in neonatal intensive care:
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
in neonatal intensive care:
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, promotor
Dr. 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-out Louise de Kruijf isBN 978-94-6191-355-5
copyright © 2012, 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.
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 I’ve seen christmas lights, reflect in your eyes You got wires, going in You got wires, coming out of your skin There’s dry blood, on your wrist Your dry blood on my fingertip Running down corridors, through automatic doors Got 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 You’ll be alright Artist: Athlete
General introduction
1.1 introduction
1.2 Preterm infants, definitions & prevalence 1.3 Prematurity, causes & outcome 1.4 Prematurity & oxidative stress related
diseases
1.4.1 Bronchopulmonary dysplasia 1.4.2 Infant respiratory distress syndrome 1.4.3 Patent ductus arteriosus
1.4.4 Retinopathy of prematurity
1.5 supplemental oxygen therapy
1.5.1 A brief overview of history of supplemental oxygen therapy
1.6 iV therapy
1.6.1 A brief overview of history of IV therapy
1.7 Problem statements
1.7.1 Supplemental oxygen therapy 1.7.2 IV therapy
1.8 objectives
1.8.1 Part I Supplemental oxygen therapy 1.8.2 Part II IV therapy
1.9 thesis outline 1.10 references
PArt i suPPLemeNtAL oxygeN therAPy chAPter 2
Oxygenation in preterm infants; background, target ranges & monitoring techniques
2.1 introduction
2.2 oxygen in the human body
2.2.1 The oxygen dissociation curve
2.3 monitoring of oxygenation
2.3.1 Physical assessment of the skin 2.3.2 Blood gas analysis
2.3.3 Continuous intra-arterial blood gas monitoring
2.3.4 Transcutaneous oxygen measurement 2.3.5 Pulse oximetry
2.3.6 Near infrared spectroscopy 2.3.7 Capnography
2.4 reference values for blood oxygen levels
2.4.1 Reference values for oxygen saturation 2.4.2 Reference values for partial pressure of
oxygen
2.4.3 Target ranges & outcome
2.5 monitoring oxygenation in preterm infants: future perspectives 11 13 14 15 15 18 19 21 24 25 26 57 59 60 62 69 72 75 77 78 80 86 89 91 93 94 95 102 105 33 35 37 38 41 47 49
New-generation pulse oximeters in extremely low birth weight infants: how do they perform in clinical practice? 3.1 introduction 3.2 methods 3.2.1 Patients 3.2.2 Study set-up 3.2.3 Experimental set-up 3.2.4 Data analysis 3.3 results 3.3.1 SpO2 values 3.4 Discussion 3.5 references chAPter 4
Manual adjustments of the inspired oxygen fraction in extremely low birth weight infants
4.1 introduction 4.2 methods
4.2.1 Patients
4.2.2 Experimental set-up 4.2.3 Data collection 4.2.4 Target levels for SpO2 4.2.5 FiO2 adjustments
4.3 results
4.3.1 Patients
4.3.2 Manual FiO2 adjustments 4.3.3 SpO2 levels
4.4 Discussion 4.5 references chAPter 5
Pulse oximetry alarm limits in extremely low birth weight infants: when do deviations from the protocol occur?
5.1 introduction 5.2 methods
5.2.1 Working situation
5.2.2 Policy for pulse oximetry alarm limits 5.2.3 Data analysis
5.3 results
5.3.1 Occurrence of alarm limits 5.3.2 FiO2 levels
5.3.3 SpO2 levels
5.3.4 Characteristics of the alarm limit adjustments
5.4 Discussion 5.5 references
6.1 introduction 6.2 methods
6.2.1 The questionnaire
6.3 results
6.3.1 Manual control of oxygenation 6.3.2 Pulse oximetry
6.3.3 Pulse oximetry alarm limits 6.3.4 Suggestions for improvement
6.4 Discussion 6.5 references chAPter 7
Defining hazards of supplemental oxygen therapy in neonatology using the Failure Mode and Effects Analysis (FMEA) tool
7.1 introduction
7.1.1 FMEA
7.2 methods 7.3 results
7.3.1 Step 1. Defining the topic 7.3.2 Step 2. Team assembly 7.3.3 Step 3. Process analysis 7.3.4 Step 4. Hazard analysis
7.3.5 Step 5. Develop risk reduction methods
7.4 Discussion
7.4.1 Lessons learnt by the FMEA-team
7.5 references
PArt ii iV therAPy chAPter 8
Flow-rate variability in neonatal IV therapy: what do we know about the flow?
