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    On-ward observations

    in neonatal intensive care:Towards saer supplemental oxygen & IV therapy

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    PROEFSCHRIFT

    ter verkrijging van de graad van doctor

    aan de Technische Universiteit Delft,

    op gezag van de Rector Magnificus prof. ir. K.C.A.M. Luyben,

    voorzitter van het College voor Promoties,

    in het openbaar te verdedigen op maandag 24 september 2012 om 15.00 uur

    door

    Anne Catherine VAN DER EIJK

    Ingenieur in Biomedical Engineering

    geboren te Zwolle

    On-ward observations

    in neonatal intensive care:Towards saer supplemental oxygen & IV therapy

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    Dit proefschrift is goedgekeurd door de promotoren:

    Prof. dr. J. Dankelman

    Prof. dr. H.J. Simonsz

    Copromotor:

    Dr. B.J. Smit

    Samenstelling promotiecommissie:

    Rector Magnificus, Technische Universiteit Delft, voorzitter

    Prof. dr. J. Dankelman, Technische Universiteit Delft, promotor

    Prof. dr. H.J. Simonsz, Erasmus Medisch Centrum Rotterdam, promotorDr. B.J. Smit, Erasmus Medisch Centrum Rotterdam, copromotor

    Prof. dr. ir. C.A. Grimbergen, Technische Universiteit Delft

    Academisch Medisch Centrum Amsterdam

    Prof. dr. S. Bambang Oetomo, Technische Universiteit Eindhoven

    Maxima Medisch Centrum Veldhoven

    Prof. dr. F. van Bel, Universitair Medisch Centrum Utrecht

    Prof. dr. ir. R.M. Verdaasdonk, VU Medisch Centrum Amsterdam

    Prof. dr. ir. R.H.M. Goossens, Technische Universiteit Delft, reservelid

    The research presented in this thesis was partially supported by

    Philips Medical Systems, Boeblingen, Germany

    ODAS foundation, Delft, The Netherlands

    Lay-outLouise de Kruijf

    ISBN 978-94-6191-355-5

    Copyright , A.C. van der Eijk

    All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means,

    without the prior written permission of the author.

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    Wires

    You got wires, going in

    You got wires, coming out of your skin

    You got tears, making tracks

    I got tears, that are scared of the facts

    Running down corridors, through automatic doors

    Got to get to you, got to see this through

    I see hope is here, in a plastic box

    Ive seen christmas lights, reflect in your eyes

    You got wires, going in

    You got wires, coming out of your skin

    Theres dry blood, on your wrist

    Your dry blood on my fingertip

    Running down corridors, through automatic doorsGot to get to you, got to see this through

    First night of your life, curled up on your own

    Looking at you now, you would never know

    I see it in your eyes, I see it in your eyes

    Youll be alright

    Artist: Athlete

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    CHAPTER

    General introduction

    . Introduction

    . Preterm infants, definitions & prevalence

    . Prematurity, causes & outcome

    . Prematurity & oxidative stress related

    diseases

    .. Bronchopulmonary dysplasia.. Inant respiratory distress syndrome

    .. Patent ductus arteriosus

    .. Retinopathy o prematurity

    . Supplemental oxygen therapy

    .. A brie overview o history o supplemental

    oxygen therapy

    . IV therapy

    .. A brie overview o history o IV therapy

    . Problem statements

    .. Supplemental oxygen therapy

    .. IV therapy

    . Objectives

    .. Part I Supplemental oxygen therapy

    .. Part II IV therapy

    . Thesis outline

    . References

    PART I SUPPLEMENTAL OXYGEN THERAPY

    CHAPTER

    Oxygenation in preterm inants; background,

    target ranges & monitoring techniques

    . Introduction

    . Oxygen in the human body

    .. The oxygen dissociation curve

    . Monitoring of oxygenation

    .. Physical assessment o the skin

    .. Blood gas analysis

    .. Continuous intra-arterial blood gas

    monitoring

    .. Transcutaneous oxygen measurement

    .. Pulse oximetry

    .. Near inrared spectroscopy

    .. Capnography

    . Reference values for blood oxygen levels

    .. Reerence values or oxygen saturation

    .. Reerence values or partial pressure o

    oxygen

    .. Target ranges & outcome

    . Monitoring oxygenation in preterm infants:

    future perspectives

    . References

    TABLE OF CONTENTS

    CHAPTER

    New-generation pulse oximeters in extremely

    low birth weight inants: how do they perorm

    in clinical practice?

    . Introduction

    . Methods

    .. Patients

    .. Study set-up.. Experimental set-up

    .. Data analysis

    . Results

    .. SpO2 values

    . Discussion

    . References

    CHAPTER

    Manual adjustments o the inspired oxygen

    raction in extremely low birth weight inants

    . Introduction

    . Methods

    .. Patients

    .. Experimental set-up

    .. Data collection.. Target levels or SpO2

    .. FiO2 adjustments

    . Results

    .. Patients

    .. Manual FiO2 adjustments

    .. SpO2 levels

    . Discussion

    . References

    CHAPTER

    Pulse oximetry alarm limits in extremely low birth

    weight inants: when do deviations rom the

    protocol occur?

    . Introduction

    . Methods

    .. Working situation

    .. Policy or pulse oximetry alarm limits

    .. Data analysis

    . Results

    .. Occurrence o alarm limits

    .. FiO2 levels

    .. SpO2 levels

    .. Characteristics o the alarm limit

    adjustments

    . Discussion

    . References

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    CHAPTER

    Manual control o oxygenation in extremely low

    birth weight inants: what is the nurses point

    o view?

    . Introduction

    . Methods

    .. The questionnaire

    . Results

    .. Manual control o oxygenation

    .. Pulse oximetry

    .. Pulse oximetry alarm limits

    .. Suggestions or improvement

    . Discussion

    . References

    CHAPTER

    Defining hazards o supplemental oxygen therapy

    in neonatology using the Failure Mode and Effects

    Analysis (FMEA) tool

    . Introduction

    .. FMEA

    . Methods

    . Results

    .. Step 1. Defining the topic

    .. Step 2. Team assembly

    .. Step 3. Process analysis

    .. Step 4. Hazard analysis.. Step 5. Develop risk reduction methods

    . Discussion

    .. Lessons learnt by the FMEA-team

    . References

    PART II IV THERAPY

    CHAPTER

    Flow-rate variability in neonatal IV therapy: what

    do we know about the flow?

    . Introduction

    . Methods

    . Results

    .. Factor 1: Vertical syringe or patient

    displacement

    .. Factor 2: Syringes

    .. Factor 3: Inusion tubing

    .. Factor 4: Check valves & anti-siphon valves

    .. Factor 5: Inline filters

    .. Factor 6: Add-on devices

    .. Factor 7: Vascular access devices

    . Discussion

    . References

    CHAPTER

    Flow-rate variability in neonatal IV therapy

    caused by the use o check valves

    . Introduction

    . Methods

    .. Check valves

    .. Experimental set-up

    .. Study set-up

    . Results

    .. Experiment I: Adding syringes

    .. Experiment II: Changing height

    . Discussion. References

    CHAPTER

    General discussion

    . Main conclusions

    .. Supplemental oxygen therapy

    .. IV therapy

    . On the research approach

    .. Supplemental oxygen therapy

    .. IV therapy

    . The need for standardization

    . Future work

    .. Changes in culture

    .. Technical improvements

    . Conclusion. References

    APPENDICES

    SUMMARY

    SAMENVATTING

    DANKWOORD

    ABOUT THE AUTHOR

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    General introduction

    CHAPTER

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    CHAPTER

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    General introduction

    . INTRODUCTION

    Preterm infants are infants that are born before the expected date of birth. Due to their im-

    maturity, they often require intensive care to survive with a good health outcome. Intensive

    care is the division of medicine that is concerned with the continuous monitoring and sup-

    port of vital functions of critically ill patients. To be able to meet the specific needs of preterm

    infants, dedicated neonatal intensive care units (NICUs) have been established worldwide. In

    these NICUs virtually all preterm infants receive supplemental oxygen therapy and intrave-

    nous (IV) therapy. Both therapies, essential but potentially dangerous, will be studied in this

    thesis.

    Supplemental oxygen therapy reers to the therapy where a gas mixture with >21% o oxy-

    gen is supplied to the patient via (mechanical) ventilation. Due to the immaturity o the pre-

    term inants lungs, supplemental oxygen therapy is oten needed immediately ater birth to

    reach and maintain adequate oxygenation o the preterm inant. Unortunately supplemen-

    tal oxygen therapy is not without risk. Both too high and too low blood oxygen levels may

    have severe consequences or the development o the preterm inant.

    The immaturity o organs and/or severe illness are also reasons why IV therapy is essential

    or preterm inants hospitalised on a NICU. In IV therapy various types o nutrition, drugs,

    and/or fluids are administered directly into the veins o the patient via a vascular access

    device. Because o the limited vascular access possibilities, multi-inusion is used. In multi-

    inusion therapy, several inusions are supplied to the inant via a single catheter. To ad-

    minister the IV fluids with a pre-programmed flow-rate into the patient, syringe pumps are

    requently used. Although it is expected that the IV substances are supplied to the patient

    with the pre-programmed flow-rate, it has been shown that the actual volume delivered

    to the patient can vary over time. Especially in preterm inants, these changes in delivered

    volume can have severe consequences.

    In the next paragraphs the background o prematurity, supplemental oxygen therapy, and

    IV therapy are discussed in more detail. In the final paragraphs o this chapter (1.7 to 1.9)

    the problem statements, objectives, and thesis outline are presented.

    To be able to meet the specific needs of preterm

    infants, dedicated neonatal intensive care units

    have been established worldwide.

