Article pulmonology

Neonatal Pulmonary Hemorrhage

Riad Abou Zahr, MD,*
Ahmad Ashfaq, MD,*
Mary Marron-Corwin,
MD* †
Author Disclosure
Drs Zahr, Ashfaq, and
Marron-Corwin have
disclosed no financial
relationships relevant
to this article. This
commentary does not
contain a discussion of
an unapproved/
investigative use of
a commercial product/
device.
Abstract
Pulmonary hemorrhage in the newborn is an ominous condition that has a high neo-
natal mortality rate. Several risk factors have been associated with the development
of pulmonary hemorrhage, but the exact pathogenesis remains obscure. As a conse-
quence, no curative treatment exists. In this review, we focus on the current understand-
ing of pulmonary hemorrhage: its pathogenesis, associated risk factors, up-to-date
management, and prognosis.
Objectives After completing this article, readers should be able to:
1. Recognize pulmonary hemorrhage.
2. Discuss the accepted theories in the pathogenesis of pulmonary hemorrhage.
3. Identify risk factors associated with pulmonary hemorrhage.
4. Familiarize the clinician with current modes of therapy in the management of
pulmonary hemorrhage.
5. Acquaint the clinician with long-term sequelae after pulmonary hemorrhage.
Introduction
Pulmonary hemorrhage (PH) is a well-recognized condition in term and preterm newborns
that was first described as early as 1855. (1) It usually represents an ominous sign of wors-
ening clinical status. PH refers to the appearance of fresh blood in the endotracheal tube
(ET) or trachea. The hematocrit of the hemorrhagic fluid is often 15 to 20 percentage
points below the venous hematocrit. PH involves clinical deterioration with vasoconstric-
tion, poor perfusion, and worsening respiratory status, accompanied by a drop in hemat-
ocrit and abnormal chest radiographic findings. The incidence of PH is 1 to 12 per 1,000
live births. This rate rises to 50 per 1,000 live births among high-risk groups such as pre-
mature or intrauterine growth-restricted infants. (2) PH occurs most commonly in the first
few days after birth. Mortality rates as high as 50% have been reported.

Pathogenesis
The exact pathogenesis of PH remains unknown, although several theories have been sug-
gested. Cole et al (3) found that lung effluent in most cases represented hemorrhagic
edema fluid rather than whole blood and attributed the direct cause to left ventricular fail-
ure secondary to asphyxia. Twenty years later, West et al (4) showed that stress failure of the
pulmonary capillaries causes breakage in the endothelial bar-
rier with resultant leakage of hemorrhagic fluid into the al-
veoli. They described three major forces involved in the
Abbreviations process: (1) circumferential tension in the capillary wall sec-
ET: endotracheal tube ondary to capillary transmural pressure, (2) surface tension
KU: Klobusitzky unit of the alveoli that supports the bulging capillaries, and (3)
PDA: patent ductus arteriosus longitudinal tension in the alveoli, as a result of lung infla-
PEEP: positive end-expiratory pressure tion. (2)(4) Currently, the most accepted theory is that a de-
PH: pulmonary hemorrhage crease in pulmonary vascular resistance may increase left to
rFVIIa: activated recombinant factor VII right shunting through a patent ductus arteriosus (PDA)
TIPP: Trial of Indomethacin Prophylaxis in Preterms which in turn will increase pulmonary blood flow. Amizuka
et al demonstrated significant inhibitory activity against

*Columbia University the Affiliation at Harlem Hospital Center, New York, NY.
†
Newborn Services, Harlem Hospital Center, New York, NY.