8.1 introduction 8.2 methods 8.3 results
8.3.1 Factor 1: Vertical syringe or patient displacement
8.3.2 Factor 2: Syringes 8.3.3 Factor 3: Infusion tubing
8.3.4 Factor 4: Check valves & anti-siphon valves 8.3.5 Factor 5: Inline filters
8.3.6 Factor 6: Add-on devices 8.3.7 Factor 7: Vascular access devices
8.4 Discussion 8.5 references 9.2 methods 9.2.1 Check valves 9.2.2 Experimental set-up 9.2.3 Study set-up 9.3 results
9.3.1 Experiment I: Adding syringes 9.3.2 Experiment II: Changing height
9.4 Discussion 9.5 references chAPter 10
General discussion
10.1 main conclusions
10.1.1 Supplemental oxygen therapy 10.1.2 IV therapy
10.2 on the research approach
10.2.1 Supplemental oxygen therapy 10.2.2 IV therapy
10.3 the need for standardization 10.4 future work 10.4.1 Changes in culture 10.4.2 Technical improvements 10.5 conclusion 10.6 references APPeNDices summAry sAmeNVAttiNg DANKwoorD ABout the Author 111 112 112 116 118 121 123 124 126 131 133 135 137 139 140 140 155 157 164 168 173 176 179 181 182 183 185 187 188 191 201 207 213 221
1.1
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 refers to the therapy where a gas mixture with >21% of oxy-gen is supplied to the patient via (mechanical) ventilation. Due to the immaturity of the pre-term infants’ lungs, supplemental oxygen therapy is often needed immediately after birth to reach and maintain adequate oxygenation of the preterm infant. Unfortunately supplemen-tal oxygen therapy is not without risk. Both too high and too low blood oxygen levels may have severe consequences for the development of the preterm infant.
The immaturity of organs and/or severe illness are also reasons why IV therapy is essential for preterm infants hospitalised on a NICU. In IV therapy various types of nutrition, drugs, and/or fluids are administered directly into the veins of the patient via a vascular access device. Because of the limited vascular access possibilities, infusion is used. In multi-infusion therapy, several multi-infusions are supplied to the infant via a single catheter. To ad-minister the IV fluids with a pre-programmed flow-rate into the patient, ‘syringe pumps’ are frequently 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 infants, these changes in delivered volume can have severe consequences.
In the next paragraphs the background of prematurity, supplemental oxygen therapy, and IV therapy are discussed in more detail. In the final paragraphs of 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
1.2
Preterm iNfANts, DefiNitioNs & PreVALeNce
A term, healthy newborn infant is born after a pregnancy duration of 37 to 42 weeks with a birth weight (BW) of approximately 3.5 kg. The pregnancy duration, or ‘gestational age (GA)’, is calculated from the first day of the last menstruation of the mother. When an in-fant is born with a GA ≤37 weeks it is classified as ‘preterm’, ‘very preterm’ (<30 weeks), or ‘extremely preterm’ (<28 weeks). When the birth weight of the infant is less than 2500 grams, it is defined as ‘low birth weight’ (LBW), ‘very low birth weight’ (≤1500 g.; VLBW) or, ‘extremely low birth weight’ (≤1000 g.; ELBW).
In the past, infants born preterm and/or with a low birth weight had little chance of survival due to a lack of knowledge about the needs of this specific group of patients. Since the term ‘neonatology’ was first mentioned in a textbook in 1960, major developments in neonatal
care have been made.1, 2 Thanks to on-going research and improved treatment, both survival
rates and long term outcome of preterm infants have improved enormously.3 Nowadays,
infants born after only 24 weeks of pregnancy are more likely to survive than ever before. While the medical care for (preterm) newborn infants has advanced, the prevalence of
pre-term births has also been increasing.4-6 Currently, in the United States the preterm delivery
rate is about 12 to 13%; in Europe it is lower, about 5 to 9%. Worldwide, about 80% of the pre-term infants is born after a pregnancy duration of 32 to 36 weeks. About 15% is born between
28 and 31 weeks, and 5% is born before 28 weeks.7 In the Netherlands, in the first decade of
the 21st century, the percentage of births <32 weeks (including still births) was between 1.4
and 1.6%. Figure 1.1 presents the corresponding number of births <32 weeks and the number of survivors at postnatal day 28.
