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Conducting and Reporting Systematic Reviews of
Adverse Events
by
Liliane Medianeira Zorzela
A thesis submitted in partial fulfillment of the requirements for the degree of

Doctor of Philosophy

Medical Sciences - Pediatrics
University of Alberta

© Liliane Medianeira Zorzela, 2015
 

 
 
Abstract  
 
Introduction  
Systematic  reviews  (SRs)  synthesize  published  and  sometimes  unpublished  data  and  are  often  
based   on   randomized   controlled   trials   (RCTs).   However,   RCTs   are   known   to   be   poor   at  
identifying   and   reporting   harms.   The   PRISMA   (Preferred   Reporting   Items   for   Systematic  
Reviews   and   Meta-­‐Analysis)   Statement   was   published   in   2009   to   offer   guidance   on   the  
minimum  reporting  standards  when  publishing  a  SR.  Thus  far,  PRISMA  has  mainly  focused  on  
efficacy,  but  there  is  a  need  for  evidence  on  both  efficacy  and  harms  of  interventions.  

Propofol  is  an  anesthetic  intervention  used  for  pediatric  sedation,  but  there  have  been  several  
case   reports   of   ‘propofol   infusion   syndrome’   (PRIS),   a   poorly   understood   syndrome   often  
leading   to   death.   In   several   countries,   regulatory   agencies   have   contraindicated   the   use   of  
propofol   infusion   in   pediatric   intensive   care   units.   However,   propofol   is   still   used   despite   the  
liability  concerns.    

The   overall   goals   of   this   thesis   were   to   improve   methods   of   conducting   and   reporting  
systematic   reviews   of   adverse   events.   More   specifically,     (i)   to   develop   an   extension   for   the  
PRISMA  Statement,  for  SRs  addressing  adverse  events  (AEs):  the  PRISMA  Harms;  (ii)  to  identify  
if   propofol   is   associated   with   serious   AEs   in   children   and   measure   if   the   inclusion   of   non-­‐
randomized  studies  in  a  SR  of  AEs  provides  further  information  than  data  from  RCTs  alone.    

ii

Methods  
There  were  2  distinct  methods  used  in  this  doctoral  thesis.  The  first  was  to  develop  the  PRISMA  
Harms   guideline.   We   followed   the   recommended   steps   for   guideline   development:   1)   to  
document   if   there   is   need   for   the   development   of   a   guideline;   2)   to   employ   a   Delphi   process   to  
identify   relevant   items   to   be   included   in   the   reporting   guideline;   3)   to   have   an   in-­‐person  
consensus  building  meeting;  and  4)  to  write  the  guideline.  

The   second   was   to   identify   if   propofol   infusion   is   associated   with   serious   AEs   in   pediatric  
patients   and   to   measure   if   the   inclusion   of   non-­‐randomized   studies   provides   more   relevant  
data   than   clinical   trials   alone,   we   conducted   a   SR   of   propofol   infusion   in   pediatric   patients  
including  both  clinical  trials  and  observational  studies.    

Results  
For   the   PRISMA   Harms   development,   the   first   step   identified   309   reviews   of   AEs   and  
documented   weaknesses   in   reporting   and   the   need   for   a   guideline.   The   second   step   conducted  
three   Delphi   rounds   sent   to   352   participants,   166   responses   were   received.   The   in-­‐person  
meeting   had   25   participants   and   the   final   PRISMA   Harms   manuscript   was   developed   after  
multiple   revisions   containing   4   mandatory   items   and   14   recommended   items   for   reviews  
addressing  harms.    

The   propofol   SR   identified   91   serious   AEs   (PRIS   or   cardiac   arrest)   associated   with   propofol  
infusion,  21  identified  in  a  single  unpublished  RCT  and  all  the  other  serious  AEs  emerged  from  
non-­‐randomized  studies.  In  the  included  studies,  a  total  of  5633  children  received  propofol  for  

iii

more   than   60   minutes   and   did   not   have   any   serious   events   (i.e.,   PRIS   or   cardiac   arrest)  
associated  with  it.  

Conclusion    
Through   this   work   we   developed   PRISMA   Harms,   an   international   reporting   guideline   to  
improve  harms  reporting  in  SRs.    

