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University of Alberta

Nausea and Vomiting after Posterior Fossa Craniotomy in Children.
by
Susan Michelle Neufeld
A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment
of the requirements for the degree of Doctor of Philosophy
Faculty of Nursing
Edmonton, Alberta
Spring 2009
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Abstract
Managing nausea and vomiting is an important component of the clinical care of children
and adults after surgery. Because of the proximity of many neurosurgical procedures to
important anatomical correlates of nausea and vomiting, this patient population may also
be at high risk for nausea and vomiting. The possibility of adverse events such as raised
intracranial pressure, bleeding at the surgical site, and failure of dural and/or skin
closures, makes the prevention of nausea and vomiting after neurosurgery a priority for
the entire clinical team. This dissertation is composed of five inter-related papers that
address the issue of nausea and vomiting after neurosurgery, with a final focus on
children after posterior fossa procedures. The first paper is a systematic review of the
efficacy of 5-HT3 receptor antagonists in preventing nausea and vomiting in adults after
craniotomy. This paper is followed by a second paper on the efficacy of this same class
of anti-emetics in children after craniotomy. In the first paper, efficacy can be shown for
intraoperative administration of 5-HT3 receptor antagonists in preventing vomiting in
adults but not for nausea. In the second paper, efficacy of the 5HT3 receptor antagonists
remains to be established for children. In the third paper, a systematic review, knowledge
about risk factors for nausea and vomiting after neurosurgery shows significant gaps in
research related to children. Due to the heterogeneity of children requiring craniotomy, I
focused my research study on a subgroup of children who clinically appeared to be at
high risk for nausea and vomiting. Thus, the fourth paper contains the results of my
study of nausea and vomiting in children after posterior fossa surgery. Recommendations
for nurses caring for children after posterior fossa craniotomy are summarized in the fifth
paper, with a focus on currently published clinical practice guidelines.
Acknowledgements
I want to first thank my doctoral committee. My co-supervisor, Dr. Jane Drummond,
provided unwavering support. Co-supervisor, Dr. Christine Newburn-Cook, went beyond
all expectations in helping me execute my projects and get my work published. Dr.
Thierry Lacaze encouraged me to gain a broad perspective of research through the
Canadian Child Health Clinician Scientist Program (CCHCSP). Dr. Gwen Remple
brought the perspective of a relatively new child health researcher and Dr. Linda Ogilvie
provided wisdom and experience.
I also gratefully acknowledge Dr. Brian Rowe in the Department of Public Health
Sciences, Marlene Dorgan who is a Librarian at the John Scott Library, and Statistician
Ben Vandermeer at ARCHE (all at the University of Alberta) for their help with the
systematic reviews and meta-analyses. Dr. Don Schopflocher provided invaluable
statistical advice for the posterior fossa study. Dr. Shannon Scott provided much needed
advice and support throughout my doctoral studies.
The Pediatric Oncology Group of Ontario provided financial support for the posterior
fossa study, specifically data collection at the Hospital for Sick Children. The research
grant from the Killam Foundation also helped me complete the dissertation.
Belinda Dundon, Herta Yu, and Maria Lamberti-Pasculli provided invaluable help at the
Hospital for Sick Children. Dr. Keith Aronyk did the same at the Stollery Children's
Hospital. Elizabeth and Donald James entered data. Tim Neufeld kept the computers
working. Jennifer Thenu helped with formatting of the thesis.
During my studies I was grateful to receive an honorary IWK Doctoral Award, an Isobel
Secord Doctoral Scholarship, a Jenetta MacPhail Doctoral Award, and the Canadian
Nurses Foundation Helen Preston Glass Doctoral Fellowship.
I could not have completed my studies without the educational, moral, social, and
financial support of the CCHCSP, lead by Dr. Norman Rosenblum. Heather Nash
ensured that the program remained wonderful. Dr. Bob Bortolussi kept it fun. The
Stollery Children's Hospital, University of Alberta Faculty of Medicine Department of
Paediatrics, and University of Alberta Faculty of Nursing also provided essential matched
funding so that I could participate fully as a doctoral trainee with the CCHCSP.
Finally, I thank my Mom and Dad for their love and support as well as Walter and Jackie
Grapel for the same.
Table of Contents
Page
Integrating Chapter 1
My Motivation 1
Paper 1: Efficacy of 5-HT3 Receptor Antagonists for the Prevention of Postoperative Nausea and
Vomiting Following Craniotomy: A Meta-Analysis 2
Paper 2: The Efficacy of 5-HT3 Receptor Antagonists for the Prevention ofPostoperative Nausea
and Vomiting Following Craniotomy, Part Two: The Paediatric Studies 4
Paper 3: Risk and Protective Factors for Nausea and Vomiting after Neurosurgery: A Systematic
Review 4
Paper 4: Children's nausea and vomiting following posterior fossa surgery: A retrospective study.. 5
Paper 5: Strengths and limitations of currently proposed clinical practice guidelines
for preventing and treating nausea and vomiting in children after posterior fossa
craniotomy 7
References 9
Paper 1 11
Efficacy of 5-HT3 Receptor Antagonists for the Prevention of Postoperative Nausea
and Vomiting Following Craniotomy: A Meta-Analysis 11
Methods 13
Selection of Studies 13
Inclusion Criteria 14
Study Outcomes 15
Assessment of Methodological Quality 15
Statistical Analysis 16
Results 17
Cumulative Postoperative Emesis 18
Cumulative Postoperative Nausea 18
Rescue Antiemetic Use 19
Evidence of Safety 19
Discussion 19
Reference List 23
Paper 2 32
The Efficacy of 5-HT3 Receptor Antagonists for the Prevention of Postoperative
Nausea and Vomiting Following Craniotomy Part Two: The Paediatric Studies.... 32
Methods 34
Selection of Studies 34
Inclusion Criteria 34
Study Outcomes 34
Assessment of Methodological Quality 35
Statistical Analysis 35
Results 36
Search Results 36
Meta-analysis 37
Discussion 37
Reference List 39
Paper 3 47
Methods
Selection of Studies
Inclusion and Exclusion Criteria
49
50
Study Outcomes 50
Assessment of Methodological Quality 51
Results 51
Discussion 56
Reference List 62
Paper 4: 76
Children's nausea and vomiting following posterior fossa surgery: A retrospective
study 76
Methods 80
Sample Selection & Sample Size Estimation 80
Data Collection Procedures 81
Measurement 82
Data Analysis 84
Results 86
Sample Characteristics 86
Description of PON, POVandPONV 86
Analysis of risk and protective factors 87
Co-morbidities 90
References 99
Paper5 114
Strengths and limitations of currently proposed clinical practice guidelines for
preventing and treating nausea and vomiting in children after posterior fossa
craniotomy 114
Practice Guidelines for the Prevention and Treatment of PONV 116
ASPAN'S Evidence-Based Clinical Practice Guideline for Preoperative Patient Management
of PONV 117
Use of Preoperative Risk Scores or Prognostic Models 118
Anaesthetic considerations 120
Efficacy and effectiveness of prophylactic anti-emetics 121
Other Considerations 124
ASPAN'S Evidence-Based Clinical Practice Guideline for Management of PONV 125
Assessment of Nausea 125
Efficacy and effectiveness of anti-emetics 127
ASPAN'S Evidence-Based Clinical Practice Guideline for Management of PDNV 128
Future Research for PONV in Children after Posterior Fossa Craniotomy 130
References 134
General Discussion and Conclusions 145
Reference 149
Appendix 1 150
Appendix 2 159
Appendix 3 167
Appendix 4 172
Appendix 5 174
Appendix 6 179
Appendix 7 180
Appendix 8 185
List of Tables
Page
Table 1.1 26
Table 2.1 41
Table 3.1 65
Table 3.2 68
Table 3.3 70
Table 3.4 74
Table 4.1 102
Table 4.2 104
Table 4.3 105
Table 4.4 106
Table 4.5 108
Table 4.6 109
Table 4.7 110
Table 5.1 139
Table 5.2 140
Table 5.3 141
List of Figures
Page
Figure 0.1 10
Figure 1.1 27
Figure 1.2 28
Figure 1.3 29
Figure 1.4 30
Figure 1.5 31
Figure 2.1 44
Figure 2.2 45
Figure 2.3 46
Figure 3.1 75
Figure 4.1 I l l
Figure 4.2 112
Figure 4.3 113
Figure 5.1 142
Figure 5.2 143
Figure 5.3 144
Integrating Chapter
Nursing care of children after neurosurgery is highly rewarding, complex, but
often unpredictable, with few evidence-based nursing practices. Nursing care experience
with these children, especially at different ages and developmental stages, takes years to
garner and requires a team approach. General guidelines around the physical care of
children after neurosurgery such as care of external ventricular drains, application of
dressings, and taking neuro-vital signs, can be provided in the form of policies and
procedures. However, in the acute postoperative period, issues of how to manage pain,
nausea and vomiting, agitation and resultant disabilities remain poorly understood by the
health care team. In this integrating chapter, I will outline my motivation for choosing
postoperative nausea and vomiting (PONV) after craniotomy as a topic for doctoral
research, in particular my choice of PONV after posterior fossa procedures. I will then
introduce each paper in the dissertation.
My Motivation
This dissertation is about an area of postoperative care selected based on my
clinical interest in caring for children after posterior fossa procedures. Prior to beginning
Doctor of Philosophy Studies in Nursing, I had spent the previous five years of my career
as a Clinical Nurse Specialist in children's neurosurgery at the Stollery Children's
Hospital. Before that, I had worked for a number of years in the pediatric intensive care
units at the Royal Alexandra Hospital and the Stollery Children's Hospital (among other
activities such as completing my MN and working in home care for children with
complex needs). From my experience and observations, and from discussions with other
nurses who worked in children's neurosurgery, as well as with neurosurgeons, these
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children seemed to have difficulty with PONV. Thus, I felt that focusing on this
"problem" for my studies would lead to some useful answers to take directly back to the
clinical area for the benefit of these children.
The papers in this dissertation comprise my search for answers to the problem of
PONV in children after posterior fossa craniotomy. Figure 0.1 contains an illustration of
how the papers inform, and are related to, each other. The first two papers are systematic
reviews of potential prophylactic anti-emetics. With only two small studies on children,
from differing clinical groups, no decisions could be made about their care. The findings
of these papers revealed a need to investigate risk and protective factors of PONV after
craniotomy. The results of a systematic review on this topic are presented in the third
paper. The need for study in children and/or particular types or anatomical locations of
surgery became clear through this systematic review. This reinforced the need for
exploration of an initial idea that was the result of a discussion with Dr. Vivek Mehta, a
paediatric neurosurgeon at the Stollery Children's Hospital, of a study of nausea and
vomiting in children following posterior fossa craniotomy. Therefore, the results of a
retrospective study on PONV in children after posterior fossa surgery are presented in the
fourth paper. Issues surrounding the adoption of current clinical practice guidelines for
the care of these children and directions for future research are the topics of the final
paper.
Paper 1: Efficacy of 5-HT3 Receptor Antagonists for the Prevention of
Postoperative Nausea and Vomiting Following Craniotomy: A Meta-Analysis
I first sought to find evidence for the efficacy of anti-emetics for the prevention
and treatment of PONV in children after posterior fossa craniotomy. Given how common
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that I felt the problem was, there must be a solution already in the literature. Believing
that prevention was essential, I began with a systematic review of the literature. This
review started with the question: "What is the efficacy of anti-emetics in preventing
postoperative nausea and vomiting in children after posterior fossa procedures?" When
my search revealed no such studies, I changed my question to: "What is the efficacy of
anti-emetics in preventing postoperative nausea and vomiting in children after
craniotomy?" To this query, I retrieved only one paper that met my inclusion criteria,
written more than ten years previously (Furst et al., 1996). This paucity of information
then prompted me to focus on adults, after craniotomy, and, eventually, only one class of
drugs: the 5HT3 receptor antagonists.
Thus, the purpose of this meta-analysis was to assess the efficacy of prophylactic
administration of 5-HT3 receptor antagonists for PONV in neurosurgical patients at 24
hours and 48+ hours. Following a systematic search, seven published, randomized
placebo-controlled trials, involving 448 craniotomy patients (222 treatment, 226 control),
were included in the meta-analysis. Study drugs included ondansetron, granisetron, and
tropisetron. The cumulative incidence of emesis was significantly reduced in the
treatment group at 24 hours (RR=0.50, 95% CI: 0.38-0.66) and 48+ hours (RR=0.52,
95% CI: 0.36-0.75). There were no differences between the treatment and control groups
in the cumulative incidence of nausea at 24 hours (RR=0.76, 95% CI: 0.54-1.06) and 48+
hours (RR=0.81, 95% CI: 0.62-1.06). The cumulative incidence of both nausea and
vomiting continued to increase after 24 hours in both groups. Despite the ability of 5-HT3
receptor antagonists to reduce emetic episodes, future investigations should seek to
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address the control of postoperative nausea and to reduce further postoperative emesis in
this population. Focusing on those patients at highest risk for PONV is essential.
Paper 2: The Efficacy of 5-HT3 Receptor Antagonists for the Prevention of
Postoperative Nausea and Vomiting Following Craniotomy, Part Two: The
Paediatric Studies
A short time after completing the systematic review, I was updating my search
and found a second paediatric paper. Published by Subramaniam and colleagues (2007),
the study included young adults up to 21 years of age. Thus, two published randomized
placebo-controlled trials were combined, for a total of 135 participants aged 2-21 (79
treatment and 56 controls). The only study drug was ondansetron. The combined relative
risk (RR) of vomiting was not statistically significant in the treatment group compared to
the control group (RR = 0.77; 95% CI: 0.50-1.19). There was also no evidence of
efficacy for ondansetron in reducing the use of rescue anti-emetics in the treatment group
compared to the control group (RR = .71; 95% CI: 0.34-1.49). While combining these
randomized placebo controlled trials did not show efficacy for ondansetron in preventing
POV in craniotomy patients aged 2-21, a clinically significant effect could not be
excluded, as even the combined sample size remained small.
Paper 3: Risk and Protective Factors for Nausea and Vomiting after Neurosurgery:
A Systematic Review
The third paper highlighted my efforts to identify studies of PONV in children
after posterior fossa surgery. It is the formalization of the literature search that provided
the basis of my research proposal. As in the studies of the efficacy of the 5HT3 receptor
antagonists (Papers 1 and 2), the focus of the review was expanded to include adults,
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children and all types of neurosurgery. Importantly, the papers that were used in this
review informed my doctoral research study and supported the direction that it took (i.e.,
retrospective and focused on a particular sample of children).
The purpose of this systematic review was to identify and summarize risk factor
research for PONV in adults and children after neurosurgical procedures. Of 272 papers
identified though a systematic search, 13 studies met the criteria for this review. These
studies varied considerably in their outcome measurement, risk factors studied, and target
populations. The time frame of observation (for prospective studies) or chart review (for
retrospective studies) ranged from one hour after surgery to the entire length of the
hospital stay. For these reasons, it was difficult to compare results among the studies.
Overall, the methodological quality of the studies was fair, with few studies controlling
for confounders and many with limited explanations of how the risk factors and/or
outcomes were measured. Despite these limitations, many authors examined unique risk
factors for neurosurgical patients such as location of surgery (i.e., infratentorial vs.
supratentorial), awake vs. general anaesthesia, and use of fat grafting for cerebral spinal
fluid leak in transsphenoidal procedures. The findings may challenge traditional thinking
about risk factors for PONV and guide future studies. Nausea and vomiting after
craniotomy in children remains understudied and related factors have not been delineated.
Paper 4: Children's nausea and vomiting following posterior fossa surgery: A
retrospective study
In this paper, I discussed results from the retrospective study of children's nausea
and vomiting following posterior fossa surgery. My clinical observations were confirmed
by the results of this study, justifying the importance of identifying interventions that
5
work for these children and the need for further, appropriate, research. I also learned
about the limitations of my study and encountered barriers along the way. For example,
the outcome of vomiting was so common that the number of risk factors that could
confidently be examined was limited. Also disappointing was that the level of
documentation of nausea was too poor for a meaningful analysis of this symptom.
Overall, the purpose of this study was to describe the incidence, frequency,
duration of symptoms, and risk and protective factors for PONV in children after
posterior fossa surgery. A six year retrospective chart audit of all children at two hospital
sites found 249 children who met the study criteria. Of these children, 47.8% of them had
documented postoperative retching or vomiting (POV) by 24 hours, 72.7% by 120 hours,
and 76.7% by 240 hours. Although 15.3% of children had only one POV event, 51.0%
had three or more events. The length of time over which POV events were recorded
ranged from less that one hour to over the entire time that POV was studied (240 hours).
Similar results could not be found for nausea, as lack of clear documentation of nausea
made data extraction difficult.
In a multivariable logistic regression to identify potential risk factors, children
aged 12-<17 had decreased odds of POV by 120 hours, while Chiari I malformation
surgery, use of desflurane (alone or in combination with another volatile anaesthetic), and
use of perioperative ondansetron had increased odds of POV by 120 hours. A number of
confounding effects emerged in the analysis as variables were entered in a hierarchical
fashion. Controlling for the use of desflurane showed a confounding influence by
showing an increased odds of vomiting at the Hospital for Sick Children as a significantly
greater proportion of children at the Stollery Children's Hospital received this
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emetogenic volatile anaesthetic. Both preoperative vomiting and the interaction of
ondansetron and use of desflurane confounded the odds ratio for Chiari I malformation
surgery. Overall, POV in children after posterior fossa surgery was common and
frequent. Research is required to determine the efficacy of preventive and treatment
measures for this group of patients, and patient groups may be stratified by the risk and
protective factors that were identified in this study.
Paper 5: Strengths and limitations of currently proposed clinical practice guidelines
for preventing and treating nausea and vomiting in children after posterior fossa
craniotomy
The purpose of this final paper was to highlight some of the challenges for
preventing and treating PONV in children after posterior fossa craniotomy, given that
children after posterior fossa craniotomy are at high risk for this distressing outcome. The
best practice guidelines for preventing and treating PONV published by the American
Society for PeriAnesthesia Nursing (2006) supplemented by the paediatric guidelines that
are in the Society for Ambulatory Anesthesia (Gan et al. 2007) were used to guide the
discussion. The lack of a valid risk scoring tool, limited evidence to support prevention
and treatment strategies, and the need for a rigorous approach to the assessment of nausea
are all identified as concerns. Attitudes and beliefs around PONV and the related care of
children may range from, "It happens - so what" to "It is not a problem at our
institution." Both of these extremes need to be addressed prior to implementing change.
Finally, directions for research including strategies to address the continuum of care that
children with brain tumours may require related to nausea and vomiting, are identified.
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To summarize, POV for children after posterior fossa surgery, once collectively
but informally identified as a problem, is now described in a two-site retrospective
research study. I have made suggestions by which current knowledge can fit within
evidence-based clinical practice guidelines, but it must be taken from studies from areas
such as adult craniotomy and/or other areas of children's surgery because there has been
little research into PONV in children after craniotomy. It is likely that a multimodal,
multidisciplinary effort will be required, as the "problem" of PONV for these children
has not been solved — just further elucidated.
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References
American Society of Peri Anesthesia Nurses (2006). ASPAN's evidence-based clincial
practice guideline for the prevention and/or management of PONV/PDNV.
Journal of PeriAnesthesia Nursing, 27(4), 230-250.
Gan, T. J., Meyer, T. A., Apfel, C. C., Chung, F., Davis, P. J., Habib, A. S., et al. (2007).
Society for Ambulatory Anesthesia guidelines for the management of
postoperative nausea and vomiting. Anesthesia & Analgesia, 105(6), 1615-1628,
table of contents.
Furst, S. R., Sullivan, L. J., Soriano, S. G., McDermott, J. S., Adelson, P. D., & Rockoff,
M. A. (1996). Effects of ondansetron on emesis in the first 24 hours after
craniotomy in children. Anesthesia & Analgesia, 83(2), 325-328.
Subramaniam, K., Pandia, M. P., Dash, M., Dash, H. H., Bithal, P. K., Bhatia, A., et al.
(2007). Scheduled prophylactic ondansetron administration did not improve its
antiemetic efficacy after intracranial tumour resection surgery in children.
European Journal of Anesthesiology, 24(7), 615-619.
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FIGURE 0.1
Relationships among the five dissertation papers
Paper 5 - Nausea and vomiting in children after
posterior fossa surgery:
Directions for clinical practice and research
Paper 4 - Children's nausea and
vomiting following posterior fossa
surgery: A retrospective study
Paper 2 - The Efficacy of 5-HT3
Receptor Antagonists for the
Prevention of Postoperative Nausea
and Vomiting Following
Craniotomy Part Two: The Pediatric
Studies
Paper 3 - Risk and Protective
Factors for Nausea and
Vomiting after Neurosurgery:
A Systematic Review
Papcrl:
Efficacy of 5-HT.i Receptor Antagonists
for the Prevention of Postoperative
Nausea and Vomiting Following
Craniotomy: A Meta-Analysis
Paper 1
Efficacy of 5-HT3 Receptor Antagonists for the Prevention of
Postoperative Nausea and Vomiting Following Craniotomy: A Meta-Analysis
A version of this paper has been published as:
Neufeld, S.M & Newburn-Cook, C.V (2007). The Efficacy of 5-HT
3
Receptor Antagonists for the Prevention of
Postoperative Nausea and Vomiting Following Craniotomy: A Meta-Analysis. Journal of Neurosurgical
Anaesthesiology, 19( 1), 10-17.
11
The successful management of nausea and vomiting is a fundamental part of
postoperative recovery and has been studied across numerous patient populations.
Predictive factors for postoperative nausea and vomiting (PONV) include age (childhood
after infancy or young adults), gender (female after puberty), prior history of PONV or
motion sickness, non-smoking status, type of anesthesia (administration of nitrous oxide
or use of volatile anesthetics), duration of anesthesia, type of surgery, and postoperative
opiods (1). PONV in neurosurgical patients has unique challenges that warrant its study
separate from other surgical groups. First, estimates of PONV in adults requiring
craniotomy, in the absence of prophylactic anti-emetics, have been as high as 39% for
emesis (2) and 67% for nausea (3). There are also potentially deleterious consequences of
PONV for these patients. For example, elevated arterial, venous, and intracranial
pressures may increase the risk of hemorrhage and neurological complications (2).
Clinicians must carefully select an antiemetic for patients undergoing craniotomy. The
need for ongoing neurocognitive monitoring makes the use of sedating anti-emetics (such
as anticholinergics, antihistamines, benzamides, butyrophenones, and dopamine receptor
antagonists) undesirable.
The 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists are a relatively new
class of anti-emetics that are non-sedating and have few reported adverse effects (4).
Several systematic reviews and meta-analyses have established the efficacy of 5-HT3
receptor antagonists alone (5-8), or in combination with droperidol (9), or dexamethasone
(10) in the prophylactic control of PONV. Moreover, recent consensus guidelines include
the prophylactic use of 5-HT3 receptor antagonists for individuals at moderate or high risk
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for PONV (11). Unfortunately, none of these reviews contains an analysis specific to
prevention of PONV following craniotomy.
Recently, Audibert and Vial (12) published a synopsis of the literature on PONV
after neurosurgery that included a recommendation for the use of 5-HT3 receptor
antagonists. However, their report did not have the rigor of a systematic review; nor did it
include a meta-analysis of the results in order to quantify the degree of benefit. Given the
publication of more recent randomized controlled trials that have addressed the efficacy
of 5-HT3 receptor antagonists in craniotomy, a systematic review and meta-analysis for
this clinical population was justified. Therefore, the purpose of this systematic review and
meta-analysis was to determine the relative efficacy and safety of 5-HT
3
receptor
antagonists in the prevention of PONV for patients who underwent craniotomy.
Methods
Selection of Studies
We conducted a systematic search to identify relevant randomized controlled
trials in which the antiemetic effects of 5-HT3 receptor antagonists were compared with a
placebo in the control of PONV in patients undergoing craniotomy. We selected trials for
review from an electronic search of MEDLINE (1990-2005), EMBASE (1988-2005),
CINAHL (1990-2005), the Cochrane Library, DARE (Database of Abstracts of Reviews
of Effectiveness), PubMed, Web of Science, and dissertation abstracts. The appropriate
search filters (provided by The University of Alberta Library Website) were used to limit
the search to clinical trials in humans in any language. The following MeSH headings
and text (keywords) were used: "neurosurgery", "neurosurgical procedure", "brain
surgery", "craniotomy", "brain neoplasm" and "serotonin antagonists", "5-HT
3
receptor
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antagonists", "azasetron", "dolasetron", "granisetron", "itasetron", "ondansetron",
"ramosetron", "tropisetron", and "postoperative nausea and vomiting", "PONV" ,
"nausea", or "vomiting". A search of the grey literature included Online Computer
Library Center Conference Paper and Proceedings Indexes and Google Scholar. We
crossed-checked references in the retrieved articles and the review articles to locate other
potential studies. The scientific advisors of the pharmaceutical companies were also
contacted for reports on any unpublished data and ongoing trials. Lastly, we contacted the
authors of two studies in an attempt to obtain data that were not included in the retrieved
material (13, 14).
The selection of studies involved three steps. First, the primary author (SN)
initially screened the abstracts retrieved from the database searches by title to rule out
studies that obviously did not pertain to the focus of the systematic review. Second, both
authors (SN, CNC) independently reviewed the preliminary results by title, abstract,
MeSH Headings, and keywords to identify all potentially relevant articles. The full texts
of these articles were then obtained for review. Any disagreements were resolved by
discussion and consensus.
Inclusion Criteria
Studies were included in the systematic review and meta-analysis if they were
randomized placebo controlled trials that examined the efficacy of intraoperative 5-HT3
prophylaxis in the management of PONV in adults undergoing craniotomy. Studies were
included regardless of the location of the surgery (supratentorial vs. infratentorial) or type
of 5-HT3 receptor antagonist used. If more than one antiemetic was investigated, findings
were included if at least one arm of the trial included a 5-HT3 receptor antagonist and one
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arm included a placebo. The other arms of the study were not included in the meta-
analysis.
Study Outcomes
We developed a standard form to extract descriptive and outcome data. To ensure
accuracy, we independently extracted the outcome data. All data were entered into
RevMan 4.0.8 (15) by the primary author (SN), who also identified and resolved any
discrepancies. The outcomes included the cumulative incidence (number of new
cases/total number cases) of nausea, vomiting and use of rescue antiemetic therapy for
the 24 hour and 48+ hour time periods. We also evaluated evidence of safety through
reported adverse events.
Assessment of Methodological Quality
We independently assessed the methodological quality of the trials selected for
inclusion in the meta-analysis using the Jadad Scale (16). The Jadad Scale evaluated the
internal validity of each of the selected trials using the following criteria: 1) the
randomization of the study participants to the treatment and control groups; 2) blinding of
the patients, caregivers, and those assessing study outcomes; and, 3) a complete
description of the subject withdrawals and dropouts. Studies were assigned an overall
score between 0 and 5 points. One point was allotted for each of the above items, with
two additional points given if the randomization was concealed and the method used for
double blinding was appropriate. Trials receiving three or more points were assessed as
being methodologically appropriate (high quality) and were included in the meta-
analysis.
15
Statistical Analysis
The RevMan Analysis 1.0.3 program was used to combine trial data (17).
Following Deeks's suggestion for evaluating preventive interventions (18), we chose to
determine the relative risk of harm (RR) for greatest consistency (i.e., that the treatment
effect allows for variation in baseline risk with increasing absolute benefit with
increasing risk) and ease of interpretation. Specifically, the RR calculated would be the
risk of the event (nausea, vomiting, and use of rescue antiemetics) in the group receiving
a 5-HT3 receptor antagonist relative to the risk of the event in the control group. We
selected a random effects model (19) to assess the efficacy of 5-HT3 receptor antagonists
"on average" in preventing PONV across heterogeneous studies, rather than using a fixed
effects model that assumes that a true effect is the same for each study (20). To clarify the
findings for clinicians and compare findings to other meta-analyses, the number needed
to treat (NNT), i.e. the number of people required to receive the drug in order to prevent
one event, was calculated from the statistically significant meta-analytic estimates (21).
0 0
Study heterogeneity was examined by estimating the I statistic. The I statistic
describes the percentage of total variation across studies due to heterogeneity as opposed
to chance (22). The I
2
statistic does not depend on the number of studies included in the
meta-analysis (i.e., can be used when the number of relevant studies is limited), it can be
used for investigation of the contribution of study level covariates to heterogeneity, and
lastly, it can be used to examine the influence of a single study (23). I
2
values of 25%,
50%, and 75% indicate low, moderate, and high heterogeneity, respectively (24).
16
Publication bias was evaluated using a visual inspection of the funnel plot of the
fixed effect RR of each study on the x-axis and the standard error of the variance of the
log RR on the y-axis. An asymmetrical appearance would indicate potential bias (20).
Results
Seventeen abstracts were identified as potentially relevant from 54 titles obtained
from the computerized search. Eleven of these abstracts met our criteria for full text
review; seven studies were ultimately included in the meta-analysis. Of the four excluded
studies: one did not have a placebo arm (25); another was conducted using a pediatric
population (26); and a third had one group receiving a combined regimen of
intraoperative and postoperative ondansetron and one group receiving a placebo (27). The
third excluded study design did not have an intraoperative ondansetron alone arm that
could be used in our meta-analysis. The final excluded study, while meeting our inclusion
criteria, did not separate postoperative nausea data from vomiting data for us to include
the results in the meta-analysis (14). Scientific advisors from Aventis Pharmaceuticals
Inc. (dolasetron), Roche Pharmaceuticals (granisetron), and GlaxoSmithKline
(ondansetron) identified that there was no additional information or ongoing studies on
the use of their respective drugs for neurosurgical patients.
The characteristics of the seven studies that met the criteria for review (28) are
summarized in Table 1.1 (13, 29-33). Included studies were all single site, with relatively
small sample sizes (ranging from 40-152 participants). There were 448 patients included
in the meta-analysis (222 treatment, 226 control). There were no differences between the
treatment and control groups regarding patient age (weighted mean difference (WMD):
1.49, 95% confidence interval (CI): -0.98-3.95), gender (odds ratio males to females:
17
1.03, 95% CI: 0.71-1.50) or length of administration of anaesthetic (WMD:-13.01, 95%
CI: -31.64-5.62). Exclusion criteria were similar across studies. For example, all studies
excluded patients presenting with nausea and/or vomiting or those patients who had
already taken an antiemetic.
Cumulative Postoperative Emesis
The 24 hour and 48+ hour findings for each study and the pooled results are
shown in the first two forest plots for cumulative postoperative emesis (Figures 1.1 and
1.2). There were significant differences favoring treatment for both time periods.
Because there was no measured heterogeneity between the studies (I =0), we did not
conduct subgroup analyses.
Cumulative Postoperative Nausea
As shown in the final two forest plots (Figures 1.3 and 1.4), there were no
differences between the treatment and control groups for nausea at the 24 hour and 48+
>y
hour time periods. The moderate heterogeneity (I = 48%) in the data at 24 hours
suggested the need for an exploratory subgroup analysis.
Kathirvel and colleagues (30) only measured nausea if it occurred without
vomiting. Removing this study reduced heterogeneity (I
2
= 7%) and yielded a statistically
significant treatment effect of the 5-HT3 receptor antagonists on 24 hour postoperative
nausea (RR: 0.72, 95% CI: 0.57-0.91). However, this effect was weak because the upper
end of the 95% CI approached 1.00. Therefore, its clinical significance was negligible.
The use of a funnel plot to detect publication bias was limited by the number of
studies (20), but appeared fairly symmetrical with a gap at the bottom right of the plot
(Figure 1.5). This finding could not allow us to rule out publication bias.
18
Rescue Antiemetic Use
As shown in Table 1.1, rescue antiemetic use varied considerably between the
studies included in this analysis. The meta-analytic findings are therefore limited for this
outcome, but the combined studies reporting rescue antiemetic use in the first 24 hours
(30-33) favoured treatment, with moderate heterogeneity (RR=0.49, 95% CI: 0.27-0.87,
I
2
=59.3%). The combined results of those who reported at the 48+ hour time period (28,
29, 31, 32) showed no difference (RR=0.85, 95% CI: 0.59-1.22,1
2
=41.7%).
Evidence of Safety
None of the studies contained reports of significant adverse events in either the
control or the treatment group. One study reported the problem of protracted
postoperative nausea and vomiting in 2/20 treatment and 9/20 controls (28), while
another mentioned one patient with this complication but did not provide details (32).
There were no significant differences reported regarding the occurrence of constipation
or diarrhea, which have been identified as common side-effects of the 5-HT3 receptor
antagonists in other PONV studies (8). Headache was not examined as an adverse event,
likely due to its universal prevalence in craniotomy patients.
Discussion
Adults who were given prophylactic 5-HT3 receptor antagonists exhibited a
reduced risk of vomiting at 24 hours and 48+ hours (NNTs of 3.8 and 3.6 respectively)
compared to those who received placebo. There were no significant differences in nausea
except on subgroup analysis at 24 hours, which still indicated lower efficacy for nausea.
Our findings are comparable to larger meta-analyses of prophylactic 5-HT
3
receptor
antagonists for multiple types of surgeries. Figueredo and Canosa (6) reported non-
19
weighted NNTs of 5.7 and 5.1 for 4mg and 8mg intravenous ondansetron vs. placebo for
preventing postoperative vomiting in adults. Tramer and colleagues (8) reported NNTs
between 5 and 6 with an intravenous dose of 8mg of ondansetron vs. placebo in
preventing vomiting. These authors also reported lower efficacy of ondansetron for
nausea.
In addition to looking exclusively at PON adn POV among craniotomy patients,
there are other reasons why our results differed from those reported in other meta-
analyses. First, we only found a few small studies to combine. Second, we did not
differentiate one type of 5-HT3 receptor antagonist from another in this meta-analysis.
However, other researchers (7,11) reported no difference among the 5-HT3 receptor
antagonists in preventing PONV. Our meta-analysis also had more studies from Asia and
the Middle East than usual; however, given the homogeneity of the findings between the
included studies, this factor did not seem to influence the results.
Finally, and perhaps most importantly, the varying doses of dexamethasone,
traditionally used in craniotomy to reduce cerebral edema, may have influenced our
findings compared to the studies of surgical populations without perioperative
dexamethasone. Specifically, the "placebo" for the control groups in a number of these
studies could be dexamethasone with the experimental group receiving dexamethasone
and a 5-HT3 receptor antagonist (29-33). A protective effect for PONV in the control
group and/or synergetic effect with the 5-HT3 receptor antagonists in the treatment group
could influence the results of these studies compared to studies that did not use
intraoperative dexamethasone.
20
We recognize a number of other limitations of this meta-analysis. First, as
highlighted by White and Watcha (34), the findings from pooled, single site, small
studies are in no way a substitute for large scale, multi-center trials. As indicated by our
systematic search, such studies have not been conducted in craniotomy patients. The
ability to pool data from diverse studies is also a limitation of any meta-analysis.
However, despite the differences in measuring and reporting events, drugs and doses, use
of dexamethasone, sites of surgery and countries of study, the findings of the meta-
analysis were remarkably homogenous. Finally, in using cumulative incidence as our
outcome measure, we were unable to examine differences in the severity of the patients'
experience of PONV except by the surrogate outcome of rescue antiemetic use.
While the findings of this review favor the use of intraoperative 5-HT3 receptor
antagonists, at least to decrease vomiting, clinicians and researchers need to reflect on
whether the findings are acceptable. Despite a significant treatment effect, the rates of
postoperative emesis in the treatment groups remained high. For example, by 48+ hours,
the combined weighted risk of emesis among patients who received a 5-HT3 receptor
antagonist was 34% (range across studies 15% - 45%). Nausea, which patients have
highly ranked as undesirable after surgery (35), remains a common symptom in both the
treatment and control groups. If the nausea and vomiting were combined as an outcome
measure, as they were in one of the excluded studies (14), the overall efficacy of this
class of drugs for PONV may be lower due to the high rates of nausea and lack of
efficacy of the 5-HT3 receptor antagonists in preventing nausea. Future research could be
focused on the efficacy of drug combinations that target nausea and vomiting in this
patient population.
21
The investigation of combination therapy, intermittent administration of 5HT3
receptor antagonists after surgery compared to a single dose intraoperatively, and non-
pharmacologic means, could lead to further strategies to reduce PONV. Given the
established efficacy of the 5HT3 receptor antagonists for reducing emesis in patients
requiring craniotomy, researchers must also reconsider the use of intra-operative placebo
in future studies for these patients.
22
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25
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a
g
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n
i
s
t
s