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pulmonary surfactant in the first lung effluent obtained
from neonates with PH, suggesting that surfactant dys-
function was implicated in the pathogenesis. (5) Re-
cent evidence suggests that intrauterine neutrophil
activation may predispose to the development of PH
in preterm newborns with respiratory distress (syn-
drome). (6)
Risk Factors
Many risk factors have been associated with the develop-
ment of PH such as prematurity, intrauterine growth
restriction, PDA with a left to right shunt, asphyxia,
coagulopathy, respiratory distress syndrome, polycythe-
mia, hypoxemia, disseminated intravascular coagulation,
mechanical ventilation, sepsis, hypothermia, male gender,
cold injury, multiple births, oxygen toxicity, urea cycle
defects, and, more recently, surfactant therapy. In a case-
control study by Berger et al, (2) antenatal glucocorticoids
were protective, whereas thrombocytopenia and need for
delivery room resuscitation with positive pressure venti-
lation were associated with an increased risk of PH in
preterm infants (Fig 1). Among term/near-term infants,
meconium aspiration, hypotension, and need for posi-
tive pressure ventilation in the delivery room were sig-
nificant risk factors for PH (Fig 2).
The association between PDA and PH has been well
described in the literature. (7)(8) In the Trial of Indo-
methacin Prophylaxis in Preterms (TIPP) by Schmidt
et al, PH was among the short-term secondary outcomes
studied. No statistically significant difference was demon-
strated between the indomethacin and placebo groups.
(9) Upon further post hoc analysis of the data in this trial,
Figure 1. Autopsy slide of a preterm neonate showing pulmonary
hemorrhage.
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pulmonology neonatal pulmonary hemorrhage
Figure 2. Pulmonary hemorrhage in an autopsy of a term
newborn.
Alfaleh et al demonstrated that prophylactic indometha-
cin reduced PH rates in the first few days after birth and
attributed this to its effect on PDA closure. Prophylactic
indomethacin, however, did not decrease the rate of PH
beyond the first week. (10)
Several studies analyzed the difference in PH between
the presurfactant and postsurfactant eras with conflicting
results. This conflict is probably due to the variation in
the definition of PH and the type of surfactant used.
Stevenson et al reported an increase in the rate of PH
with synthetic surfactant therapy by using Exosurf. (11)
In 1993, a meta-analysis of randomized clinical trials of
surfactant therapy demonstrated a slightly increased risk
of PH after surfactant therapy (12) (relative risk 1.47
[95% confidence interval 1.05–2.07]), which was hy-
pothesized to be due to an improvement in lung com-
pliance after surfactant therapy, with resultant decrease
in pulmonary vascular resistance resulting in increased
left to right shunting, which, in turn, predisposes to
PH. A retrospective case-control study of 58 very low
birth weight infants identified surfactant therapy as
the sole risk factor for PH. (13) In contrast, in another
case-control study, Braun et al found no change in the
incidence of severe PH with surfactant use. (1)
Although rare in the USA, in some countries, neonatal
cold injury is associated with PH. In vitro, hypothermia
causes platelet aggregation that would result in throm-
bocytopenia, a process that continues or accelerates
upon warming. (14) The end result of this process could
be hemorrhage, assuming that platelets behave similarly
in vivo. Of note, rapid aggressive warming shortens the
period of thrombocytopenia and might improve the
prognosis.
NeoReviews Vol.13 No.5 May 2012 e303
pulmonology neonatal pulmonary hemorrhage
Presentation
The typical presentation of the infant with PH is a prema-
ture infant who suddenly presents with frothy pink-
tinged secretions from an ET. Over the next minutes
to hours, the infant often requires increased ventilatory
support and has increased work of breathing. As increas-
ing amounts of blood are suctioned from the ET, PCO2
starts to rise, as does the need for oxygen. If the PH con-
tinues, the infant will develop apnea, generalized pallor,
become cyanotic, with concomitant bradycardia and a drop
in blood pressure. Chest radiography results are non-
specific. Based on severity and timing of the PH, the chest
radiograph may have fluffy opacities, focal ground-glass
opacities, or appear as a complete “white out” if the PH
is massive.
Management
Management of PH is aimed at preventing exsanguina-
tion while ensuring proper gas exchange. The trachea
should first be suctioned to ensure that blood clots have
not obstructed the ET. A number 6.5F catheter should
be used for a 2.5-mm ET and an 8.0F catheter if the
ET is 3.0 or 3.5 mm. Measurements should be taken be-
fore suctioning the ET to allow the correct depth of
placement of the suction catheter. The FiO2 should be
increased as guided by the oxygen saturation of the in-
fant. The standard therapy is to raise the positive end-
expiratory pressure (PEEP) to 6 to 8 cm H2O. PEEP
may provide tamponade of the pulmonary capillaries.
However, risks of PEEP are hyperventilation and hyper-
capnia. (15) In the rabbit lung model, applications of
moderate levels of PEEP were shown to lessen pulmo-
nary rupture, edema formation, and lung hemorrhage.
(16) To decrease PH, the mean airway pressure should
be increased in an attempt to reverse or slow down hem-
orrhagic pulmonary edema. In some cases, high-frequency
oscillatory ventilation may be needed to increase the mean
airway pressure. High-frequency oscillatory ventilation has
been studied in very low birth weight infants with massive
PH, and significant reduction in the oxygenation index
was noted. (17)
Endotracheal or nebulized epinephrine has been used
in the treatment of PH because of its vasoconstrictive and
inotropic effects, (18) most commonly in a dose of 0.1
mL/kg of epinephrine in a 1:10,000 dilution. However,
this therapy remains controversial, because there have
been no controlled trials to demonstrate any clear benefit.
Immediate radiography of the chest should be obtained.
Once the hemorrhage has resolved, the chest radiograph
will show improvement within w24 to 48 hours. Because
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the radiographic appearance of PH is difficult to distin-
guish from pneumonia, therapy often includes antibiotics
until infection is ruled out. An echocardiograph should
be done to rule out left to right shunting through a
PDA. In this setting, surgical treatment for PDA may
be safer than medical treatment with indomethacin be-
cause the latter may exacerbate bleeding. Phytonadione
(vitamin K) should be given to correct prothrombinemia.
Based on an estimate of the volume of blood lost, packed
red blood cells and platelets should be given after a com-
plete blood count, prothrombin time, activated partial
thromboplastin time, D-dimers, and fibrinogen are ob-
tained. An ammonia level is useful because urea cycle
defects have been occasionally associated with PH. Be-
cause of the potential association with metabolic dis-
ease, it is helpful to perform any screening for these
disorders, including state-mandated screens, before any
transfusion is given if the patient is reasonably stable.
The administration of recombinant factor VII should
be considered.
Activated recombinant factor VII (rFVIIa) has been
successfully used to treat severe PH refractory to conven-
tional ventilator management in very low birth weight
infants. (19)(20) It is a vitamin K-dependent glycopro-
tein that works by activating the extrinsic pathway and
binds to tissue factor which ultimately will seal sites of
vascular injury and restore hemostasis. This effect is en-
hanced when platelets are coadministered. It is approved
for use in severe hemorrhage secondary to hemophilia
A and B. One advantage of rFVIIa is its relatively low
volume in comparison with the transfusion of blood
products. In one report, a dose of 50 mg/kg twice daily
administered 3 hours apart for 2 to 3 days was successfully
used to treat two very low birth weight infants. (19)
Cerebral venous thrombosis is a potential complication
of high-dose rFVIIa that has occurred in adults but has
not been reported in newborns. Although no random-
ized controlled trials have been conducted to further sup-
port the use of rFVIIa, in our experience, we have had
considerable success using it.
Surfactant has also been used in the treatment of PH.
This is based on the observation made in animal models
and in vitro that hemoglobin, red blood cell membranes,
lipids, and proteins increased surface tension, probably
secondary to inactivating surfactant. The resultant de-
crease in lung compliance was reversed after administra-
tion of exogenous surfactant. (21) A retrospective case
series of 15 neonates with PH treated with surfactant
demonstrated significant improvement in oxygenation
index and no deterioration. (22) Another retrospective
study of 27 neonates found a good response to exogenous

