Optimal Blood Pressure in Preterm Infants

Abstract

Many neonatologists routinely treat infants whose mean arterial blood pressure in mm Hg is less than their gestational age in weeks (GA) but there is uncertainty regarding diagnosis and treatment of hypotension. This addresses the definition of permissive hypotension based on the principles of cardiovascular physiology, and reviews the tools available at the bedside to examine the complex relationship among blood pressure, systemic organ blood flow, and tissue oxygen delivery and oxygen demand in preterm infants (skin color, capillary refill time, urine output, serum lactate level, and acidosis). Importantly, absolute blood pressure values are only one indicator of circulatory status and this review confirms that a mean blood pressure less than gestational age in weeks alone is not a predictor of poor outcome. Global assessment of cardiovascular status and intervention for hypotension restricted to infants with poor perfusion may be associated with good clinical outcomes and should be further evaluated.

Full text

Abstract
Many neonatologists routinely treat infants whose mean arterial blood pressure
in mm Hg is less than their gestational age in weeks (GA) but there is uncertainty
regarding diagnosis and treatment of hypotension. This addresses the definition
of permissive hypotension based on the principles of cardiovascular physiology,
and reviews the tools available at the bedside to examine the complex relationship
among blood pressure, systemic organ blood ow, and tissue oxygen delivery and
oxygen demand in preterm infants (skin color, capillary refill time, urine output,
serum lactate level, and acidosis). Importantly, absolute blood pressure values are
only one indicator of circulatory status and this review conrms that a mean blood
pressure less than gestational age in weeks alone is not a predictor of poor outcome.
Global assessment of cardiovascular status and intervention for hypotension restricted
to infants with poor perfusion may be associated with good clinical outcomes and
should be further evaluated.
Key Words: Hypotension, Preterm infant, Systemic blood ow, Echocardiography
INTRODUCTION
Hypotension is a commonly diagnosed and treated complication in preterm infants, but
enormous variation in diagnosis, management, and clinical practice has been documented
1)
.
In extremely low gestational age newborns, the majority of neonatologists (73%) defines
hypotension as a mean blood pressure in mmHg less than the gestational age in weeks
2)
. The
majority (85%) uses volume administration as the initial intervention and dopamine is the
inotrope most commonly used initially (80% of cases)
1,3)
. If the initial inotrope therapy fails,
dobutamine is the most popular second-line therapy (28% of cases)
4)
.
In preterm infants during the first days of life, there is a poor association between blood
pressure and systemic blood flow, with some data even showing an inverse correlation in
the rst hours after birth
5)
. Low superior vena cava (SVC) ow is a risk factor for mortality and
morbidity in preterm infants, but hypotension itself is not reliable in detecting low systemic
blood flow
6-8)
. Functional echocardiography allows assessment of cardiovascular status,
including measurement of systemic blood ow in preterm infants
9)
.
Received: 18 April 2014
Revised: 26 April 2014
Accepted: 28 April 2014
Correspondence to:
Hyun-Kyung Park, M.D., Ph.D.
Department of Pediatrics, Hanyang
University College of Medicine,
17 Haengdang-dong, Seongdong-
gu, Seoul 133-792, Korea
Tel: +82-2-2290-8397
Fax: +82-2-2297-2380
E-mail: neopark@hanyang.ac.kr
Review Article
Optimal Blood Pressure in Preterm Infants
Hyun-Kyung Park, M.D., Ph.D.
Department of Pediatrics, Hanyang University College of Medicine, Seoul, Korea
Neonatal Med 2014 May;21(2):99-105
http://dx.doi.org/10.5385/nm.2014.21.2.99
pISSN 2287-9412 . eISSN 2287-9803
Copyright(c)
By Korean Society of Neonatology.
All right reserved.
This is an Open-Access article distributed
under the terms of the Creative Commons
Attribution Non-Commercial License
(http://creativecommons.org/licenses/
by-nc/3.0), which permits unrestricted
non-commercial use, distribution, and
repro duction in any medium, provided the
original work is properly cited.