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    CHAPTER

    .PRETERM INFANTS, DEFINITIONS & PREVALENCE

    A term, healthy newborn inant is born ater a pregnancy duration o 37 to 42 weeks with

    a birth weight (BW) o approximately 3.5 kg. The pregnancy duration, or gestational age

    (GA), is calculated rom the first day o the last menstruation o the mother. When an in-

    ant is born with a GA 37 weeks it is classified as preterm, very preterm (

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    General introduction

    .PREMATURITY, CAUSES & OUTCOME

    Preterm inants are either born spontaneously (40 to 45%), by induced labour or by

    caesarean section. The latter two are perormed because o preterm premature rupture o

    membranes (25 to 30%) or because o maternal or oetal indications (30 to 35%).7The cause

    or prematurity is multiactorial and includes maternal characteristics like race, age, weight,

    health in general, and pregnancy history. The educational status, socio-economic status,

    and marital status o the mother are also known to influence the pregnancy duration. 8-14

    Women who are exposed to drugs, heavy alcohol use, or tobacco use during pregnancy are

    known to be more likely to have babies with a low birth weight.15-17

    Characteristics o thepregnancy, like assisted reproductive technologies and multiple gestation, are also risk ac-

    tors or preterm labour: about 50 to 60% o all multiple gestation pregnancies end in pre-

    term birth. While only 2 to 3% o the inants is part o a multiple gestation, they account or

    15 to 20% o all preterm births.7, 18

    Although the chances o survival or preterm inants have increased enormously in the last

    decades, there is still a large part o the surviving inants that suffer rom disorders or dis-

    abilities. The disabilities cover, amongst others, cerebral palsy, developmental delay, visual

    or hearing impairment, speech and language difficulties, and chronic lung disease. 19, 20

    The risk o adverse outcome is strongly related to the pregnancy duration and birth weight.

    Hille et al.21showed that in the Netherlands 36% o the ELBW inants had moderate to se-

    vere problems in overall outcome at the age o 19 years. However, it is difficult to interpret

    these numbers because the medical care provided to newborn inants develops continuous-

    ly, and long term outcome data are always behind on the current status o neonatal care.

    .PREMATURITY & OXIDATIVE STRESS RELATED DISEASES

    Being born is, from a physiological point of view, a very dramatic event. The intrauterine

    environment (i.e. in the womb) is warm, sterile, and dark. Oxygen and nutrition are supplied

    from the mother to the foetus via the umbilical cord. One of the major changes between

    the intrauterine environment and the extrauterine environment (i.e. outside world) is the

    difference in oxygen tension, the partial pressure of oxygen (PO2). The intrauterine PO2 is

    about 3 kPa (20 to 25 mmHg), this is comparable with the atmosphere at the top of the MountEverest. Thus, foetal development takes place in a relative hypoxic environment compared to

    the atmosphere at sea level where the PO2 is about 21 kPa (155 to 160 mmHg).22-24

    The sudden change in oxygen tension ater birth results in a sharp increase in reactive oxy-

    gen species (ROS). ROS are chemically reactive molecules that contain oxygen. At low levels,

    ROS contribute to homeostasis and cell signalling processes. At higher levels, ROS can lead

    to oxidative stress in the cell. Oxidative stress is defined as the imbalance between oxidants

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    CHAPTER

    and antioxidants. Although oxidants and antioxidants both are necessary or maintaining

    lie, an imbalance in avour o the oxidants may result in cell damage or even cell death. The

    imbalance can occur due to an increase in oxidant production and/or an inadequate anti-

    oxidant production. To prevent oxidative stress ater birth, several processes take place in

    the oetus in the final weeks beore term birth. These processes comprise, amongst others,

    an increase in both antioxidants and lung suractant. Suractant is a fluid that lowers the

    surace tension o the lungs, making it easier to inflate them. 23, 25

    Preterm inants lack the preparation or the sudden increase in oxygen tension because

    they are born too early. Consequently, their deence system or antioxidants is immature,and thereore, they are at increased risk or oxidative stress ater birth. The risk or oxida-

    tive stress increases even more when preterm inants receive supplemental oxygen therapy

    and/or develop inections.26-28

    In 1988 Saugstad was the first to mention the term oxygen radical disease o the newborn.29

    He stated that several diseases in preterm inants have a common pathogenesis via oxi-

    dative stress. Since then, it became clear that diseases typical or neonatal intensive care like

    bronchopulmonary dysplasia, inant respiratory distress syndrome, necrotizing enterocoli-

    tis, retinopathy o prematurity, patent ductus arteriosus and periventricular leukomalacia

    are associated with oxidative stress. However, it is not always clear whether the presence o

    oxidative stress is a cause or a result o the disease process.26, 29-31To show examples o the

    possible consequences o suboptimal or incorrect use o supplemental oxygen therapy, our

    o the disorders mentioned above are discussed in more detail in the next paragraphs.

    ..BRONCHOPULMONARY DYSPLASIA

    Bronchopulmonary dysplasia (BPD) is a disorder characterised by respiratory distress and

    airway inflammation.32The disorder was first described in 1967 by Northway et al.,33 and

    diagnosed when there was a need or supplemental oxygen therapy at a postnatal age o

    28 days. Because since then the GA o surviving preterm inants decreased, the definition

    is not valid anymore. Thereore, the term new-BPD was introduced. New-BPD is diag-

    nosed when there is need or supplemental oxygen therapy or ventilatory support at a post-

    menstrual age o 36 weeks, regardless o the GA or postnatal age.

    Studies on the prevalence o BPD ound the disorder in 22% o all inants with a birth weight

    between 501 and 1500 grams.34, 35The exact pathogenesis o BPD is unclear, but it seems to bemultiactorial. Risk actors are, amongst others, low birth weight, mechanical ventilation,

    and supplemental oxygen therapy. To treat the symptoms o BPD several types o medi-

    cation, like corticosteroids, are available. In some cases special mechanical ventilation is

    needed to prevent urther lung damage.36-39

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    General introduction

    ..INFANT RESPIRATORY DISTRESS SYNDROME

    In order to breathe normally, the alveoli in the lungs need to be inflated. To inflate the

    alveoli, suractant is required. Due to the short pregnancy duration, in very preterm in-

    ants, there is oten a suractant deficiency. As a result o this lack o suractant, the alveoli

    collapse and the total lung capacity decreases. This phenomenon is reerred to as (Inant)

    respiratory distress syndrome ((I)RDS). Symptoms include laboured and ast breathing,

    cyanosis, grunting, and nasal flaring.

    To diagnose IRDS, radiography is used: a low lung volume is one o the signs or IRDS.

    Due to the decreased lung capacity, mechanical ventilation and supplemental oxygentherapy are required. The incidence o IRDS is inversely related to the pregnancy duration.

    Thanks to the use o both antenatal steroids to promote lung maturation and the use o

    suractant therapy ater birth, the incidence o IRDS in preterm inants has been reduced

    enormously.36, 40

    ..PATENT DUCTUS ARTERIOSUS

    The blood circulation o a oetus includes a connection between the main pulmonary

    artery and the aorta. This connection, the ductus arteriosus, allows the blood to bypass

    the not yet ventilated lungs. Ater birth, several physiological changes cause the closure o

    the ductus arteriosus to make sure that oxygen-poor blood starts to enter the lungs. When

    the ductus arteriosus does not close (completely) within 24 to 72 hours ater birth, a patent

    ductus arteriosus (PDA) is diagnosed.41

    About 65% o the inants born with a GA

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    CHAPTER

    .SUPPLEMENTAL OXYGEN THERAPY

    Ater the outline about the diseases that are caused or ollowed by suboptimal oxygenation

    it is obvious why maintaining adequate oxygenation in preterm inants is a major issue. In

    healthy adults and children adequate oxygenation is maintained by a network o complex

    processes with multiple parameters influencing each other. To reach and maintain adequate

    oxygenation in preterm inants, it would be desirable or neonatologists to be able to moni-

    tor and control these parameters (continuously). Although current mechanical ventilators

    and monitoring techniques are sophisticated, it is still difficult to monitor and control therelevant parameters in preterm inants.

    One o the parameters that can be monitored is the arterial oxygen saturation (SaO2). In

    preterm inants the SaO2 is determined intermittently by blood gas analysis, and conti-

    nuously with a non-invasive sensor, the pulse oximeter. The SaO2 determined by pulse

    oximetry is reerred to as SpO2. When the SpO2 level is outside the desired range an alarm

    sounds. To recover the SpO2 level NICU staff can, amongst others, adjust the raction o

    inspired oxygen (FiO2) in the gas mixture supplied to the inant. The FiO2 can be adjusted

    rom 21% (room air) to 100% (pure oxygen).

    Currently, in neonatal intensive care the FiO2 level is adjusted manually, mainly by the

    nursing staff. A simplified block scheme o this process is shown in Figure 1.2. Although

    supplemental oxygen therapy increased chances o survival ater preterm birth, it has been

    known or about 60 years that supplemental oxygen therapy in preterm inants is not with-

    out risks.75-77

    FIGURE .The process o controlling oxygenation. The input o the system is the target level o oxygen

    saturation (SaO2) at the let side o the figure. The desired SaO2 level is compared with the SaO2 level

    measured by a sensor (e.g., by a pulse oximeter). When the difference between the desired SaO2 level

    and the measured SaO2 level is too large, an alarm sounds. The human controller can decide to take

    action, or instance adjusting the raction o inspired oxygen (FiO2). The FiO2 is supplied to the patient

    by a ventilator used or respiration. In the blood o the patient, the SaO2 level changes due to the change

    in FiO2. The sensor measures a new SaO2 level which is again compared with the desired SaO2 level.

    -

    Targetlevel

    SaO2

    SaO2level in

    blood

    Human

    controller Patient

    Sensor

    Alarm

    +

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    ..A BRIEF OVERVIEW OF HISTORY OF SUPPLEMENTAL OXYGEN THERAPY

    Soon ater the discovery o oxygen in 1774, this lie-giving gas was used or medical pur-

    poses. In 1780 the Frenchman Chaussier was the first who used oxygen or newborn inants

    with respiratory problems. From then it took one and a hal century beore oxygen was

    widely and liberally used or respiratory support in newborn inants in the 1940s.76-78The

    negative effects o the use o oxygen became clear several years later. In 1951, Dr. Camp-

    bell was the first who assumed there was a relation between supplemental oxygen therapy

    and retrolental fibroplasia, the blindness disorder now better known as ROP (see 1.4.4).79

    Several other studies confirmed her hypothesis.80, 81

    In 1954 a large trial was perormed to investigate the risks o supplemental oxygen therapy.

    The conclusion o this trial was that it was sae to give oxygen to newborn inants as long

    as the FiO2 was below 40%.82, 83Although some serious methodological errors were made

    in this trial, the results were widely accepted. It was so strongly believed that FiO2 >40%

    was harmul that, when an inant developed ROP, the hospital was accused or malpractice.

