Nutritional abnormalities in patients receiving long-term home parenteral nutrition

324 Pages·2017·4.75 MB·English

by  Sean Dodington

Nutritional abnormalities in patients receiving
long-term home parenteral nutrition

Sean Rhys Dodington

A thesis submitted in accordance with the conditions governing
candidates for the degree of

Philosophiæ Doctor in Cardiff University

Cardiff School of Pharmaceutical Sciences
Cardiff University

May 2018
DECLARATION

This work has not been submitted in substance for any other degree or award
at this or any other university or place of learning, nor is being submitted
concurrently in candidature for any degree or other award.
Signed: (Sean Dodington) Date: 02 May 2018

STATEMENT 1
This thesis is being submitted in partial fulfilment of the requirements for the
degree of PhD.
Signed: (Sean Dodington) Date: 02 May 2018

STATEMENT 2
This thesis is the result of my own independent work/investigation, except
where otherwise stated. Other sources are acknowledged by explicit
references. The views expressed are my own.
Signed: (Sean Dodington) Date: 02 May 2018

STATEMENT 3:
I hereby give consent for my thesis, if accepted, to be available online in the
University’s Open Access repository and for inter-library loan, and for the title
and summary to be made available to outside organisations.
Signed: (Sean Dodington) Date: 02 May 2018
ACKNOWLEDGEMENTS
First of all, I would like to thank my supervisors Dr Rebecca Price-Davies and
Dr Allan Cosslett for welcoming me into their lab and for providing constant
unwavering support, friendship and guidance throughout the project.
Ultimately, they have helped me to grow as a professional researcher.

Secondly, I give thanks to my postgraduate peers, laboratory colleagues and
family (you know who you are). Studying for a PhD would have been a far
harder task without the technical advice, emotional support, highs and lows,
banter, laughs and cries, tea and cake, encouragement and feedback from close
friends/family. Be it whingey phone calls, post-grad social drinks or
presentation feedback, good company has made the last few years a very
enjoyable period.

My thanks also extend to Susanna Harwood and the nutrition support team at
UHW; by working alongside them I was able to learn everything I needed to
know about PN and it also helped me to engage with the research area.
Furthermore, I thank my colleagues at St Mary’s Pharmaceutical Unit, Paul
Spark, Sarah Hiom and Brenda Manley, who hosted my data collection, gave
me the opportunity to continue working as a pharmacist throughout my
studies and enabled a happy, collaborative research network between the
University and the NHS.

Last but not least, I am grateful towards the HPN patients and their kind
agreement to take part in this PhD study, without whom this project would not
have been possible.

Overall, this has been one of the most challenging, yet enjoyable and rewarding
experiences of my life. I’m grateful to everyone who has made this journey
possible.
SUMMARY
The last two decades have seen an increased drive to administer parenteral nutrition
(PN) to patients in their home environments, thereby reducing associated hospital
costs and improving patient quality of life.

The occurrence of deranged nutritional biochemistry results has baffled PN experts
for years because PN additives are marketed for the general needs of patients and PN
is tailored to each patient’s requirements (both formulation and regimen).

This thesis documents the investigations into HPN population characteristics, the
extent of nutritional abnormalities (deficiencies and excesses) in a cohort of LT PN
patients in Wales. Both cross-sectional and longitudinal retrospective study designs
were employed alongside small-scale laboratory efforts to investigate stability of
vitamin D in PN additives using High Performance Liquid Chromatography (HPLC).

Characteristics of the HPN population in Wales were shown to be variable in terms of
PN requirements for a predominantly female sample population (2:1); in whom
78.6% of patients received PN for indications relating to short bowel syndrome (SBS).

A database analysis of micronutrient test results revealed a high prevalence of
deficiencies of vitamin D and selenium, as well as excesses of manganese and water-
soluble vitamins; which can lead to clinically relevant effects in patients.

The sample population was shown to have impaired bone health since first receiving
PN; respective sites of the femoral neck and total hip presented 58% and 60.8% of
patients had osteopenia, while 28% and 19.6% had osteoporosis. Evidence in the
literature links these clinical outcomes of metabolic bone disease (MBD) to patients’
inadequate vitamin D status.

