Treatment of Hypotension of Prematurity (TOHOP)
Treatment of Hypotension of Prematurity (TOHOP)
Hypotension in the very preterm infant (gestational age [GA] <32 wks) is a frequently
 occurring clinical problem. Although no real consensus has been reached on the definition of
 hypotension in these infants, in clinical practice a mean blood pressure (mean 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/
 morbidity exists, there is no evidence of causality between hypotension (meanBP <GA in
 completed weeks) and neonatal mortality/morbidity. In addition, using mean BP alone as the
 indication of treatment of neonatal cardiovascular compromise without taking into
 consideration the status of tissue perfusion may lead to unnecessary exposure of neonates to
 vasoactive medication. This medication can be potentially harmful to these extremely
 vulnerable patients.

 The aim of this study is to compare neonatal mortality and short-term neurodevelopmental
 outcome (cerebral ultrasound during the first 7 days of life, advanced MRI indices of
 structural brain injury at term 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 3 days of life. 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 University Medical Centre Utrecht (UMCU) while "Group B" will receive no cardiovascular
 support for hypotension unless they have evidence of compromised tissue perfusion and
 end-organ function ((i.e. near infrared-monitored regional cerebral oxygen saturation (ScO2)
 <50% despite optimized ventilatory support and FiO2 administration, plasma lactate >6 mmol/L;
 and/or urine output <0.6 mL/kg/hour) or mean BP >5mmHg lower than the current guideline.

 The investigators hypothesize that there will be no differences between the two groups
 concerning short and long-term neurodevelopmental outcomes.
Rationale: 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.

 Objective: 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 policy 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 (see below).

 Study design: 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.

 Study population: All preterm infants with a GA of <30 weeks admitted on day of postnatal
 life 0 to the NICU at the UMCU. Patients will be managed according to their randomization to
 Group A or B until the end of postnatal day 3.

 Intervention 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% 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 (see below).

 Main study parameters/endpoints: To determine whether refraining (group B) from
 anti-hypotensive treatment has a negative, positive or no effect on the composite outcome of
 mortality and neurodevelopmental outcome (determined by BSID-III) at 24 months of age.
 Secondary outcome measures will include 1) differences between the groups in the incidence of
 PIVH during the first 7 postnatal days detected by head ultrasound, 2) differences in the
 incidence of white matter injury PVL and gray matter injury not detected within the first 7
 days by ultrasound using advanced MRI parameters of the brain at the adjusted postmenstrual
 age of 40 weeks as well as the ability to maintain CBF autoregulation during the first three
 postnatal days.
Inclusion Criteria:

 -  Idiopathic arterial hypotension as defined by a mean BP in mmHg less than the GA in
 weeks at birth.

 -  Written parental consent

 Exclusion Criteria:

 -  Prior inclusion indirect clinical or direct laboratory evidence of poor organ/tissue
 perfusion (plasma lactate >6 mmol/L on two consecutive measurements and/or urine
 production <0.6 mL/kg/h for a 6-hour period

 -  Clinically and/or microbiologically proven sepsis

 -  Major congenital abnormalities

 -  Postnatal age at the time of the development of systemic hypotension >72 hours

 -  No arterial line for continuously monitoring of blood pressure