    Ater all, the ROP was the proo that FiO2 had exceeded the 40%.75, 84

    In the years after the large trial the incidence of ROP reduced dramatically. However, the

    incidence of cerebral palsy and mortality increased.85, 86As a result of this change in preva-

    lence of both mortality and morbidity and the fact that it became possible to monitor blood

    oxygen levels, clinicians recognised more and more that they should not restrict the supply

    of FiO2, but that they should restrict the actual blood oxygen levels of the preterm infant

    itself. This understanding led to a more accurate control of blood oxygen levels and a more

    tailored approach to the use of supplemental oxygen therapy in the NICU.87-89

    .IV THERAPY

    In IV therapy, various types o parenteral nutrition, drugs, and/or fluids are administered

    directly into the veins o the patient. To deliver these IV substances with a pre-programmed

    flow-rate to the patient, a mechanical pump pushes the plunger o a syringe with a pre-

    programmed velocity into the syringe. The IV substance in the syringe flows into the

    patient via flexible tubing and a vascular access device.

    Oten, because intravenous access in preterm inants is limited and several IV substancesneed to be administered simultaneously, multi-inusion is used. In multi-inusion, several

    syringe pumps are connected via tubing to a single vascular access device. These connec-

    tions are conducted with add-on devices. A schematic overview o a multi-inusion set up

    is shown in Figure 1.3. Although multi-inusion creates the possibility to provide various

    substances simultaneously, the accuracy and the predictability o the volumes delivered to

    the patient is limited.

    General introduction

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    CHAPTER

    FIGURE .Schematic overview o multi inusion intravenous (IV) therapy. Two or more syringe pumps

    are connected to one vascular access device via inusion tubing and an add-on device (e.g., a stopcock

    with 3-way valves).

    ..A BRIEF OVERVIEW OF HISTORY OF IV THERAPY

    The first attempts o IV therapy were already made in the Middle Ages. In 1492 the ill Pope

    Innocent VIII was transused with blood rom three boys via vein-to-vein anastomosis. Re-

    grettably the pope and donors died. From then until the second hal o the 17 thcentury the

    knowledge o blood, the blood circulation, and IV therapy increased enormously. This in-

    crease in knowledge was realised by perorming numerous experiments with blood transu-

    sions in and between animals and humans. However, because these experiments requently

    resulted in the death o the subjects, several governments and churches decreed the peror-

    mance o blood transusions as a criminal act.90, 91

    In the 1800s, the work o Dr. William Brooke OShaughnessy and his student Thomas Latta

    ormed the basis or modern IV therapy. During the cholera epidemic in England in the

    1830s, OShaughnessy realised that the typical thick black blood o the cholera victims was

    a result o a shortage o water, saline, and alkali. Thereore, he indicated that the patients

    needed injections o water and salts in the bloodstream. In 1832, Thomas Latta applied the

    recommendations, and saved 8 o the 25 victims he treated with intravenous saline using a

    small silver tube attached to a syringe.90, 92

    Infusion tubing

    Vascularacces device

    To patient

    Syringe pumps withsyringes

    Stopcock with

    3-way valves

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    General introduction

    Ater the results o OShaughnessy and Latta, it lasted until the two World Wars beore

    urther innovations in IV therapy were made. In 1933 IV solutions came on the market in a

    vacuum bottle, which eliminated microbial growth and pyrogens. In 1940, the Massachu-

    setts General Hospital started the first IV team. This idea o organizing special IV teams

    became very popular during the 1970s. Since then great advances in IV therapy were made.

    These advances were, amongst others, the result o the development o plastic IV materials.

    Today, virtually all hospitalised patients receive IV therapy.90, 91

    In newborn inants IV therapy is more complicated than in adults due to, amongst others,

    the small size o the vessels. Fortunately, together with the progress in the development omaterials or IV therapy in adults, the manuacturing o dedicated materials or (preterm)

    newborn inants advanced as well. For example, today it is possible to buy vascular access

    devices with an outer diameter o only 0.35 mm to serve the needs or ELBW inants. How-

    ever, despite the presence o dedicated materials or the smallest patients, the accuracy o

    the actual delivered IV substances still needs to be improved. 93-101

    .PROBLEM STATEMENTS

    Both supplemental oxygen therapy and IV therapy are necessary, but potentially dangerous

    therapies. In the next paragraphs, the problem statements or both therapies are discussed

    separately.

    ..SUPPLEMENTAL OXYGEN THERAPY

    In supplemental oxygen therapy the FiO2 can be adjusted rom 21% (room air) to 100%

    (pure oxygen) manually. Manual control o the oxygenation as described in Figure 1.2 is

    time consuming and very difficult to do accurately, mainly because o the requent and un-

    predictable fluctuations o the SpO2.102-107When SpO2 is outside the desired range an alarm

    sounds. The high rate o alarms may lead to anxiety o patients and their amily, and to a

    reduced or delayed reaction o the nursing staff.108Although supplemental oxygen therapy

    has been widely used in newborn inants or more than 60 years, there is still no consensus

    about the target ranges or blood oxygen levels, and the best methods to give (preterm)

    newborn inants this treatment.75-77

    To increase the quality o supplemental oxygen therapy and to reduce workload o thenursing staff, several groups worldwide have developed devices or (semi-)automatic control

    o the oxygenation. Most o the devices or (semi-)automatic control o oxygenation adjust

    the FiO2 supplied to the patient (semi-)automatically when SpO2 deviates rom the target.

    The first devices that were developed were dedicated servo systems.109-112With the develop-

    ment o computer aided control the devices became more advanced: Proportional-Integral-

    Derivative control with or without adaptive models,52, 56, 103, 113-117dual control methods,118-120

    state machine106, 121and uzzy logic control122have all been developed and tested.

    To test the devices some groups used patient simulators, 52, 114, 119or animals,111, 117but most of

    the groups tested their controller on patients.106, 109, 110, 112, 115, 116, 118, 122-125 The first studies did not

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    First author

    Time SpO2 is within target range

    Manual control [%] Dedicated control [%](semi-)

    Automatic control [%]

    Beddis109, Collins110 -

    Dugdale112 -

    Taube113

    Bhutani115

    Morozoff121 -

    Morozoff116 -

    Sun122, 128 -

    Claure105, 118

    Urschitz106Open loop

    Urschitz106Closed loop

    Morozoff123State machine 57

    Morozoff123Adaptive model

    Morozoff123Closed loop, PID

    Claure124

    Claure125

    CHAPTER

    use an objective way to test the effectiveness of their automatic controller. This resulted in

    no or weak conclusions.56, 111, 113, 116, 119, 121, 126-128Some more recent papers included tests that actu-

    ally show significant improvement. Amongst the tests was the time spent within the target

    range for SpO2 for manual, dedicated, and (semi-)automatic control (Table 1.1). Comparing

    the devices with each other is hampered by the fact that the nurse:patient ratio, the subject

    characteristics, the study period, and the study methods varied between studies. However,

    although the results of the developed devices are promising, differences between manual and

    (semi-)automatic control are major, and effects on long term outcome are still unknown. 129

    TABLE .Time spent within the target range or SpO2 or periods on manual, dedicated manual, and

    (semi-)automatic control.

    The term manual control is used to reer to the situation in normal daily NICU care. Dedicated con-

    trol is a situation where a physician or nurse stays at the bedside o the patient and is ocussing on

    the control o the SpO2 only. In (semi-)automatic control a device controls SpO2 automatically, and/or

    advises the NICU staff to make an adjustment in FiO2. Amongst others, the study methods and patient

    characteristics differed, thus results between studies are difficult to compare.

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    To improve outcome or those situations where oxygenation is controlled manually, two

    studies ocused on the development o protocols to standardise when, why, and how FiO2

    should be adjusted.130, 131One o these studies actually showed a reduction in the incidence

    o ROP.131However, both studies mention difficulties with implementation o the protocol

    and compliance to it. Because none o the studies actually quantified the perormed manual

    FiO2 adjustments, knowledge about the actual behaviour o NICU personnel with respect

    to control o the oxygenation is still lacking.

    ..IV THERAPY

    IV therapy is hampered by a number o complications and limitations. The most well-known are related to inections, and extravasation. While these complications are very

    relevant, they are outside the scope o this thesis. The ocus in this thesis is on a, probably

    underestimated, limitation in IV therapy: flow-rate variability. This flow-rate variability

    is caused by multiple actors and complicates the accuracy and predictability o the actual

    volumes delivered to the patient. Moreover, the flow-rate variability can lead to, or instance,

    changes in the haemodynamics and oxygenation o newborn inants.93, 97, 99, 132, 133 Thereore, it

    is important to minimise flow-rate variability in IV therapy in clinical practice.

    Two o the actors that affect the flow-rate variability are backflow and siphonage. In si-

    phonage, there is uncontrolled emptying or ree flow o substances rom a syringe into

    the patient. Siphonage can occur when the syringe is not clamped or is poorly clamped in

    the syringe pump or when there are air leaks in the IV-administration set.101, 134-136Backflow

    can occur when multiple inusions are interconnected to each other (e.g., via a stopcock).

    Because o differences in resistance in the IV-administration set, it is possible that fluids do

    not flow rom the syringe into the patient but into another line instead. 137

    To prevent backflow and/or siphonage there are various types of check valves available that

    can be inserted in the IV-administration set. Paradoxically, while check valves are imple-

    mented in IV-administration sets to minimise backflow and/or siphonage, it has been shown

    that the presence of these valves can enhance flow-rate variability as well.101, 138Thus, to be able

    to increase the accuracy and predictability of the volume delivered to the patient, the factors

    influencing the flow-rate variability should be known and, where possible, controlled.

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    CHAPTER

    . OBJECTIVES

    The primary objective o this thesis is to determine the limitations o supplemental oxygen

    therapy and IV therapy in current neonatal intensive care and to identiy areas or improve-

    ment. To distinguish between supplemental oxygen therapy and IV therapy, the thesis is

    divided in two parts. The secondary objectives are listed in the next two paragraphs.

    ..PART I SUPPLEMENTAL OXYGEN THERAPY

    In Part I o the thesis, the work related to supplemental oxygen therapy in preterm inants

    is discussed. The secondary objectives are:I.I To obtain background inormation regarding oxygenation o the human body, to get

    an overview o literature on target ranges or blood oxygen levels in newborn inants,

    and to evaluate methods or monitoring oxygenation in neonatology.