A final study exploring the adequacy of the trace element (TE) preparation
Additrace®, found it lacking in selenium and excessive in manganese for the general
requirements of the PN population. Clinician-directed supplementation of PN outside
of Additrace® was associated with better micronutrient status in patients and more
test results within range.
ABBREVIATIONS

AKI acute kidney injury
AMA American Medical Association
ANOVA analysis of variance
APR acute phase response
AP-spine anterior-posterior spine
ASPEN American Society for Parenteral and Enteral Nutrition
BANS British Artificial Nutrition Survey
BAPEN British Association for Parenteral and Enteral Nutrition
BMD bone mineral density
BPNG British Pharmaceutical Nutrition Group
BW body weight
CAD charged aerosol detection
C&V UHB Cardiff and Vale University Health Board
CRP C-reactive protein
DEXA dual energy x-ray absorptiometry
EFAD essential fatty acid deficiency
EN enteral nutrition
ESPEN The European Society for Clinical Nutrition and
Metabolism
fA (femto)-ampere
FRAX Fracture Risk Assessment Tool
GI gastrointestinal
HPLC high performance liquid chromatography
HPN home parenteral nutrition
IBD inflammatory bowel disease
IF intestinal failure
IPFR individual patient funding request
IV intravenous
LCMS liquid chromatography-mass spectroscopy
LCT long-chain triglyceride
LOD limit of detection
LOQ limit of quantitation
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LT long-term
MCT medium-chain triglyceride
MBD metabolic bone disease
MCP multi-component preparation
MRI magnetic resonance imaging
NHS National Health Service
NICE National Institute for Health and Care Excellence
NST nutrition support team
pA (pico)-ampere
PIS participant information sheet
PN parenteral nutrition
PNALD PN-associated liver disease
PTH parathyroid hormone
QOL quality of life
R&D Research and Development
RDA recommended dietary allowance
REC Research Ethics Committee
RNI reference nutrient intake
RP-HPLC reverse phase HPLC
SBS short bowel syndrome
SD standard deviation
S/N signal to noise ratio
SE service evaluation
TE trace element
UHW University Hospital of Wales
UK United Kingdom
US United States
UV ultraviolet
WHSSC Welsh Health Specialised Services Committee
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TABLE OF CONTENTS