100
Hyun-Kyung Park
Hypotension in Preterm Infants
Without understanding the underlying cardiovascular prin-
ciples of transition, appropriate interventional trials cannot be
designed. erefore, more comprehensive monitoring and assess-
ment of systemic blood flow and tissue oxygenation must be
explored in preterm infants.
DEFINITION OF HYPOTENSION IN PERTERM
INFANTS
Hypotension is defined in clinical trials and in practice as any
value that falls below the fth or tenth percentile for gestational and
postnatal age, respectively
2)
. Although acceptable blood pressure
ranges are not known for the extremely low birth weight (ELBW)
infant, many neonatologists routinely treat infants whose mean
arterial blood pressure is less than their gestational age in weeks
10)
.
Hypotension occurs in approximately 50% of very low birth
weight infants admitted to the intensive care unit. Three levels
of compromised cerebral blood flow (CBF) may also be used to
dene hypotension (Figure 1)
2,11)
. Furthermore, the absolute blood
pressure values at which these thresholds occur are ill-defined
and likely to vary among individual patients and the underlying
pathological processes. us, the clinical denition of hypotension
and a selected group such as very preterm infants (not the phy
-
siological denition itself) should be considered (Figure 1)
2)
.
We do not know the mean arterial blood pressure value at
which cerebrovascular autoregulation is lost in the preterm infant,
although recent studies suggest that it may be as high as 28 to 30
mmHg even in ELBW infants
12)
. There is an association between
the loss of autoregulation, the resultant CBF fluctuations, and
morbidity and mortality in preterm infants
13)
.
In animal models, the ischemic blood pressure threshold is
reached when the corresponding CBF is approximately 50% of the
resting CBF
14)
. However, the “ischemic blood pressure threshold” is
unknown in preterm neonates and is likely to vary with the level of
maturity, intercurrent or pre-existing patho
physiological conditions
and physiological variables such as pH, PaCO
2
, and PaO
2
.
ASSESSMENT OF HEMODYNAMICS BY
ECHOCARDIOGRAPHY
The use of functional echocardiography in recent prospective
clinical trials has contributed to our better understanding of the
hemodynamic changes associated with postnatal transition
2,14)
.
Although there is no evidence that its use is associated with
better outcomes, it provides a more accurate assessment of the
pathophysiology of cardiovascular compromise and is likely
to become an essential part of the hemodynamic evaluation of
preterm infants (Table 1)
15)
.
The left ventricular (LV) ejection fraction (EF) and fractional
shortening (FS) are commonly used to estimate LV systolic
function, although EF and FS are largely influenced by preload,
afterload, and heart rate
15)
. Thus, these load-dependent indices
cannot be reliably used to evaluate cardiac function in the unstable
circulation of infants shortly after birth. Instead, an index known
as the “stress-velocity relationship” has been used clinically for ill
infants as a sensitive and relatively load-independent index. This
index is calculated from the end-systolic wall stress (ESWS), which
is an index of LV afterload, and the LV rate-corrected mean velocity
of circumferential fiber shortening (mVcfc), which is an index of
LV pump function. ESWS is calculated from blood pressure values
and LV dimensions by echocardiographic mea
surement, and
mVcfc is calculated from the LV FS, ejection time, and heart rate
(Table 1, Figure 2).
HYPOTENSION AND SYSTEMIC PERFUSION
Preterm infants with a mean arterial blood pressure lower
Figure 1.
Denition of hypotension by three pathophysiological
phenomena of increasing severity: the ‘autoregulatory, functional
and ischemic thresholds’ of hypotension. Cerebral cellular function
and structural integrity are not affected at the ‘autoregulatory
threshold’ and cerebral function becomes compromised at the
‘functional blood pressure threshold’ and finally, structural integrity is
compromised at the ‘ischemic blood pressure threshold’. Autore-
gulation is limited and ‘ischemic blood pressure threshold’, that
is likely to vary with the level of maturity, is unknown in preterm
infants. CBF, cerebral blood ow; MBP, mean blood pressure; CrCP,
critical closing pressure. From Cayabyab R, et al. J Perinatol 2009;
29:S58-62 [2].