Further,   we   documented   serious   AEs   associated   with   propofol   infusion   in   children   and   the  
relevance   of   including  non-­‐randomized  and   unpublished   studies   in  SRs  of  AEs,   providing   both  
clinical  and  methodological  significant  information.    
 

 

 

iv

Preface  
 
This  thesis  is  an  original  work  by  Liliane  Medianeira  Zorzela.  
Some   of   the   research   conducted   for   this   thesis   was   informed   by   an   international   research  
group,   The   PRISMA   Harms   Group:   with   David   Moher   at   Ottawa   Health   Research   Institute  
(OHRI);  Doug  Altman  at  University  of  Oxford;  Jan  Vandenbroucke  at  Leiden  University;  John  P.  
Ioannidis   at   Stanford   University;   Lina   Santaguida   at   McMaster   University;   Yoon   Loke   at  
University   of   East   Anglia;   Su   Golder   at   University   of   York;   and   Sunita   Vohra   at   University   of  
Alberta   as   the   group   lead.   As   part   of   this   thesis   work,   L.   Zorzela   developed   an   extension   for   the  
PRISMA  statement,  the  PRISMA  Harms.  L.  Zorzela  collected  the  data,  analysed  the  results  and  
wrote   the   review   basis   for   the   development   of   PRISMA   Harms   (chapter   2,   published   at   BMJ  
2014;348:f7668  doi:  10.1136/bmj.f7668);  developed,  employed  and  analysed  the  results  for  the  
Delphi   process   and   wrote   the   manuscript   (chapter   3);   organized   and   participated   in   the   face   to  
face   meeting   and   composed   the   manuscript   “PRISMA   Harms”   (chapter   4).   All   the   PRISMA  
Harms   related   chapters   were   revised   by   the   PRISMA   Harms   Group   and   by   L.   Zorzela’s   thesis  
committee  group.    
The   development   of   the   PRISMA   Harms   (chapters   2,   3   and   4)   which   is   part   of   this   thesis,  
received   research   ethics   approval   from   the   University   of   Alberta   Research   Ethics   Board,   Project  
name   “PRISMA   Harms   Extension”,   Pro   00021294,   May   27,   2011.   The   PRISMA   Harms   received  
partial  funding  support  from  “Alberta  Innovates:  Health  Solutions”.  
L.   Zorzela   developed   the   protocol   for   the   review   in   chapter   5   (appendix   1),   published   at   the  
Cochrane  Database  of  Systematic  Reviews  Volume  (4),  2012,  under  title  “Propofol  infusion  for  
paediatric   sedation”.   L.   Zorzela   was   the   lead   person   for   data   screening,   data   collection,   data  
analysis  and  manuscript  elaboration  for  the  final  Cochrane  review  (chapter  5).  The  protocol  and  
final   review   were   revised   by   L.   Zorzela’s   thesis   supervisor,   thesis   steering   committee   group   and  
all  the  co-­‐authors.  
 

 

v

Dedication  
 
I  would  like  to  dedicate  this  work  to  my  new  family,  my  beloved  daughter  Isabel  and  my  life  
partner,  Robert.    
 
 

 

vi

Acknowledgments  
 
First   of   all   I   would   like   to   thank   my   parents,   Ivo   and   Laureci,   without   them   this   work   would   not  
be  possible.  
 
I  would  like  to  thank  my  thesis  steering  committee  members,  Lisa  Hartling,  Ari  Joffe  and  Yoon  
Loke  for  their  expertise,  guidance  and  treasured  support  during  all  these  years.    
 
I  would  like  to  thank  the  PRISMA  Harms  Group,  Sunita  Vohra,  David  Moher,  Doug  Altman,  John  
P.  Ioannidis,  Lina  Santaguida,  Yoon  Loke,  Jan  Vandenbroucke  and  Su  Golder  for  their  expertise  
and  guidance  on  the  development  of  the  PRISMA  Harms.  I  also  would  like  to  thank  all  the  25  
PRISMA   Harms   meeting   participants   that   came   to   Banff-­‐   Alberta   to   discuss   and   help   in   the  
development  of  the  PRISMA  Harms.    
 
I  would  like  to  thank  Katherine  Pohlman,  Yali  Liu  and  Salima  Punja  for  their  persistence  and  help  
during  the  systematic  review’s  development.    
 