    I.II To evaluate the perormance o new-generation pulse oximeters o three different

    brands in ELBW inants.

    I.III To quantiy manual adjustments in the FiO2 perormed by NICU personnel in ELBW

    inants, in relation to SpO2 and bedside care.

    I.IV To study the compliance to the protocol or pulse oximetry alarm limits in ELBW

    inants in relation to FiO2, SpO2, and bedside care.

    I.V To explore the decision making processes and obtain insight in the knowledge,

    opinions, and attitude o the nursing staff towards supplemental oxygen therapy

    in ELBW inants.

    I.VI To prospectively evaluate hazards in the process o supplemental oxygen therapy

    in very preterm inants hospitalised in a NICU.

    .. PART II INTRAVENOUS THERAPY

    In Part II o the thesis the work related to IV therapy in newborn inants is discussed. The

    secondary objectives are:

    II.I To study which actors are responsible or flow-rate variability in IV therapy with

    syringe pumps.

    II.II To evaluate the effect o three different types o check valves on flow characteristics

    in a low-flow multi-inusion set.

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    . THESIS OUTLINE

    To meet the objectives, five studies were perormed. These studies orm, together with the

    literature reviews on the discussed subjects, the basis o this thesis.

    The first part o this thesis is about supplemental oxygen therapy in preterm inants. Chap-

    ter 2is the first chapter o Part I and provides a literature review to meet objective I.I. First

    the background inormation regarding oxygenation o the human body and especially that

    o preterm inants is described. Next, the working principles and (dis)advantages o current

    developed methods or monitoring oxygenation are elaborated on. Thereater, an over-view o literature on target ranges or blood oxygen levels in (preterm) newborn inants

    is provided. Finally, a uture perspective o the needs or oxygen monitoring in (preterm)

    newborn inants is discussed. Chapter 3 describes a study to the perormance o new-

    generation pulse oximeters in ELBW inants to meet objective I.II. In this study three di-

    erent brands o pulse oximeters were compared by dual SpO2 monitoring in nine ELBW

    inants. In Chapter 4and Chapter 5an observational study is discussed. During this obser-

    vational study on-ward video and data recording was perormed to obtain insights in the

    manual control o oxygenation in ELBW inants by healthcare proessionals. This obser-

    vational study was set up to meet both objectives I.III and I.IV. Chapter 6provides the re-

    sults o a survey amongst 24 NICU nurses. The questionnaire in this study was developed

    to meet objective I.V. The questions assessed the knowledge, opinions, and attitude o the

    nursing staff towards supplemental oxygen therapy in ELBW inants. The final chapter

    o Part I is Chapter 7. In this chapter the hazards in the process o supplemental oxygen

    therapy in preterm inants are evaluated prospectively to meet objective I.VI. The hazards

    were analysed by a multidisciplinary team using the Failure Mode and Effects Analysis

    (FMEA)-tool.

    Part II o the thesis is about IV therapy in newborn inants and starts with Chapter 8where

    a literature review is discussed to meet objective II.I. Chapter 9describes an in-vitro study

    to the effect o three different types o check valves on the flow characteristics o a low-flow

    multi-inusion set. This study was set up to meet objective II.II.

    Chapter 10provides the general discussion about both supplemental oxygen therapy and

    IV therapy. The main conclusions and the research approach o the work perormed in this

    thesis are presented together with recommendations or uture work.

    It should be noted that Chapters 3 to 9 are written as separate papers, consequently, there

    is a certain amount o overlapping inormation within these chapters. Furthermore, in this

    thesis the masculine orm is used or all healthcare proessionals and patients, merely to

    simpliy the text. No discrimination is intended.

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    CHAPTER

    14. Thompson J, Irgens LM, Rasmussen S, Daltveit AK.

    Secular trends in socio economic status and the im-

    plications or preterm birth. Paediatric and Perinatal

    Epidemiology. 2006;20(3):182-187.

    15. Andres RL, Day MC. Perinatal complications

    associated with maternal tobacco use. Seminars

    in Neonatology. 2000;5(3):231-241.

    16. Cnattingius S. The epidemiology o smoking during

    pregnancy: smoking prevalence, maternal character-

    istics, and pregnancy outcomes. Nicotine & TobaccoResearch. 2004;6(Suppl 2):S125-140.

    17. Mullally A, Cleary BJ, Barry J, Fahey TP, Murphy DJ.

    Prevalence, predictors and perinatal outcomes o

    peri-conceptional alcohol exposure - retrospective

    cohort study in an urban obstetric population in

    Ireland. BMC Pregnancy and Childbirth. 2011;11(1):27.

    18. Jackson RA, Gibson KA, Wu YW, Croughan MS.

    Perinatal outcomes in singletons ollowing in vitro

    ertilization: A meta-analysis. Obstetrics &

    Gynecology. 2004;103(3):551-563.

    19. Malloy MH, Hoffman HJ. Prematurity, sudden

    inant death syndrome, and age o death. Pediatrics.

    1995;96(3):464-471.

    20. Robertson CMT, Howarth TM, Bork DLR, Dinu IA.

    Permanent bilateral sensory and neural hearing loss

    o children ater neonatal intensive care because o

    extreme prematurity: A thirty-year study. Pediatrics.

    2009;123(5):e797-e807.

    21. Hille E, Weisglas-Kuperus N, Van Goudoever JB,

    Jacobusse GW, Ens-Dokkum MH, de Groot L, et

    al. Functional outcomes and participation in young

    adulthood or very preterm and very low birth weight

    inants: The Dutch project on preterm and small or

    gestational age inants at 19 years o age. Pediatrics.

    2007;120(3):e587-595.

    22. Frank L. Developmental aspects o experimental

    pulmonary oxygen toxicity. Free Radical Biology and

    Medicine. 1991;11(5):463-494.

    23. Maltepe E, Saugstad OD. Oxygen in health and

    disease: regulation o oxygen homeostasis-clinical

    implications. Pediatric Research. 2009;65(3):261-268.

    24. Vento M. Titrating oxygen needs in the very preterm

    newborn in the delivery room. Journal o Neonatal-

    Perinatal Medicine. 2010;3(3):161-169.

    25. Friel JK, Friesen RW, Harding SV, Roberts LJ. Evidence

    o oxidative stress in ull-term healthy inants.

    Pediatric Research. 2004;56(6):878-882.

    .REFERENCES

    1. Schaffer AJ, Avery ME. Disease o the newborn.

    Philadelphia: WB Saunders Co; 1960.

    2. Philip AGS. The evolution o neonatology.

    Pediatric Research. 2005;58(4):799-815.

    3. Saigal S, Doyle LW. Preterm birth 3: An overview o

    mortality and sequelae o preterm birth rom inancy

    to adulthood. The Lancet. 2008;371(9608):261269.

    4. Craig E, Thompson J, Mitchell E. Socioeconomic

    status and preterm birth: New Zealand trends,

    1980 to 1999. Arch Dis Child Fetal Neonatal Ed.2002;86(3):F142-146.

    5. Branum AM, Schoendor KC. Changing patterns o

    low birthweight and preterm birth in the United

    States, 198198. Paediatric and Perinatal Epidemiol-

    ogy. 2002;16(1):8-15.

    6. Alexander GR, Slay M. Prematurity at birth:

    trends, racial disparities, and epidemiology.

    Mental Retardation and Developmental Disabilities

    Research Reviews. 2002;8(4):215-220.

    7. Goldenberg RL, Culhane JF, Iams JD, Romero R.

    Preterm birth 1: Epidemiology and causes o preterm

    birth. The Lancet. 2008;371(9606):75-84.

    8. Copper RL, Goldenberg RL, Das A, Elder N, Swain M,

    Norman G, et al. The preterm prediction study:

    maternal stress is associated with spontaneous

    preterm birth at less than thirty-five weeks

    gestation. American Journal o Obstetrics and Gyne-

    cology. 1996;175(5):1286-1292.

    9. Fiscella K. Race, perinatal outcome, and amni-

    otic inection. Obstetrical & Gynecological Survey.

    1996;51(1):60-66.

    10. Goldenberg RL, Cliver SP, Mulvihill FX, Hickey CA,

    Hoffman HJ, Klerman LV, et al. Medical, psychoso-

    cial, and behavioral risk actors do not explain the

    increased risk or low birth weight among black

    women. American Journal o Obstetrics and

    Gynecology. 1996;175(5):1317-1324.

    11. Neggers Y, Goldenberg RL. Some thoughts on body

    mass index, micronutrient intakes and pregnancy out-

    come. Journal o Nutrition. 2003;133(5):1737S-1740S.

    12. Conde-Agudelo A, Rosas-Bermdez A, Kaury-

    Goeta AC. Birth spacing and risk o adverse

    perinatal outcomes: a meta-analysis. JAMA.

    2006;295(15):1809-1823.

    13. Brett KM, Strogatz DS, Savitz DA. Employment,

    job strain, and preterm delivery among women in

    North Carolina. American Journal o Public Health.

    1997;87(2):199-204.

  • 7/26/2019 Proefschrift Definitief Lage Resolutie

    28/225

    General introduction

    26. Saugstad OD. Oxidative stress in the newborn-

    a 30-year perspective. Biology o the Neonate.

    2005;88(3):228-236.

    27. Saugstad OD. Oxygen and oxidative stress in

    bronchopulmonary dysplasia. Journal o Perinatal

    Medicine. 2010;38(6):571-577.

    28. Buonocore G, Perrone S, Longini M, Vezzosi P,

    Marzocchi B, Paffetti P, et al. Oxidative stress in

    preterm neonates at birth and on the seventh day

    o lie. Pediatric Research. 2002;52(1):46-49.29. Saugstad OD. Hypoxanthine as an indicator of hypoxia:

    Its role in health and disease through free radical

    production. Pediatric Research. 1988;23(2):143-150.

    30. Saugstad OD. Oxygen radical disease in neonatology.

    Seminars in Neonatology. 1998;3(3):229-238.

    31. Saugstad OD. The oxygen radical disease o neona-

    tology. Indian J Paediatrics. 1989;56:585-593.

    32. Baraldi E, Carraro S, Filippone M. Bronchopulmonary

    dysplasia: Definitions and long-term respiratory out-

    come. Early Human Development. 2009;85(10):S1-3.