figure 1.1 Number of births (including still births) <32 weeks, and the number of survivors at postnatal
day 28 in the Netherlands from 2001 to 2008. (Graph based on data obtained from ‘Stichting Perinatale Registratie Nederland’). 3000 2500 2000 1500 1000 500 0 N umber of births 2001, B irths 2001, S urviv ors 2002, B irths 2002, S urviv ors 2003, B irths 2003, S urviv ors 2004, B irths 2004, S urviv ors 2005, B irths 2005, S urviv ors 2006, B irths 2006, S urviv ors 2007 , B irths 2007 , S urviv ors 2008, B irths 2008, S urviv ors 22.0-23.6 wks 24.0-24.6 wks 25.0-25.6 wks 26.0-27.6 wks 28.0-31.6 wks
1.3
PremAturity, cAuses & outcome
Preterm infants are either born spontaneously (40 to 45%), by induced labour or by caesarean section. The latter two are performed because of preterm premature rupture of
membranes (25 to 30%) or because of maternal or foetal indications (30 to 35%).7 The cause
for prematurity is multifactorial and includes maternal characteristics like race, age, weight, health in general, and pregnancy history. The educational status, socio-economic status,
and marital status of 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 of the
pregnancy, like assisted reproductive technologies and multiple gestation, are also risk fac-tors for preterm labour: about 50 to 60% of all multiple gestation pregnancies end in pre-term birth. While only 2 to 3% of the infants is part of a multiple gestation, they account for
15 to 20% of all preterm births.7, 18
Although the chances of survival for preterm infants have increased enormously in the last decades, there is still a large part of the surviving infants that suffer from 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 of adverse outcome is strongly related to the pregnancy duration and birth weight.
Hille et al.21 showed that in the Netherlands 36% of the ELBW infants had moderate to
se-vere problems in overall outcome at the age of 19 years.However, it is difficult to interpret
these numbers because the medical care provided to newborn infants develops continuous-ly, and long term outcome data are always behind on the current status of neonatal care.
1.4
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 Mount Everest. 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 after birth results in a sharp increase in reactive oxy-gen species (ROS). ROS are chemically reactive molecules that contain oxyoxy-gen. 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
and antioxidants. Although oxidants and antioxidants both are necessary for maintaining life, an imbalance in favour of 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 after birth, several processes take place in the foetus in the final weeks before term birth. These processes comprise, amongst others, an increase in both antioxidants and lung surfactant. Surfactant is a fluid that lowers the
surface tension of the lungs, making it easier to inflate them.23, 25
Preterm infants lack the preparation for the sudden increase in oxygen tension because they are born too early. Consequently, their defence system for antioxidants is immature, and therefore, they are at increased risk for oxidative stress after birth. The risk for oxida-tive stress increases even more when preterm infants receive supplemental oxygen therapy
and/or develop infections.26-28
In 1988 Saugstad was the first to mention the term ‘‘oxygen radical disease of the newborn’’.29
He stated that several diseases in preterm infants have a common pathogenesis via oxi-dative stress. Since then, it became clear that diseases typical for neonatal intensive care like bronchopulmonary dysplasia, infant respiratory distress syndrome, necrotizing enterocoli-tis, retinopathy of prematurity, patent ductus arteriosus and periventricular leukomalacia are associated with oxidative stress. However, it is not always clear whether the presence of
oxidative stress is a cause or a result of the disease process.26, 29-31 To show examples of the
possible consequences of suboptimal or incorrect use of supplemental oxygen therapy, four of the disorders mentioned above are discussed in more detail in the next paragraphs.
1.4.1 BroNchoPuLmoNAry DysPLAsiA
Bronchopulmonary dysplasia (BPD) is a disorder characterised by respiratory distress and
airway inflammation.32 The disorder was first described in 1967 by Northway et al.,33 and
diagnosed when there was a need for supplemental oxygen therapy at a postnatal age of 28 days. Because since then the GA of surviving preterm infants decreased, the definition is not valid anymore. Therefore, the term ‘new-BPD’ was introduced. New-BPD is diag-nosed when there is need for supplemental oxygen therapy or ventilatory support at a post- menstrual age of 36 weeks, regardless of the GA or postnatal age.