F
o
r

t
h
e

P
r
e
v
e
n
t
i
o
n

o
f

P
o
s
t
o
p
e
r
a
t
i
v
e

N
a
u
s
e
a

a
n
d

V
o
m
i
t
i
n
g

F
o
l
l
o
w
i
n
g

C
r
a
n
i
o
t
o
m
y

C
o
m
p
a
r
i
s
o
n
:

0
1

C
u
m
u
l
a
t
i
v
e

P
o
s
t
o
p
e
r
a
t
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v
e

E
m
e
s
i
s

O
u
t
c
o
m
e
:

0
1

T
i
m
e
=
2
4
h
r

S
t
u
d
y

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r

s
u
b
-
c
a
t
e
g
o
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y

T
r
e
a
t
m
e
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t

n
/
N

C
o
n
t
r
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l

n
/
N

R
R

(
r
a
n
d
o
m
)

9
5
%

C
I

W
e
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g
h
t

%

R
R

(
r
a
n
d
o
m
)

9
5
%

C
I

S
i
n
h
a

(
2
8
)

F
a
b
l
i
n
g

(
2
9
)

K
a
t
h
i
r
v
e
l

(
3
0
)

F
a
b
l
i
n
g

(
3
1
)

E
l

S
h
o
b
a
k
i

(
3
2
)

M
a
d
e
n
o
g
l
u

(
3
3
)

2
/
2
0

8
/
2
0

1
8
/
7
4

6
/
2
3

4
/
2
0

8
/
3
0

T
o
t
a
l

(
9
5
%

C
I
)

1
8
7

T
o
t
a
l

e
v
e
n
t
s
:

4
6

(
T
r
e
a
t
m
e
n
t
)
,

9
8

(
C
o
n
t
r
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l
)

T
e
s
t

f
o
r

h
e
t
e
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g
e
n
e
i
t
y
:

C
h
i
2

=

3
.
8
8
,

d
f

=

5

(
P

=

0
.
5
7
)
,

l
z

=

0
%

T
e
s
t

f
o
r

o
v
e
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l
l

e
f
f
e
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t
:

Z

=

4
.
7
8

(
P

<

0
.
0
0
0
0
1
)

1
0
/
2
0

1
1
/
2
0

3
4
/
7
8

1
4
/
2
3

1
1
/
2
0

1
8
/
3
0

1
9
1

4
.
2
3

1
8
.
2
7

3
6
.
1
1

1
4
.
0
1

8
.
7
9

1
8
.
5
9

1
0
0
.
0
0

2
0

7
3

5
6

4
3

3
6

4
4

[
0
.
0
5
,

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0
.
3
7
,

[
0
.
3
5
,

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0
.
2
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,

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0
.
1
4
,

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0
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2
3
,

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.
8
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0

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.
6
6
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F
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s

t
r
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t

F
a
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l

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g
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1
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n

t
h
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f
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r
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t

t
w
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c
o
l
u
m
n
s
.

(
n
=
n
u
m
b
e
r

o
f

p
e
o
p
l
e

e
x
p
e
r
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n
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g

t
h
e

e
v
e
n
t
,

N
=
t
o
t
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o
f

p
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p
l
e

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n

t
h
e

g
r
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u
p
)
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T
h
e

b
l
a
c
k

s
q
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s

a
n
d

b
l
a
c
k

l
i
n
e
s

c
o
r
r
e
s
p
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n
d

t
o

t
h
e

r
e
l
a
t
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v
e

r
i
s
k

a
n
d

9
5
%

c
o
n
f
i
d
e
n
c
e

i
n
t
e
r
v
a
l

(
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I
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f

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h
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n
d
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v
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l

s
t
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s

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c
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s
p
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g

t
o

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h
e

n
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m
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s

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c
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l
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n
)
.

T
h
e

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f

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s
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p
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n
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s

t
h
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w
e
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g
h
t

t
h
a
t

t
h
e

t
r
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l

c
o
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t
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s

t
o

t
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m
e
t
a
-
a
n
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y
s
i
s

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c
o
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s
p
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g

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h
e

p
e
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t
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t

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T
h
e

b
l
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d
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a
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n
d

s
h
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s

t
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e

c
o
m
b
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e
d

r
e
l
a
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e

r
i
s
k

a
n
d

9
5
%

C
I
.

T
h
e

c
o
m
b
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n
e
d

r
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l
a
t
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v
e

r
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s
k

a
n
d

9
5
%

C
I

a
r
e

a
l
s
o

r
e
p
o
r
t
e
d

i
n

t
h
e

b
o
t
t
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m

r
o
w

o
f

t
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e

f
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n
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l

c
o
l
u
m
n

(
1
7
)
.

t
o

-
o

F
I
G
U
R
E

1
.
2

F
o
r
e
s
t

p
l
o
t

s
h
o
w
i
n
g

4
8
+

h
o
u
r

c
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m
u
l
a
t
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v
e

i
n
c
i
d
e
n
c
e

o
f

e
m
e
s
i
s

R
e
v
i
e
w
:

5
H
T
3

R
e
c
e
p
t
o
r

A
n
t
a
g
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n
i
s
t
s

F
o
r

t
h
e

P
r
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v
e
n
t
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o
n

o
f

P
o
s
t
o
p
e
r
a
t
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v
e

N
a
u
s
e
a

a
n
d

V
o
m
i
t
i
n
g

F
o
l
l
o
w
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n
g

C
r
a
n
i
o
t
o
m
y

C
o
m
p
a
r
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s
o
n
:

0
1

C
u
m
u
l
a
t
i
v
e

P
o
s
t
o
p
e
r
a
t
i
v
e

E
m
e
s
i
s

O
u
t
c
o
m
e
:

0
2

T
i
m
e
=
4
8
+
h
r

S
t
u
d
y

T
r
e
a
t
m
e
n
t

C
o
n
t
r
o
l

R
R

(
r
a
n
d
o
m
)

W
e
i
g
h
t

R
R

(
r
a
n
d
o
m
)

o
r

s
u
b
-
c
a
t
e
g
o
r
y

n
/
N

n
/
N

9
5
%

C
I

%

9
5
%

C
I

S
i
n
h
a

(
2
8
)

3
/
2
0

1
3
/
2
0

1
0

1
0

0

2
3

[
0

0
8
,

0

6
9
]

F
a
b
l
i
n
g

(
2
9
)

9
/
2
0

1
1
/
2
0


1

2
1

2
1

0

8
2

[
0

4
4
,

1

5
3
]

F
a
b
l
i
n
g

(
3
1
)

8
/
2
3

1
5
/
2
3

2
3

7
8

0

5
3

[
0

2
8
,

1

0
1
]

W
a
n
g

(
1
3
)

6
/
3
5

1
7
/
3
5


a


1
6

7
5

0

3
5

[
0

1
6
,

0

7
9
]

E
l

S
h
o
b
a
k
i

(
3
2
)

8
/
2
0

1
4
/
2
0

2
5

1
6

0

5
7

[
0

3
1
,

1

0
5
]

T
o
t
a
l

(
9
5
%

C
I
)

1
1
8

1
1
8

4

1
0
0

0
0

0

5
2

[
0

3
6
,

0

7
5
]

T
o
t
a
l

e
v
e
n
t
s
:

3
4

(
T
r
e
a
t
m
e
n
t
)
,

7
0

(
C
o
n
t
r
o
l
)

T
e
s
t

f
o
r

h
e
t
e
r
o
g
e
n
e
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t
y
:

C
h
i
2

=

5
.
4
1
,

d
f

=

4

(
P

=

0
.
2
5
)
,

I
2

=

2
6
.
1
%

T
e
s
t

f
o
r

o
v
e
r
a
l
l

e
f
f
e
c
t
:

Z

=

3
.
4
8

(
P

=

0
.
0
0
0
5
)

0
.
0
1

0
.
1

1

1
0

1
0
0

F
a
v
o
u
r
s

t
r
e
a
t
m
e
n
t

F
a
v
o
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r
s

c
o
n
t
r
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l

F
i
g
u
r
e

1
.
2
:

T
r
i
a
l
s

a
r
e

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n

o
r
d
e
r

o
f

p
u
b
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c
a
t
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n

y
e
a
r
.