    33. Northway Jr WH, Rosan RC, Porter DY. Pulmonary

    disease ollowing respirator therapy o hyaline-mem-

    brane disease. Bronchopulmonary dysplasia. New

    England Journal o Medicine. 1967;276(7):357-368.

    34. Miller NE. Techniques o early respiratory manage-

    ment o very low and extremely low birth weight

    inants. Neonatal Netw. 2010;29(3):153-160.

    35. Fanaroff AA, Stoll BJ, Wright LL, Carlo WA,

    Ehrenkranz RA, Stark AR, et al. Trends in neonatal

    morbidity and mortality or very low birthweight

    inants. American Journal o Obstetrics and Gynecol-

    ogy. 2007;196(2):147.e141-e148.

    36. Donn SM, Sinha SK. Invasive and noninvasive

    neonatal mechanical ventilation. Respiratory Care.

    2003;48(4):426-439.

    37. Jobe AJ. The new BPD: an arrest o lung develop-

    ment. Pediatric Research. 1999;46(6):641-643.

    38. Schroeder P, Gortner L. Predicting bronchopulmonary

    dysplasia. Intensive Care Medicine. 1999;25(2):241.

    39. Saugstad OD. Chronic lung disease: Oxygen dogma

    revisited. Acta Paediatr. 2001;90(2):113-115.

    40. Rodriguez RJ. Management o respiratory dis-

    tress syndrome: An update. Respiratory Care.

    2003;48(3):279-287.

    41. Smith G. The pharmacology o the ductus arteriosus.

    Pharmacological Reviews. 1998;50(1):35-58.

    42. Koch J, Hensley G, Roy L, Brown S, Ramaciotti C,

    Roseneld CR. Prevalence o spontaneous closure o

    the ductus arteriosus in neonates at a birth weight o

    1000 grams or less. Pediatrics. 2006;117(4):1113-1121.

    43. Hagan R, Minutillo C, French N, Reese A, Landau L,

    LeSoue P. Neonatal chronic lung disease, oxygen

    dependency, and a amily history o asthma. Pediatric

    Pulmonology. 1995;20(5):277-283.

    44. Clyman R, Cassady G, Kirklin JK, Collins M, Philips

    III JB. The role o patent ductus arteriosus ligationin bronchopulmonary dysplasia: Reexamining a

    randomized controlled trial. Journal o Pediatrics.

    2009;154(6):873-876.

    45. Hellstrom A, Perruzzi C, Ju M, Engstrom E, Hard AL,

    Liu JL, et al. Low IGF-I suppresses VEGF-survival

    signaling in retinal endothelial cells: Direct correlation

    with clinical retinopathy o prematurity. Proc Natl

    Acad Sci USA. 2001;98(10):5804-5808.

    46. Cunningham S, Fleck BW, Elton RA, McIntosh N.

    Transcutaneous oxygen levels in retinopathy o

    prematurity. The Lancet. 1995;346(8988):1464-1465.

    47. Steinkuller PG, Du L, Gilbert C, Foster A, Collins ML,

    Coats DK. Childhood blindness. Journal o AAPOS.

    1999;3(1):26-32.

    48. Jegatheesan P, Ianus V, Buchh B, Yoon G, Chorne N,

    Ewig A, et al. Increased indomethacin dosing or per-

    sistent patent ductus arteriosus in preterm Inants:

    A multicenter, randomized, controlled trial.

    Journal o Pediatrics. 2008;153(2):183-189.

    49. Rekha S, Battu RR. Retinopathy o prematu-

    rity: incidence and risk actors. Indian Pediatrics.

    1996;33(12):999-1003.

    50. Holmstrm G, Broberger U, Thomassen P.

    Neonatal risk actors or retinopathy o prematurity

    a population based study. Acta Ophthalmologica

    Scandinavica. 1998;76(2):204-207.

    51. Liu PM, Fang PC, Huang CB, Kou HK, Chung MY,

    Yang YH, et al. Risk actors o retinopathy o prema-

    turity in premature inants weighing less than 1600 g.

    American J Perinatol. 2005;22(2):115-120.

    52. Tehrani FT, Bazar AR. A eedback controller or

    supplemental oxygen treatment o newborn inants:

    A simulation study. Medical Engineering and Physics.

    1994;16(4):329-333.

  • 7/26/2019 Proefschrift Definitief Lage Resolutie

    29/225

    CHAPTER

    53. Seiberth V, Linderkamp O, Seiberth P, r Augen-

    heilkunde K, Osnabrck M. Risk actors in retinopa-

    thy o prematurity; A multivariate statistical analysis.

    Ophthalmologica. 2000;214(2):131-135.

    54. Tin W, Milligan DWA, Penneather P, Hey E. Pulse

    oximetry, severe retinopathy, and outcome at one

    year in babies o less than 28 weeks gestation. British

    Medical Journal. 2001;84(2):F106-110.

    55. Chen M, itil A, McCabe F, Leicht KM, Fiascone J,

    Dammann CEL, et al. Inection, oxygen, and im-maturity: interacting risk actors or retinopathy o

    prematurity. Neonatology. 2010;99(2):125-132.

    56. Kotanchek ME, Helerty JP, Murray WB, Palmer C.

    Application o data usion to neonate oxygenation

    control. In: Multisensor Fusion and Integration or

    Intelligent Systems IEEE International Conerence on

    MFI; 1994; 1994. p. 509-514.

    57. Anderson CG, Benitz WE, Madan A. Retinopathy

    of prematurity and pulse oximetry: A national survey

    of recent practices. J Perinatol. 2004;24:164-168.

    58. Brooks SE, Marcus DM, Gillis D, Pirie E, Johnson

    CMH, Bhatia J. The effect o blood transusion pro-

    tocol on retinopathy o prematurity: A prospective,

    randomized study. Pediatrics. 1999;104(3):514-518.

    59. Filho JBF, Bonomo PP, Maia M, Procianoy RS.

    Weight gain measured at 6 weeks ater birth as a

    predictor or severe retinopathy o prematurity:

    Study with 317 very low birth weight preterm babies.

    Graees Archive or Clinical and Experimental

    Ophthalmology. 2009;247(6):831-836.

    60. Hellstrom A, Hard AL, Engstrom E, Niklasson A,

    Andersson E, Smith L, et al. Early weight gain

    predicts retinopathy in preterm inants: new,

    simple, efficient approach to screening. Pediatrics.

    2009;123(4):e638-645.

    61. Gunn TR, Easdown J, Outerbridge EW, Aranda JV.

    Risk actors in retrolental fibroplasia. Pediatrics.

    1980;65(6):1096-1100.

    62. Sacks LM, Schaffer DB, Anday EK, Peckham GJ,

    Delivoria-Papadopoulos M. Retrolental fibroplasia

    and blood transusion in very low-birth-weight

    inants. Pediatrics. 1981;68(6):770-774.

    63. Shohat M, Reisner SH, Krikler R, Nissenkorn I, Yassur

    Y, Ben-Sira I. Retinopathy o prematurity: Incidence

    and risk actors. Pediatrics. 1983;72(2):159-163.

    64. Hagadorn JI, Richardson DK, Schmid CH, Cole CH.

    Cumulative illness severity and progression rom

    moderate to severe retinopathy o prematurity.

    J Perinatol. 2007;27(8):502-509.

    65. Palmer EA, Flynn JT, Hardy RJ, Phelps DL, Phillips

    CL, Schaffer DB, et al. Incidence and early course

    o retinopathy o prematurity. The Cryotherapy or

    Retinopathy o Prematurity Cooperative Group.

    Ophthalmology 1991;98(11):1628-40.

    66. Hussain N, Clive J, Bhandari V. Current incidence o

    retinopathy o prematurity, 1989-1997. Pediatrics.

    1999;104(3):e26.

    67. Gilbert C, Rahi J, Eckstein M, OSullivan J, Foster A.

    Retinopathy o prematurity in middle-incomecountries. The Lancet. 1997;350(9070):12-14.

    68. Terry TL. Fibroblastic overgrowth o persistent

    tunica vasculosa lentis in inants born prematurely: II.

    Report o cases - Clinical aspects. Transactions o the

    American Ophthalmological Society. 1942;40:262-284.

    69. Munoz B, West SK. Blindness and visual impairment

    in the Americas and the Caribbean. British Journal o

    Ophthalmology. 2002;86(5):498-504.

    70. Sanchez ME, Andrews BJ, Karr D, Lansingh V,

    Winthrop KL. The emergence o retinopathy o

    prematurity in guatemala. Journal o pediatric oph-

    thalmology and strabismus. 2010;47:e1-4.

    71. Gilbert C, Fielder A, Gordillo L, Quinn G, Semiglia

    R, Visintin P, et al. Characteristics o inants with

    severe retinopathy o prematurity in countries with

    low, moderate, and high levels o development:

    implications or screening programs. Pediatrics.

    2005;115(5):518-525.

    72. Palmer EA, Flynn JT, Hardy RJ, Phelps DL, Phillips CL,

    Schaffer DB, et al. Incidence and early course

    o retinopathy o prematurity. The cryotherapy or

    retinopathy o prematurity cooperative group.

    Ophthalmology. 1991;98(11):1628-1640.

    73. Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps

    DL, Quintos M, et al. The incidence and course o

    retinopathy o prematurity: findings rom the early

    treatment or retinopathy o prematurity study.

    Pediatrics. 2005;116(1):15-23.

    74. Clark D, Mandal K. Treatment of retinopathy of pre-

    maturity. Early human development. 2008;84(2):95-99.

    75. Silverman WA. A cautionary tale about supplemental

    oxygen: The albatross o neonatal medicine.

    Pediatrics. 2004;113(2):394-396.

    76. Dennery PA, Phyllis AD. Oxygen administration in

    the care o neonates: A double-edged sword. Chinese

    Medical Journal. 2010;123(20):2938-2942.

    77. Tin W. Oxygen therapy: 50 years o uncertainty.

    Pediatrics. 2002;110(3):615-616.

  • 7/26/2019 Proefschrift Definitief Lage Resolutie

    30/225

    General introduction

    78. Sternbach GL, Varon J. The discovery and redis-

    covery o oxygen. Journal o Emergency Medicine.

    2005;28(2):221-224.

    79. Campbell K. Intensive oxygen therapy as a possible

    cause o retrolental fibroplasia; a clinical approach.