surfactant among the majority of patients, which was pos-
itively affected by shorter interval between onset of PH
and administration of surfactant and by higher disaturated
phosphatidylcholine concentrations in the airway epithelial
lining fluid. (5) Despite the above studies that recom-
mended surfactant therapy for PH, no randomized con-
trolled trials have been conducted. (23)
Hemocoagulase has been reported as a new effective
treatment for PH. Hemocoagulase is a purified mixture
of enzymes derived from the venom of the Brazilian
snake Bothrops atrox. It is free of neurotoxins and has
a thromboplastin-like effect by converting prothrombin
to thrombin and fibrinogen to fibrin. (24) Hence, it de-
creases bleeding time and enhances coagulation at sites of
bleeding. One Klobusitzky unit (KU) of the enzyme is
the amount needed to coagulate human plasma incu-
bated at 37°C in 60 – 20 seconds. In a prospective study
of 48 premature neonates with PH on mechanical venti-
lation, 28 neonates were treated with 0.5 KU of hemo-
coagulase administered endotracheally every 4 to 6 hours
until hemorrhage stopped. The other 20 patients were
treated with mechanical ventilation only. (25) A signif-
icant reduction in the duration of PH, the duration of
mechanical ventilation, and mortality was noted in the
hemocoagulase group. Another study by the same group
investigated the prophylactic use of hemocoagulase to
prevent PH in premature neonates. (26) In that study,
the use of 0.25 KU of hemocoagulase every 4 to 6
hours for 3 to 5 days was associated with a decrease
in the incidence and duration of PH but not mortality.
The results of both of these hemocoagulase trials
should not be generalized because of several flaws in
the study design. (24) Thus, hemocoagulase may be
used as a last resort in unresponsive cases, bearing in
mind that no large, well-designed, randomized con-
trolled trials have been conducted to test its efficacy
and safety profile.
Prognosis
Although some studies failed to show adverse outcomes
in infants who had PH, (13) post hoc analysis of the TIPP
study showed that risks of death or survival with neuro-
sensory impairment were doubled after serious PH. (10)
Sixty percent of premature infants who survive PH will
develop bronchopulmonary dysplasia. An increased inci-
dence of cerebral palsy and cognitive delay (odds ratio
2.86 and 2.4, respectively) have been reported. (10)
PH is also associated with an increased risk of seizures
and periventricular leukomalacia in survivors at 18 months
of age. (8)
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pulmonology neonatal pulmonary hemorrhage
ACKNOWLEDGEMENTS. Carlos Navarro-Pescador, MD,
and Teodorico Figurasin, MD, of the Department of Pa-
thology, Harlem Hospital, are acknowledged for the slides
on pulmonary hemorrhage.
American Board of Pediatrics Neonatal-Perinatal
Medicine Content Specifications
• Plan the ventilatory therapy for infants
with respiratory failure of different
etiologies.
• Know the indications for and techniques
of high-frequency ventilation.
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 Neonatal Pulmonary Hemorrhage
Riad Abou Zahr, Ahmad Ashfaq and Mary Marron-Corwin
NeoReviews 2012;13;e302
DOI: 10.1542/neo.13-5-e302

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 Neonatal Pulmonary Hemorrhage
Riad Abou Zahr, Ahmad Ashfaq and Mary Marron-Corwin
NeoReviews 2012;13;e302
DOI: 10.1542/neo.13-5-e302

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://neoreviews.aappublications.org/content/13/5/e302

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