T
h
e

r
i
s
k

f
o
r

4
8
+

h
o
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r

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m
e
s
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s

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n

t
h
e

t
r
e
a
t
m
e
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t

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d

c
o
n
t
r
o
l

g
r
o
u
p
s

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n

e
a
c
h

s
t
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d
y

a
r
e

f
o
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n
d

i
n

t
h
e

f
i
r
s
t

t
w
o

c
o
l
u
m
n
s
.

(
n
=
n
u
m
b
e
r

o
f

p
e
o
p
l
e

e
x
p
e
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n
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g

t
h
e

e
v
e
n
t
,

N
=
t
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t
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l

o
f

p
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o
p
l
e

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n

t
h
e

g
r
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u
p
)
.

T
h
e

b
l
a
c
k

s
q
u
a
r
e
s

a
n
d

b
l
a
c
k

l
i
n
e
s

c
o
r
r
e
s
p
o
n
d

t
o

t
h
e

r
e
l
a
t
i
v
e

r
i
s
k

a
n
d

9
5
%

c
o
n
f
i
d
e
n
c
e

i
n
t
e
r
v
a
l

(
C
I
)

o
f

t
h
e

i
n
d
i
v
i
d
u
a
l

s
t
u
d
i
e
s

(
c
o
r
r
e
s
p
o
n
d
i
n
g

t
o

t
h
e

n
u
m
b
e
r
s

i
n

t
h
e

f
i
n
a
l

c
o
l
u
m
n
)
.

T
h
e

s
i
z
e

o
f

e
a
c
h

b
l
a
c
k

s
q
u
a
r
e

r
e
p
r
e
s
e
n
t
s

t
h
e

w
e
i
g
h
t

t
h
a
t

t
h
e

t
r
i
a
l

c
o
n
t
r
i
b
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t
e
s

t
o

t
h
e

m
e
t
a
-
a
n
a
l
y
s
i
s

(
c
o
r
r
e
s
p
o
n
d
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n
g

t
o

t
h
e

p
e
r
c
e
n
t
a
g
e

w
e
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g
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t

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n

t
h
e

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e
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t

c
o
l
u
m
n
)
.

T
h
e

b
l
a
c
k

d
i
a
m
o
n
d

s
h
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w
s

t
h
e

c
o
m
b
i
n
e
d

r
e
l
a
t
i
v
e

r
i
s
k

a
n
d

9
5
%

C
I
.

T
h
e

c
o
m
b
i
n
e
d

r
e
l
a
t
i
v
e

r
i
s
k

a
n
d

9
5
%

C
I

a
r
e

a
l
s
o

r
e
p
o
r
t
e
d

i
n

t
h
e

b
o
t
t
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m

r
o
w

o
f

t
h
e

f
i
n
a
l

c
o
l
u
m
n

(
1
7
)
.

t
o

o
o

F
I
G
U
R
E

1
.
3

F
o
r
e
s
t

p
l
o
t

s
h
o
w
i
n
g

2
4

h
o
u
r

c
u
m
u
l
a
t
i
v
e

i
n
c
i
d
e
n
c
e

o
f

n
a
u
s
e
a

R
e
v
i
e
w
:

5
H
T
3

R
e
c
e
p
t
o
r

A
n
t
a
g
o
n
i
s
t
s

F
o
r

t
h
e

P
r
e
v
e
n
t
i
o
n

o
f

P
o
s
t
o
p
e
r
a
t
i
v
e

N
a
u
s
e
a

a
n
d

V
o
m
i
t
i
n
g

F
o
l
l
o
w
i
n
g

C
r
a
n
i
o
t
o
m
y

C
o
m
p
a
r
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s
o
n
:

0
2

C
u
m
u
l
a
t
i
v
e

P
o
s
t
o
p
e
r
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t
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e

N
a
u
s
e
a

O
u
t
c
o
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e
:

0
3

T
i
m
e
=
2
4
h
r

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t
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d
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r

s
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b
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c
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t
e
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y

T
r
e
a
t
m
e
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t

n
/
N

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o
n
t
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l

n
/
N

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R

(
r
a
n
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o
m
)

9
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%

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I

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e
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t

%

R
R

(
r
a
n
d
o
m
)

9
5
%

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I

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a
b
l
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g

(
2
9
)

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t
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r
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l

(
3
0
)

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a
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l
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g

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3
1
)

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l

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k
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3
2
)

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a
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u

(
3
3
)

7
/
2
0

1
0
/
7
4

1
7
/
2
3

1
1
/
2
0

9
/
3
0

1
4
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2
0

4
/
7
8

2
0
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7
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2
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4
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H
B
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1
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6
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7
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8
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0
4
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8
5

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6
4
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r
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t
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o
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l
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)
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2

=

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.
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%

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F
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v
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r
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t
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t

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a
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i
g
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s

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h
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h
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l

g
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f
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t

t
w
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c
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l
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s
.

(
n
=
n
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m
b
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o
f

p
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p
l
e

e
x
p
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n
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g

t
h
e

e
v
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n
t
,

N
=
t
o
t
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l

o
f

p
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p
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n

t
h
e

g
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)
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T
h
e

b
l
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n
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l
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k

l
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c
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s
p
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d

t
o

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r
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l
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t
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r
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s
k

a
n
d

9
5
%

c
o
n
f
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e

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n
t
e
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l

(
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I
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f

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s
t
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t
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w
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t
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t
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t
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c
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m
e
t
a
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a
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s

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c
o
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s
p
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h
e

p
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h
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b
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k

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9
5
%

C
I
.

T
h
e

c
o
m
b
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d

r
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l
a
t
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v
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r
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k

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d

9
5
%

C
I

a
r
e

a
l
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o

r
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p
o
r
t
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d

i
n

t
h
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b
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m

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w

o
f

t
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c
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l
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m
n

(
1
7
)
.

t
o

F
I
G
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R
E

1
.
4

F
o
r
e
s
t

p
l
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t

s
h
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w
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g

4
8
+

h
o
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r

c
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m
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l
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e

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n
c
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f

n
a
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a

R
e
v
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e
w
:

5
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T
3

R
e
c
e
p
t
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r

A
n
t
a
g
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s

F
o
r

t
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e

P
r
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v
e
n
t
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n

o
f

P
o
s
t
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p
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t
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N
a
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a

a
n
d

V
o
m
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t
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n
g

F
o
l
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w
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g

C
r
a
n
i
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t
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m
y

C
o
m
p
a
r
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s
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n
:

0
2

C
u
m
u
l
a
t
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v
e

P
o
s
t
o
p
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r
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e

N
a
u
s
e
a

O
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t
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0
4

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i
m
e
=
4
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+
h
r

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t
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d
y

T
r
e
a
t
m
e
n
t

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o
n
t
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l

R
R

(
r
a
n
d
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m
)

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e
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g
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t

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R

(
r
a
n
d
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m
)

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r

s
u
b
-
c
a
t
e
g
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r
y

n
/
N

n
/
N

9
5
%

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I

%

9
5
%

C
I

S
i
n
h
a

(
2
8
)

F
a
b
l
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n
g

(
2
9
)

F
a
b
l
i
n
g

(
3
1
)

W
a
n
g

(
1
3
)

E
l

S
h
o
b
a
k
i

(
3
2
)

4
/
2
0

8
/
2
0

1
8
/
2
3

3
/
3
5

1
6
/
2
0

1
0
/
2
0

1
4
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2
0

2
0
/
2
3

3
/
3
5

1
7
/
2
0

T
o
t
a
l

(
9
5
%

C
I
)

1
1
8

T
o
t
a
l

e
v
e
n
t
s
:

4
9

(
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r
e
a
t
m
e
n
t
)
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6
4

(
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o
n
t
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l
)

T
e
s
t

f
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t
y
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h
i
2

=

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.
1
0
,

d
f

=

4

(
P

=

0
.
1
9
)
,

I
2

=

3
4
.
4
%

T
e
s
t

f
o
r

o
v
e
r
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l
l

e
f
f
e
c
t
:

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=

1
.
5
2

(
P

=

0
.
1
3
)

1
1
8

6
.
6
5

1
4
.
7
8

3
8
.
8
9

2

.
9
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3

6
.
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8

1
0
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0
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0
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4
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5
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0
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,

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0
.
3
1
,

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6
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2
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,

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9
4

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7
1
,

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.
0
7
]

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.
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.
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.

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]

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.
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8
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.
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2
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.
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6
]

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F
a
v
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r
s

t
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t

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r

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n

t
h
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t
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l
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n
=
n
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m
b
e
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f

p
e
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p
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e

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x
p
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,

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=
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f

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p
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n

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g
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)
.

T
h
e

b
l
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k

s
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s

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n
d

b
l
a
c
k

l
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n
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s

c
o
r
r
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s
p
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n
d

t
o

t
h
e

r
e
l
a
t
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v
e

r
i
s
k

a
n
d

9
5
%

c
o
n
f
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d
e
n
c
e

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n
t
e
r
v
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l

(
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I
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o
f

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e

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n
d
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v
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l

s
t
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d
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s

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c
o
r
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s
p
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n
d
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n
g

t
o

t
h
e

n
u
m
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r
s

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n

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l

c
o
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n
)
.

T
h
e

s
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f

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a
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h

b
l
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c
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s
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p
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n
t
s

t
h
e

w
e
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g
h
t

t
h
a
t

t
h
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t
r
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l

c
o
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t
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b
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t
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s

t
o

t
h
e

m
e
t
a
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a
n
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s
i
s

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c
o
r
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e
s
p
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n
g

t
o

t
h
e

p
e
r
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n
t
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n

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e
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t

c
o
l
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m
n
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.

T
h
e

b
l
a
c
k

d
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a
m
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n
d

s
h
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w
s

t
h
e

c
o
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b
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e
d

r
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l
a
t
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v
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r
i
s
k

a
n
d

9
5
%

C
I
.

T
h
e

c
o
m
b
i
n
e
d

r
e
l
a
t
i
v
e

r
i
s
k

a
n
d

9
5
%

C
I

a
r
e

a
l
s
o

r
e
p
o
r
t
e
d

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n

t
h
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b
o
t
t
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m

r
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w

o
f

t
h
e

f
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n
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l

c
o
l
u
m
n

(
1
7
)
.

F
I
G
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R
E

1
.
5

F
u
n
n
e
l

P
l
o
t

t
o

E
x
a
m
i
n
e

P
u
b
l
i
c
a
t
i
o
n

B
i
a
s

R
e
v
i
e
w
:

5
H
T
3

R
e
c
e
p
t
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r

A
n
t
a
g
o
n
i
s
t
s

F
o
r

t
h
e

P
r
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v
e
n
t
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n

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f

P
o
s
t
o
p
e
r
a
t
i
v
e

N
a
u
s
e
a

a
n
d

V
o
m
i
t
i
n
g

F
o
l
l
o
w
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n
g

C
r
a
n
i
o
t
c

C
o
m
p
a
r
i
s
o
n
0
2

C
u
m
u
l
a
t
i
v
e

P
o
s
t
o
p
e
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t
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e

E
m
e
s
i
s

O
u
t
c
o
m
e
:

0
1

T
i
m
e
=
2
4
h
r

-
i
-
O
.
O

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Paper 2
The Efficacy of 5-HT
3
Receptor Antagonists for the Prevention of Postoperative Nausea
and Vomiting Following Craniotomy Part Two: The Paediatric Studies
A version of this paper has been accepted for publication as:
Neufeld, S.M. & Newburn-Cook, C.V. The Efficacy of 5-HT
3
Receptor Antagonists for the Prevention of Postoperative
Vomiting Following Craniotomy: Results of two studies in children and young adults. Canadian Journal of
Neuroscience Nursing.
32
Post-operative nausea and vomiting (PONV) frequently occurs after craniotomy
(1), and children after craniotomy may be at particularly high risk for this adverse
outcome (2). Currently, the 5-HT3 receptor antagonists are considered the first choice for
preventing post-operative vomiting (POV) in at-risk children (3). However, the efficacy
of 5HT3 receptor antagonists in preventing POV in children after craniotomy has not
been established. Neither the randomized controlled trial (RCT) published in 1996 by
Furst and colleagues (2) nor the recent RCT by Subramaniam and colleagues (4) had
sufficient sample sizes to confidently conclude whether or not ondansetron, a 5HT3
receptor antagonist, was more effective than placebo in preventing POV in children.
The efficacy of intraoperative administration of 5-HT3 receptor antagonists in
adults after craniotomy has been estimated by pooling the results of seven RCTs using
meta-analysis (5). By combining these seven published RCTs, with a combined sample
size of 448 (222 treatment, 226 control), we estimated a relative risk for postoperative
vomiting by 24 hours of 0.55 (95% confidence interval (CI): 0.38-0.66) in the treatment
group compared with controls receiving a placebo. No evidence for efficacy was
established for nausea (relative risk 0.76, 95% CI: 0.54-1.06).
Notably, our systematic review and meta-analysis (5) was limited to adults
because the literature search revealed only one pediatric study (2). With the recent
publication of another RCT on the efficacy of ondansetron in children after craniotomy
(4), we felt that we could now combine the two studies using meta-analysis to further
estimate its efficacy in children. In this paper, we will describe the search strategy that
identified the additional study and our inclusion criteria for the selection of studies. We
will then present the results of the meta-analysis and discuss the findings.
33
Methods
Selection of Studies
We updated our previous systematic review, as described in Table 2.1, to include
studies from January 2006-December 2007. We then limited the findings to children. For
our search update we added palenosetron to our list of 5-HT3 receptor antagonists and we
used PubMed to search the last 180 days for recently published studies. Studies from the
electronic search were independently evaluated by the authors, based on the inclusion
criteria below.
Inclusion Criteria
Studies were included in the meta-analysis if they met the following inclusion
criteria: 1) Study sample of children up to age 21 years undergoing craniotomy with a
dural opening; 2) Intervention consisted of the administration of an intraoperative 5-HT3
receptor antagonist; 3) Controls received a placebo; 4) Outcome of occurrence of post-
operative vomiting was measured over any time period; 5) Design was a randomized
placebo controlled trial.
Study Outcomes
The primary outcome for the meta-analysis was the occurrence of an emetic event
in the first 24 hours after surgery. The secondary outcome was the use of a rescue
antiemetic in this time period. We used a standard form to extract descriptive and
outcome data, and independently extracted the outcome data to ensure accuracy. The data
were entered into RevMan 4.0.8 (3) by the primary author, who identified and resolved
any discrepancies.
34
Assessment of Methodological Quality
We used the Jadad Scale (6) to describe the scientific quality of the studies. A
maximum score on the Jadad score is 5, indicating that appropriate efforts were made to
reduce study bias and that these efforts were reported in the manuscript. One point is
given for the answer "yes" to each of the following: 1) Was the study described as
randomized? 2) Was the study described as double blind? 3) Was there a description of
withdrawals and dropouts? One additional point was given for each of questions 1 and 2
if the methods for generating the randomization and/or blinding were appropriate.
Statistical Analysis
The RevMan Analysis 1.0.3 program was used to combine trial data (7), and the
relative risk of harm (RR) was calculated from the combined data for the outcomes of
POV and use of rescue antiemetics. The relative risk of harm (RR) provides the greatest
consistency for the evaluation of preventive studies (8) and is easy to interpret.
Specifically, the RR is the risk of the event (POV or use of rescue antiemetics) in the
group receiving ondansetron relative to the risk of the event in the control group. Odds
ratios (OR) were used for descriptive differences between the studies.
We combined the study results using a random effects model (9) to assess the
efficacy of ondansetron, on average, in preventing POV across heterogeneous
studies(lO). Study heterogeneity was examined by estimating the I
2
statistic, which
describes the percentage of total variation across studies due to heterogeneity as opposed
to chance (11). The I
2
statistic does not depend on the number of studies included in the
meta-analysis (12). We felt that it was therefore an appropriate statistic for the
35
combination of only two studies. I values of 25%, 50%, and 75% indicate low,
moderate, and high heterogeneity respectively (13).
Results
Search Results
Our search results showed one additional published pediatric article since our last
search (Figure 2.1). The two paediatric studies are described in Table 2.2. Both these
studies showed good methodological quality and together included 135 children (79
treatment, 56 control). Differences in the patient selection were present, with Furst and
colleagues (2) having a broader range of procedures and younger age limit. Anaesthetic
protocols were controlled and similar in both studies, but the use of dexamethasone was
not controlled for in the study by Subramaniam and colleagues (4). Differences in the
measurement of vomiting were also noted, as Furst and colleagues did not count retching
as an emetic event (2).
Descriptive data could not be combined and summarized for age due to
differences in reporting, but gender and location of tumor could be combined. There was
high heterogeneity between the studies for gender (I =83) but the combined odds ratio for
males to females was not significant (OR=2.77, 95%CI=0.83-9.26). Analysis of
individual studies showed that Subramanian and colleagues (4) had a male to female odds
ratio of 2.82 (95%CI=1.73-4.60), whereas Furst and colleagues (2) did not have a gender
difference (OR=1.49; 95%CI=0.73-3.07). The studies showed no heterogeneity in their
ratios of supratentorial and infratentorial tumors (I
2
=0), with significantly more children
with supratentorial tumours overall (OR=2.33; 95% CI 1.43-3.80).
36
Meta-analysis
Because Subramaniam and colleagues (4) had two similar intervention groups
(one received an intraoperative dose of ondansetron while the second group received a
second dose six hours later), we decided to combine them into one intervention group for
the meta-analysis. The combined results showed no difference between the treatment and
control groups for males to females (OR=1.19; 95% CI=0.57-2.46) or supratentorial to
infratentorial (OR= 1.16; 95% CI 0.56-2.40). As shown in the first Forest plot (Figure
2.2), there was no evidence for the efficacy for the use of ondansetron in reducing the
incidence of postoperative vomiting in the first 24 hours following craniotomy, by
combining the two studies (RR = 0.77 and 95% CI 0.50-1.19). There is also no evidence
that ondansetron reduces the use of rescue antiemetics in this patient group (Figure 2.3:
RR = .71 and 95% confidence interval 0.34-1.49).
Discussion
Two small randomized controlled trials have been conducted to look at the
efficacy of ondansetron in reducing POV following craniotomy in children. It appears
that other 5-HT3 receptor antagonists have not been studied in this population. As other
risk factors and mechanisms of nausea and vomiting may be present which are beyond
the usual postoperative risk factors, the efficacy of delivering prophylactic antiemetics to
these children is important to establish. By combining two studies, we concluded that the
administration of peri-operative ondansetron does not show a large effect in reducing
POV in children after craniotomy. The combined sample was still too small to establish
whether or not ondansetron shows a smaller but clinically significant effect.
37
Interestingly, Subramanian and colleagues (4) noted an unexpectedly low
incidence of vomiting in their study. This may be partially explained by the gender
differences, with a significantly high number of males in their study. Furst and colleagues
(2) noted a significant gender difference in their control group for POV, and gender in
adults is a confirmed risk factor for POV(14).
Like the study limitations that were discussed in our meta-analysis of the 5HT3
receptor antagonists in adults (5), the outcome measurement for these two studies may
limit their overall clinical utility. Following craniotomy, children may begin to vomit
and/or continue to vomit well past the 24 hour postoperative time period. Thus, the
efficacy of antiemetics in reducing the severity of vomiting, and the length of time
children experience vomiting, remain important areas of concern. Nausea can be
measured directly in children as young as five (15), and attempts to do so should be
included in children's PONV research. Child and parent satisfaction with care of PONV
is another neglected area of research (16). Finally, as with other clinical populations, it is
likely that a combination of drugs and non-pharmacologic interventions, in the form of a
multidisciplinary postoperative care protocol, will best serve these children.
38
Reference List
1. Fabling, JM, Gan, TJ, Guy, J, Borel, CO, el-Moalem, HE, and Warner, DS.
Postoperative nausea and vomiting. A retrospective analysis in patients
undergoing elective craniotomy. J Neurosurg Anesthesiol. 1997; 9, 308-12.
2. Furst, SR, Sullivan, LJ, Soriano, SG, McDermott, JS, Adelson, PD, and Rockoff, MA.
Effects of ondansetron on emesis in the first 24 hours after craniotomy in
children. Anesth Analg. 1996; 83: 325-28.
3. Kovac AL. Management of postoperative nausea and vomiting in children. Paediatr
Drugs. 2007; 9:47-69.
4. Subramaniam K, Pandia MP, Dash M, Dash HH, Bithal PK, Bhatia A, Subramaniam
B. Scheduled prophylactic ondansetron administration did not improve its
antiemetic efficacy after intracranial tumour resection surgery in children. Eur J
Anaesthesiol. 2007; 24:615-19.
5. Neufeld SM, Newburn-Cook CV. The efficacy of 5-HT3 receptor antagonists for the
prevention of postoperative nausea and vomiting after craniotomy: a meta-
analysis. J Neurosurg Anesthesiol. 2007; 19:10-17.
6. Jadad, AR, Moore, RA, Carroll, D., Jenkinson, C., Reynolds, DJ, Gavaghan, D J, and
McQuay, HJ. Assessing the quality of reports of randomized clinical trials: is
blinding necessary? Control Clin Trials. 1996; 17:1-12.
7. RevMan Analysis . The Cochrane Collaboration. 2003. Copenhagen: The Nordic
Cochrane Centre.
8. Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical
trials with binary outcomes. Stat Med. 2002; 21:1575-600.
9. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;
7:177-88.
10. Green S, Higgins J, eds. Cochrane Handbook for Systematic Reviews of Interventions
4.2.5. [Cochrane web site]. Available at:
http://www.cochrane.dk/cochrane/handbook/handbook.htm . Accessed November
14, 2005.
11. Higgins J, Thompson S, Deeks J, Altman D. Statistical heterogeneity in systematic
reviews of clinical trials: a critical appraisal of guidelines and practice. J Health
Serv Res Policy. 2002; 7:51-61.
12. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med
2002;21:1539-58.
39
13. Higgins, JP, Thompson, SG, Deeks, J J, and Altaian, DG. Measuring inconsistency in
meta-analyses. BMJ. 2003; 327:557-60.
14. Gan TJ. Risk factors for postoperative nausea and vomiting. Anesth Analg. 2006;
102:1884-98.
15. Zeltzer LK, LeBaron S, Richie DM, Reed D, Schoolfield J, Prihoda TJ. Can children
understand and use a rating scale to quantify somatic symptoms: Assessment of
nausea and vomiting as a model. J Consult Clin Psychol. 1988; 56:567-72.
16. Fisher DM. The "big little problem" of postoperative nausea and vomiting: do we
know the answer yet? Anesthesiology. 1997; 87:1271-3.
40
TABLE 2.1
Initial Search Strategy
Electronic Sources MEDLINE (1990-2005), EMBASE (1988-2005),
CINAHL (1990-2005), the Cochrane Library, DARE
(Database of Abstracts of Reviews of Effectiveness),
PubMed, Web of Science, and dissertation abstracts.
Search Filters Search filters from The University of Alberta
Library Website were used to limit searches to
clinical trials in humans in any language.
MeSH Headings and Text
(Keywords) Used
"neurosurgery", "neurosurgical procedure", "brain
surgery", "craniotomy", "brain neoplasm" and
"serotonin antagonists", "5-HT3 receptor
antagonists", "azasetron", "dolasetron",
"granisetron", "itasetron", "ondansetron",
"ramosetron", "tropisetron", and "postoperative
nausea and vomiting", "PONV" , "nausea", or
"vomiting".
Grey Literature Search Online Computer Library Center Conference
(OCLC) Paper and Proceedings Indexes and Google
Scholar.
From: Neufeld, S.M. & Newburn-Cook, C.V. (2007). The efficacy of 5-HT3 receptor
antagonists in the prevention of postoperative nausea and vomiting after craniotomy: a
meta-analysis.. Journal of Neurosurgical Anesthesiology 2007; 19:10-17.
41
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Paper 3
Risk and Protective Factors for Nausea and Vomiting after Neurosurgery:
A Systematic Review
A version of this paper has been published as:
Neufeld, S.M & Newburn-Cook, C. V. (2008). What are the risk factors for nausea and vomiting after neurosurgery: A
systematic review. Canadian Journal of Neuroscience Nursing, 30(1), 23-34.
The management of postoperative nausea and vomiting (PONV) is an important
but challenging component of neurosurgical nursing care. PONV may cause fluid and
electrolyte imbalance, airway compromise, suture tension and dehiscence, venous
hypertension, and bleeding (Scuderi & Conlay, 2003). For neurosurgical patients,
increased intracranial pressure during retching and vomiting may also pose a significant
threat to their postoperative recovery (Fabling et al., 1997). Efficacious interventions are
therefore needed for prevention and treatment of PONV in this patient population to
decrease the potential for further adverse events and to increase patient comfort after their
neurosurgical procedures.
Due to the complex nature of PONV, it is widely recognized that
multidisciplinary and multimodal interventions are necessary to effectively prevent and
treat PONV. These practices may include the choice of anaesthetic techniques,
administration of perioperative antiemetics and/or dexamethasone, hydration strategies,
effective pain management, and complimentary medicine interventions (American
Society of Peri Anesthesia Nurses, 2006). Some practices, such as the use of a
combination of antiemetics, may carry with them the potential for medication-related side
effects and increased institutional costs. It is important then to target interventions to
those at highest risk for PONV and/or those who would suffer from related deleterious
effects (Gan et al., 2003). Knowledge about risk factors helps healthcare providers
navigate the course of a disease or condition, promotes informed treatment decisions
(Hayden, Cote, & Bombardier, 2006), helps guide research design, and may even add
insight into mechanisms of disease (Altman & Lyman, 1998).
48
While a recent systematic review by Gan (2006) has played an important role in
determining what is currently known about PONV overall, "neurosurgery" is only
identified as a potential risk factor in this review. Risk factors such the location of
surgery, fluctuating intracranial pressures, and/or the need for cerebral spinal fluid
management, are unique to neurosurgical patients and warrant separate study in this
population. Audibert and Vail (2004) reviewed incidence and risk factors for PONV in
neurosurgery, but their report did not have the rigor of a systematic review; nor did they
evaluate the methodological quality of the research for studies included in their review.
Therefore, we conducted a systematic review to identify what is currently known about
the risk factors for PONV in neurosurgery and included recently published studies, as
well as a methodological quality assessment of the studies selected for inclusion.
Methods
Selection of Studies
We conducted a systematic search to identify relevant prognostic and risk factor
studies of PONV in neurosurgery. The search filters for best sensitivity to detect
prediction studies (Wong, Wilczynski, Haynes et al., 2003) and prognostic studies
(Wilczynski & Haynes, 2004) were combined to complete the search. A search for
unpublished literature included Online Computer Library Center Conference Paper and
Proceedings Indexes, Dissertation Abstracts, and Google Scholar. To complete our
search, we crossed-checked the references in the retrieved papers and used SCOPUS to
explore articles that cited the retrieved articles.
The selection of studies involved two steps. First, both authors independently
screened the preliminary electronic search results by title and abstract to exclude studies
49
that clearly did not fit the selection criteria and to identify potentially relevant articles.
Second, the full text of the articles that one or both reviewers identified as potentially
relevant were retrieved and reviewed for the final selection. This procedure was repeated
for the references in the retrieved articles and their citing articles. Any disagreements
were resolved by discussion and consensus.
Inclusion and Exclusion Criteria
Studies were included in the systematic review if associations between one or
more risk factors and the occurrence of postoperative nausea and/or vomiting in
neurosurgical patients were explored. As suggested by Altaian (2001), clinical studies of
predictive variables, epidemiological studies of aetiology, and epidemiological studies of
risk factors were all considered. Studies could be prospective or retrospective. Studies
were also included regardless of the location of the neurosurgical procedures considered
(supratentorial, infratentorial, spinal). Craniofacial surgery, disc surgery, and traumatic
brain injury studies were excluded, as were randomized placebo controlled trials of
interventions, case studies of individuals, and case series of less than twenty participants.
Study Outcomes
The primary study outcome needed to include at least one measure of nausea or
vomiting (or together as in PONV) as a primary outcome. The use of rescue antiemetics
was considered a secondary outcome. To ensure accuracy, we independently extracted
the data using a standardized form. We sought to extract 95% Confidence intervals (CI) if
they were reported in the manuscript; otherwise, we extracted the reported probability of
Type I error (i.e. p<.05 means that there is less than a 5% chance that the statistical
50
finding is not true). The first author identified and resolved any discrepancies in data
extraction.
Assessment of Methodological Quality
To assess the methodological quality of the selected studies we used the
guidelines proposed by Hayden et al. (2006) for assessing quality in prognostic studies.
These authors included six areas of potential bias for prognostic studies in their
guidelines: study participation; study attrition; prognostic (risk) factor measurement;
outcome measurement; confounding measurement and account; and statistical analysis.
For each area of potential bias, Hayden et al. provided items to consider when
determining the extent that the potential bias was limited. The items that were relevant
for the studies in this systematic review were compiled as shown in Appendix 1. Using
this tool, we independently reviewed each of the selected studies for methodological
quality and resolved discrepancies through discussion and consensus. The final result
enabled an examination of how well bias was addressed in each study and areas that
overall were not well addressed.
Results
The results of the systematic search for relevant articles are summarized in Figure
3.1. There were 15 titles and abstracts identified as potentially relevant from 266 titles
obtained from the computerized search. Five additional studies were identified through
cross-checking the reference lists of included articles (Park, Gleason, Madsen,
Goumnerova, & Scott, 1997; Quiney, Stoneham, & Walters, 1996), citing articles (Leslie
et al., 2003), and the authors' own libraries (Stieglitz et al., 2005; Manninen, Raman,
Boyle, & El-Beheiry, 1999). Of the 21 studies retrieved for full text review, 13 studies
51
met the final inclusion criteria with 91% agreement between the two authors. Of the
excluded studies: four did not have a measure of postoperative nausea and/or vomiting
(Gokalp et al., 1998; Peretta et al., 2006; Park et al., 1997; Skucas & Artru, 2006); two
were review articles (Audibert & Vial, 2004; Leslie & Williams, 2005); one study did not
examine any risk factors for postoperative nausea and/or vomiting (Taghipour,
Zamanizadeh, & Judaki, 2004); and, one focused only on vertebral discectomy (Chillemi,
Sinardi, Marino, Mantarro, & Campisi, 2002).
The characteristics of the included studies are summarized in Table 3.1. All of the
studies were single site with sample sizes that ranged from 52 to 877. Six studies were
prospective and seven were retrospective. Study samples varied from being broadly noted
as adults requiring neurosurgery to those requiring a specific procedure. Only two of the
studies included children (Kramer et al., 1994; Quiney et al., 1996), and none identified
risk factors specific to children after neurosurgery.
As shown in Table 3.2, the outcomes (i.e., nausea, vomiting, PONV, and use of
rescue antiemetics) and their measurement varied between the studies. The observation
time reported also varied, ranging from the first two hours after surgery (Irefin et al.,
2003) to the entire hospitalization (Stieglitz et al., 2005). Most of the studies used a
bivariate (yes/no) approach to statistical analysis of the outcome variables except for
Stieglitz et al. (2005), who measured the length of time that symptoms were experienced
and Quiney et al. (1996), who used an ordinal scale.
The results of the studies are summarized in Table 3.3. The differences in
measurement of outcomes, patient groups studied, and duration of observation for PONV,
made it difficult to compare results across the studies. For example, the lowest reported
52
incidence of emesis was 7.5% in a sample of patients following endonasal
transsphenoidal surgery (Flynn & Nemergut, 2006), but data were only collected until the
patient was discharged from the post-anaesthesia recovery unit (PACU). The highest
reported incidence of nausea and/or vomiting was 64% by the end of the first
postoperative day in a sample of patients following cranial or spinal surgery (Leslie et al.,
2003).
The risk factors for nausea, emesis, PONV and/or use of rescue antiemetics that
were examined using univariate statistics in the various studies are also presented in
Table 3.3. The most commonly studied risk factor was gender. Females were found to
experience significantly more symptoms than males in some studies (Fabling et al., 1997;
Stieglitz et al., 2005; Meng & Quinlan, 2006 ) but not in others (Kurita et al. 2004,;
Flynn & Nemergut, 2006).
The anatomical location of surgery was also examined in a number of studies.
Fabling et al.(1997) found that infratentorial surgery (vs. supratentorial) was a risk factor
for nausea but not for emesis or use of rescue antiemetics. Kurita et al. (2004) and
Manninen and Tan (2002) both found that infratentorial surgery was a risk factor for
PONV. Manninen et al. (1999) found increased PONV in spinal surgery compared to
brain tumour surgery, vascular surgery and other neurosurgical procedures. Somewhat
contrary to these findings, Irefin et al. (2003) did not find a relationship between nausea
and location of surgery (infratentorial, supratentorial, or spinal). Additionally, PONV
showed no relationship to: cranial vs. spinal procedures (Leslie et al., 2004);
supratentorial, infratentorial, intracranial vascular, transsphenoidal, vs. extracranial
53
procedures (Wong, O'Regan, & Irwin, 2006); or temporal, parietal, frontal, vs. occipital
locations (Quiney et al., 1996).
Anaesthetic techniques were also examined in a number of studies. Differences
between awake anaesthesia and general anaesthesia and nausea, emesis, and use of rescue
anaesthetics were only found for the first four hours after surgery (Manninen & Tan,
2002) and not for later outcome periods (Fabling et al., 1997; Manninen & Tan, 2002).
The use of desflurane compared to other volatile agents increased PONV (Manninen &
Tan). A cumulative fentanyl dose > 250 meg increased the risk of PONV in one study but
the result was then accounted for in multivariable analysis (Meng & Quinlan, 2006) as
did the use of fentanyl compared to remifentanil in another (Meng, Lasica, & Sullivan,
2006). Intraoperative fentanyl dose showed no relationship to PONV in a third study
(Kurita et al., 2004).
Unique risk factors for specific neurosurgical study populations were studied by a
number of authors. For example, Kramer et al. (1994) found no relationship between
PONV and the type of recording technique used for intracranial monitoring (depth
electrodes, subdural grids and/or strips). Stieglitz et al. (2005) found that the mean
number of days of nausea was greater for the smallest Grade 1 vestibular schwannomas
than the largest grade 4b vestibular schwannomas. Flynn & Nemergut (2006) found risk
factors for emesis for adults after endonasal transsphenoidal procedures including fat
grafts for cerebral spinal fluid leak, intraoperative use of a lumbar drain, and
craniopharyngiomas. Finally, Meng and Quinlan (2006) found that PONV was increased
in patients requiring retromastoid craniectomy with microvascular decompression of
Cranial Nerve V compared to Cranial Nerves VII, IX, and X.
54
Multivariate statistical analysis of risk factors was reported in only two studies
(Fabling et al., 1997; Meng & Quinlan, 2006). Fabling et al. used a backward selection
multivariate logistic regression to find that female gender (Odds Ratio (OR) =2.4,
p=.004) and infratentorial surgery (OR=2.0, p=.032) predicted nausea; female gender
(OR=2.2, p=.012) and younger age (1.29 times for every 10 year difference, 95% CI:
1.02-1.64 and 2.15 times for every 30 year difference, 95% CI: 1.07-4.43) predicted
emesis; and, female gender alone (OR=2.1, p=.01) predicted use of rescue antiemetics.
Excluded variables included anaesthetic technique, duration of anaesthetic, total fentanyl
dose, intraoperative antiemetics and postoperative opiate use. Meng and Quinlan used
multivariate logistic regression by entering variables with p<.15 on univariate analysis
together. Their final model for PONV was: Decompressive Surgery of Cranial Nerve V
(OR=2.8, 95% CI: 1.4-5.7) + Use of Desflurane (OR=2.8, 95% CI: 1.4-5.4) + Female
gender (OR=3.0, 95% CI: 1.4-6.7) - Prophylactic use of transdermal scopolamine patch
(OR=0.3, 95% CI: 0.2-0.7). Postoperative opiate use and Fentanyl dose ^250 meg
remained in the model but were not statistically significant. Finally, Meng, Lasica et al.
(2006) identified that they conducted a multivariate analysis but did not provide the
results. None of these authors reported model fitting statistics to describe how much
variance is explained by the overall statistical model.
For the analysis of methodological quality, we had excellent agreement on
independent review (94%) and easily resolved discrepancies for the final assessment as
presented in Table 3.4. While each study met some of the applicable criteria, few authors
controlled for confounders, and clear definitions of the risk factors and/or outcomes were
often lacking. A number of the studies were retrospective (Fabling et al., 1997; Kramer et
55
al., 1994; Kurita et al., 2004; Flynn & Numergut (2006); Meng & Quinlan, 2006; Meng,
Lasica, et al. 2006; Stieglitz et al., 2005) which has the advantage of being an
inexpensive way of gathering a large sample size for a confident statistical analysis, but is
limited in that the researcher has no control over how well the data were recorded and the
risk factors that can be studied (Guyatt, 2006). To initially identify risk factors, the
benefits of a retrospective design may outweigh the disadvantages, especially in difficult
to access study populations, if other quality indicators are present. Of the retrospective
designs presented in this systematic review, only the study by Meng and Quinlan (2006)
fully met the indicators of methodological quality; none of the prospective studies did.
Discussion
Thirteen studies of nausea and/or vomiting following neurosurgical procedures
were identified in this systematic review. These studies varied in their target populations,
risk factors considered, and measurement of the outcome variable of interest. Few of the
studies controlled for confounding variables and there were no studies that used risk
factors to create prognostic models or risk scoring systems for individual patients. The
assessment of methodological quality using valid and reliable tools is another issue for
risk factor studies and studies of prognosis. We had excellent agreement with the quality
assessment tool that we adapted from the guidelines of Hayden et al. (2006) but this tool
does not provide a score or rating for comparison. Our overall assessment of
methodological quality is that the studies were methodologically fair, but with only one
study fully meeting the relevant criteria for methodological quality (Meng & Quinlan,
2006).
56
Despite these limitations, there are a number of findings from this review that can
guide clinical practice and future research. In their evidence-based practice guideline for
the prevention and/or management of PONV, The American Society of PeriAnesthesia
Nurses (2006) recommend that, if there is an increased risk of surgical complications
related to POV, an individual should have the combination of antiemetics recommended
for the next higher level of risk when using a risk scoring tool.
Theoretically, patients after neurosurgery are at risk for surgical complications
related to vomiting, although none of the studies in this review specifically examined any
such adverse events. Our systematic review did not reveal any research related to the
development of prognostic models or risk scores for PONV after neurosurgery despite
using a search filter for prognostic studies. Additionally, current risk scoring tools do not
appear to have been specifically validated in neurosurgical populations, and may not
provide an accurate prediction for individual patients (Neufeld, Newburn-Cook, &
Drummond, 2008). Thus, issues such as valid and reliable outcome measures, length of
required follow-up, and lack important predictor variables that are unique to neurosurgery
may be challenges to validating existing tools. In the absence of valid and reliable clinical
prediction tools, the reported incidence of nausea, vomiting, and/or PONV across these
studies may be considered sufficiently high in itself to warrant prophylaxis in
neurosurgical patients as a group. However, the risk factors identified in the studies
reviewed can not be used to predict outcomes in individual patients.
In his systematic review, Gan (2006) summarized established risk factors derived
from a large number of studies from the overall PONV literature. These included: patient-
related risk factors of female gender after puberty, non-smoking status, history of PONV
57
or motion sickness and childhood (after infancy) or young adulthood; the surgery- related
risk factor of increasing duration of the procedure; and anaesthesia-related risk factors of
the use of volatile anaesthetics, nitrous oxide, balanced vs. total intravenous anaesthesia,
a large dose of neostigmine, and use of intraoperative and postoperative opioids (or larger
doses of opioids). Given the small sample sizes of many of the studies in the present
review, there is a high likelihood of Type II error (the probability that true effects were
not found). Therefore, while some of the studies confirmed what are now considered
established risk factors for PONV, none of these risk factors could confidently be
excluded from consideration for patients requiring most neurosurgical procedures.
However, Flynn and Nemergut (2006) rejected a number of established risk factors
including: female gender; age; and perioperative use of nitric oxide or neostigmine (dose
level not examined) with a fairly large sample size of 877 patients after transsphenoidal
procedures. This rejection of established risk factors in other patient groups further
highlights the need for validation of risk scoring tools in patients requiring neurosurgery
prior to clinical use as their contents may not apply to this patient population.
A number of the authors did investigate factors of unique interest to neurosurgery
which may enhance our understanding of PONV in this patient population or challenge
our traditional thinking. Clearly, the finding that awake craniotomy only showed a
protective effect for the first four hours after craniotomy (Manninen & Tan, 2002)
challenges the idea that the use of general anaesthesia is a major risk factor for PONV in
this population. The relationship between the location of surgery and PONV was also
investigated, using both univariate and multivariable analysis, with equivocal results.
Interestingly, while controlling for other variables, Fabling et al. (1997) identified
58
infratentorial location of surgery to be a risk factor for PON but not for POV. This
finding seems counterintuitive to clinical wisdom and neuro-anatomical knowledge of
vomiting pathways but confirms the importance of examining risk factors for nausea and
vomiting separately, as recommended by Apfel, Roewer and Kortilla (2002). Separation
of vomiting and nausea in the statistical analysis was only clearly completed in two of the
studies in this review (Fabling et al.; Manninen & Tan, 2002). Future studies of risk
factors for PONV in neurosurgical patients need to look at nausea and vomiting as
separate but related entities that may have different risk factors.
Also counterintuitive was the greater risk of postoperative nausea in those with
the lowest vestibular schwannoma grade of tumour compared to the highest (Stieglitz et
al., 2005). Stieglitz et al. proposed that less manipulation of the cerebral tissues was
required to remove the highest grade of tumour or that the brain had become accustomed
to the larger tumour and less sensitive to nausea-evoking stimuli. Flynn and Nemergut
(2006) found that the incidence of POV increased for adults having endonasal
transsphenoidal surgery if they required an intraoperative fat graft for cerebral spinal
fluid leak and/or an intraoperative lumbar drain. This finding is suggestive of the role that
cerebral spinal fluid dynamics may play in postoperative vomiting, with low pressure
being a possible causal factor. It also points to the need for further investigation into the
role of cerebral spinal fluid management practices and their contribution to PONV as
there does not appear to be any other studies in this area.
The studies contained in this systematic review highlight the heterogeneity within
neurosurgical procedures and patient populations, with some focusing broadly and others
focusing on a specific procedure. Further studies of PONV in children's neurosurgery,
59
neuro-oncology and posterior fossa procedures will help further delineate related risk
factors to aid in clinical decision making. Such research could target neurosurgery-
specific risk factors such as presenting symptoms or location of lesions (i.e., for posterior
fossa surgery, midline tumours compared to those in the cerebellar hemispheres). Future
studies require multivariable analysis to control for established risk factors in order to
determine the significance of the ones under investigation.
There were a number of retrospective studies in this systematic review.
Retrospective studies are limited in that the research has no control over the measurement
of variables, thus important predictors may not be delinieated. Prospective validation of
results derived from retrospective analyses will help further define risk groups within
neurosurgery, but this method is expensive and time consuming (Guyatt, 2006).
Resources may be better spent on trials of interventions in high risk patients. Thus,
retrospective studies remain an economical and non-invasive way to collect large
amounts of data over a number of years to identify high risk groups, to establish the
rationale for studies of interventions, and to provide baseline information on the
incidence of postoperative nausea, vomiting or PONV.
Future studies need clear descriptions of how the outcomes were defined and
measured. The measurement of risk factors also needs to be clear and specific, even in
retrospective studies. For example, the anatomical location of the procedure should be
taken directly from reading the operative reports not from imaging results, databases or
admission/discharge records. Specifically, imaging results may be clouded by cerebral
edema, presence of cysts, and experience of the radiologist reporting the results.
Databases and admission/discharge records may only provide the general area of the
60
surgery, for example posterior fossa tumour, instead of fourth ventricular tumour. The
time period of follow-up for nursing studies should also go beyond the first 24-48 hours.
For example, investigations of PONV over the entire postoperative course would help
nurses ensure that prophylactic antiemetics are administered over an adequate period of
time. Attempts should also be made in prospective studies to quantify the severity of
symptoms using patient report and satisfaction with care for PONV. For retrospective
studies, severity is more difficult to quantify but the number of days over which vomiting
and/or nausea were charted in the nursing notes; the number of events recorded or even
overall impression of two or more independent data collectors using an ordinal scale
(none, mild, moderate or severe) may be more descriptive than simply whether or not an
event occurred. Ultimately, the findings of future studies will continue to challenge our
beliefs, add to our understanding of why patients who require neurosurgical procedures
may be at risk for PONV, and identify potential areas for prevention and treatment in this
vulnerable group of patients.
61
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64
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3

R
i
s
k

f
a
c
t
o
r
s

i
d
e
n
t
i
f
i
e
d

t
h
o
u
g
h

u
n
i
v
a
r
i
a
t
e

a
n
a
l
y
s
i
s

R
e
f
e
r
e
n
c
e

K
r
a
m
e
r

e
t
a
l
.