    The Medical Journal o Australia. 1951;2(2):48-50.

    80. Patz A, Hoeck LE, De La Cruz E. Studies on the

    effect o high oxygen administration in retrolental

    fibroplasia. I. Nursery observations. American Journal

    o Ophthalmology. 1952;35(9):1248-1253.81. Crosse V, Evans PJ. Prevention o retrolental fibropla-

    sia. Archives o Ophthalmology. 1952;48(1):83-87.

    82. Guy LP, Lanman JT, Dancis J. The possibility o total

    elimination o retrolental fibroplasia by oxygen

    restriction. Pediatrics. 1956;17(2):247-249.

    83. Kinsey VE, Jacobus JT, Hemphill F. Retrolental fibro-

    plasia: Cooperative study o retrolental fibroplasia

    and the use o oxygen. Archives o Pediatrics and

    Adolescent Medicine. 1956;92(4):395-397.

    84. Alberman ED. Epidemiology o retinopathy o

    prematurity. Contemporary Issues in Fetal and

    Neonutal Medicine. 1985;2:249-266.

    85. Avery M, Oppenheimer E. Recent increase in

    mortality rom byaline membrane disease*.

    Journal o Pediatrics. 1960;57(4):553-559.

    86. McDonald AD. The aetiology o spastic diplegia

    a synthesis o epidemiological and pathological

    evidence. Developmental Medicine & Child

    Neurology. 1964;6(3):277-285.

    87. Bolton DP, Cross KW. Further observations on cost

    o preventing retrolental fibroplasia. The Lancet.

    1974;303(7855):445-448.

    88. Cross KW. Cost o preventing retrolental fibroplasia?

    The Lancet. 1973;302(7835):954-956.

    89. Usher RH. Clinical investigation of the respiratory

    distress syndrome of prematurity. Interim report. New

    York State Journal of Medicine. 1961;61:1677-1696.

    90. Millam D. The history o intravenous therapy. Journal

    o Inusion Nursing. 1996;19(1):5-14.

    91. Rivera AM, Strauss KW, Van Zundert A, Mortier E.

    The history o peripheral intravenous catheters:

    How little plastic tubes revolutionized medicine.

    Acta Anaesthesiologica Belgica. 2005;56(3):271-282.

    92. Cosnett JE. Origins o intravenous fluid therapy.

    The Lancet. 1989;1(8641):768-771.

    93. Schulze KF, Graff M, Schimmel MS, Schenkman A,

    Rohan P. Physiologic oscillations produced by an infu-

    sion pump. Journal of Pediatrics. 1983;103(5):796-798.

    94. Klem S, Farrington J, Leff R. Influence o inusion

    pump operation and flow rate on hemodynamic

    stability during epinephrine inusion. Critical Care

    Medicine. 1993;21(8):1213-1217.

    95. Kern H, Kuring A, Redlich U, Dopmer U, Sims N,

    Spies C, et al. Downward movement o syringe

    pumps reduces syringe output. British Journal o

    Anaesthesia. 2001;86(6):828-831.

    96. Evans A, Winslow E. Oxygen saturation and hemody-

    namic response in critically ill, mechanically ventilatedadults during intrahospital transport. American

    Journal o Critical Care. 1995;4(2):106-111.

    97. Hurlbut JC, Thompson S, Reed MD, Blumer JL,

    Erenberg A, Leff RD. Influence o inusion pumps on

    the pharmacologic response to nitroprusside. Critical

    Care Medicine. 1991;19(1):98-101.

    98. Neal D, Lin J. The effect o syringe size on reliability

    and saety o low-flow inusions. Pediatric Critical

    Care Medicine. 2009;10(5):592-596.

    99. Capes DF, Dunster KR, Sunderland VB, McMillan D,

    Colditz PB, McDonald C. Fluctuations in syringe-

    pump inusions: association with blood pressure

    variations in inants. American Journal o Health-

    System Pharmacy. 1995;52(15):1646-1653.

    100. Weiss M, Neff T, Gerber A, Fischer J. Impact o inu-

    sion line compliance on syringe pump perormance.

    Pediatric Anesthesia. 2000;10(6):595-599.

    101. McCarroll C, McAtamney D, Taylor R. Alteration in

    flow delivery with antisyphon devices. Anaesthesia.

    2000;55(4):355-357.

    102. Dimaguila MAVT, Di Fiore JM, Martin RJ, Miller MJ.

    Characteristics o hypoxemic episodes in very low

    birth weight inants on ventilatory support.

    Journal o Pediatrics. 1997;130(4):577-583.

    103. Tehrani FT. Automatic control o mechanical

    ventilation and the inspired raction o oxygen in the

    premature inant: A simulation study. In: Proceedings

    o the First Joint BMES/EMBS Conerence; 1999;

    Atlanta, GA, USA 1999. p. 339.

    104. Shiao SYPK. Desaturation events in neonates

    during mechanical ventilation. Critical Care Nursing

    Quarterly. 2002;24(4):14-29.

    105. Claure N, Ozdamar O, Bancalari E. A system or

    automatic adjustment o the inspired oxygen in

    mechanically ventilated premature inants. In:

    Engineering in Medicine and Biology Society,

    Proceedings o the 25th Annual International

    Conerence o the IEEE; 2003; 2003. p. 454-455.

  • 7/26/2019 Proefschrift Definitief Lage Resolutie

    31/225

    CHAPTER

    106. Urschitz MS, Horn W, Seyang A, Hallenberger A,

    Herberts T, Miksch S, et al. Automatic control o the

    inspired oxygen raction in preterm inants: A ran-

    domized crossover trial. American Journal o Respira-

    tory and Critical Care Medicine. 2004;170(10):1095-

    1100.

    107. Laptook AR, Salhab W, Allen J, Saha S, Walsh M.

    Pulse oximetry in very low birth weight inants:

    can oxygen saturation be maintained in the desired

    range? J Perinatol. 2006;26:337-341.108. Lawless ST. Crying wol: False alarms in a

    pediatric intensive care unit. Critical Care Medicine.

    1994;22(6):981-985.

    109. Beddis IR, Collins P, Levy NM, Godrey S, Silverman

    M. New technique or servo-control o arterial

    oxygen tension in preterm inants. Arch Dis Child.

    1979;54(4):278-280.

    110. Collins P, Levy NM, Beddis IR, Godrey S, Silverman

    M. Apparatus or the servocontrol o arterial oxygen

    tension in preterm inants. Medical and Biological

    Engineering and Computing. 1979;17(4):449-452.

    111. Sano A, Kikucki M. Adaptive control o arterial oxygen

    pressure o newborn inants under incubator oxygen

    treatments. In: Control Theory and Applications, IEE

    Proceedings D; 1985; 1985. p. 205-211.

    112. Dugdale RE, Cameron RG, Tealman GT. Closed-loop

    control o the partial pressure o arterial oxygen in

    neonates. Clinical Physics and Physiological

    Measurement. 1988;9(4):291-305.

    113. Taube J, Bhutani V. Automatic control o neonatal

    ractional inspired oxygen. In: Engineering in Medicine

    and Biology Society Proceedings o the Annual

    International Conerence o the IEEE; 1991; 1991. p.

    2176-2177.

    114. Tehrani FT, Bazar AR. An automatic control system

    or oxygen therapy o newborn inants. In: Pro-

    ceedings o the Annual International Conerence

    o the IEEE Engineering in Medicine and Biology

    Society; 1991; 1991. p. 2180-2182.

    115. Bhutani VK, Taube JC, Antunes MJ, Delivoria-

    Papadopoulos M. Adaptive control o inspired oxy-

    gen delivery to the neonate. Pediatric Pulmonology.

    1992;14(2):110-117.

    116. Morozoff PE, Evans RW, Smyth JA. Automatic control

    o blood oxygen saturation in premature inants. In:

    Second IEEE Conerence on Control Applications

    1993; Vancouver, BC , Canada 1993. p. 415-419.

    117. Yu C, He WG, So JM, Roy R, Kauman H, Newell

    JC. Improvement in arteral oxygen control using

    multiple-model adaptive control procedures. In:

    Biomedical Engineering, IEEE Transactions on; 2007;

    2007. p. 567-564.

    118. Claure N, Gerhardt T, Everett R, Musante G, Herrera

    C, Bancalari E. Closed-loop controlled Inspired oxy-

    gen concentration or mechanically ventilated very

    low birth weight Inants with requent episodes o

    hypoxemia. Am Acad Pediatrics. 2001;107(5):1120-1124.119. Tehrani FT. A control system or oxygen therapy o

    premature inants. In: Proceedings o the 23rd Annual

    International Conerence o the IEEE Engineering in

    Medicine and Biology Society; 2001; 2001.

    p. 2059-2062.

    120. Tehrani F, Rogers M, Lo T, Malinowski T, Auwape S,

    Lum M, et al. A dual closed-loop control system or

    mechanical ventilation. Journal o Clinical Monitoring

    and Computing. 2004;18(2):111-129.

    121. Morozoff PE, Evans RW. Closed-loop control o

    SaO2 in the neonate. Biomed Instrum Technol.

    1992;26(2):117-127.

    122. Sun Y, Kohane IS, Stark AR. Computer-assisted

    adjustment o inspired oxygen concentration

    improves control o oxygen saturation in newborn

    inants requiring mechanical ventilation. Journal o

    Pediatrics. 1997;131(5):754-756.

    123. Morozoff EP, Smyth JA. Evaluation o three automatic

    oxygen therapy control algorithms on ventilated low

    birth weight neonates. In: 31st Annual International

    Conerence o the IEEE, EMBS.

    Minneapolis, Minnesota, USA; 2009. p. 3079-3082.

    124. Claure N, DUgard C, Bancalari E. Automated adjust-

    ment o inspired oxygen in preterm inants with

    requent fluctuations in oxygenation: A pilot clinical

    trial. Journal o Pediatrics. 2009;155(5):640-645.

    125. Claure N, Bancalari E, DUgard C, Nelin L, Stein M,

    Ramanathan R, et al. Multicenter crossover study o

    automated control o inspired oxygen in ventilated

    preterm inants. Pediatrics. 2011;127(1):e76-83.

    126. Zhang L, Cameron RG. A real-time expert control

    strategy or blood gas management inneonates

    under ventilation treatment. In: IEEE Colloquium on

    exploiting the knowledge base: Applications o rule

    based control; 1989; London, UK; 1989. p. 4/1-4/7.