Studies on the prevalence of BPD found the disorder in 22% of all infants with a birth weight
between 501 and 1500 grams.34, 35 The exact pathogenesis of BPD is unclear, but it seems to be
multifactorial. Risk factors are, amongst others, low birth weight, mechanical ventilation, and supplemental oxygen therapy. To treat the symptoms of BPD several types of medi-cation, like corticosteroids, are available. In some cases special mechanical ventilation is
1.4.2 iNfANt resPirAtory Distress syNDrome
In order to breathe normally, the alveoli in the lungs need to be inflated. To inflate the alveoli, surfactant is required. Due to the short pregnancy duration, in very preterm in-fants, there is often a surfactant deficiency. As a result of this lack of surfactant, the alveoli collapse and the total lung capacity decreases. This phenomenon is referred to as ‘(Infant) respiratory distress syndrome ((I)RDS)’. Symptoms include laboured and fast breathing, cyanosis, grunting, and nasal flaring.
To diagnose IRDS, radiography is used: a low lung volume is one of the signs for IRDS. Due to the decreased lung capacity, mechanical ventilation and supplemental oxygen therapy are required. The incidence of IRDS is inversely related to the pregnancy duration. Thanks to the use of both antenatal steroids to promote lung maturation and the use of surfactant therapy after birth, the incidence of IRDS in preterm infants has been reduced
enormously.36, 40
1.4.3 PAteNt Ductus Arteriosus
The blood circulation of a foetus 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. After birth, several physiological changes cause the closure of 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 after birth, a patent
ductus arteriosus (PDA) is diagnosed.41
About 65% of the infants born with a GA <30 weeks suffers from PDA.42 A PDA may have a
negative effect on (amongst others) the cerebral oxygenation and the pulmonary function
of the infant.43 The diagnosis of PDA is typically confirmed by echocardiography and can be
treated with medication or surgical ligation.44
1.4.4 retiNoPAthy of PremAturity
Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina in preterm infants and an important, potentially preventable, cause of blindness in childhood. In in-fants with ROP, the vascularisation of the retina is disturbed during the first weeks of extra-
uterine life.45, 46 The most important risk factors for the development of ROP are
prema-turity and supplemental oxygen therapy. Furthermore, factors like low birth weight, blood
transfusions, neonatal sepsis, and BPD are also associated with higher rates of ROP.47-67
ROP was first described by Terry in the 1940’s.68 Nowadays the disorder is diagnosed
most frequently in middle income countries where there is a lack of qualified personnel,
resources, and screening and treatment programs.69-71 However, even in the more equipped
centres with a long established neonatal intensive care, the incidence of ROP in infants
with a birth weight ≤1250 gram is still 10% to 15%.72, 73 Treatment of ROP includes the retinal
ablation of the avascular retina by cryotherapy or laser photocoagulation. The best method
1.5
suPPLemeNtAL oxygeN therAPy
After the outline about the diseases that are caused or followed by suboptimal oxygenation it is obvious why maintaining adequate oxygenation in preterm infants is a major issue. In healthy adults and children adequate oxygenation is maintained by a network of complex processes with multiple parameters influencing each other. To reach and maintain adequate oxygenation in preterm infants, it would be desirable for neonatologists to be able to moni-tor and control these parameters (continuously). Although current mechanical ventilamoni-tors and monitoring techniques are sophisticated, it is still difficult to monitor and control the relevant parameters in preterm infants.
One of the parameters that can be monitored is the arterial oxygen saturation (SaO2). In preterm infants 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 referred 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 fraction of inspired oxygen (FiO2) in the gas mixture supplied to the infant. The FiO2 can be adjusted from 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 of this process is shown in Figure 1.2. Although supplemental oxygen therapy increased chances of survival after preterm birth, it has been known for about 60 years that supplemental oxygen therapy in preterm infants is not
with-out risks.75-77
figure 1.2 The process of controlling oxygenation. The input of the system is the target level of oxygen
saturation (SaO2) at the left side of 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, for instance adjusting the fraction of inspired oxygen (FiO2). The FiO2 is supplied to the patient by a ventilator used for respiration. In the blood of 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.