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Neonatal Med 2014 May;21(2):99-105
http://dx.doi.org/10.5385/nm.2014.21.2.99
than their gestational age in weeks often have no clinical signs of
shock, presumably have adequate tissue oxygen delivery, and may
therefore not need treatment
16)
.
The principal role of the circulation is to ensure adequate de
-
livery of oxygen and nutrients to tissues so that their metabolic
demand and is achieved by maintaining appropriate perfusion
pressure and cardiac output (CO) in the systemic and pulmonary
circulations demand
9)
. In the systemic circulation, the interaction
between CO and systemic vascular resistance (SVR) regulates BP
according to the relationship: BP=CO×SVR (Figure 3). However,
in clinical practice, we rely primarily on the information obtained
from BP monitoring and, at present, cannot routinely assess the
changes in CO and/or SVR when hypotension and/or cardio
-
vascular compromise are diagnosed and treated
10)
.
As maintenance of cardiovascular wellbeing is complicated,
neonatologists try to assess continuous heart rate, BP, arterial oxy-
gen saturation monitoring, and continuous CO monitoring with
or without assessment of the SVR together (Figure 3)
9)
. Under the
circumstance of neonatal shock, its early “compensated phase”
shows that blood flow and oxygen delivery are maintained to the
vital organs (brain, heart, and adrenal glands)
17)
. The vessels of
vital organs vasodilate when perfusion pressure decreases (high-
priority), whereas the vessels of non-vital organs respond with
vasoconstriction to a decrease in BP (low-priority). Recently, near
infrared spectroscopy (NIRS) can monitor, in real-time, the vital
and non-vital organ mixed venous tissue oxygen saturation
18)
.
Laboratory indices of perfusion, such as serum lactate and
acidosis (base excess) during anaerobic metabolism, frequently
used in the diagnosis of poor tissue perfusion (Table 1). Especially,
lactate values have been analyzed in a number of clinical situa
-
tions in the preterm infant and elevated values on the first
day of postnatal life are associated with increased mortality
in preterm and term newborns
19)
. In contrast, Wardle et al
20)
Figure 2.
Stress-velocity relationship [mVcfc (an index of LV pump
function) - ESWS (an index of LV afterload) relationship]. The
changes in mVcfc were opposite to the changes in ESWS. ere
were signicant correlations between ESWS and mVcfc in both
groups (mVcfc = 3.76×ESWS
-0.4
;
P
<0.01, R=0.56). Group 1: infants
with complications (pulmonary hemorrhage, intraventricular
hemorrhage, and periventricular leukomalacia; n=9). Group 2:
infants without complications (n=24). Systolic blood pressure
(sBP) and mean blood pressure (mBP) changed over time, with
no differences between the groups. This indicates that the LV
pump function of preterm infants can easily be suppressed by
a subtle increase in afterload, causing reduced cardiac output.
mVcfc, mean velocity of circumferential ber shortening; ESWS,
end-systolic wall stress; LV, left ventricle. From Toyoshima K, et
al. J Formos Med Assoc. 2013;112:510-7 [15].
Table 1.
Assessment of Cardiovascular Function and Organ Perfusion in Preterm Infants at the Bedside. From Toyoshima K, et al. J Formos
Med Assoc 2013;112:510-7 [15].
Vital signs HR, BP, urine
Blood examination lactic acid, BNP (brain natriuretic peptide), BE (base excess)
Echocardiography Preload
LVIDd (left ventricle internal diameter in diastole)
LA volume; LA (left atrium) / Ao (aorta)
Afterload
ESWS (end-systolic wall stress)
Pump function
EF (ejection fraction)
FS (fractional shortening)
mVcfc (mean velocity of circumferential ber shortening)
PDA : shunt assessment
Cardiac output : SVC (superior vena cava) ow

102
Hyun-Kyung Park
Hypotension in Preterm Infants
found no difference in lactate levels between normotensive
and hypotensive preterm infants. Correlation between lactate
values with systemic blood flow was improved by combining
capillary filling time; lactate >4 mmol/L plus prolonged capillary
refill times >4 s showed high positive predictive value (80%) and
negative predictive value (88%) for identifying low SVC ow. is
highlights the importance of combining clinical and biochemical
parameters in the assess
ment of the adequacy of end-organ blood
ow
8,9)
.
