demonstrated improved survival
with permissive hypercapnea, gentle ventilation and delayed surgical
repair in infants with CDH. |
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This retrospective cohort study grouped patients into 3 eras based on treatment strategies.
- Era
1 included 12 infants treated with paralysis, hyperventilation,
alkalization, hyperoxia, and surgical repair within the first 24 hours.
ECMO was not available.
- Era 2 included 14 patients
treated with paralysis, hyperventilation, alkalization, and ECMO if
needed. Ventilator pressures were moderated and hyperoxia was used less
vigorously. Surgery was delayed for >24 hours in most patients.
- Era
3 included 53 infants treated with low pressure ventilation and
sedation but not paralysis. Bicarbonate was given if the arterial pH
was below 7.20. Inhaled NO and ECMO were used if necessary. Surgery was
delayed for at least 24 hours or until the patient was stable.
Survival rates were 17% in era 1, 50% in era 2, and 89% in era 3. Birth
weight, gestational age, Apgar score at 1 and 5 minutes, and the
incidence of serious but nonlethal anomalies were similar in all three
groups. The number of infants with liver and or stomach herniated into
the chest was similar in all groups. The number of prenatally diagnosed
hernias rose significantly from era 1 to 2 to 3 (from 0 to 36% to 41%).
In eras 1 and 2, hyperventilation was successful in decreasing PaCO2
initially but was not sustainable. The incidence of pneumothorax
decreased throughout the eras. The addition of NO did not improve
survival or decrease the need for ECMO. The need for ECMO did not
change between eras 2 and 3. ECMO survival increased significantly in
era 3 (29% in era 2 and 83% in era 3).
The authors concluded that hyperventilation and alkalization had
detrimental effects on infants with CDH. Abandoning these treatment
modalities, along with the use of gentle ventilation, improved survival
with and without ECMO.
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(For non-journal subscribers, an additional fee may apply for full text article)
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view journal abstract |
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CHALLENGING CONVENTIONAL TREATMENT THEORY: THE COLUMBIA EXPERIENCE
Boloker
J, Bateman DA, Wung JT, Stolar CJH. Congenital Diaphragmatic Hernia in
120 Infants Treated Consecutively With Permissive
Hypercapnea/Spontaneous Respiration/Elective Repair J of Ped Surgery
March 2002; 37 (3).
The
results of this large retrospective study indicate that conventional
treatments may increase the incidence of iatrogenic lung injury and
thereby reduce survival |
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Data
from 120 infants with CDH were collected retrospectively. All infants
were placed on conventional "low-rate" ventilation. If this protocol
was not adequate, the infant was changed to high frequency positive
pressure ventilation (HFPPV) and then to HFOV if necessary. PIP was
kept <25 if possible. Oxygen was given to maintain preductal
saturations 90-95% and was weaned to keep delivery at a minimum.
Hyperventilation and muscle relaxants were not used. Sedation was used
sparingly with no continuous infusions. Inhaled NO and ECMO were
initiated if necessary. Surgery was delayed until the ductal saturation
gradient subsided, echocardiography showed minimal evidence of
pulmonary hypertension, and ventilator support was minimized. No infant
had surgical repair before 36 hours of life. No prophylactic chest
tubes were placed.
No survivors required a PIP >25, while
58% of non-survivors required PIP >25. 50% of survivors required
HFPPV to ventilate, while 78.2% of non-survivors were treated with
HFPPV. ECMO was used in 8.9% of patients. Non-survivors had lower pH
and higher PaCO2 values at all times despite using higher PIP values.
Survivors exhibited decreasing FiO2 requirements and an average PaCO2
of 47.4 ± 9.3 over the first day of life. Only a moderate increase in
ventilator management was needed postoperatively. No patient required
ECMO postoperatively if not required preoperatively. The survival rate
was 75.8%, excluding lethal anomalies, pre-ECMO neurological
complications and lethal lung hypoplasia.
The authors conclude that preventing iatrogenic lung injury, thus
decreasing the need for ECMO, improves survival. They postulate that
intraoperative chest tube placement causes hyperinflation of the
hypoplastic lung, leading to increased pulmonary vascular resistance,
lung damage and cardiopulmonary instability. Finally, the study
demonstrated that delayed surgical repair was associated with decreased
ECMO need and improved survival rate, leading the authors to conclude
that a more stable infant is better able to tolerate the decreased
compliance following surgery.
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TREATMENT: FETAL SURGERY TECHNIQUE
Harrison
MR, Keller RL, Hawgood SB, Kitterman JA, Sandberg PL, Farmer DL, Lee H,
Filly RA, Farrell JA, Albanese CT. A Randomized Trial of Fetal
Endoscopic Tracheal Occlusion for Severe Fetal Congenital Diaphragmatic
Hernia N Engl J Med Nov 13, 2003; 349 (20): 1916-1924
Occlusion
of the trachea was shown to stimulate lung growth in a number of animal
models. Initial studies also suggested improved survival in human
fetuses with severe CDH. This is the first randomized, controlled trial
in humans to evaluate this technique |
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Twenty-four
women carrying fetuses 22-27 weeks gestation with left-sided CDH were
randomized to fetal endoscopic tracheal occlusion (n=11) or standard
care (n=13). Eligibility requirements included liver herniation, no
preterm labor, and LHR <1.4, determined previously by these authors
to correspond to a survival rate of approximately 20%. Randomization
was stratified according to LHRs. The primary outcome was survival at
90 days of life.