(
1
9
9
4
)

P
O
N
V

I
n
c
i
d
e
n
c
e

5
0
%

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

N
o
n
e
.

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

C
h
i
l
d
r
e
n

v
s
.

a
d
u
l
t
s
,

t
y
p
e

o
f

r
e
c
o
r
d
i
n
g

t
e
c
h
n
i
q
u
e

u
s
e
d
.

Q
u
i
n
e
y

e
t
a
l
.

(
1
9
9
5
)

P
O
N
V

I
n
c
i
d
e
n
c
e

N
o
n
e
:

2
9
%
,

M
o
d
e
r
a
t
e

n
a
u
s
e
a
:

3
5
%
,

S
e
v
e
r
e

n
a
u
s
e
a

o
r

v
o
m
i
t
i
n
g
:

3
7
%

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

N
o
n
e

i
d
e
n
t
i
f
i
e
d

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

S
i
t
e

o
f

o
p
e
r
a
t
i
o
n

(
t
e
m
p
o
r
a
l
,

p
a
r
i
e
t
a
l
,

f
r
o
n
t
a
l
,

o
r

o
c
c
i
p
i
t
a
l
)
.

F
a
b
l
i
n
g

e
t
a
l
.

(
1
9
9
7
)

N
a
u
s
e
a

I
n
c
i
d
e
n
c
e

5
0
%

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

F
e
m
a
l
e
s

(
6
1
%
)

v
s
.

m
a
l
e
s

(
3
7
%

p
=
.
0
0
1
)

I
n
f
r
a
t
e
n
t
o
r
i
a
l

s
u
r
g
e
r
y

(
6
5
%
)

v
s
.

s
u
p
r
a
t
e
n
t
o
r
i
a
l

s
u
r
g
e
r
y

(
4
3
%

p
=
.
0
3
8
)

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

P
o
s
t
o
p
e
r
a
t
i
v
e

o
p
i
o
i
d

u
s
e
,

A
n
a
e
s
t
h
e
t
i
c

t
e
c
h
n
i
q
u
e

(
g
e
n
e
r
a
l

v
s
.

a
w
a
k
e
)
,

a
n
d

I
n
t
r
a
o
p
e
r
a
t
i
v
e

a
n
t
i
e
m
e
t
i
c
s

E
m
e
s
i
s

I
n
c
i
d
e
n
c
e

3
9
%

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

F
e
m
a
l
e
s

(
4
6
%
)

v
s
.

m
a
l
e
s

(
3
1
%

p
=
.
0
2
9
)

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

S
u
r
g
e
r
y

s
i
t
e

(
i
n
f
r
a
t
e
n
t
o
r
i
a
l

s
u
r
g
e
r
y

v
s
.

s
u
p
r
a
t
e
n
t
o
r
i
a
l
)
,

P
o
s
t
o
p
e
r
a
t
i
v
e

o
p
i
o
i
d

u
s
e
,

A
n
a
e
s
t
h
e
t
i
c

t
e
c
h
n
i
q
u
e

(
g
e
n
e
r
a
l

v
s
.

a
w
a
k
e
)
,

a
n
d

I
n
t
r
a
o
p
e
r
a
t
i
v
e

a
n
t
i
e
m
e
t
i
c
s

R
e
s
c
u
e

A
n
t
i
e
m
e
t
i
c
s

I
n
c
i
d
e
n
c
e

6
1
%

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

F
e
m
a
l
e
s

(
6
9
%
)

v
s
.

m
a
l
e
s

(
5
1
%

p
=
.
0
1
3
)

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

I
n
f
r
a
t
e
n
t
o
r
i
a
l

S
u
r
g
e
r
y
,

P
o
s
t
o
p
e
r
a
t
i
v
e

O
p
i
o
i
d

u
s
e
,

A
n
a
e
s
t
h
e
t
i
c

t
e
c
h
n
i
q
u
e

(
g
e
n
e
r
a
l

v
s
.

a
w
a
k
e
)
,

I
n
t
r
a
o
p
e
r
a
t
i
v
e

a
n
t
i
e
m
e
t
i
c
s

T
a
b
l
e

3
.
1

(
C
o
n
t
i
n
u
e
d
)

M
a
n
n
i
n
e
n

e
t

a
l
.

(
1
9
9
9
)

P
O
N
V

I
n
c
i
d
e
n
c
e

3
8
.
7
%

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

S
p
i
n
e

(
5
0
%
)

c
o
m
p
a
r
e
d

t
o

b
r
a
i
n

t
u
m
o
u
r

(
2
8
%
)
,

v
a
s
c
u
l
a
r

(
3
8
%
)

a
n
d

o
t
h
e
r

(
3
4
%
,

p
<
.
0
5
)
.

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

N
o

o
t
h
e
r

r
i
s
k

f
a
c
t
o
r
s

e
x
a
m
i
n
e
d
.

M
a
n
n
i
n
e
n

a
n
d

T
a
n

(
2
0
0
2
)

O
v
e
r
a
l
l

P
O
N
V

I
n
c
i
d
e
n
c
e

2
9
%

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

P
r
o
c
e
d
u
r
e
s

>
6

h
o
u
r
s

(
4
2
%
)

v
s
.

<

6

h
o
u
r
s

(
2
2
%
,

p
=
.
0
0
9
)
,

I
n
f
r
a
t
e
n
t
o
r
i
a
l

p
r
o
c
e
d
u
r
e
s

(
5
7
%
)

v
s
.

S
u
p
r
a
t
e
n
t
o
r
i
a
l

(
2
1
%
,

p
=
.
0
0
1
)

P
r
o
c
e
d
u
r
e
s

<
6
h
o
u
r
s

(
n
=
1
0
7
)

N
a
u
s
e
a

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

A
w
a
k
e

a
n
a
e
s
t
h
e
s
i
a

(
4
%
)

v
s
.

g
e
n
e
r
a
l

a
n
a
e
s
t
h
e
s
i
a

a
t

4

h
o
u
r
s

(
2
3
%

p
=
.
0
1
2
)

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

A
w
a
k
e

a
n
a
e
s
t
h
e
s
i
a

v
s
.

g
e
n
e
r
a
l

a
n
a
e
s
t
h
e
s
i
a

a
t

t
i
m
e

p
e
r
i
o
d
s

4
-
2
4

h
o
u
r
s

a
n
d

>
2
4

h
o
u
r
s
.

E
m
e
s
i
s

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

A
w
a
k
e

a
n
a
e
s
t
h
e
s
i
a

a
t

4

h
o
u
r
s

(
0
%
)

v
s
.

g
e
n
e
r
a
l

a
n
a
e
s
t
h
e
s
i
a

a
t

4

h
o
u
r
s

(
1
1
%
,

p
=
.
0
5
2
)
.

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

A
w
a
k
e

a
n
a
e
s
t
h
e
s
i
a

v
s
.

g
e
n
e
r
a
l

a
n
a
e
s
t
h
e
s
i
a

a
t

t
i
m
e

p
e
r
i
o
d
s

4
-
2
4

h
o
u
r
s

a
n
d

>
2
4

h
o
u
r
s

R
e
s
c
u
e

A
n
t
i
e
m
e
t
i
c
s

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

A
w
a
k
e

a
n
a
e
s
t
h
e
s
i
a

a
t

4

h
o
u
r
s

(
1
6
%
)

v
s
.

g
e
n
e
r
a
l

(
4
0
%
,

p

v
a
l
u
e

n
o
t

r
e
p
o
r
t
e
d
)
.

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

A
w
a
k
e

a
n
a
e
s
t
h
e
s
i
a

v
s
.

g
e
n
e
r
a
l

a
n
a
e
s
t
h
e
s
i
a

a
t

t
i
m
e

p
e
r
i
o
d
s

4
-
2
4

h
o
u
r
s

a
n
d

>
2
4

h
o
u
r
s

I
r
e
f
i
n

e
t

a
l
.

(
2
0
0
3
)

N
a
u
s
e
a

I
n
c
i
d
e
n
c
e

5
9
%

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

N
o
n
e

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

L
o
c
a
t
i
o
n

o
f

s
u
r
g
e
r
y

(
i
n
f
r
a
t
e
n
t
o
r
i
a
l

v
s
.

s
u
p
r
a
t
e
n
t
o
r
i
a
l

v
s
.

s
p
i
n
a
l
)

L
e
s
l
i
e

e
t

a
l
.

(
2
0
0
3
)

P
O
N
V

I
n
c
i
d
e
n
c
e

6
4
%

d
a
y

1
,

4
2
%

d
a
y

2
,

3
2
%

d
a
y

3
,

2
5
%

d
a
y

3
0
,

2
7
%

d
a
y

9
0
.

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

N
o
n
e
.

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

C
r
a
n
i
a
l

v
s
.

s
p
i
n
a
l

s
u
r
g
e
r
y
.

T
a
b
l
e

3
.
3

(
C
o
n
t
i
n
u
e
d
)

K
u
r
i
t
a

e
t

a
l
.

(
2
0
0
4
)

P
O
N
V

I
n
c
i
d
e
n
c
e

4
9
%

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

I
n
f
r
a
t
e
n
t
o
r
i
a
l

s
u
r
g
e
r
y

(
7
5
%
)

v
s
.

s
u
p
r
a
t
e
n
t
o
r
i
a
l

s
u
r
g
e
r
y

(
4
5
%
,

p
=
0
.
0
0
1
)

N
o
n
-
s
i
g
n
i
f
i
c
a
n
t

f
a
c
t
o
r
s

G
e
n
d
e
r
,

a
g
e
,

w
e
i
g
h
t
,

h
e
i
g
h
t
,

s
i
z
e

o
f

b
r
a
i
n

t
u
m
o
u
r
,

a
n
a
e
s
t
h
e
t
i
c

t
e
c
h
n
i
q
u
e

(
i
n
h
a
l
a
t
i
o
n

v
s

i
n
t
r
a
v
e
n
o
u
s

w
i
t
h

n
i
t
r
i
c

o
x
i
d
e
)
,

i
n
t
r
a
o
p
e
r
a
t
i
v
e

f
e
n
t
a
n
y
l

d
o
s
e
,

a
n
d

i
n
t
r
a
o
p
e
r
a
t
i
v
e

p
o
s
t
u
r
e
.

S
t
i
e
g
l
i
t
z

e
t

a
l
.

(
2
0
0
5
)

N
a
u
s
e
a

M
e
a
n

±

S
D

(
R
a
n
g
e
)

2
.
3

d
a
y
s

±

0
.
2
6

(
0
-
1
6

d
a
y
s
)

R
i
s
k

f
a
c
t
o
r
s

(
p
<
.
0
5
)

G
r
a
d
e

1

(
3
.
5

d
a
y
s
)

v
s
.

G
r
a
d
e

4
b

T
u
m
o
u
r
s

(
1

d
a
y
,

p
=
.
0
2
4
)
,

f
e
m
a
l
e
s

(
3
.
0

d
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e

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n
t
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e
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e

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r
.