PERMISSIVE HYPOTENSION IN ELBW INFANTS
Global assessment of cardiovascular status includes assessment
of other easily evaluable physical observations including capillary
refill, skin color, heart rate, urine output, level of activity, and
biochemical observations, in particular the degree of acidosis
10)
.
Although this assessment of the adequacy of end-organ perfu
sion
is crude and not infallible, and each nding taken in isolation may
be a poor indicator of perfusion, together they may provide more
information than absolute blood pressure values alone. There is
no evidence that attempts to achieve a “normal” blood pressure
based on absolute reference values will improve out
comes, and
the therapies available may be potentially toxic or dangerous.
Dempsey et al
10)
evaluated this approach in ELBW infants in the
first 72 h of life and patients were grouped as either nor
motensive
(BP never less than gestational age), hypotensive untreated (BP
less than gestational age but with signs of good perfusion; we
termed this “permissive hypotension”), or hy
potensive treated
(BP less than gestational age with signs of poor perfusion). Blood
pressure spontaneously improved in ELBW infants during the rst
24 h and the outcome of infants hypotensive by gestational age
criteria but with clinical evidence of good perfusion was as good as
that of normotensive patients.
Figure 3.
Interaction among and monitoring of blood pressure (BP), blood ow, blood ow
distribution and systemic vascular resistance (SVR). To satisfy cellular metabolic demand, the
intricate relationship among blood ow, vascular resistance, and BP takes place. Regulation
of organ blood ow distribution, capillary recruitment and oxygen extraction is also essential
for the maintenance of hemodynamic homeostasis. Among these three fundamental
factors determining basic cardiovascular function, cardiac output (CO) and SVR are the
independent variables that are regulated by the body and BP is the dependent variable
by the two independent variables. Abbreviations: CBF, cerebral blood flow; NIRS, near
infrared spectroscopy; OBF, organ blood ow; rSO2, regional tissue oxygen saturation. From
Soleymani S, et al. J Perinatol 2010;30:S38-45 [9].

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Neonatal Med 2014 May;21(2):99-105
http://dx.doi.org/10.5385/nm.2014.21.2.99
THERAPEUTIC APPROACHES TO HYPOTENSION
The stress-velocity relationship showed a steep slope in the low
ESWS range, as seen in Figure 2
15,21)
. e ESWS or afterload is lower
in younger age groups than in older age groups. Therefore, the
cardiac pumping function is easily impaired and mVcfc is easily
decreased by even a small increase in afterload or ESWS in smaller
or younger infants with low ESWS. All previous reports on the
stress-velocity relationship relate to preterm infants who were not
treated with circulatory agonists, and there have been no reports
on the changes in these parameters in preterm infants treated with
catecholamines.
Central venous pressure (CVP) monitoring is not practical in the
circulatory management of preterm infants. In CVP monitoring,
emphasis is placed largely on blood pressure. However, an
increase in cardiac preload or venous pressure due to excessive
afterload cannot be predicted by blood pressure or urine volume
alone
15)
. The aim of circulatory management in preterm infants
should be to avoid the increase in venous pressure caused by
excessive afterload.
Toyoshima et al
15)
investigated how circulatory agonists affect
excessive afterload and evaluated the changes in the stress-
velocity relationship prior to and after the use of dobutamine
and a vasodilator nitroglycerin in very low birth weight infants.
