Treatment of hypotension of prematurity: a non-blinded cohort clinical trial

Hypotension in the very preterm infant (gestational age [GA] <32wks) is a
frequently occurring clinical problem. Although no real consensus has been
reached on the definition of hypotension in the very preterm baby, in clinical
practice a mean blood pressure (BP) in mmHg lower than the GA age in weeks is
considered to be the starting point for anti-hypotensive therapy. However,
although an association between neonatal hypotension and mortality and
morbidity exists, there is no evidence of causation between hypotension and
neonatal mortality and morbidity (including neurodevelopmental outcome at 2 and
3 years of age). In addition, using mean BP alone as the indication of
treatment of neonatal cardiovascular compromise without taking into
consideration information on the status of tissue perfusion may lead to
unnecessary exposure of neonates to forceful vasoactive medications potentially
causing harm to these extremely vulnerable patients.

To compare neonatal mortality and short-term (advanced MRI indices of
structural brain injury at 40 weeks* GA) and long-term neurodevelopmental
outcomes (Bayley scales of infant development III [BSID-III] at 24 months)
between two groups of very preterm infants presenting with hypotension without
clinical and laboratory evidence of compromised tissue perfusion during the
first 72 postnatal hours (3 days). Hypotension will be defined as the mean BP
(in mm Hg) lower than the infant*s GA (in weeks). Patients randomized to *Group
A* will be treated according to the treatment protocol operative in the
Neonatal Intensive Care Unit (NICU) of the Wilhelmina Children*s
Hospital/University Medical Centre Utrecht (UMCU) while *Group B* will receive
no cardiovascular support for hypotension unless they have a mean BP lower than
the current limit minus 5 mmHg and/or evidence of compromised tissue perfusion
and end-organ function and thus meet established criteria
The hypothesis is that accepting lower blood pressure limits (5mmHg) is safe
for the preterm organs, especially the brain don't cause any short an/or long
term injury

A single-centre randomized non-blinded cohort study in the NICU at the UMCU of
preterm neonates <30 weeks* gestation during postnatal days 0 to 3.

Patients randomized to *Group A* will be treated for hypotension according to
the treatment protocol operative in the NICU at the UMCU. Patients randomized
to *Group B* will receive no cardiovascular supportive therapy irrespective of
their BP value unless their mean BP is >5 mmHg below GA in weeks for 30 minutes
and/or they have indirect clinical or direct laboratory evidence of tissue
hypoperfusion and/or end-organ dysfunction (i.e. rScO2 is <50% (55?)despite
optimized ventilatory support and FiO2 administration, plasma lactate >6
mmol/L; and/or urine output <0.6 mL/kg/hour).
As CO2 is the most potent regulator of cerebral blood flow (CBF), it is
understandable why changes in arterial CO2 tension (PaCO2) has been associated
with increased incidence of peri-intraventricular hemorrhage (PIVH) in preterm
neonates with significant hypercapnia and with white matter injury
(periventricular leukomalacia; PVL) in preterm neonates with hypocapnia during
the immediate postnatal period. Therefore, in the present study, ventilation
will be closely followed and PaCO2 values monitored and attempted to be kept
within normal limits (40-to-50 mmHg) during the first three postnatal days to
control for the potential impact of this confounding variable as far as the
primary and secondary outcome measures are concerned

Hypotension of prematurity is a frequently made diagnosis in neonatology and
once the diagnosis has been made, it triggers initiation of treatment with
volume boluse(s), and administration of vasopressor/intoropes or inotropes with
or without the addition of corticosteroids. As the gestational- and
postnatal-age dependent BP values causing increased morbidity and mortality are
not known in the preterm neonate during the first 3 postnatal days, and since
additional factors such as the underlying pathology likely affect the severity
of tissue hypoperfusion associated with a certain level of BP value, it is very
likely that both over- and under-treatment of neonates with the suspected
diagnosis of *hypotension of prematurity* occur in clinical practice. It*s
important to note that potential overtreatment carries the risk of (brain)
injury caused by the vasoactive medications, as there is only little knowledge
of the potential side effects of vasopressor/intoropes or inotropes in the very
preterm neonate during the transitional period. As for the corticosteroids used
in the management of these infants, dexamethasone administered during the first
postnatal days has been demonstrated to exert long-term negative effects on
brain development and thus neurodevelopmental outcome and on the adult
cardiovascular system, while the use of low-dose hydrocortisone in combination
with the frequently used drug indomethacin/ibuprofen, has been associated with
increased incidence of spontaneous intestinal perforation in these patients. On
the other hand, there is very little to no prospectively collected evidence
that withholding anti-hypotensive treatment in very preterm neonates based on
the BP value alone but without evidence of tissue hypoperfusion, if the patient
is properly monitored and the treatment is appropriately guided, would harm the
infant. Therefore, the present study is aimed at investigating whether, in very
preterm neonates presenting with hypotension defined by the current BP
standards but without evidence of tissue hypoperfusion, the use of vasoactive
medications during the first three postnatal days is harmful, helpful or has no
impact on clinically most relevant outcomes. In addition, the study also
provides information on the possibility of under-treatment of hypotension
defined by BP values alone in very preterm neonates during the first three
postnatal days.