-Target level SaO2 SaO2 level in blood Human controller Patient Sensor Alarm+
1.5.1 A Brief oVerView of history of suPPLemeNtAL oxygeN therAPy
Soon after the discovery of oxygen in 1774, this ‘life-giving gas’ was used for medical pur-poses. In 1780 the Frenchman Chaussier was the first who used oxygen for newborn infants with respiratory problems. From then it took one and a half century before oxygen was
widely and liberally used for respiratory support in newborn infants in the 1940’s.76-78 The
negative effects of the use of 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 performed to investigate the risks of supplemental oxygen therapy. The conclusion of this trial was that it was safe to give oxygen to newborn infants as long
as the FiO2 was below 40%.82, 83 Although some serious methodological errors were made
in this trial, the results were widely accepted. It was so strongly believed that FiO2 >40% was harmful that, when an infant developed ROP, the hospital was accused for malpractice.
After all, the ROP was the ‘proof’ 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, 86 As 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
1.6
iV therAPy
In IV therapy, various types of parenteral nutrition, drugs, and/or fluids are administered directly into the veins of the patient. To deliver these IV substances with a pre-programmed flow-rate to the patient, a mechanical pump pushes the plunger of 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.
Often, because intravenous access in preterm infants is limited and several IV substances need to be administered simultaneously, multi-infusion is used. In multi-infusion, 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 of a multi-infusion set up is shown in Figure 1.3. Although multi-infusion creates the possibility to provide various substances simultaneously, the accuracy and the predictability of the volumes delivered to the patient is limited.
figure 1.3 Schematic overview of multi infusion intravenous (IV) therapy. Two or more syringe pumps
are connected to one vascular access device via infusion tubing and an add-on device (e.g., a stopcock with 3-way valves).
1.6.1 A Brief oVerView of history of iV therAPy
The first attempts of IV therapy were already made in the Middle Ages. In 1492 the ill Pope Innocent VIII was transfused with blood from three boys via vein-to-vein anastomosis.
Re-grettably the pope and donors died. From then until the second half of the 17th century the
knowledge of blood, the blood circulation, and IV therapy increased enormously. This in-crease in knowledge was realised by performing numerous experiments with blood transfu-sions in and between animals and humans. However, because these experiments frequently resulted in the death of the subjects, several governments and churches decreed the
perfor-mance of blood transfusions as a criminal act.90, 91
In the 1800’s, the work of Dr. William Brooke O’Shaughnessy and his student Thomas Latta formed the basis for modern IV therapy. During the cholera epidemic in England in the 1830’s, O’Shaughnessy realised that the typical thick black blood of the cholera victims was a result of a shortage of water, saline, and alkali. Therefore, he indicated that the patients needed injections of water and salts in the bloodstream. In 1832, Thomas Latta applied the recommendations, and saved 8 of the 25 victims he treated with intravenous saline using a
small silver tube attached to a syringe.90, 92
Infusion tubing
Vascular acces device
To patient Syringe pumps with
syringes
Stopcock with 3-way valves
After the results of O’Shaughnessy and Latta, it lasted until the two World Wars before further 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 of organizing special IV teams became very popular during the 1970’s. Since then great advances in IV therapy were made. These advances were, amongst others, the result of the development of plastic IV materials.
Today, virtually all hospitalised patients receive IV therapy.90, 91
In newborn infants IV therapy is more complicated than in adults due to, amongst others, the small size of the vessels. Fortunately, together with the progress in the development of materials for IV therapy in adults, the manufacturing of dedicated materials for (preterm) newborn infants advanced as well. For example, today it is possible to buy vascular access devices with an outer diameter of only 0.35 mm to serve the needs for ELBW infants. How-ever, despite the presence of dedicated materials for the smallest patients, the accuracy of
the actual delivered IV substances still needs to be improved.93-101
1.7
ProBLem stAtemeNts
Both supplemental oxygen therapy and IV therapy are necessary, but potentially dangerous therapies. In the next paragraphs, the problem statements for both therapies are discussed separately.
1.7.1 suPPLemeNtAL oxygeN therAPy
In supplemental oxygen therapy the FiO2 can be adjusted from 21% (room air) to 100% (pure oxygen) manually. Manual control of the oxygenation as described in Figure 1.2 is time consuming and very difficult to do accurately, mainly because of the frequent and
un-predictable fluctuations of the SpO2.102-107 When SpO2 is outside the desired range an alarm
sounds. The high rate of alarms may lead to anxiety of patients and their family, and to a
reduced or delayed reaction of the nursing staff.108 Although supplemental oxygen therapy
has been widely used in newborn infants for more than 60 years, there is still no consensus about the target ranges for blood oxygen levels, and the best methods to give (preterm)
newborn infants this treatment.75-77
To increase the quality of supplemental oxygen therapy and to reduce workload of the nursing staff, several groups worldwide have developed devices for (semi-)automatic control of the oxygenation. Most of the devices for (semi-)automatic control of oxygenation adjust the FiO2 supplied to the patient (semi-)automatically when SpO2 deviates from the target.