Dobutamine, at a dose of 4 mg
ᆞ
kg
-1
ᆞ
min
-1
, increased blood
pres sure in all infants. However, the stress-velocity relationship
showed that the cardiac pump function improved in only half
of the infants, whereas ESWS increased and cardiac pump
function deteriorated in the other half. Dobutamine did not
clearly improve low mVcfc, particularly when ESWS increased. By
contrast, a dose of 0.5-1.5 mg
ᆞ
kg
-1
ᆞ
min
-1
nitroglycerin, which
was used for elevated ESWS, reduced ESWS and increased mVcfc.
Dempsey et al
22)
recently established the HIP (Hypotension
in Preterm Infants) Consortium, comprising neonatologists,
scientists, pharmacologists and industry partners (Figure 4) to
provide assessment protocols for determining when we should
treat hypotension in the extremely preterm babies (< 28 weeks of
gestation) and in using the most commonly used dopamine.
Figure 4.
Treatment algorithm for the management of low BP in extremely preterm
infants during the rst 72 h of life; e HIP (hypotension in preterm infant) Trial. HIP
is designed to evaluate two strategies in a randomized controlled trial, and dene the
ecacy of the most commonly used inotropic medication, dopamine. From Dempsey EM,
et al. Neonatol 2014;105:275-81 [22].

104
Hyun-Kyung Park
Hypotension in Preterm Infants
CONCLUSION
In a neonatal intensive care setting, many extremely preterm
infants receive treatment for hypotension, but a blood pressure less
than the gestational age does not necessarily need to be treated.
Global assessment of cardiovascular status and intervention for
hypotension restricted to infants with poor perfusion (skin color,
capillary refill rate, urine output, blood lactate level, and acidosis)
may have good clinical outcomes
10,16,23)
. Prospective randomized
studies of clinical outcomes with standard versus restricted
treatment of hypotension are essential.
REFERENCES
1) Stranak Z, Semberova J, Barrington K, O'Donnell C, Marlow
N, Naulaers G, et al. International survey on diagnosis and
management of hypotension in extremely preterm babies.
Eur J Pediatr 2014 Jan 4. doi:10.1007/s00431-013-2251-9.
2) Cayabyab R, McLean CW, Seri I. Definition of hypotension
and assessment of hemodynamics in the preterm neonate. J
Perinatol 2009;29 Suppl 2:S58-62.
3) Batton B, Li L, Newman NS, Das A, Watterberg KL, Yoder BA,
et al. Use of antihypotensive therapies in extremely preterm
infants. Pediatrics 2013;131:e1865-73.
4) Osborn DA, Paradisis M, Evans N. The effect of inotropes on
morbidity and mortality in preterm infants with low systemic
or organ blood flow. Cochrane Database Syst Rev 2007:
CD005090. doi: 10.1002/14651858.CD005090.pub2.
5) Groves AM, Kuschel CA, Knight DB, Skinner JR. Relationship
between blood pressure and blood flow in newborn preterm
infants. Arch Dis Child Fetal Neonatal Ed 2008;93:F29-32.
6) Shah DM, Condò M, Bowen J, Kluckow M. Blood pressure or
blood flow: which is important in the preterm infant? a case
report of twins. J Paediatr Child Health 2012;48:E144-6.
7) Kluckow M, Evans N. Low superior vena cava flow and intra-
ventricular haemorrhage in preterm infants. Arch Dis Child
Fetal Neonatal Ed 2000;82:F188-94.
8) Miletin J, Dempsey EM. Low superior vena cava ow on day 1
and adverse outcome in the very low birthweight infant. Arch
Dis Child Fetal Neonatal Ed 2008;93:F368-71.
9) Soleymani S, Borzage M, Seri I. Hemodynamic monitoring in
neonates: advances and challenges. J Perinatol 2010;30 Suppl:
S38-45.
10) Dempsey EM, Al Hazzani F, Barrington KJ. Permissive hypo-
tension in the extremely low birthweight infant with signs of
good perfusion. Arch Dis Child Fetal Neonatal Ed 2009;94:
F241-4.
11) Azhan A, Wong FY. Challenges in understanding the impact of
blood pressure management on cerebral oxygenation in the
preterm brain. Front Physiol 2012;3:471. doi: 10.3389/fphys.