Declaration .................................................................................................................................. 2
STATEMENT 1 ....................................................................................................................... 2
STATEMENT 2 ....................................................................................................................... 2
STATEMENT 3: ..................................................................................................................... 2
Acknowledgements .................................................................................................................. 3
Summary ...................................................................................................................................... 4
Abbreviations ............................................................................................................................. 5
Table of contents ....................................................................................................................... 7
List of figures ............................................................................................................................14
List of tables ..............................................................................................................................15
1.1. Introduction to parenteral nutrition (PN) and HPN .........................................19
1.1.1. PN .................................................................................................................................19
1.1.2. Indication for PN ....................................................................................................20
1.1.3. Background for HPN .............................................................................................22
1.1.4. Monitoring in LT HPN ..........................................................................................23
1.1.5. HPN prevalence ......................................................................................................24
1.1.6. Homecare services ................................................................................................25
1.1.7. Initiation for LT PN (flow diagram) ................................................................27
1.2. Components of PN and typical patient requirements ......................................28
1.2.1. Energy sources and provision in PN ...............................................................29
1.2.2. Carbohydrate provision in PN ..........................................................................30
1.2.3. Lipid provision in PN ............................................................................................31
1.2.4. Protein provision in PN .......................................................................................32
1.2.5. Water and electrolytes .........................................................................................32
1.2.6. Micronutrients (vitamins and TE) ...................................................................33
1.3. Complications of PN ......................................................................................................34
1.3.1. Central catheter care and line infections ......................................................34
1.3.2. Acute metabolic complications .........................................................................35
1.3.2.1. Refeeding syndrome .....................................................................................35
1.3.3. Long-term metabolic complications ...............................................................35
1.3.3.1. Nutritional abnormalities ...........................................................................35
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1.3.3.2. Liver steatosis and cholestatic liver disease .......................................36
1.3.3.3. Cholelithiasis and acalculous cholecystitis ..........................................37
1.3.3.4. Bone disease ....................................................................................................37
1.4. Stability of PN ..................................................................................................................38
1.4.1. Contamination of PN .............................................................................................39
1.5. Introduction to thesis ...................................................................................................40
1.5.1. Research outline .....................................................................................................40
1.5.2. Research question .................................................................................................44
1.5.3. Aims .............................................................................................................................44
1.5.4. Objectives ..................................................................................................................45
2.1. Introduction .....................................................................................................................48
2.2. Research approvals and permissions .....................................................................48
2.2.1. NHS research ethics committees (REC) ........................................................48
2.2.2. National Health Service (NHS) management permission ......................48
2.3. Participant recruitment ...............................................................................................48
2.3.1. Participant recruitment protocol and consent ...........................................48
2.3.2. Sampling ....................................................................................................................50
2.3.2.1. Inclusion criteria ............................................................................................50
2.3.2.2. Exclusion criteria ...........................................................................................50
2.3.3. Finalised recruitment ...........................................................................................52
2.4. Data collection .................................................................................................................54
2.4.1. Anonymisation and data security ....................................................................54
2.5. Service evaluation approval .......................................................................................54
3.1. Introduction .....................................................................................................................56
3.1.2. Background and rationale ..................................................................................56
3.2. Methods ..............................................................................................................................61
3.2.1. Research permissions ..........................................................................................61
3.3. Study design ................................................................................................................61
3.3.1. Data collection and sample population ....................................................61
3.3.2. Data handling, storage and analysis ..........................................................62
3.3.3. Data parameters ................................................................................................63
3.4. Results ................................................................................................................................67
3.4.1. Patient-related factors .........................................................................................67
3.4.2. Disease-related factors ........................................................................................68
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3.4.3. PN-related factors ..................................................................................................70
3.4.4. Co-prescribed medicines ....................................................................................72
3.5. Discussion .........................................................................................................................73
3.5.1. Patient-related factors .........................................................................................73
3.5.2. Disease-related factors ........................................................................................75
3.5.3. PN-related factors ..................................................................................................78
3.5.4. Technical aspects ...................................................................................................81
3.5.5. Co-prescribed medicines ....................................................................................81
3.5.6. Other discussion points .......................................................................................82
3.6. Conclusions .......................................................................................................................83
4.1. Introduction .....................................................................................................................85
4.1.1. Micronutrients - background ............................................................................85
4.1.2. Micronutrient status in HPN ..............................................................................85
4.1.3. Commercial micronutrient preparations .....................................................86
4.1.4. Nutritional abnormalities - background .......................................................89
4.1.5. Guidelines and monitoring of micronutrient status .................................93
4.1.5.1. Accuracy of micronutrient assessment .................................................94
4.1.5.2. Contamination of PN admixtures. ...........................................................96
4.2. Review of relevant literature .....................................................................................97
4.2.1. Noteworthy micronutrient abnormalities - TE ..........................................98
4.2.1.1. Copper ................................................................................................................98
4.2.1.2. Iron ................................................................................................................... 100
4.2.1.3. Manganese ..................................................................................................... 101
4.2.1.4. Selenium ......................................................................................................... 103
4.2.1.5. Zinc ................................................................................................................... 106
4.2.1.6. Other notable TE abnormalities ........................................................... 107
4.2.2. Noteworthy micronutrient abnormalities – vitamins .......................... 112
4.2.2.1. Vitamin A (retinol) ..................................................................................... 112
4.2.2.2. Vitamin B9 (folate/folic acid) ................................................................ 113
4.2.2.3. Vitamin B12 (cobalamin) ........................................................................ 114
4.2.2.4. Vitamin D (chole/ergo-calciferol) ........................................................ 115
4.2.2.5. Vitamin E (tocopherol) ............................................................................. 120
4.2.2.6. Other notable vitamin abnormalities ................................................. 122
4.3. Summary ......................................................................................................................... 130
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5.1. Introduction .................................................................................................................. 132
5.1.1. Chapter aims ......................................................................................................... 132
5.1.2. Rationale................................................................................................................. 132
5.1.3. Reference range definition .............................................................................. 134
5.2. Methods ........................................................................................................................... 135
5.2.1. Research permissions ....................................................................................... 135
5.2.2. Study design .......................................................................................................... 135
5.2.2.1. Data collection and sample population .............................................. 135
5.2.2.2. Data handling, storage and analysis .................................................... 136
5.2.2.3. Data parameters.......................................................................................... 136
5.2.2.4. Methods of analysis ................................................................................... 142
5.3. Results ............................................................................................................................. 143
5.3.1. Total results for participant cohort. ............................................................ 143
5.3.1.1. Trace elements and ferritin .................................................................... 143
5.3.1.2. Vitamins ......................................................................................................... 143
5.3.1.3. Mean (±SD) and range for all micronutrient blood test data .... 144
5.3.2. Comparative group analyses .......................................................................... 145
5.3.2.1. IF pathophysiological classification .................................................... 145
5.3.2.2. Underlying disease (that causes IF) .................................................... 146
5.4. Discussion ...................................................................................................................... 148
5.4.1. General discussion and main findings ........................................................ 148
5.4.1.1 Trace elements and ferritin ..................................................................... 149
5.4.1.2. Vitamins ......................................................................................................... 153
5.4.1.3. Comparative group analyses .................................................................. 157
5.4.2. Limitations ............................................................................................................. 159
5.4.3. Future work .......................................................................................................... 162
5.5. Conclusion ...................................................................................................................... 165
6.1. Introduction .................................................................................................................. 167
6.2. Background and rationale ........................................................................................ 168
6.2.1. General vitamin D stability .............................................................................. 168
6.2.2. Vitamin D stability in PN .................................................................................. 169
6.3. High performance liquid chromatography (HPLC) investigations into
vitamin D stability ............................................................................................................... 171
6.3.1. HPLC system ......................................................................................................... 171
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