Infants in both groups were intubated in the
delivery room and given pancuronium and sedatives. Conventional
ventilation was used with the goal of maintaining pCO2 45-60 mmHg and
preductal oxygen saturations >90%. If ventilation and oxygenation
were inadequate, HFOV, iNO, and ECMO were used. Surgery was performed
when the infant's respiratory status had stabilized.
Morbidity in the intervention group included preterm premature rupture
of membranes in all women and chorioamnionic separation in 64% of the
women. Infants in the intervention group were delivered at a mean
gestational age of 30.8 ± 2.0 weeks, while the mean in the control
group was 37.0 ± 1.5 weeks. There was no difference in survival between
the two groups of infants (77% of controls vs. 73% of intervention).
Overall, there was a direct association between higher LHR and
increased survival. There were no differences in the rates of
respiratory, gastrointestinal, or neurologic complications and no
differences in the ages at time of repair, extubation, or discharge, or
in the proportion of infants requiring supplemental oxygen at discharge.
Enrollment in the study was terminated early due to the absence of a
significant difference in outcome between the two groups of infants as
well as a higher than expected survival rate in the standard care
group. The authors concluded that fetal tracheal occlusion did not
improve outcome for fetuses with severe CDH over standard care. They
postulate that the benefits of improved lung growth due to fetal
tracheal occlusion may be outweighed by the adverse effects of
premature delivery caused by the intervention.
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(For non-journal subscribers, an additional fee may apply for full text article)
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REFERENCES AND ADDITIONAL SOURCES OF INFORMATION:
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(For non-journal subscribers, an additional fee may apply for full text article)
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1.
Stege G, Fenton A, Jaffray B. Nihilism in the 1990s: the true mortality
of congenital diaphragmatic hernia. Pediatrics 2003; 112:532-535
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view journal abstract |
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2. Sydorak RM, Harrison MR. Congenital diaphragmatic hernia: advances in prenatal therapy. Clin Perinatol 2003; 30:465-479.
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view journal abstract |
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3.
Jesudason EC. Challenging embryological theories on congenital
diaphragmatic hernia: future therapeutic implications for paediatric
surgery. Ann R Coll Surg Engl 2002; 84:252-259.
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view journal abstract |
view full article |
back to top |
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| Accreditation back to top |
| Physicians |
The
Johns Hopkins University School of Medicine is accredited by the
Accreditation Council for Continuing Medical Education to provide
continuing medical education for physicians.
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| Nurses |
The
Institute for Johns Hopkins Nursing is accredited as a provider of
continuing education in nursing by the American Nurses Credentialing
Center's Commission on Accreditation.
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| Credit Designations back to top |
| Physicians |
The
Johns Hopkins University School of Medicine designates this educational
activity for a maximum of 0.5 category 1 credits toward the AMA
Physician's Recognition Award. Each physician should claim only those
credits that he/she actually spent in the activity.
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| Nurses |
The Institute for Johns Hopkins Nursing designates this activity for a maximum of 0.5 contact hours for this eNewsletter.
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| Respiratory Therapists |
Contact
your state licensing board to confirm that AMA PRA category 1 credits
are accepted toward fulfillment of RT requirements.
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| Target Audience back to top |
This
activity has been developed for Neonatologists, NICU Nurses and
Respiratory Therapists working with Neonatal patients. There are no
fees or prerequisites for this activity.
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| Learning Objectives back to top |
The
Johns Hopkins University School of Medicine and The Institute for Johns
Hopkins Nursing take responsibility for the content, quality, and
scientific integrity of this CE activity. At the conclusion of this
activity, participants should be able to:
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Evaluate the studies presented to develop an understanding of current research into CHD.
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Understand the positives and negatives of current conventional treatment protocols.
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Use the information presented herein as a basis to consul parents regarding potential interventional treatments.
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| Faculty Disclosure Policy Affecting CE Activities back to top |
As
sponsors accredited by the Accreditation Council for Continuing Medical
Education and American Nursing Credentialing Center, it is the policy
of The Johns Hopkins University School of Medicine and The Institute of
Johns Hopkins Nursing to require the disclosure of the existence of any
significant financial interest or any other relationship a faculty
member or a sponsor has with the manufacturer(s) of any commercial
product(s) discussed an education presentation. The presenting faculty
reported the following:
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Dr.
Nogee has indicated a financial relationship of grant/research support
with Forest Laboratories and has received an honorarium from Forest
Laboratories.
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Dr.
Lawson has indicated a financial relationship of grant/research support
from the NIH. He also receives financial/material support from Nature
Publishing Group as the Editor of the Journal of Perinatology.
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All other faculty have indicated that they have not received financial
support for consultation, research, or evaluation, nor have financial
interests relevant to this e-Newsletter.
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unapproved uses of drugs or devices.
No faculty member has indicated that their presentation will include information on off label products.
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