I  would  like  to  thank  my  daughter,  Isabel,  for  her  good  behavior  in  utero  and  during  her  first  
months  of  life,  allowing  me  to  complete  this  work.    
 
Mainly,   I   would   like   to   thank   my   supervisor,   Dr.   Sunita   Vohra,   for   her   patience,   teaching   and  
support,  but  foremost  for  transforming  me  into  a  research  believer.  I  learned  how  research  can  
be  exciting  and  fulfilling  when  done  with  ethics  and  passion.          
 

 

vii

Table  of  Contents  
Chapter  1  
Thesis  Background  .......................................................................................................................................  2  
Systematic  reviews  ..................................................................................................................................  2  
The  need  to  improve  knowledge  synthesis  of  harms  ..............................................................................  2  
Improving  reporting  in  systematic  reviews  .............................................................................................  3  
Why  a  PRISMA  Harms  extension  is  important  .........................................................................................  3  
Clinical  context  ........................................................................................................................................  4  
Goal  of  this  doctoral  thesis  ..........................................................................................................................  4  
Thesis  Outline  ..............................................................................................................................................  5  
Improving  the  report  of  adverse  events  in  systematic  reviews  ...............................................................  5  
Improving  the  estimate  of  adverse  events  ..............................................................................................  5  
Manuscript  based  thesis  chapters  ...............................................................................................................  5  
Chapter  2:  Quality  of  reporting  in  systematic  reviews  of  adverse  events:  systematic  review  ................  5  
Chapter  3:  The  development  of  PRISMA  Harms  using  a  modified  Delphi  technique  ..............................  6  
Chapter  4:  PRISMA  Harms  .......................................................................................................................  6  
Chapter  5:  Propofol  infusion  for  paediatric  sedation  ..............................................................................  6  
References  ...................................................................................................................................................  7  
Chapter  2  
Quality  of  reporting  in  systematic  reviews  of  adverse  events:  systematic  review  ....................................  11  
Abstract  .................................................................................................................................................  12  
Introduction  ...............................................................................................................................................  13  
Methods  ....................................................................................................................................................  14  
Development  of  the  checklist  items  ......................................................................................................  14  
Search  strategy  ......................................................................................................................................  14  
Eligibility  criteria  ....................................................................................................................................  15  
Screening  and  data  extraction  ...............................................................................................................  15  
Outcome  ................................................................................................................................................  16  
Data  analysis  ..........................................................................................................................................  16  
Results  .......................................................................................................................................................  17  
Titles  and  abstracts  ............................................................................................................................  18  

viii

Introduction  and  rationale  .................................................................................................................  18  
Methods  ............................................................................................................................................  18  
Results  ...............................................................................................................................................  19  
Discussion  ..............................................................................................................................................  20  
Principal  findings  ................................................................................................................................  20  
Conclusions  ............................................................................................................................................  23  
What  this  paper  adds  .........................................................................................................................  25  
What  is  already  known  on  this  topic  .................................................................................................  25  
References  .............................................................................................................................................  25  
Table  1.Glossary  .................................................................................................................................  29  
Table  2.  Definition  of  Reporting  Items.  ..............................................................................................  30  
Table  3  Summary  of  Findings  .............................................................................................................  33  
Chapter  3  
The  development  of  PRISMA  Harms  using  a  modified  Delphi  technique  ..............................................  41  
Abstract  .............................................................................................................................................  41  
Introduction  .......................................................................................................................................  42  
Methods  ............................................................................................................................................  43  
Results  ...............................................................................................................................................  45  
Discussion  ..........................................................................................................................................  47  
Conclusion  .........................................................................................................................................  49  
References  .........................................................................................................................................  49  
Chapter  4  
PRISMA  Harms:  improving  harms  reporting  in  systematic  reviews  ......................................................  64  
Abstract  .............................................................................................................................................  64  
Introduction  .......................................................................................................................................  65  
Development  of  PRISMA  Harms  ........................................................................................................  66  
Discussion  ..........................................................................................................................................  93  
Conclusion  .............................................................................................................................................  94  
Examples  references:  .........................................................................................................................  94  
References  .........................................................................................................................................  97  
           Chapter  5  
           Propofol  infusion  for  paediatric  sedation.  A  systematic  review  of  serious  adverse  events.  ..............  106  

ix


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