2012.00471.
12) Munro MJ, Walker AM, Barfield CP. Hypotensive extremely
low birth weight infants have reduced cerebral blood flow.
Pediatrics 2004;114:1591-6.
13) Tsuji M, Saul JP, du Plessis A, Eichenwald E, Sobh J, Crocker R,
et al. Cerebral intravascular oxygenation correlates with mean
arterial pressure in critically ill premature infants. Pediatrics
2000;106:625-32.
14) Greisen G. Autoregulation of cerebral blood flow in newborn
babies. Early Hum Dev 2005;81:423-8.
15) Toyoshima K, Kawataki M, Ohyama M, Shibasaki J, Yamaguchi
N, Hoshino R, et al. Tailor-made circulatory management based
on the stress-velocity relationship in preterm infants. J Formos
Med Assoc 2013;112:510-7.
16) Ahn SY, Kim ES, Kim JK, Shin JH, Sung SI, Jung JM, et al. Per-
missive hypotension in extremely low birth weight infants
(≤1000 gm). Yonsei Med J 2012;53:765-71.
17) Noori S, Stavroudis TA, Seri I. Systemic and cerebral hemody-
namics during the transitional period after premature birth.
Clin Perinatol 2009;36:723-36.
18) van Bel F, Lemmers P, Naulaers G. Monitoring neonatal regional
cerebral oxygen saturation in clinical practice: value and pitfalls.
Neonatology 2008;94:237-44.
19) Groenendaal F, Lindemans C, Uiterwaal CS, de Vries LS. Early
arterial lactate and prediction of outcome in preterm neonates
admitted to a neonatal intensive care unit. Biol Neonate 2003;
83:171-6.
20) Wardle SP, Yoxall CW, Weindling AM. Peripheral oxygenation
in hypotensive preterm babies. Pediatr Res 1999;45:343-9.
21) Takahashi Y, Harada K, Kishkurno S, Arai H, Ishida A, Takada
G. Postnatal left ventricular contractility in very low birth
weight infants. Pediatr Cardiol 1997;18:112-7.
22) Dempsey EM, Barrington KJ, Marlow N, O'Donnell CP, Miletin J,
Naulaers G, et al. Management of hypotension in preterm in-
fants (The HIP Trial): a randomised controlled trial of hypo-
tension management in extremely low gestational age new-
borns. Neonatology 2014;105:275-81.
23) Alderliesten T, Lemmers PM, van Haastert IC, de Vries LS, Bo-
nestroo HJ, Baerts W, et al. Hypotension in preterm neonates:
low blood pressure alone does not aect neurodevelopmental
outcome. J Pediatr 2014 Jan 28. doi: 10.1016/j.jpeds.2013.12.042.

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미숙아에서의 적정 혈압
한양대학교 의과대학 소아과학교실
박현경
대부분의 신생아 의사들은 미숙아에서의 저혈압을 치료함에 있어, 재태기간 수치와 비교하여 그보다 낮은 평균 동맥압
을 보이는 경우를 대상으로 하지만, 그 진단 및 치료에 있어서는 모호한 상황이다. 저자는 심혈관계 생리를 근거로 한
미숙아에서의 permissive hypotension의 개념을 살펴보고, 혈압과 더불어 기관으로의 혈류 및 조직으로의 산소 전달 간
의 복잡한 관계를 규명할 수 있는 검사 방법 및 조직의 산소 요구량을 임상적 측면에서 검토하고자 한다. 절대적 혈압
수치는 단지 순환계 상태를 나타내는 하나의 지표에 지나지 않으며, 재태기간보다 낮은 평균 혈압으로는 예후를 예측
하지 못함을 강조한다. 포괄적인 심혈관계 상태의 판단 및 조직 관류 상태에 근거한 적절한 저혈압 치료만이 좋은 임상
적 경과를 나타낼 것으로 사료되며, 향후 심도있는 연구가 요구된다.