FIGURE 3.1
Flow Diagram of Search Findings
75
Paper 4:
Children's nausea and vomiting following posterior fossa surgery:
A retrospective study
A version of this paper has been accepted pending revisions as:
Neufeld, S.M, Newburn-Cook, C.V., Dundon, B.
(
Yu, H, Schopflocher, D. & Drummond, J. (2008). Vomiting after
posterior fossa surgery in children: A retrospective study. BMC Nursing.
The successful management of nausea and vomiting is an important component in
the care of children after surgery. Postoperative nausea and vomiting (PONV) may cause
discomfort and distress, put pressure on surgical incisions, cause dehydration and
electrolyte imbalance, delay recovery, and prolong hospitalization (Macario, Weinger,
Carney, & Kim, 1999; Scuderi & Conlay, 2003). Children are at high risk for
experiencing PONV (Apfel, Kranke et al., 2002; Rose & Watcha, 1999; Rowley &
Brown, 1982), and estimates of postoperative vomiting (POV) for children requiring
craniotomy have been as high as 66% (Furst et al., 1996). The effects of increased
intracranial pressure during retching and vomiting may be especially problematic after
craniotomy (Fabling et al., 1997). Therefore, children after craniotomy may be at
particular risk for experiencing PONV and for suffering related negative outcomes.
Tramer (2007) describes three rules of practice to ensure optimal management of
PONV: identify those at risk using predictive factors; modify anaesthesia techniques to
keep the baseline risk as low as possible; and administer antiemetics rationally with
consideration to their efficacy, additive properties, and adverse effects. Of these, Tramer
concedes that knowledge of risk factors remains an under-researched area, especially for
children. In one of the few multivariable studies of predictive factors of POV in children,
(Eberhart et al., 2004) the combination of the following factors could be used to
determine a child's risk of POV after surgery: history of POV in the child or PONV in
father, mother or siblings; age over three years; length of surgery over thirty minutes; and
strabismus surgery. This research did not have the participation of children requiring
77
craniotomy. If these results were used to predict POV in children after craniotomy, age
and history of POV or PONV in father, mother, or siblings would be the only variables
that could be used to predict POV.
POV and/or PONV after craniotomy in children have not been well described in
the literature. Two small randomized controlled trials of ondansetron, a 5-HT
3
receptor
antagonist, have estimates of 24 hour POV in children after craniotomy that range from
24% (Subramaniam et al., 2007) to 66% (Furst et al., 1996), whereas PONV in older
children was estimated at 32% (Subramaniam et al., 2007). Although some clinicians
believe that the use of prophylactic antiemetics decreases the incidence of POV in these
children, neither study could show efficacy for intraoperative administration of
ondansetron in reducing children's POV by 24 hours. Subramaniam et al. could not show
evidence for an extra scheduled postoperative dose of ondansetron either. Finally,
intermittent dosing of any class of antiemetics does not appear to have been studied in
this patient population. In order to effectively design such studies, knowledge of the
incidence of PONV and associated risk and protective factors must be first established to
know the extent of the problem and ensure that the children at highest risk are targeted
for prophylaxis.
Children who appear to be at high risk for nausea and vomiting are those who
require posterior fossa craniotomy. Posterior fossa surgery takes place below the
tentorium cerebelli in the posterior cranial fossa. The posterior cranial fossa houses
structures that include: the cerebellum; brainstem; and cranial nerves III-XII. Although
the reticulospinal tracts, diencephalon, limbic system, and discrete areas of the cerebral
78
hemispheres may all be involved in nausea, retching, and vomiting, the coordination of
the autonomic changes associated with retching and vomiting occurs at the level of the
medulla oblongata in the posterior fossa (Hornby, 2001; Miller, 1999; Miller, Nonaka,
Jakus, & Yates, 1996). Thus, from an anatomical perspective, procedures that are
proximal to this area may place patients at especially high risk for vomiting. Previous
studies in children after craniotomy (Furst et al., 1996; Subramaniam et al., 2007) have
been too small to allow this conclusion to be drawn, but studies in adults suggest that
posterior fossa procedures are related to greater postoperative nausea (Fabling et al.,
1997) and PONV (Gottschalk et al., 2007; Kurita et al.,; Manninen & Tan, 2002) when
compared to supratentorial procedures.
Children who require craniotomy form a heterogeneous group. By specifically
studying children after posterior fossa surgery, the research questions can be focused on
the unique risk and protective factors for PONV for this group of children while limiting
the heterogeneity in the sample. This approach has shown success in determining risk and
protective factors specific to the location of the neurosurgery in adult studies (Flynn &
Nemergut, 2006; Meng & Quinlan, 2006; Stieglitz et al., 2005).
Thus, the purpose of this study was to describe PONV in children requiring
posterior fossa surgery, to explore risk and protective factors for PONV, and to examine
the relationship of PONV to adverse outcomes. Results could then be used to guide the
design of future studies and provide the rationale for implementing improvements to
clinical practice.
79
Methods
The hospital charts of children who required posterior fossa surgery at two
children's hospital sites, the Stollery Children's Hospital in Edmonton and the Hospital
for Sick Children in Toronto, were reviewed for the study. A retrospective study design
was chosen as an efficient and cost effective way to describe nausea and vomiting in this
group of children. Specifically, for the acute postoperative period, we sought to
determine:
1) The cumulative incidence of nausea and vomiting by: hours 4, 8, and 24; and during
subsequent 24 hour periods.
2) The frequency distribution of number of days that nausea and vomiting were
experienced.
3) The frequency distribution of number of vomiting events.
4) The significant risk and protective factors for nausea and vomiting.
5) The co-morbidities that children with nausea and vomiting experience.
Sample Selection & Sample Size Estimation
Following institutional ethical review and administrative approval at each centre,
all patients under age seventeen who had posterior fossa surgery between March 1, 2001
and March 1, 2007 were identified for chart retrieval through two separate paediatric
neurosurgeons' databases (Stollery Children's Hospital) and a central paediatric
neurosurgery database (Hospital for Sick Children). The upper limit for age was
determined by the age of qualification for admission to both children's hospitals. Fourth
ventricular shunt procedures, operations without dural openings (outside the brain),
80
surgery for traumatic brain injury, and children requiring prolonged intubation (greater
than 48 hours) were excluded. If more than one posterior fossa procedure was required
for a child over the study period, the earliest one was included in the study. Prospectively,
we estimated data from two sites to involve approximately 300 children. This would
allow for an estimation of incidence within a 6% margin of error (Lenth, 2006). It would
also allow for a multivariable analysis of 10-15 variables if the incidence of an outcome
ranged from 30-70%, which would allow for one independent variable per ten outcomes
(Peduzzi, Concato, Kemper, Holford, & Feinstein, 1996).
Data Collection Procedures
A case report form was developed specifically for the study in collaboration with
a paediatric educator in surgery, a neurosurgeon, and clinical nurse specialists/nurse
practitioners in children's neurosurgery. Data were collected by review of the child's in-
patient chart. The data collection period extended over the course of a child's
neurosurgical postoperative hospital stay, up to ten days. Thus, data collection ended
when the child went home, was transferred from neurosurgical care to rehabilitation care
(i.e. to a rehabilitation hospital or rehabilitation unit), was transferred from neurosurgery
care to oncology care for further treatments, or at 240 hours after the recorded time that
the anaesthetic was finished. The first ten postoperative days were chosen by the study
team to ensure that an adequate length of time was captured for the exploratory analysis.
The final outcomes for analysis of risk and protective factors were then determined based
on these exploratory results.
81
One nurse with paediatric neurosurgical experience at each site collected data
(including the author at the Stollery Children's Hospital). To ensure reliability, the two
data collectors trained on ten charts. Revisions to the data collection form were then
made as necessary. For example, the child's activity and diet at each time period were
initially part of the case report form. Due to gaps in charting, these data could not be
collected reliably. Once the case report was finalized, each person then reviewed the
same five randomly selected charts to establish inter-rater reliability: 100% inter-rater
reliability was achieved for the main study outcomes and adverse events; 100% inter-
rater reliability was achieved for all independent variables except for whether or not an
antiemetic was given before POV, as one case report had a missing value (thus 80%
reliability for this variable). Weekly contact was maintained between the two sites to
discuss issues that arose during data collection.
Measurement
The term postoperative nausea and vomiting (PONV) covers one or more of three
symptoms: nausea; retching; and vomiting (Gan, 2006). Nausea is the unpleasant
sensation of the urge to vomit that occurs along with neurological changes such as
excessive salivation and swallowing (Apfel, Roewer, & Korttila, 2002). Each time nausea
was charted in the nurses' notes, it was recorded on the study case report form.
Documented children's statements or behaviours that referred to nausea, such as states
that he feels "like throwing up" or "appears nauseous," were also included.
Retching is the first phase of vomiting (Hornby, 2001) and is commonly defined
as an unproductive attempt to vomit (Apfel, Roewer, & Korttila, 2002). Vomiting is the
82
forceful expulsion of stomach contents through the mouth that involves coordinated
autonomic processes in the brain and gut (Hornby, 2001). Because of their similar
physiology, retching and vomiting should be considered together in the data analysis,
whereas nausea should be considered separately (Korttila, 1992). To screen for retching
and vomiting events (POV), the post-anaesthesia recovery room record was first
reviewed, followed by the in and out flow sheets. The time of the event was noted and the
nurses' notes were then read for further events and for more accurate time of the event if
it corresponded to the in-and-out flow sheets. The medication administration records
were also reviewed and the use of opioids and timing of antiemetics were noted. If an
antiemetic was administered, the nurses' notes were reviewed a second time to look for a
documented event around the time of the administration of the antiemetic. Administration
of an antiemetic was not considered indication of nausea, retching or vomiting, although
antiemetic administration was recorded on the case report form.
Data on potential risk factors were collected from the admission records,
physician notes, anaesthesia records, operative reports, and medication flow sheets. For
analysis, age was examined in quartiles rounded to the year: 0-<4; 4-<7; 7-<12; and 12-
<17. A number of variables were dichotomized for analysis. The use of desflurane has
been shown to be a risk factor in adults requiring retromastoid craniectomy, compared to
other volatile anaesthetics (Meng & Quinlan, 2006). We therefore examined the use of
desflurane (alone or in combination with another volatile anaesthetic) compared to all
other volatile anaesthetics. This was the only variable with missing values (n=13; either
undocumented in the chart or illegible) and, due to the likelihood that the missing value
83
was not desflurane, we included the missing values in the "other" category. Intra-
operatively, ondansetron was the only antiemetic used and dexamethasone the only
steroid.
Due to the wide variability in the use of postoperative antiemetics, their use was
considered prophylactic if documentation showed administration prior to the first
recorded POV. Postoperative opioid use was dichotomized to examine whether or not
any opioid was used in the first 24 hours. Potential co-morbidities, including
development of a pseudomeningocele, wound failure or cerebral spinal fluid leak through
the incision, and wound infection, were noted by examining the nursing notes, physician
notes, discharge summary, and/or reasons for readmission to the neurosurgical service.
Reports of postoperative imaging studies were also reviewed for possible documentation
of a pseudomeningocele.
Data Analysis
Data analysis was conducted using SPSS Version 15.0 software. Demographic
and study variables were summarized using descriptive statistics that were appropriate to
their level of measurement. Cumulative incidence (number of children with at least one
recorded event by the specified time period / total number of children in the study) was
used to calculate outcomes at: 4, 8, and 24 hours; and for subsequent 24 hour periods
until the end of the study period. The number of days that an outcome was experienced
was calculated by subtracting the time of the first recorded event from the last recorded
event, and was summarized using a frequency distribution. A frequency distribution was
also used for counts of recorded events.
84
Univariate logistic regression was first conducted to examine the relationships
between each variable and the outcomes. The univariate analysis was followed by
multivariable logistic regression to examine important risk and protective factors for the
outcomes while controlling for other variables. To determine confounding effects,
variables were entered into the multivariable model in an a-priori determined,
hierarchical fashion based on sequential events (Figure 4.1). If a variable grouping
changed the regression coefficients of a previously entered statistically significant
variable by >15%, it was considered to be confounding (i.e., related to both the variable
and the outcome). Thus it would be considered to account for some or all of an effect.
Conversely, if a variable that was not previously statistically significant became so with a
change of >15%, that grouping was also considered confounding. Individual variables
within that grouping were then tested individually to examine their relationship to the
confounded variable. On completion of the model, plausible interactions of statistically
significant variables were tested to determine if any moderating effects were present (i.e.,
moderation - that the relationship that one variable has with an outcome changes
depending on the value of another variable). Multicollinearity, associations among the
independent variables in the model, was reviewed by looking for correlations above 0.8
between any two variables.
To finish the analysis, cross tabulations were used to examine the relationship
between the final outcomes and other adverse events. The phi statistic (<\>) for nominal by
nominal variables was used to summarize these relationships. This statistic was also used
85
to examine relationships between categorical confounding variables, whereas a Pearson's
correlation (r) was used for continuous variables.
Results
Sample Characteristics
Table 4.1 contains a description of the study sample. A total of 249 children met
the criteria for the study, from 329 potential candidates who were identified from three
neurosurgery databases. Of those excluded, 23 were wrongly coded as posterior fossa
procedures in the database, 22 were intubated for more than 48 hours, 13 had Chiari I
bony decompressions without a dural opening, 13 had a supratentorial component to their
surgery (other than EVD/shunt insertion), 7 had ventriculo-peritoneal shunt procedures
only, and 2 had no corresponding hospital record.
Description of PON, POV and PONV
The cumulative incidence of PON, POV and PONV over the first ten days is
presented in Table 4.2. As shown in this table, there was a discrepancy in the
documentation of PON and POV. Because we felt that PON was not reliably measured
and documented, the remainder of the data analysis was refocused to examine POV. The
frequency distribution of the time from first recorded POV to last recorded POV is
presented in Figure 4.1. The frequency distribution of POV events that were recorded
over the study period is shown in Figure 4.2. These figures indicate that there was
considerable variation in length of time that children experienced vomiting as well as
number of recorded events. Close to 47% of children experienced vomiting over a time
course greater than 24 hours, while 20% continued to vomit over a time course greater
86
than 120 hours. Recorded events, shown in Figure 4.3 show a positively skewed
distribution with 23% children with no events, 36% of children with only one to three
recorded events, and 41% with over three events.
Analysis of risk and protective factors
Based on the initial exploratory data analysis, we decided to examine the risk
and/or protective factors for two outcomes: POV in the first 120 hours (the acute
postoperative period), and early (an event recorded by 24 hours or less) compared to late
POV (the first event occurring after 24 hours up to 120 hours). The decision to make the
cut-off for the acute postoperative period 120 hours, despite data collection that went up
to 240 hours, was to control factors such as early discharge, the requirement for sedation
for procedures or tests, or the need for further surgery that were emerging in the data after
120 hours. After data collection, it was clear that some potential risk factors could not be
reliably collected due to lack of documentation or inconsistent documentation. These
included: a history of postoperative nausea and vomiting in the child or family member; a
history of motion sickness; and pain ratings.
The initial univariate logistic regressions (Table 4.3) indicated that only Chiari I
Malformation surgery was a statistically significant risk factor for POV by 120 hours.
Additionally, children in the two middle age quartiles (4 to <7 and 7 to <12) showed
lesser odds of late vomiting compared to early. Thus, while overall they did not have
greater odds of vomiting than children, they were more likely to have early vomiting than
the other age groups.
87
In the first multivariate analysis (Table 4.4), controlling for the other variables in
the model, the use of desflurane, intraoperative administration of ondansetron, Chiari I
malformation surgery and surgery at the Hospital for Sick Children site emerged as
significant risk factors for vomiting by 120 hours. The fourth age quartile (12 to <17) and
the interaction term of intraoperative ondansetron with any use of desflurane were
significant protective factors for POV by 120 hours. Thus, ondansetron moderated the
effect of desflurane on vomiting in that children who received intraoperative ondansetron
and desflurane were less likely to vomit than those who received desflurane without
intraoperative ondansetron. The interaction of site with the use of desflurane and site with
intraoperative administration of ondansetron were tested and not statistically significant.
Interactions between age and other statistically significant variables (site, any use of
desflurane, and intraoperative administration of ondansetron) were not tested due to
sample size restrictions, as each interaction term would use three more degrees of
freedom.
There were a number of variables which appeared to confound the effects of
previously entered variables in the model. When the factor of whether or nor a child
presented with vomiting was added (model 3), the odds ratio for POV by 120 hours for
Chiari I surgery increased. A greater proportion of children with brain tumours presented
with vomiting than those with Chiari I malformations or other procedures (72% vs. 5%
vs. 7%, phi statistic for correlation of nominal variables ($) =.0.65, p<.001); thus,
controlling for whether or not the child presented with vomiting proportionally decreased
the odds of vomiting for children with brain tumours compared to those with Chiari I
88
malformations. The combined surgery category of "other" was too small (n=15) to
determine if there was similar effect. The odds ratio for hospital site changed to being
significantly greater for the Hospital for Sick Children after the intraoperative variables
were entered (model 4). Desflurane and intraoperative ondansetron were used
proportionately more at the Stollery Children's Hospital than at the Hospital for Sick
Children (69% vs. 9% for use of desflurane, <f) = 0.59, p<.001 and 62% vs. 43% for
ondansetron, ((() = -0.16, p=.01). There were no differences between the sites for the use
of dexamethasone ((f) = 0.08, p=.23) or length of surgery (r= -0.02 p=.74). Thus,
controlling for the combination of intraoperative risk factors, notably any use of
desflurane and administration of intraoperative ondansetron, resulted in a proportionately
higher reduction in the risk of vomiting by 120 hours at the Stollery Children's Hospital
compared to the Hospital for Sick Children. These findings highlight the challenges that
can be found in types of procedures and/or sites with different proportions of children
exposed to potential risk or protective factors.
Finally, the addition of the interaction term of any use of desflurane and the
administration of ondansetron (model 6) also showed a change in the odds of POV by
120 hours for children requiring Chiari I surgery to a statistically significant result. As
there were no differences in the proportion of children in the three surgery categories who
received both ondansetron and desflurane (13% vs. 17% vs. 13%, (j)=.06, p=.68), this
result may reflect a lack of stability in the coefficients with the increasing number of
variables in the model (i.e. model overspecification). Thus, an increase in the number of
variables in the model beyond what the sample size can support may result in wide
89
confidence intervals and unstable results, and this appears to occur to a number of
variables in the later statistical models.
The second multivariate modelling (4.5) indicates that, controlling for the other
variables in the model, the use of desflurane and children in the two middle age quartiles
(4 to <7 and 7 to <12) are protective for late vomiting (or, conversely, risk factors for
early vomiting). By examining the results of the two multivariate models together, there
are increased odds for early vomiting with the use of desflurane compared to late
vomiting and this increase is enough to have an overall statistically significant effect for
its use and POV by 120 hours. Children in the two middle age quartiles have greater odds
for early vomiting, but by 120 hours they are no different than the youngest age group
(age 0 to <4, the reference category). The age category of 12 to <17 however, shows
statistically significant lower odds of POV by 120 hours.
Assessment for multicollinearity (Table 4.6), showed no estimates with
correlations above .80. These results are suggestive that multicollinearity may not play a
large role in the statistical model. The statistically significant correlations in this part of
the statistical analysis correspond to the results already identified in the assessment for
confounding effects (i.e. variables in a model that are related to each other and the
outcome).
Co-morbidities
With the exception of infection, adverse events were frequently reported in the
sample. Because posterior fossa syndrome is most commonly associated with brain
tumours, the relationship between posterior fossa syndrome and POV by 120 hours was
90
examined for brain tumours only. As shown in Table 4.7, there was no relationship
between POV by 120 hours and the development of pseudomeningocele, wound failure
or cerebral spinal fluid leak, infection, or posterior fossa syndrome.
Discussion
The results of this study support our clinical experience that POV is a common
adverse outcome for children after posterior fossa surgery. Overall, POV is common
enough to regard all children who require posterior fossa surgery as being at high risk for
the development of POV. However, a number of risk and protective factors for having
one or more episodes of POV by 120 hours after surgery were also identified in a
multivariable analysis.
When POV occurred, counts of vomiting events formed a positively skewed
distribution in this sample. These results are similar to those shown by the data collected
by Rowley and Brown (1982) in their classic post-operative vomiting study of 1183
children after surgery. Many children in their sample experienced one or two episodes,
with the number of events that a child experienced quickly tapering off. Rowley and
Brown urged researchers to identify the recurrent, frequent, and distressing vomiting that
fewer children experience but that results in significant distress and negative
consequences for recovery. In this study, many children experienced greater than three
events and/or experienced vomiting for time periods much longer than twenty four hours.
This finding also has to be taken in the context of the use of intra-operative ondansetron
for 47% of the children and use of postoperative antiemetics in 80% of the children.
91
Thus, even with current efforts to prevent and treat POV, it was a frequent, recurrent and
potentially long-lasting problem in this sample of children.
In this study, some risk and protective factors were identified for POV in children
after posterior fossa surgery. These results may lead to the development of predictive
tools or the identification of areas for stratification for future research. They will also
help to identify challenges for future research, especially multi-site studies. That one
hospital site showed greater odds of POV by 120 hours, once intraoperative variables
were entered, highlights the difficulty in comparing between sites that may have varying
intraoperative practices. A similar problem was encountered with the variable of
presenting with vomiting and type of surgery. Surgery for Chiari I Malformation showed
greater odds for POV by 120 hours than did brain tumour and "other" procedures. Within
the category of brain tumour surgery, there may be children who are at much higher risk
for POV, balanced out by those at lower risk. A secondary analysis of these data for
children with posterior fossa brain tumours, in particular, would be useful.
That the oldest age quartile (12 to <17 years) emerged as a protective factor for
POV by 120 hours is consistent with research in children following other types of
surgery (Kovac, 2007), but has not been supported in research for POV after craniotomy
(Subramaniam et al., 2007). The two middle quartiles (ages 4 to <7 and 7 to <12 years)
were more likely to vomit earlier, but their odds of vomiting are no different than those
under four years of age by 120 hours. Infants and young children in this group of children
may present later with vomiting and "catch-up" to school aged children by 120 hours.
This result points to the importance of examining POV beyond the first 24 hours and
92
continuing prophylactic use of antiemetics beyond 24 hours in at-risk groups.
Interestingly, gender was not shown to be a significant risk factor and, therefore, an
interaction effect of gender and age was not examined, despite the idea that females after
puberty may be at higher risk for POV(Kovac, 2007).
Any use of desflurane was identified as a risk factor for early vomiting. The
increased odds of POV by 24 hours carried over into POV by 120 hours after surgery.
This finding must be taken in the context of a small sample size and very wide
confidence intervals when all other variables in the model were controlled for. Also, the
Stollery Children's Hospital site had a greater proportion of exposed children than the
Hospital for Sick Children and the influence of individual clinicians was not accounted
for. However, the use of desflurane has been previously identified as a significant risk
factor when compared to other volatile anaesthetics in a multivariable analysis of risk
factors for PONV for adults requiring microvascular decompression of cranial nerves
(Meng & Quinlan, 2006). The use of desflurane in children has the advantage of rapid
recovery (Lerman, 2007) which must be clinically balanced with any potential
disadvantages in this clinical population.
Children who received intraoperative ondansetron showed greater odds of POV
by 120 hours in the multivariable analysis. This finding may be due to use of clinical
judgment in administering ondansetron, a drug which has not been shown to have
efficacy in preventing vomiting in children after craniotomy (Furst et al., 1996;
Subramaniam et al., 2007). Thus, the administration of the drug, while not protective for
vomiting, was predictive of vomiting, possibly due to its administration to those correctly
93
judged likely to vomit. Interesting is the significant protective finding of the interaction
between any use of desflurane with the administration of intraoperative ondansetron.
Thus, overall, ondansetron did not appear to have a protective effect, but odds of POV by
120 hours for children receiving desflurane significantly decreased when ondansetron
was administered concomitantly. Future studies of the efficacy of ondansetron, and other
5-HT3 receptor antagonists, in preventing POV in this group of children might then
include stratification for characteristics of the volatile anaesthetic used.
The intraoperative use of dexamethasone was not shown to be a protective factor
for POV by 120 hours. Like ondansetron, its use may have been targeted to children
clinically perceived to be at high risk for POV, and so a protective effect might not
emerge in a retrospective study. Additionally, we did not control for the use of
preoperative dexamethasone because, with the exception of one child, preoperative
dexamethasone was given to children with brain tumours, and thus collinearity with type
of surgery would be a problem. Subramaniam et al. (2007) did look at preoperative
dexamethasone treatment in children with brain tumours in their randomized controlled
trial of ondansetron. These authors found no difference in PONV between children who
received dexamethasone preoperatively and those who did not. Length of surgery as a
continuous variable was also not a significant risk factor for POV by 120 hours in this
sample, which is consistent with previous research where the cut off for a protective
effect for length of surgery was 30 minutes (Eberhart et al., 2004; Rowley & Brown,
1982).
94
The final two variables entered into the model, the use of opioids in the first 24
hours and the prophylactic use of an antiemetic, were not significant risk or protective
factors; nor were they confounders for other variables in the model. We did not attempt to
quantify the use of postoperative opioids, or classify by type of opioid used, which limits
this finding. Increased vomiting with postoperative opioids in children after craniotomy
was also not supported in a recent retrospective study of morphine infusions (Ou, 2008).
There was also considerable variation in the use of postoperative antiemetics; thus,
measurement may have played a role in finding that preemptive postoperative antiemetics
were not a protective factor for POV.
Finally, associations between POV by 120 hours and a number of negative
consequences for recovery ~ the development of a pseudomeningocele, infection, wound
failure/cerebral spinal fluid leak, and posterior fossa syndrome (in children with brain
tumours) — could not be identified in the data. These outcomes may be better studied
prospectively with consideration of the severity of POV. A prospective study would also
aid in identifying a causal pathway in the relationship between negative outcomes and
POV.
The primary limitation of this study is its retrospective nature as it limits the
researchers' control over the data that can be collected. For the outcomes of nausea,
vomiting, and retching, the quality of the charting by health care professionals was
paramount. The exact count of vomiting episodes was likely underestimated, as severe
events were often identified as "+ + + vomiting," but the cumulative incidence of
vomiting at the specified time period should be accurate. Additionally, retching may have
95
been charted if it occurred without vomiting, especially in the post-anaesthesia recovery
room or paediatric intensive care. Once the child was cared for in the general nursing care
unit, it may have been unobserved by the health care team and thus not documented.
Subjective measures of nausea, expressed by the child, were rarely charted. In adults
after craniotomy, risk factors for nausea may be different than those for vomiting
(Fabling et al., 1997). As we were unable to evaluate risk and protective factors for
nausea, the results of this study can not be applied to postoperative nausea.
There were also challenges in conducting the study at two sites. Differences in the
way that postoperative neurosurgical care was provided and the timing of transfer of the
child either home, for rehabilitation, or for oncology treatment, varied between
institutions. Differences in documentation styles and charting practices between the
participating sites may have also affected data collection. Defining what constituted the
acute postoperative period was also difficult and the outcomes for analysis of risk and
protective factors were decided once the data were collected and descriptive statistics
completed.
Sample size issues also became apparent in the final stages of the multivariable
analysis, as shown by the wide confidence intervals for some variables. Initially we had
estimated a sample size of approximately 300. There were more children with exclusion
criteria than expected, which decreased the final sample. The high incidence of vomiting,
even when the outcome was limited to POV by 120 hours, resulted in only four children
without vomiting per variable, instead of the desired ten, for the final multivariable
96
model. The results, such as specific odds ratios and non-significant findings, must
therefore be interpreted cautiously.
Due to the retrospective nature of the data collection, the multivariable models
developed in this study can be used to identify risk and protective factors for POV in
children after posterior fossa surgery in general. The models were not developed for
prognosis or risk scoring at the individual level. The study does not show the effect of
treatments, only their contribution as possible risk or protective factors. A further
limitation of the study is that the outcomes examined for the risk and protective factors
were one or more events of POV by 120 hours and early vs. late POV. Severity of POV,
an important outcome that is often clinically observed in children after posterior fossa
surgery, and may be inferred from the frequency of events and length of time that POV
was experienced, was not quantified for the analysis of risk and protective factors.
In conclusion, the findings of risk and protective factors in this study support the
suggestion that current prognostic models and risk scoring systems for POV should not
be used in children after craniotomy (Neufeld, Drummond, & Newburn-Cook, 2008).
Given the descriptive findings of how common POV is in this group of children after
posterior fossa surgery, guidelines such as those proposed by The Society for Ambulatory
Anesthesia (Gan et al., 2007) for POV in high risk populations should be considered.
These guidelines include the use of two or three prophylactic drugs from different classes
for children who are at high risk for POV. With established POV, drugs from another
class than that already in use ought to be considered. Of particular note is the absence of
evidence that any class of drug is effective for preventing or treating POV in children
97
after craniotomy overall; thus, further research is required for this population, and current
knowledge and treatment guidelines are limited to what is known in other patient
populations.
98
References
Apfel, C. C., Kranke, P., Katz, M. H., Goepfert, C., Papenfuss, T., Rauch, S., et al.
(2002). Volatile anaesthetics may be the main cause of early but not delayed
postoperative vomiting: a randomized controlled trial of factorial design. Br J
Anaesth, 88(5), 659-668.
Apfel, C. C., Roewer, N., & Korttila, K. (2002). How to study postoperative nausea and
vomiting. Acta Anaesthesiol Scand, 46(8), 921-928.
Eberhart, L. H., Geldner, G., Kranke, P., Morin, A. M., Schauffelen, A., Treiber, H., et al.
(2004). The development and validation of a risk score to predict the probability
of postoperative vomiting in pediatric patients. Anesth Analg, 99(6), 1630-1637,
table of contents.
Fabling, J. M., Gan, T. J., Guy, J., Borel, C. O., el-Moalem, H. E., & Warner, D. S.
(1997). Postoperative nausea and vomiting. A retrospective analysis in patients
undergoing elective craniotomy. J Neurosurg Anesthesiol, 9(4), 308-312.
Flynn, B. C., & Nemergut, E. C. (2006). Postoperative nausea and vomiting and pain
after transsphenoidal surgery: a review of 877 patients. Anesth Analg, 703(1),
162-167, table of contents.
Furst, S. R., Sullivan, L. J., Soriano, S. G., McDermott, J. S., Adelson, P. D., & Rockoff,
M. A. (1996). Effects of ondansetron on emesis in the first 24 hours after
craniotomy in children. Anesth Analg, 83(2), 325-328.
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postoperative nausea and vomiting. Anesth Analg, 105(6), 1615-1628, table of
contents.
Gottschalk, A., Berkow, L. C., Stevens, R. D., Mirski, M., Thompson, R. E., White, E.
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Hornby, P. J. (2001). Central neurocircuitry associated with emesis. Am J Med, 111 Suppl
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Suppl 1), 20S-23S.
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Kurita, N., Kawaguchi, M., Nakahashi, K., Sakamoto, N., Horiuchi, T., Takahashi, M., et
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155), 2004.
Lenth, R. V. (2006). Piface (Version 1.64).
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100
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101
TABLE 4.1
Sample Characteristics
Parameter
Number of Patients
Site n(%)
Stollery Children's Hospital
Hospital for Sick Children
Age in years (Mean + SD, Range)
Age in Quartiles n(%)
0 to <4 years
4 to <7 years
7 to < 12years
12 to <17 years
Male: Female (Ratio %)
Surgery n(%)
Brain Tumour
Chiari I Malformation
Other
Chiari II Malformation
Vascular Malformation
Cyst or Aspiration of Pus
Presenting with vomiting n(%)
249
55(22.1%)
194 (77.9%)
7.6 ±4. 4, 0.3 -16.8
65(26.1%)
61(24.5%)
75(30.1%)
48(19.3%)
128(51.4%):121(48.6%)
153(61.4%)
81(32.5%)
15(6.0%)
7(2.8%)
4(1.6%)
4(1.6%)
115(46.2%)
Table 4.1 Continued
Preoperative Dexamethasone n(%)* 136(54.6%)
Intraoperative Ondansetron n(%) 117(47.0%)
Intraoperative Dexamethasone (%) 131(52.6%)
Length of surgery in hours (Mean ± SD, Range) 5:01 ±2:10(1:39-17:56)
Length of anaesthesia in hours (Mean ± SD, Range) 6:22 ±2: 20 (2:05-20:15)
Type of volatile anaesthetic
Isoflurane 126(50.6%)
Desflurane 46(18.5%)
Isoflurane + Sevoflurane 32(12.9%)
Sevoflurane 22(8.8%)
Isoflurane + Desflurane 8(3.2%)
Sevoflurane + Desflurane 2(0.8%)
Not recorded/not legible 13(5.2%)
Timing of First Postoperative Antiemetic (%)
Not prophylactic 161(64.7%)
Given after first recorded vomiting or retching 111(44.6%)
None given and no recorded vomiting or retching 50(20.1%)
Prophylactic 88(35.3%)
Given before first recorded vomiting or retching 74(29.7%)
Given and no recorded vomiting or retching 14(5.6%)
Opioid administration initiated by the first 24 hours (%)
228(91.6%)
* All but one child who received preoperative dexamethasone had a brain tumour.
103
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F
I
G
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R
E