  • 7/26/2019 Proefschrift Definitief Lage Resolutie

    32/225

    General introduction

    127. Azhar N, Karim U. Automatic eedback control o

    oxygen therapy using pulse oximetry. In: Engineering

    in Medicine and Biology Society, Proceedings o the

    Annual International Conerence o the IEEE; 1991;

    1991. p. 1614-1615.

    128. Sun Y, Kohane I, Stark AR. Fuzzy logic assisted control

    o inspired oxygen in ventilated newborn inants. In:

    Proceedings o the Annual Symposium on Computer

    Application in Medical Care; 1994; 1994. p. 757-761.

    129. ODonnell CP. Automated adjustment o oxygen inventilated preterm inants: turn on, tune in, ROP out?

    Journal o Pediatrics. 2009;155(5):606-608.

    130. Wilkinson DJ, Andersen CC. Bedside algorithms

    or managing desaturation in ventilated preterm

    inants: A randomised crossover trial. Neonatology.

    2008;95(4):306-310.

    131. Chow LC, Wright KW, Sola A. Can changes in clinical

    practice decrease the incidence o severe retinopa-

    thy o prematurity in very low birth weight inants?

    Pediatrics. 2003;111(2):339-345.

    132. Stowe CD, Storgion SA, Lee KR, Phelps SJ. Hemody-

    namic response to intentionally altered flow conti-

    nuity o dobutamine and dopamine by an inusion

    pump in inants. Pharmacotherapy. 1996;16(6):1018-

    1023.

    133. Cunningham S, Deere S, McIntosh N. Cyclical

    variation o blood pressure and heart rate in

    neonates. Arch Dis Child. 1993;69(1 Spec No):64-67.

    134. Rooke GA, Bowdle A. Syringe pumps or

    inusion o vasoactive drugs. Anesthesia & Analgesia.

    1994;78(1):150-156.

    135. Lnnqvist PA, Lqvist B. Design flaw can convert

    commercially available continuous syringe pumps

    to intermittent bolus injectors. Intensive Care

    Medicine. 1997;23(9):998-1001.

    136. Southern DA, Read MS. Lesson o the Week: Over-

    dosage o opiate rom patient controlled analgesia

    devices. British Medical Journal. 1994;309(6960):1002.

    137. Levi DS, Peterson N, Shah SD, Rakholia B, Haught A,

    Carman G. Connecting multiple low-flow intravenous

    inusions in the newborn: Problems and possible solu-

    tions. Pediatric Critical Care Medicine. 2010;11(2):275-

    281.

    138. Weiss M, Fischer J, Neff T, Schulz G, Bnziger O. Do

    antisiphon valves reduce flow irregularities during

    vertical displacement o inusion pump systems?

    Anaesthesia and Intensive Care. 2000;28(6):680-683.

  • 7/26/2019 Proefschrift Definitief Lage Resolutie

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    Part 1supplementaloxygen therapy

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    Oxygenation in

    preterm inants:background, targetranges & monitoringtechniquesA.C. van der Eijk, J. Dankelman, B.J. Smit

    CHAPTER

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    CHAPTER

    It is inherent to their immaturity that preterm inants need some orm o physiological

    monitoring during their stay on the neonatal intensive care unit. In current neonatal

    intensive care at least the heart rate, respiration rate, skin temperature, and oxygen

    saturation are monitored continuously. In the past 60 years, various methods to monitor

    blood oxygen levels have been developed. In this chapter, background inormation about

    the oxygenation o the human body, and especially that o preterm inants, is provided.

    Subsequently, the working principles and (dis)advantages o methods that are available

    or monitoring oxygenation are elaborated on. Thereater, an overview o literature on

    target ranges or blood oxygen levels in (preterm) newborn inants is provided. Finally, a

    uture perspective o the needs or oxygen monitoring in preterm inants is discussed.

    OBJECTIVE To obtain background inormation regarding oxygenation o the human

    body, to get an overview o literature on target ranges or blood oxygen levels in new-

    born inants, and to evaluate methods or monitoring oxygenation in neonatology.

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    . INTRODUCTION

    Approximately five to ten percent o all newborn inants need active resuscitation imme-

    diately ater birth to survive.1The majority o these inants is born preterm. Due to the im-

    maturity o organs like the lungs and brain o these preterm inants, respiratory support and

    supplemental oxygen therapy are necessary to reach and maintain adequate oxygenation.

    In supplemental oxygen therapy, a gas mixture with >21% o oxygen is supplied to the

    patient via mechanical ventilation. In preterm inants this therapy is not only used imme-

    diately ater birth, but also in the first weeks ater birth. Unortunately, supplementaloxygen therapy is not without risks. Both too low and too high levels o oxygen in the

    tissues may have severe consequences or the development and outcome o preterm

    inants.2Thereore, to prevent the negative effects o supplemental oxygen therapy, blood

    oxygen levels o preterm inants need to be monitored closely during their hospitalization

    on the neonatal intensive care unit (NICU).

    In the last decades, several methods and sensors to monitor oxygenation in preterm inants

    have been developed. Regrettably, these monitoring systems did not always serve the spe-

    cific needs or the patients, the amily, and/or the healthcare proessionals in the optimal

    way. The aims o this chapter are to provide background inormation about oxygenation o

    the human body, to provide an overview o the techniques (that were) available or moni-

    toring oxygenation in preterm inants, and to discuss target ranges or blood oxygen levels

    in (preterm) newborn inants. Finally, the needs and uture perspectives or monitoring

    oxygenation in (preterm) newborn inants are discussed.

    To prevent the negative effects of supplemental

    oxygen therapy, blood oxygen levels of

    preterm infants need to be monitored closely.

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    CHAPTER

    .OXYGEN IN THE HUMAN BODY

    Cells in the human body can only unction properly when the amount o oxygen delivered

    to the cells is adequate to meet the demands o the cells. 3Because oxygen cannot be held

    in stock in the cells, a constant delivery o oxygen is needed. 4In literature, the vaguely de-

    fined term oxygenation is oten used as a measure or the amount o oxygen in the body.

    However, an adequate oxygenation depends on the systemic oxygen transport (delivery),

    the oxygen consumption (demand), and the mixed venous saturation (reserve).5The oxygen

    delivery, the demand, and the reserve depend on, and are maintained by, multiple para-

    meters. Thus, when examining whether the oxygenation is adequate or not, interpretationo multiple parameters is required.

    In humans, the inhaled oxygen diffuses in the lungs rom the alveoli to the pulmonary capil-

    lary blood (Figure 2.1). Most o the diffused oxygen is bound to haemoglobin, an intracel-

    lular protein, within the erythrocytes (i.e. red blood cells). A small proportion o oxygen is

    dissolved in blood plasma. The sum o the amount o oxygen bound to haemoglobin and

    the oxygen dissolved in the plasma is the oxygen content o blood (O2ct) (equation I).6

    O2ct = (k1 Hb SO2) + (k2 PO2)

    Where

    Hb = haemoglobin concentration (grams litre1)

    SO2 = oxygen saturation o the blood (see 2.2.1)

    PO2 = partial pressure o oxygen (see 2.2.1)

    k1 = Hners constant (in theory, each gram o Hb binds 1.39 ml o oxygen,

    in practice it is less)

    k2 = solubility coefficient o oxygen at body temperature (0.23 ml litre-1 kPa-1)

    The oxygen rich erythrocytes are transported through the body via blood vessels to the

    tissues. The oxygen delivery (DO2) is the amount o oxygen transported rom the lungs to

    the peripheral tissues, and depends on the oxygen content o arterial blood (aO2ct) and the

    cardiac output (Q) (equation II en III)

    DO2 = Q aO2ct

    Q = heart rate stroke volume

    At the places were oxygen is demanded, the oxygen dissociates rom haemoglobin and di-

    uses into the cells. Ater oxygen is released, the oxygen-poor erythrocytes are transported

    via blood vessels back to the heart and lungs. The difference in aO2ct and the oxygen con-

    tent o the venous blood (vO2ct) is the amount o oxygen delivered to the tissues. The total

    oxygen consumption (VO2) depends on Q and the amount o oxygen delivered to the tis-

    sues (see the Fick equation, IV).

    VO2 = Q (aO2ct - vO2ct)

    (I)

    (II)

    (III)

    (IV)

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    FIGURE . A schematic illustration o the lungs, the alveoli, and the diffusion o O2 and CO2

    between the lungs and the blood. Figure adapted rom [.

    ..THE OXYGEN DISSOCIATION CURVE

    As mentioned in the previous paragraph, oxygen binds to haemoglobin in the erythrocytes.

    The percentage o haemoglobin bound to oxygen divided by the sum o all the available

    haemoglobin is defined as oxygen saturation (SO2, equation V). For SO2 in the arterial

    blood the abbreviation SaO2 is used. The actual amount o oxygen bound to haemoglobin

    depends on the ability o haemoglobin to bind or release oxygen, i.e. the oxygen affinity.3

    SO2 = [HbO2] / ([HbO2] + [Hb])

    Where

    [Hb] = concentration o deoxyhemoglobin in blood (can bind to oxygen)

    [HbO2] = concentration oxyhemoglobin o blood (bound to oxygen)

    The oxygen affinity can be described by an S-shaped graph, the Oxygen Dissociation-curve

    (OD-curve, Figure 2.2). The OD-curve represents the relation between the SO2 and the par-

    tial pressure o oxygen in the blood (PO2). The PO2, or the oxygen tension is the amount

    o oxygen that has diffused across the alveolar capillary membrane and is dissolved in the

    plasma o the blood. The PO2 is an important actor in the exchange o O2 and carbon di-

    oxide (CO2) rom the blood to the tissues and vice versa. In the lungs, high levels o oxygen

    tension in arterial blood (PaO2) encourage oxygen to bind to haemoglobin. 8, 9 As can be

    seen in the OD-curve, at low PO2 levels the curve is steep. At these lower levels oxygen is

    encouraged to peruse into the tissues.