The first devices that were developed were dedicated servo systems.109-112 With the
develop-ment of computer aided control the devices became more advanced:
‘Proportional-Integral-Derivative’ control with or without adaptive models,52, 56, 103, 113-117 dual control methods,118-120
state machine106, 121 and fuzzy logic control122 have all been developed and tested.
first author
time spo2 is within target range
manual control [%] Dedicated control [%] Automatic control [%](semi-)
Beddis109, Collins110 72 - 88 Dugdale112 45 - 75 Taube113 54 69 81 Bhutani115 54 69 81 Morozoff121 17 - 46 Morozoff116 39 - 50 Sun122, 128 58 - 72 Claure105, 118 - 66 75
Urschitz106 Open loop 80 86 85
Urschitz106 Closed loop 82 91 91
Morozoff123 State machine 57 - 71
Morozoff123 Adaptive model 57 - 73
Morozoff123 Closed loop, PID 57 - 70
Claure124 42 - 58
Claure125 32 - 40
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, 126-128 Some 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 1.1 Time spent within the target range for SpO2 for periods on manual, dedicated manual, and
(semi-)automatic control.
The term ‘manual control’ is used to refer to the situation in normal daily NICU care. ‘Dedicated con-trol’ is a situation where a physician or nurse stays at the bedside of the patient and is focussing on the control of 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.
To improve outcome for those situations where oxygenation is controlled manually, two studies focused on the development of protocols to standardise when, why, and how FiO2
should be adjusted.130, 131 One of these studies actually showed a reduction in the incidence
of ROP.131 However, both studies mention difficulties with implementation of the protocol
and compliance to it. Because none of the studies actually quantified the performed manual FiO2 adjustments, knowledge about the actual behaviour of NICU personnel with respect to control of the oxygenation is still lacking.
1.7.2 iV therAPy
IV therapy is hampered by a number of complications and limitations. The most well-known are related to infections, and extravasation. While these complications are very relevant, they are outside the scope of this thesis. The focus in this thesis is on a, probably underestimated, limitation in IV therapy: ‘flow-rate variability’. This flow-rate variability is caused by multiple factors and complicates the accuracy and predictability of the actual volumes delivered to the patient. Moreover, the flow-rate variability can lead to, for instance,
changes in the haemodynamics and oxygenation of newborn infants.93, 97, 99, 132, 133 Therefore, it
is important to minimise flow-rate variability in IV therapy in clinical practice.
Two of the factors that affect the flow-rate variability are backflow and siphonage. In si-phonage, there is uncontrolled emptying or free flow of substances from 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, 134-136 Backflow
can occur when multiple infusions are interconnected to each other (e.g., via a stopcock). Because of differences in resistance in the IV-administration set, it is possible that fluids do
not flow from 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, 138 Thus, 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.
1.8
oBJectiVes
The primary objective of this thesis is to determine the limitations of supplemental oxygen therapy and IV therapy in current neonatal intensive care and to identify areas for 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.
1.8.1 PArt i suPPLemeNtAL oxygeN therAPy
In Part I of the thesis, the work related to supplemental oxygen therapy in preterm infants is discussed. The secondary objectives are:
I.I To obtain background information regarding oxygenation of the human body, to get
an overview of literature on target ranges for blood oxygen levels in newborn infants, and to evaluate methods for monitoring oxygenation in neonatology.
I.II To evaluate the performance of new-generation pulse oximeters of three different
brands in ELBW infants.
I.III To quantify manual adjustments in the FiO2 performed by NICU personnel in ELBW infants, in relation to SpO2 and bedside care.
I.IV To study the compliance to the protocol for pulse oximetry alarm limits in ELBW infants 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 of the nursing staff towards supplemental oxygen therapy in ELBW infants.
I.VI To prospectively evaluate hazards in the process of supplemental oxygen therapy in very preterm infants hospitalised in a NICU.
1.8.2 PArt ii iNtrAVeNous therAPy
In Part II of the thesis the work related to IV therapy in newborn infants is discussed. The secondary objectives are:
II.I To study which factors are responsible for flow-rate variability in IV therapy with
syringe pumps.