4
.
1

H
i
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r
a
r
c
h
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c
a
l

M
o
d
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l

f
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D
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M
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2
.

C
h
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d

C
h
a
r
a
c
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r
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s
t
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c
s



A
g
e



G
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n
d
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r



R
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q
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r
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d

S
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r
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e
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y

3
.

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n
g

S
y
m
p
t
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s

(
V
o
m
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g
)

4
.

I
n
t
r
a
o
p
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r
a
t
i
v
e

C
a
r
e



U
s
e

o
f

D
e
s
f
l
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r
a
n
e



A
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m
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r
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f

D
e
x
a
m
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t
h
a
s
o
n
e



A
d
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O
n
d
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s
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t
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n



L
e
n
g
t
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f

S
u
r
g
e
r
y

5
.

P
o
s
t
o
p
e
r
a
t
i
v
e

C
a
r
e



O
p
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o
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d

i
n
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t
i
a
t
e
d

b
y

t
h
e

f
i
r
s
t

2
4

H
o
u
r
s



P
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c

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a
n

A
n
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e
m
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t
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c

F
I
G
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R
E

4
.
2

H
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s

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m

f
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i

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F
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4
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3

N
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b
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t
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2

3

4

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0

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1

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2

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3

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4

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5

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6

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2
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C
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f