    (V)

    CO2

    Trachea

    Alveoli

    Alveoliairspace

    Capillary

    Redblood cell

    Left Lung

    O2

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    CHAPTER

    The relative position o the OD-curve on the x-axis equals the oxygen affinity, and is in-

    fluenced by several actors, amongst others the pH, CO2, 2,3-diphosphoglycerate (2,3-DPG),

    temperature and type o haemoglobin. A change in the oxygen affinity influences both the

    amount o oxygen that binds to the haemoglobin when passing the alveoli, and the amount

    o oxygen that is released in the tissues. It has been shown that the OD-curve can shit very

    quickly in preterm inants.10,11

    FIGURE .A schematic illustration of the Oxygen Dissociation-curve (OD-curve). The OD-curve links

    the oxygen saturation (SO2) to the partial pressure of oxygen in the blood (PO2). The relative position

    of the curve on the x-axis equals the oxygen affinity, and is influenced by several factors. Graph is based

    on [].

    Approximately 80% o all extremely low birth weight inants (1000 g.; ELBW) inants re-

    ceive one or more blood transusions during their first weeks o lie. When a preterm inant

    receives a blood transusions, the transused blood comes rom human adults. 12, 13Most o

    the haemoglobin present in the erythrocytes o healthy adults is adult haemoglobin (HbA).

    In preterm inants, however, most o the haemoglobin in the blood is o a different type,

    etal haemoglobin (HbF). This HbF plays an important role in the oxygenation o the oe-

    tus. Compared to HbA, HbF binds 2,3-DPG poorly. 2,3-DPG is an organophosphate, which

    is created in the erythrocytes during glycolysis. High levels o 2,3-DPG shit the curve to the

    right, while low levels o 2,3-DPG cause a letward shit. Thus, because HbF binds 2,3-DPG

    Oxygensaturation(SO2)[%]

    left shifted by:

    pH

    .-DPG

    Temperature right shifted by:

    pH

    .-DPG

    Temperature

    Partial pressure of oxygen (PO2) [mmHg]

    (7.5 mmHg = 1 kPa)

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    Oxygenation in preterm infants

    poorly, the level o 2,3-DPG in the blood o oetuses is relatively low. Consequently, the OD-

    curve is shited letward compared to the HbA-rich blood o the mother. The letward shit

    o the OD-curve represents a higher oxygen affinity compared to the mother. The higher

    oxygen affinity o the blood in oetuses accounts or a better transer o oxygen in the blood

    rom the mother to the oetus and or optimal oxygenation o the oetus under the rela-

    tively hypoxic conditions in utero. Thus, in general, the higher the percentage o HbF in the

    blood, the higher the SO2 level or a certain PO2 value, and vice versa. 14, 15

    In healthy newborns, HbF is broken down and replaced by HbA in three to six months ater

    birth. Nevertheless, this slow and regulated change o haemoglobin is not seen in preterminants in the NICU because o the blood transusions with HbA. A transusion with HbA

    can speed up the natural process o haemoglobin change to only several hours, consequent-

    ly causing a rapid right shit in the OD-curve (i.e. a decrease o oxygen affinity). Thereore,

    it is advised to transuse blood with HbA slowly, and to monitor blood oxygen levels closely

    during and ater the blood transusion.16-19

    To keep both SaO2 and PaO2 within a certain range, accurate monitoring is required. In the

    next part o this chapter the (dis)advantages o methods developed to monitor oxygenation

    in preterm inants are discussed.

    .MONITORING OF OXYGENATION

    The aim o monitoring was very well described by Murkovic:20The primary aim of moni-

    toring is to ensure that appropriate care or therapy can be given prior to the onset of complica-

    tions. Thus, inormation obtained by monitoring equipment is important to alert or a

    change in condition, and an aid or healthcare proessionals in the decision making.

    The monitoring o preterm inants is challenging.20 Preterm inants lie in an incubator

    with an air temperature around 35C and with a high humidity. Furthermore, the sensors

    used or monitoring have to be small and user-riendly or the patient, their amily and the

    healthcare proessionals. In neonatal care, this implicates that the sensors should, at least,

    not hamper the development o the preterm inant.

    Before the techniques for continuous monitoring became available, healthcare professionalscould only use physical assessment of the skin of the patient to determine their oxygenation.21

    In the recent decades, several methods and sensors have been developed, with varying tech-

    niques and functions to determine whether the total oxygen delivery achieves the total oxy-

    gen demand in preterm infants. These techniques are discussed in the following paragraphs.

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    CHAPTER

    ..PHYSICAL ASSESSMENT

    For healthcare proessionals, changes in the skin colour o patients have always been an

    important indication or changes in the oxygenation. Nowadays, this method is still used

    to determine oxygen requirement in preterm inants. However, physical assessment o the

    skin is a subjective method, and not very reliable in detecting both hypoxia and hyperoxia

    in preterm inants.22-24Thereore, the possibility to perorm blood gas analysis was a huge

    improvement in the assessment o oxygen requirement.

    ..BLOOD GAS ANALYSIS

    In blood gas analysis, a small sample o blood, either arterial, venous or capillary (mixed)blood, is taken rom the patient. This blood sample is analysed to determine the adequacy

    o ventilation, pulmonary gas exchange, and the acid-base status o the patient.25 Blood

    gas analysis rom arterial blood provides multiple parameters like the SaO2, PaO2, arterial

    carbon dioxide tension (PaCO2), pH, base excess, and ractions o different types o hae-

    moglobin. Until the 1970s blood gas analysis was the only reliable method to determine

    oxygen levels in the blood. Today, blood gas analysis is still the golden standard in medical

    practice.

    Unortunately blood gas analysis is not without drawbacks. Firstly, there is the loss o blood

    each time a sample is needed (0.3 ml). In preterm inants each drop o blood is o high value

    or the patient, thus the number o blood samples that is collected should be minimised.

    Secondly, the percutaneous puncture can lead to agitation. Regrettably, the specially de-

    veloped indwelling catheters to reduce percutaneous punctures are associated with vascular

    complications and inection.26 The third disadvantage is the act that the method provides

    only inormation about the moment the sample was taken. Thus, due to the intermittent

    sampling, ast fluctuations in oxygenation could be missed.27, 28To overcome the lack o

    inormation about oxygenation in between blood sampling, since the 1960s several groups

    worked on the development o continuous measurement o blood oxygen levels.

    ..CONTINUOUS INTRAARTERIAL BLOOD GAS MONITORING

    Continuous measurement o blood oxygen levels became possible because o the develop-

    ment o catheters or continuous intra-arterial blood gas monitoring (CIBM). These CIBM

    systems were designed to determine SaO2, PaO2, PCO2, and/or pH continuously and in-

    vasively. Initially, the CIBM systems were thought to be able to give insight in the rapid

    changes in blood oxygen levels, and reduce the need or blood sampling. These advantageswould enhance therapeutic decision making, and reduce the need or blood transusions.

    Consequently, this would presumably lead to a reduction in the risks o inection, in work-

    load o the caregivers, and in hospital costs.

    The presumed advantages o CIBM systems were tested in animals, 29 adults,30 inants,31-37

    and neonates.38-42 Various interesting review papers discuss the results o the developed

    CIBM systems in detail.28, 43, 44Two o the most recent developed devices are the Paratrend,

    and the Neotrend (Figure 2.3).29, 33-35, 41

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    FIGURE .Schematic drawing of the the Paratrend (Diametrics Medical, High Wycombe, UK). The sen-

    sors for pH, PaCO2, PaO2 and the temperature are shown. This system was commercially available in the

    1990s. Drawing is based on [].

    The Paratrend consists o a hybrid probe (diameter 0.5 mm, length 4 cm) with thermocouple,

    an electrochemical PO2 sensor, and absorbance sensors or pH and PCO2. The Neotrend is

    based on the Paratrend, and especially designed or neonates.

    Although the Paratrend, the Neotrend, and some other devices were commercially

    available, none o them were widespread in clinical use. This was due to, amongst others,

    the risk o inection, and the deposition o plasma proteins on the device. This deposition

    leads to platelet activation, adhesion and thrombus ormation.42, 45-49Another problem was

    the wall effect, a phenomenon where the PaO2 value suddenly drops. This drop is caused

    by the act that the sensor is touching the arterial wall and measures the gas values o the

    tissue instead o the blood.28, 43, 45Above that, the sensors o the CIBM systems need requent

    recalibration,37, 39and are highly ragile.28, 43, 45

    As ar as we know, today, sensors or intra-arterial measurement are not used in daily care

    in NICUs anymore. However, in the uture, the development in materials, and the improve-

    ment and miniaturization o techniques may increase new possibilities or CIBM systems.

    ..TRANSCUTANEOUS OXYGEN MEASUREMENTSimultaneously with the development o CIBM systems, transcutaneous oxygen measure-

    ment became available. In 1956 L.C. Clark invented a polarographic membrane-covered

    oxygen electrode.50When this Clark electrode is positioned on the chest o a patient it can

    measure the diffusion o oxygen through the skin into the sensor. Based on this diffusion

    the transcutaneous partial pressure o oxygen (tcPO2) and the transcutaneous partial pres-

    sure o carbon dioxide (tcPCO2) can be determined.51This technique was the first, and still

    the only, possibility to monitor PO2 and PCO2 continuous and transcutaneous.

    Temperature

    PO2

    PCO2

    pH

    . mm

    mm

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    CHAPTER

    In preterm inants, tcPO2 correlates well with the PaO2. Thereore transcutaneous oxygen

    monitoring was rapidly accepted or routine use in neonatal intensive care.52However, soon

    ater the introduction in clinical practice, it became clear that the accuracy o the measure-

    ment declined when PaO2 increased, or when skin perusion was decreased.53, 54An adequate

    skin perusion is required to obtain optimal diffusion o oxygen. To achieve adequate skin

    perusion, the skin o the preterm inant needs to be heated to approximately 43 - 44C. Un-

    ortunately, heating up the weak skin o preterm inants can lead to erythema. To prevent

    this side effect, the sensor needs to be repositioned and recalibrated every 3 to 4 hours. This

    repositioning and recalibration causes a high workload or the nursing staff.52, 55, 56

    The necessity for heating of the skin, the high workload of the technique, the relative large

    and heavy sensor, and the development of a newer technique pulse oximetry are the reason

    that transcutaneous oxygen monitoring is not used very often anymore in the NICU.56, 57

    ..PULSE OXIMETRY

    Pulse oximetry was invented in Japan in the 1970s by T. Aoyagi. 58The technique was first

    introduced in perioperative care, but it soon expanded into (neonatal) intensive care units.

    Pulse oximetry w