II.II To evaluate the effect of three different types of check valves on flow characteristics in a low-flow multi-infusion set.
1.9
thesis outLiNe
To meet the objectives, five studies were performed. These studies form, together with the literature reviews on the discussed subjects, the basis of this thesis.
The first part of this thesis is about supplemental oxygen therapy in preterm infants.
Chap-ter 2 is the first chapChap-ter of Part I and provides a liChap-terature review to meet objective I.I. First
the background information regarding oxygenation of the human body and especially that of preterm infants is described. Next, the working principles and (dis)advantages of current developed methods for monitoring oxygenation are elaborated on. Thereafter, an over-view of literature on target ranges for blood oxygen levels in (preterm) newborn infants is provided. Finally, a future perspective of the needs for oxygen monitoring in (preterm)
newborn infants is discussed. Chapter 3 describes a study to the performance of new-
generation pulse oximeters in ELBW infants to meet objective I.II. In this study three dif-ferent brands of pulse oximeters were compared by dual SpO2 monitoring in nine ELBW
infants. In Chapter 4 and Chapter 5 an observational study is discussed. During this
obser-vational study on-ward video and data recording was performed to obtain insights in the manual control of oxygenation in ELBW infants by healthcare professionals. This obser-
vational study was set up to meet both objectives I.III and I.IV. Chapter 6 provides the
re-sults of 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 of the nursing staff towards supplemental oxygen therapy in ELBW infants. The final chapter
of Part I is Chapter 7. In this chapter the hazards in the process of supplemental oxygen
therapy in preterm infants 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 of the thesis is about IV therapy in newborn infants and starts with Chapter 8 where
a literature review is discussed to meet objective II.I. Chapter 9 describes an in-vitro study
to the effect of three different types of check valves on the flow characteristics of a low-flow multi-infusion set. This study was set up to meet objective II.II.
Chapter 10 provides the general discussion about both supplemental oxygen therapy and
IV therapy. The main conclusions and the research approach of the work performed in this thesis are presented together with recommendations for future work.
It should be noted that Chapters 3 to 9 are written as separate papers, consequently, there is a certain amount of overlapping information within these chapters. Furthermore, in this thesis the masculine form is used for all healthcare professionals and patients, merely to simplify the text. No discrimination is intended.
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Part 1
supplemental
oxygen therapy
Oxygenation in
preterm infants:
background, target
ranges & monitoring
techniques
It is inherent to their immaturity that preterm infants need some form of 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 information about the oxygenation of the human body, and especially that of preterm infants, is provided. Subsequently, the working principles and (dis)advantages of methods that are available for monitoring oxygenation are elaborated on. Thereafter, an overview of literature on target ranges for blood oxygen levels in (preterm) newborn infants is provided. Finally, a future perspective of the needs for oxygen monitoring in preterm infants is discussed.
oBJectiVe To obtain background information regarding oxygenation of the human
body, to get an overview of literature on target ranges for blood oxygen levels in new-born infants, and to evaluate methods for monitoring oxygenation in neonatology.
2.1
iNtroDuctioN
Approximately five to ten percent of all newborn infants need active resuscitation imme-
diately after birth to survive.1 The majority of these infants is born preterm. Due to the
im-maturity of organs like the lungs and brain of these preterm infants, respiratory support and supplemental oxygen therapy are necessary to reach and maintain adequate oxygenation. In supplemental oxygen therapy, a gas mixture with >21% of oxygen is supplied to the patient via mechanical ventilation. In preterm infants this therapy is not only used imme- diately after birth, but also in the first weeks after birth. Unfortunately, supplemental oxygen therapy is not without risks. Both too low and too high levels of oxygen in the tissues may have severe consequences for the development and outcome of preterm
infants.2 Therefore, to prevent the negative effects of supplemental oxygen therapy, blood
oxygen levels of preterm infants 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 infants have been developed. Regrettably, these monitoring systems did not always serve the spe-cific needs for the patients, the family, and/or the healthcare professionals in the optimal way. The aims of this chapter are to provide background information about oxygenation of the human body, to provide an overview of the techniques (that were) available for moni-toring oxygenation in preterm infants, and to discuss target ranges for blood oxygen levels in (preterm) newborn infants. Finally, the needs and future perspectives for monitoring oxygenation in (preterm) newborn infants are discussed.