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g

u
p

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2
4
0

h
o
u
r
s

Paper 5
Strengths and limitations of currently proposed clinical practice guidelines for preventing
and treating nausea and vomiting in children after posterior fossa craniotomy
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Managing postoperative nausea and vomiting (PONV) through preventive
measures and effective treatment is a key component of post-anaesthesia and surgical
nursing care. The discomfort associated with nausea and the potential for new onset
intracranial bleeding or other adverse events that could accompany the increased
intracranial pressure from vomiting (Fabling et al., 1997) make the successful
management of nausea and vomiting for patients requiring neurosurgery an important
focus for clinical practice and research. In a chart audit from March 2001-March 2007 at
two children's hospital sites, Neufeld (2008a) reported that most children (76%) requiring
posterior fossa surgery had at least one emetic event (retching and/or vomiting) within 10
days after surgery or discharge (whichever was first). Counts of retching and vomiting
were easily obtained through flow sheets and nurses' notes: new onset of vomiting
peaked around 120 hours, and those children who vomited had from 1 to over 30
documented events over the timeframe of the review. Postoperative nausea, on the other
hand, was difficult to assess due to the retrospective nature of the study, as charting of
nausea was lacking - even when vomiting was charted. As such, nausea was likely
underestimated at 43%. Clearly, vomiting remains a problem for children requiring
posterior fossa surgery; likely, nausea does also.
The results of this study (Neufeld, 2008a) provide the rationale for the need for
better approaches to assessment, prevention and treatment of PONV for children after
posterior fossa surgery. One approach to these issues is to design and implement
interdisciplinary, evidence based, clinical practice guidelines. For PONV there are two
proposed guidelines that could be adapted for children after posterior fossa surgery. The
purpose of this paper is to discuss the strengths and limitations of currently proposed
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clinical practice guidelines for the prevention and treatment of PONV and post-discharge
nausea and vomiting (PDNV) as they relate to the care of children after posterior fossa
craniotomy. First, the use of risk scoring tools in this clinical population will be
examined. Second, the lack of evidence-based anti-emetic care and practices throughout
the continuum of care for this group of children will be identified. Finally, some
potential directions for clinical research, along with beliefs about PONV that may require
challenging before going forward with research, and changes to clinical practice will be
discussed.
Practice Guidelines for the Prevention and Treatment of PONV
There are two high quality, current and complementary practice guidelines for
prevention and treatment of PONV: The American Society for PeriAnesthesia Nurses
(ASPAN) Evidenced Based Practice Guideline for the Prevention and/or Management of
PONV/PDNV (ASPAN, 2006) and the Society for Ambulatory Anesthesia (SAMBA)
Guidelines for the Management of Postoperative Nausea and Vomiting (Gan et al., 2007).
Both guidelines were developed by multidisciplinary teams (i.e. anaesthesia, nursing,
surgery and pharmacy) through extensive literature review, evaluation of evidence,
synthesis of the information into concise documents and algorithms.
Due to its focus on nursing care, the ASPAN (2006) guideline and three
algorithms — Preoperative patient management of PONV; Management of PONV; and
Management of PDNV— will be primarily considered for this paper (Figures 5.1-5.3).
These algorithms are easy to follow and go beyond the use of anti-emetic drugs to
include evidence-based complementary treatments. As the ASPAN guideline was
primarily developed for adults, the SAMBA guidelines (Gan et al., 2007), which
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specifically pertain to children, will be incorporated into the discussion as needed.
Important to note is the considerable consensus between ASPAN and SAMBA with
respect to the contents of the guidelines. A number of the same individuals were
involved in the development of both guidelines and there were also previously published
high quality guidelines (Gan et al., 2003).
A limitation for both guidelines, with respect to caring for children after posterior
fossa surgery, is their focus on ambulatory surgical procedures. Significant gaps in
knowledge and clinical practice remain for ongoing inpatient postoperative care. By
recognizing their limitations, implications can be gleaned for prophylaxis of PONV,
management of PONV and discharge planning for children requiring inpatient care.
Clinicians working in these inpatient settings, such as those working with children after
posterior fossa craniotomy, will necessarily need to adapt the guidelines to best suit their
patient population and institutional resources. Critical areas for review for children after
posterior fossa surgery, organized by each of ASPAN's (2006) algorithms will be
presented.
ASPAN'S Evidence-Based Clinical Practice Guideline for
Preoperative Patient Management of PONV
ASPAN (2006), suggest in their Evidence-based Clinical Practice Guideline for
Preoperative Patient Management of PONV (Figure 5.1), that patients be first assessed
for their individual risk of PONV using a risk scoring tool. Prophylactic interventions are
then chosen on the basis of that score. These interventions are classified as anaesthetic
considerations, pharmacologic considerations and "other" considerations. There are four
main areas for consideration for children requiring posterior fossa craniotomy. First,
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using preoperative risk scores or prognostic models to predict PONV for children
requiring posterior fossa craniotomy is not appropriate as they have not been validated
for this patient population and they have unique risk factors that could be included in a
risk scoring tool. Second, the recommended anaesthetic considerations remain uncharted
territory for children after posterior fossa craniotomy. Third, the efficacy of prophylactic
anti-emetics is not established for children after any type of craniotomy. Finally,
interventions classified as "other" have also not been examined in this clinical
population.
Use of Preoperative Risk Scores or Prognostic Models
The ASPAN (2006) emphasizes the need for the use of a prognostic model or
risk-scoring tool to predict an individual's risk for developing PONV. SAMBA (Gan,
2007) recommend the use of the paediatric risk scoring tool proposed by Eberhart et al.
(2004). Variables in this risk scoring tool include: age >3; history of PONV in the child
or family member; surgery >30 minutes; and strabismus surgery. Depending on the
number of risk factors present (0 to 4), the estimated incidence for POV for the child was
9, 10, 30, 55, and 70% respectively. This risk scoring tool was developed with a sample
of children requiring a variety of inpatient and outpatient surgical procedures but not with
any children requiring craniotomy.
Using a sample similar to the development sample of Eberhart et al. (2004),
Kranke et al. (2007) found that even without the variable strabismus surgery, their risk
score was fairly robust. As neither study had children requiring craniotomy in the sample,
there is no currently validated tool to predict who will experience vomiting in this
population. Most of the variables in this tool also are not relevant for children after
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craniotomy: two variables (surgery >30 minutes and strabismus surgery) do not vary in
this population. Neufeld (2008a) in a retrospective study of children after posterior fossa
surgery, found that, although they were less likely to vomit in the first 24 hours than are
children from aged 4 to <12, the incidence of vomiting in children under age 4 who
require posterior fossa surgery "catches up" to children under 12 after 24 hours. Children
aged 12 - <17 were less likely to vomit than the other age quartiles. Additionally, in this
study, children requiring surgery for Chiari I malformation were more likely to have a
vomiting event than children requiring brain tumour surgery.
For children after posterior fossa procedures is more important to predict POV
over the entire acute postoperative period instead of only the first 24 hours. Thus tailoring
the outcome measure for a prognostic tool to the risk period of vomiting for this patient
population is required. As the incidence of vomiting appears to taper off around 120
hours (Neufeld, 2008a), this may be an outcome measure for a prognostic tool in this
patient population. Type of procedure and age <12 would need to be tested as variables in
the development of a prognostic tool for children after posterior fossa surgery as they
were shown to be preoperative risk factors. Finally, as shown in the systematic review by
Neufeld and Newburn-Cook (2008) a more general prognostic tool for neurosurgery may
include supra-tentorial vs. infratentorial surgery, female gender in adults, and with the
addition of very specific depending on the type of surgery required (i.e. use of a lumbar
drain in transphenoidal procedures).
In the current absence of a valid risk-scoring tool or prognostic model, the
incidence of POV by 24 hours in children after posterior fossa craniotomy (49%)
(Neufeld, 2008a) is sufficient to consider all of these children to be at moderate to high
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risk of POV. This number climbs to almost 73% by the end of 120 hours indicating a
very high risk of POV if the time period beyond 24 hours is included. Using the ASPAN
(2006) Evidence Based Clinical Practice Guideline for Preoperative Patient Management
of PONV, this would place these children in a situation of requiring 2 drugs from
different classes. In agreement, the SAMBA (Gan et al., 2007) recommendations indicate
that children who are at moderate or high risk for POV should receive combination
therapy with two or three prophylactic drugs from different classes.
Anaesthetic considerations
Of the anaesthetic considerations recommended by SAMBA (2006), Total
Intravenous Anaesthesia (TIVA), has been studied in adults requiring craniotomy with
inconclusive results (Pasternuk & Lanier, 2007). Most recently, Magni et al (2007) did
not find any differences in nausea and vomiting between propofol-remifentanil (TIVA)
and sevoflurane-fentanyl anesthetic techniques on PONV after supratentorial or posterior
fossa craniotomy. To date, there do not appear to be published studies of TIVA compared
to balanced anesthesia for children after craniotomy. Individual patient factors (beyond
their risk of PONV) also drive decisions about the type of anaesthetic agents to use for
patients requiring craniotomy. These decisions include: the need not to increase cerebral
blood volume; attempts to manage intracranial pressures; and keeping cerebralvascular
autoregulation intact (Englehard & Werner, 2006). Thus, these complex decisions may
not fall easily into decisions about preventing PONV, and "the optimal technique may
depend more on how drugs are used rather than the specific choice of drugs" (Pasternuk
& Lanaier, p. 79). The use of regional blocks is another recommendation by SAMBA to
decrease PONV. Beyond scalp blocks to manage postcraniotomy pain (Bali, Gupta,
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Bhardwaj, Ghai, & Khosia, 2006), regional blocks in the absence of other anesthesia are
not used for craniotomy.
One study of non-steroidal anti-inflammatories (NSAIDs) shows some evidence
of their effectiveness in preventing POV in children after posterior fossa craniotomy.
Smyth, Banks, Tubbs, Wellons and Oakes (2004) compared alternating, intermittent,
doses of ibuprofen and acetaminophen (every two hours), starting immediately after
surgery for Chiari Malformations in children, with a control group of children requiring
the same procedure who were given analgesic medication as requested. The children in
the treatment group had decreased pain scores, fewer rescue anti-emetics and narcotics,
and shortened hospital stays. While the use of rescue anti-emetics is not a direct indicator
of PONV, this study is one of the few studies of interventions for children after
craniotomy that includes any measure of PONV as an outcome.
Efficacy and effectiveness of prophylactic anti-emetics
When selecting anti-emetics for children after posterior fossa craniotomy, it must
be recognized that there is a lack of evidence for or against the efficacy of these drugs, or
complementary treatments, for children after craniotomy. In the two studies that have
been conducted on POV in children after craniotomy, Furst et al. (1996) and
Subramaniam et al. (2007) could not find evidence of efficacy of an intraoperative dose
of ondansetron, a 5HT3 receptor antagonist, in preventing POV. Combining these two
small studies, using a random effects model, still could not show evidence of efficacy for
this drug in this patient population; however, the combined sample size remained too
small for a confident assessment (Neufeld & Newburn-Cook, 2008).
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In the absence of evidence for or against the use of any class of anti-emetic in
children after craniotomy (posterior fossa or supratentorial), two areas of support may be
considered when making decisions about their use in practice: PONV studies in children
requiring other types of surgery and PONV studies in adults requiring craniotomy. The
drugs reviewed by SAMBA (Gan et al., 2007) to be effective in preventing POV in
children are summarized in Table 5.1. Additionally, the least sedating effective dose,
route, and drug should be used so that a child's neurocognitive status after craniotomy
can be accurately assessed.
Of the drugs listed, only dexamethasone and the 5HT3 receptor antagonists
(dolasetron, granestron, ondansetron, and tropisetron) are considered to be non-sedating.
Dexamethasone is often used preoperatively for patients requiring craniotomy for brain
tumours due to its effect on reducing vasogenic edema (Pasternak & Lanier, 2008).
Withholding dexamethasone for the purpose of determining its effect on PONV after
craniotomy for brain tumours is not an ethical option. The effectiveness could be
determined for children requiring procedures such as Chiari Malformations or vascular
procedures. However, evidence from studies of children requiring other types of surgery
(Tables 5.1 and 5.2) may be considered sufficient to support the use of dexamethasone, in
combination with a 5HT3 receptor antagonist, for the prevention of PONV for all children
requiring posterior fossa craniotomy. Despite the two small negative trials in children
after craniotomy already discussed (Furst et al., 1996 & Subramaniam et al., 2007), this
class of drugs should not yet be discounted for preventing POV in children after posterior
fossa craniotomy. Their sample sizes, even when combined (Neufeld & Newburn-Cook,
2007) were small, leading to a high possibility of Type II error (finding no effect when in
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truth there is an effect). As shown in Table 5.1, the 5-HT3 receptor antagonists show
evidence of efficacy through systematic review in children after other types of surgery. A
systematic review has also shown efficacy of the 5-HT3 receptor antagonists in
preventing POV (but not nausea) in adults after craniotomy (Neufeld & Newburn-Cook,
2007).
Droperidol has shown efficacy through systematic reviews in preventing POV in
children after other surgical procedures (see Table 5.1) and in a randomized controlled
trial for preventing PONV in adults after supratentorial craniotomy (Fabling, Gan, El-
Moalem, et al., 2000). The choice of droperidol as an anti-emetic, however, needs to be
also considered within the context of warnings of potential cardiotoxicity (Health
Canada, 2002), and it is currently not often chosen for children. Dimenhydrinate is
commonly prescribed "as needed" for PONV in children after craniotomy and other types
of surgery. While there is evidence that it is effective for preventing POV in children
overall (Table 5.1), its efficacy in preventing POV has not been studied in adults after
craniotomy despite being the rescue anti-emetic of choice studies of 5HT3 receptor
antagonist studies (Neufeld & Newburn-Cook, 2007). Perphenazine also shows evidence
of efficacy after other surgery in children (Table 5.1) but has not been studied in adults
after craniotomy.
Interestingly, in one retrospective study, the use of transdermal scopolamine
applied before neurosurgery showed effectiveness in a group of adults requiring
retromastoid craniectomy with microvascular decompression of cranial nerves (Meng &
Quinlan, 2006). There is also a systematic review that supports the efficacy of
transdermal scopolamine in another adult population (Kranke, Morin, Roewer, Wulf, &
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Eberhart, 2002). Future study in children requiring posterior fossa craniotomy is
warranted. Transdermal scopolamine would be easy to apply preoperatively and
scopolamine is non-sedating when delivered via this route (Novartis, 2008).
Other Considerations
ASPAN (2006) has also indentified adequate hydration, Point P-6 acupoint
stimulation and multimodal pain management as other potential ways of decreasing
PONV. Intraoperative fluid management for patients requiring craniotomy must take into
effect intracranial pressures, cerebral spinal fluid management, and the possible need for
brain relaxation through decreasing brain water content. No work has been done in this
area as to how these efforts relate to PONV after craniotomy, and further study is
required to determine how children who require craniotomy are successfully treated from
a pre and postoperative fluid management perspective. Point P-6 acupoint stimulation has
been suggested to decrease PONV in adults (Lee & Done, 2004), but has not been studied
in adults after craniotomy in particular. Because it is non-invasive and has no known
adverse effects, some children, and their families, may wish to try this intervention for
their children requiring posterior fossa craniotomy if they have concerns about PONV.
However, there have been no studies of its effectiveness in preventing PONV in children
and adults after craniotomy.
Finally, ASPAN (2006) recognize the importance of effective pain management
strategies in the prevention of PONV. Regardless of its effect on PONV, the use of
multimodal pain management strategies ought to be a part of preoperative planning for
any major surgery, especially craniotomy. Research into best multimodal pain
management strategies after posterior fossa craniotomy, are necessary as many of these
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children experience headache pain, incisional pain and neck pain postoperatively
(Neufeld, 2008b).
ASPAN'S Evidence-Based Clinical Practice Guideline for
Management of PONV
Key components of ASPAN's (2006) algorithm for Evidence-based Clinical
Practice Guideline for Management of PONV (Figure 5.2) includes ongoing
postoperative assessment for nausea and vomiting and the provision of rescue anti-emetic
therapies. If a prophylactic anti-emetic was already administered, the rescue anti-emetic
should be chosen from a class of drugs that targets a different receptor site. There are two
main areas related to this guideline that require consideration for children after posterior
fossa surgery. First, there is a need for better assessment of nausea and for research that
includes nausea as an outcome. Second, like the lack of research into prophylactic
interventions, is the lack of evidence of efficacy or effectiveness of anti-emetics to treat
PONV in these children. Given that over 40% of children after posterior fossa surgery
may have more than three retching or vomiting episodes (Neufeld, 2008a), effective
treatment of existing POV in this patient population is imperative.
Assessment of Nausea
As mentioned, the second algorithm proposed by ASPAN (2006) focuses on the
assessment and management of PONV. Ongoing assessment of nausea is highlighted in
this algorithm. Neufeld (2008a) found that nausea was not well documented for children
after posterior fossa surgery. Researchers have focused on POV in children, not on
postoperative nausea, in studies of anti-emetics (Kovac, 2007). Heyland, Dangel, &
Gerber (1997) summarized the attitude toward measurement of nausea in children after
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surgery: "because nausea is difficult to evaluate in young children, we report only
vomiting, implicating that the same conclusions are valid for nausea" (p.231). Yet,
Fabling et al. (1997) found that the risk factors for nausea in adults after craniotomy were
different than those for vomiting. Also, some anti-emetics such as droperidol and
dexamethasone have shown efficacy for nausea while others have not (Kovac, 2007).
Thus, nausea is important to evaluate in children, despite being more difficult to measure,
and treatment should be given for nausea whether or not it is accompanied by retching
and/or vomiting. This is not only a research issue but a clinical practice issue that requires
education of bedside nurses on the importance of assessment and timely treatment of
nasusea.
There is evidence from the oncology literature that nausea can be measured in
young children. A three to four item scale may be the best way to measure this subjective
experience. Children, by the age of five, have been shown to understand and use a
numeric rating scale for nausea and vomiting (Zeltzer et al., 1988). A number of studies
have rigorously established the content and construct validity of four item discrete scales
to measure the severity of nausea in paediatric oncology (Collins et al., 2000; Collins et
al., 2002; Holdsworth, Raisch, Duncan, Chavez, & Leasure, 1995) and three item faces
scales for children aged 5-7 (Varni, Katz, Seid, Quiggins, & Friedman-Bender, 1998;
Varni, Katz, Seid, Quiggins, Friedman-Bender et al., 1998). Thus, instead of a visual
analogue scale (VAS) as suggested in ASPAN's (2006) algorithm, children's nausea
would be better assessed using a three or four item scale. Importantly, non-verbal and
physiological cues can alert nurses to nausea in young children who can not articulate
their symptoms (Keller, 2004). As shown in Table 5.3, Keller categorized these cues as
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alterations of affect and behaviour, distress and physiological alterations. Nurses could
easily add an evaluation of these cues in their routine postoperative assessment, and many
may agree that these are cues that they already recognize and know.
Clinically, ongoing assessment of nausea is vital to ensuring that appropriate
treatment is initiated. Specific documentation of nausea could be incorporated into the
standardized assessment charting. If identified early, interventions aimed at reducing
nausea may result in a decrease in this symptom. It is essential to note that nausea may
not present until a few days after posterior fossa surgery, when the effects of the
anaesthetic and any associated treatments have worn off, cerebral edema has peaked, an
external ventricular drain has been removed, and the child becomes more mobile. Ideally,
children should be observed for nausea and questioned about their symptoms throughout
their hospital stay.
Efficacy and effectiveness of anti-emetics
Similar issues related to the selection of preoperative prophylactic anti-emetics
are then manifest in the management of existing PONV for children after posterior fossa
craniotomy. Eberhart et al. (2007) concluded that studies of the management of existing
PONV have not been conducted for any patients after craniotomy. Whether or not
intermittent administration of anti-emetics in the postoperative period is effective for
inpatients at high risk for PONV, or for those already experiencing PONV, are important
questions to answer. Currently, use of anti-emetics for PONV in children after posterior
fossa surgery relies on clinical acumen rather than research evidence. As such, the
administration of anti-emetics varies by prescribing clinician and, if prescribed as needed,
by the individual making the decision to administer the drug - usually the nurse who is
127
working at the bedside with the child and family. With shift work, staffing changes, and
differing beliefs among individual nurses, communication about what works for
individual children and what signs they show for nausea are essential for effectively
managing their PONV.
An interesting area of the ASPAN (2006) guideline for the Management of PONV
is the use of aromatherapy for established PONV. As aromatherapy is likely not going to
cause harm, it could be implemented for PONV in children after posterior fossa surgery,
if acceptable to the child and family. Questions for the use of aromatherapy include: Who
would provide the required products? What would they be? How would they be
regulated? and, How would they be administered in complex inpatient environments?
Perhaps "non-aroma therapy" such as keeping the child away from noxious smells in the
hospital environment, should also be considered.
ASPAN'S Evidence-Based Clinical Practice Guideline for
Management of PDNV
PDNV is an area that is also not well addressed for children after posterior fossa
surgery. A number of questions can be raised around discharge planning: How long after
vomiting should a child be discharged from hospital? Should the anti-emetics that were
used in the hospital be continued at home to prevent nausea and vomiting? How long
should these anti-emetics be continued at home? Because nausea and vomiting after
discharge may be indicative of a new postoperative problem (i.e. hydrocephalus, blocked
shunt, or pseudomeningocele), it is imperative to teach the family to contact the
neurosurgery clinic or proceed to the emergency department if the child develops
symptoms after discharge.
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If it is decided that the child may remain at home, interventions in the ASPAN
(2006) third algorithm on postdischarge nausea and vomiting ought to be considered,
again in the context of a lack of research in children after posterior fossa craniotomy. Of
note, Davis et al. (2008) found oral ondansetron disintegrating tablets effective for
preventing POV for children after ambulatory ear-nose-throat surgery when administered
at home for three days after surgery. Interestingly, in this study, 8/10 children who
required rescue anti-emetic therapy for PONV in hospital did not respond to the oral
ondansetron disintegrating tablets, compared to 7/93 children who did not require rescue
anti-emetic therapy in the early postoperative period. This finding must be considered in
the context of a small sample size but suggests the importance of focusing on preventive
strategies for PONV in children and the need for inquiry into better ways of treating
established symptoms.
Graham and Harrison (2005) cautioned that, once a clinical area to promote best
practice is identified, a "rigorous and transparent" (p.72) approach is required, that
includes: establishing an interdisciplinary guideline evaluation group; establishing a
guideline appraisal process; searching for and retrieving guidelines; assessing the
guidelines for quality, currency and content; adopting or adapting guidelines for local
use; seeking external review; finalizing the local guideline; obtaining official
endorsement and adoption of the local guideline; and scheduling review and revision.
Despite the reviewed limitations, the adaption of the ASPAN (2006) guideline for the
Prevention and Management of PONV/PDNV for the care of children after posterior
fossa surgery could be a valuable tool for nurses, with the recognition that further
research is required.
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Future Research for PONV In Children after Posterior Fossa Craniotomy
As identified in the review of clinical practice guidelines for the prevention and
treatment of PONV/PDNV, the focus of research for children after posterior fossa
surgery ought to involve the evaluation of multimodal interventions. Outcomes also
require better quantification, for example severity scales and satisfaction with care.
Pharmacological interventions that require study include: the postoperative use of
dexamethasone (often already in use with children with brain tumours but not a standard
of care for children with Chiari I malformations or other posterior fossa surgical
procedures), combined with a 5HT3 receptor antagonist delivered intermittently; and,
possibly, the use of transdermal scopolamine applied preoperatively and continued
postoperatively. The effectiveness of other interventions such as acupressure,
aromatherapy, environmental changes and massage, may require a more qualitative
approach. Because of the small number of children who require posterior fossa surgery
at any one centre, multi-centre coordination will be required for successful research.
Additionally, the need for both multimodal pain management and multimodal anti-emetic
care for these children requires a seamless approach to research across disciplines.
Children who experience PONV may be more susceptible to nausea and vomiting
during their chemo- and/or radiation therapy than those who did not (ASHSP, 1999).
Research in this area may include the continuum of care for the nausea and vomiting
experienced by children with brain tumours who require chemotherapy and/or radiation
therapy. The time frame for an observational or intervention study on PONV for this
patient population could extend beyond the acute postoperative period to their experience
with concomitant therapies. This longitudinal type approach would help develop a
130
seamless approach to managing nausea and vomiting. An important practice point can
also be made: an exploration of the child's experience with PONV and related treatment
needs to be made, upon admission to oncology, to facilitate a comprehensive approach to
anti-emetic planning.
One challenge for the care of children after posterior fossa surgery is the belief
that nausea and vomiting are a normal part of the child's postoperative experience. A
clinician once commented that "they [children after posterior fossa surgery] all puke" as
if it was an expected outcome about which nothing could be done. In a study of 39
children and their families, Woodgate and Degner (2003) indicated that parents believed
unrelieved and uncontrolled symptoms, such as nausea and vomiting, were an expected
part of their child's cancer recovery. Beliefs of health care professionals who care for
children after posterior fossa craniotomy have not been explored, but advances in care
require the underlying determination that PONV can be prevented and treated in this
patient population and that it is a topic worthy of further investigation.
Finally, a contrasting belief about PONV in children after posterior fossa surgery
is that current practices are effective and supported by evidence. For example, personal
communication with a paediatric neurosurgical nurse at a prominent American children's
hospital indicated that, "we use ondansetron so this (nausea and vomiting) is not a
problem on our unit". As discussed earlier, there is no evidence for the efficacy of
ondansetron in preventing or treating PONV in children after craniotomy. Indeed, as
previously discussed, there is no evidence to support any preventive or treatment strategy
for these children. Recognition of the current limitations to our knowledge about
preventing and treating PONV in this patient population is essential in order to make
131
informed decisions around anti-emetic use. Currently, outside of the two small negative
randomized controlled trials of ondansetron previously discussed, these decisions must be
based on research in other clinical groups.
In conclusion, POV is a problem for children after posterior fossa surgery and
improvements in research and clinical practice are required in order to decrease its
incidence. Likely, nausea is also a problem in this patient population and it requires
improvements in clinical assessment, documentation and treatment. The adaption of
clinical practice guidelines for the prevention and treatment of PONV and PDNV, such as
those proposed by ASPAN (2006), could be of benefit. The limitations of any guideline
need to be acknowledged and addressed. I hope that some of the important issues related
to PONV and children after posterior fossa surgery and the challenges in adapting and/or
developing clinical practice guidelines have been addressed here.
Interdisciplinary processes at institutional level are now required to further
address the problem and design or adapt clinical practice guidelines to best suit their
resources and patient needs. This process will then need ongoing evaluation with
revisions made with new evidence. The use of multimodal approaches to care, as
supported in other patient populations, may benefit children after posterior fossa surgery.
Research into the efficacy, effectiveness, and potential deleterious effects of preventive
and treatment interventions is required to support or refute these approaches. Departure
from the traditional time periods of study ~ such as the acute care period, after discharge
and/or during concomitant therapy ~ are required in order to determine best anti-emetic
practices for this vulnerable group of children. Finally, beliefs and attitudes surrounding
PONV need to be addressed so as to justify research to the clinical community so that
132
results can be translated into successful clinical practice strategies aimed at prevention
and treatment.
133
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135
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137
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138
TABLE 5.1
Efficacious Drugs for Prophylaxis of POV in Children
Potential Antiemetic Dose Evidence Reference
Dexamethasone 150 mcg/kg up to
5mg
Systematic
Reviews
(Henzi, Walder, & Tramer,
2000), (Mathew et al.,
2004), (Madan et al., 2005)
Dimenhydrinate 0.5 mg/kg up to 25
mg
Systematic
Reviews
(Kranke, Morin, Roewer, &
Eberhart, 2002; Vener, Carr,
Sikich, Bissonnette, &
Lerman, 1996)
Dolasetron 350 mcg/kg up to
12.5 mg
Randomized
Controlled
Trials
(Olutoye et al., 2003;
Wagner, Pandit, Voepel-
Lewis, & Weber, 2003)
Droperidol
1
10-15mcg/kg up to
1.25mg
Systematic
Review
(Henzi, Sonderegger, &
Tramer, 2000)
Granisetron 40 mcg/kg up to 0.6
mg
Randomized
Controlled
Trial
(Cieslak, Watcha, Phillips,
& Pennant, 1996)
Ondansetron 50-100 mcg/kg up
to 4mg
Systematic
Reviews
(Khalil et al., 2005; Tramer,
Reynolds, Moore, &
McQuay, 1997)
Perphenazine 70 mcg/kg up to 5
mg
Randomized
Controlled
Trial
(Splinter & Roberts, 1997)
Tropisetron 0.1 mg/kg up to 2
mg
Systematic
Review
(Kranke, Eberhart et al.,
2002)
1. American Food and Drug Administration (FDA) "black box" warning should
be considered.
Note. From: "Society for Ambulatory Anesthesia guidelines for the management of
postoperative nausea and vomiting". Gan, T. J., Meyer, T. A., Apfel, C. C.,
Chung, F., Davis, P. J., Habib, A. S., et al. (2007). Anesthesia and Analgesia,
105(6) p. 1623. Copyright 2007 International Anesthesia Research Society.
Reprinted with permission from Wolters Kluwer Health.
139
TABLE 5.1
Anti-emetic Combinations that have been efficacious in children
Combination Authors
Ondansetron 0.05mg/kg + dexamethasone (W. M. Splinter, 2001; W. M.
0.015mg/kg Splinter & Rhine, 1998)
Ondansetron O.lmg/kg + droperidol 0.015 mg/kg (Shende, Bharti, Kathirvel, &
Madan, 2001)
Tropisetron O.lmg/kg + dexamethasone 0.5 mg/kg (Holt et al., 2000)
Note. From: "Society for Ambulatory Anesthesia guidelines for the management of
postoperative nausea and vomiting". Gan, T. J., Meyer, T. A., Apfel, C. C.,
Chung, F., Davis, P. J., Habib, A. S., et al. (2007). Anesthesia and Analgesia,
105(6) p. 1622. Copyright 2007 International Anesthesia Research Society.
Reprinted with permission from Wolters Kiuwer Health.
140
TABLE 5.3 HAS BEEN REMOVED DUE TO COPYRIGHT
FIGURE 5.1
ASPAN'S Evidence-Based Clinical Practice Guideline for Preoperative Patient
Management of PONV.
Algorithm 1. Preoperative patient management.
Preoperative Patient Management
•Identify patient risk factors using Risk Assessment Tool
•Document & communicate patient risk factors to Anesthesiology & rest of surgical team
i Determine the level of prophylactic treatment needed for patient;
Level of Risk Low Ri sk Moderate Risk Severe Risk Very Severe Risk
% chance of PONV 10-20% 40% 60% 80%
# prophylactic
interventions to
consider
0 1 | 2
i
3 or more
increased risk of surgical complication risk rotated to POV would movo the patient up at (oast ens risk factor love! &
Indicate the need for additional Interventions. Examples Include, but are not limited to: maxlllomandlbuiar fixation, plastic
surgery, Intracranial surgery, etc
Patient is at Low Risk
for PONV
3 :
Patient is at Risk
for PONV
No prophylactic treatment
necessary
Consider Prophylaxis for PONV
Anesthesia Considerations
Total Intravenous Anesthesia
Regional Blocks
NSAI DS
Pharmacological Considerations
Dexamethasone
5- HT3 receptor antagonists
H1 receptor blockers
Scopolamine patch
Droperidol (corridor black box warning )
Other Considerations
Improve hydration
Multi-modal pain management
P6 acupoint stimulation
Note. From: "ASPAN'S Evidence-Based Clinical Practice Guideline for the Prevention and
Management of PONV/PDNV. By American Society of PeriAnesthesia Nurses
(2006). Journal of PeriAnesthesia Nursing 21(4) p.243. Copyright 2006 American
Society of PeriAnesthesia Nurses. Reprinted with permission from Elsevier.
142
FIGURE 5.1
ASPAN'S Evidence-Based Clinical Practice Guideline for Management of PONV
Algorithm 2. Postoperative management of PONV: Phase I PACU/phase II PACU.
Postoperative Management of PONV: Phase I PACU/Phase II PACU
:m
Assess for PONV on admission, discharge & more frequently as needed
NO
Cont i nue t o moni t or
Nausea/vomiting?
YES 1
I
If nausea is present, quantify severity using a VDS or VAS
Did patient receive prophylactic anti-emetic agent(s)
Verify adequate
hydration
NO
l i
YES
X l
Select & administer appropriate rescue anti-emetic
that impacts a different receptor site than the prophylactic agent.
Implement Rgscw i i wi i a a s " " 1
Select & administer appropriate rescue anti-emetic
5- HT receptor antagonist
H1 Receptor Blockers
Droperidol (consider black box warning)
Late considerations may include:
Low dose promethazine
Prochlorperazine
Metoclopramide
1
Aromatherapy
Note. From: "ASPAN'S Evidence-Based Clinical Practice Guideline for
the Prevention and Management of PONV/PDNV". By American
Society of PeriAnesthesia Nurses (2006). Journal of
PeriAnesthesia Nursing 21(4) p.244. Copyright 2006 American
Society of PeriAnesthesia Nurses. Reprinted with permission from
Elsevier.
143
FIGURE 5.1
ASPAN'S Evidence-Based Clinical Practice Guideline for
Management of PDNV
Algorithm 3. Management of PDNV.
v..,-..,.™.. . ' ' ' -
S
Management of Postdischarge Nausea and Vomiting e,
Note. From: "ASPAN'S Evidence-Based Clinical Practice Guideline for
the Prevention and Management of PONV/PDNV". By American
Society of PeriAnesthesia Nurses (2006). Journal of
PeriAnesthesia Nursing 27(4) p.245. Copyright 2006 American
Society of PeriAnesthesia Nurses. Reprinted with permission from
Elsevier.
144
General Discussion and Conclusions
Postoperative nausea and vomiting (PONV) is a problem for adults and children
after craniotomy. Children requiring posterior fossa craniotomy as a group are at
significant risk for postoperative retching and vomiting (POV), and likely postoperative
nausea. No treatments have shown efficacy for preventing or treating PONV in this
patient population so current clinical practice must be guided by what works in other
patient populations such as adult craniotomy and children requiring other types of
surgery. The adaptation of existing clinical practice guidelines, or developing unique
guidelines, is required to ensure best evidence is used in assessment, prevention,
treatment and evaluation of the care of PONV for these children. Educating the
interdisciplinary team on the high incidence of POV in children after posterior fossa
surgery, ensuring that their postoperative assessment includes ongoing evaluation of
nausea, and identifying protective interventions that are guided by best evidence are
required to address PONV in this patient population.
Further research specific to preventing PONV in children after craniotomy in
general is required as it appears that the 5-HT3 receptor antagonists that are effective for
postoperative vomiting (POV) in adults may not show the same efficacy in children. The
research presented in this dissertation indicates that children requiring posterior fossa
craniotomy form a high risk group. In a hierarchical multivariable logistic regreseeion
analysis using vomiting by 120 hours as an outcome, preoperative risk factors included
children under age 12 and those requiring surgery for Chiari I Malformations. These
factors could be used in the development of a prognostic model to predict vomiting for
145
individual of children and can currently be used to identify at risk groups within children
requiring posterior fossa surgery. Interventions such as the use of desflurane and
intraoperative ondansetron (likely because the anesthesiologists were good at predicting
who was going to vomit and thus used intraoperative ondansetron - a drug which has not
yet been shown to have efficacy in this patient population) were also identified as risk
factors, with ondansetron moderating the effect of desflurane. Knowledge of these factors
can help guide overall clinical decision making, aid in the development of clinical
practice guidelines, and ultimately be used to develop a prognostic tool.
To address the problem of PONV in children after posterior fossa craniotomy, a
first step is to develop clinical practice guidelines to address the need for better risk
assessment, prophylaxis, and treatment of PONV. Clinical practice guidelines will also
help to ensure that consistency of care is maintained and current best evidence used. As
discussed in the final chapter of this dissertation, appropriate clinical practice guidelines
such as those proposed by the American Society of PeriAnesthesia Nurses (2006) can be
adapted based on the knowledge of PONV after craniotomy that is outlined in the first
four chapters. Facilitation of this process by nurse clinician scientists, who would be in an
excellent position to synthesize knowledge, design and conduct studies that fill in gaps,
and use appropriate tools in an ongoing effort to evaluate their effectiveness, will be
essential to successful adaptation, implementation and ongoing reevaluation of any
clinical practice guideline or change in clinical practice.
One of the difficulties of a paper dissertation is keeping papers focused on
specific questions. The data collected within the retrospective study have a number of
directions for further exploration. Data on headache and neck pain were collected in the
146
chart audit that was discussed in the fourth paper as were data on the subjective appraisal
of severity of vomiting by the individual collecting the data. Additional research needs to
focus on the continuum of care that these children require and go beyond PONV to the
clustering of postoperative symptoms such as neck pain and headache, which are two
separate entities that require different approaches to care.
Anecdotal data were also collected in the retrospective study, for example: "child
vomiting, ondansetron not available on the unit, ginger-ale given, effective." Of all the
charts reviewed, there were only three documented entries of non-pharmacological
efforts to help the child with PONV: ginger-ale (twice) and a cool cloth (once). How
many times have nurses removed the food cart, placed a child away from the kitchen, or
provided a cool cloth over their eyes and forehead and not documented these
interventions? Occasionally, children (and their families) with severe vomiting began to
refuse offered anti-emetics stating that "they don't work" with a rising sense of
helplessness appearing in the nurses' charting. Many of these children would be going for
radiation and chemotherapy next making the successful management of their symptoms
even more imperative. As the risk factors for children with brain tumours may be
different than those requiring other posterior fossa procedures, there is a plan for a
secondary analysis looking specifically at children with posterior fossa brain tumours and
severe unremitting vomiting.
Appropriate prevention and management of PONV for children after posterior
fossa surgery ultimately requires a team approach with staff in admitting, nurses
providing preoperative care and education, anesthesiologists, neurosurgeons,
perianaesthesia nurses, nurses in the intensive care, nurses on the care units, and those
147
involved in discharge planning collaborating. The unique contribution of my work
through this dissertation is to confirm the high incidence of vomiting in children after
posterior fossa surgery through the lens of a practicing nurse (i.e. examining the problem
for longer than 24 hours), identify risk factors that are different from other patient
populuations, highlight the gaps in the research, including a basic knowledge of what
anti-emetics are effective, and to provide some guidance for how this knowledge can be
integrated into bedside nursing care, as well as the care of the entire neurosurgical team.
148
Reference
American Society of Peri Anesthesia Nurses (2006). ASPAN'S evidence-based clincial
practice guideline for the prevention and/or management of PONV/PDNV.
Journal of PeriAnesthesia Nursing, 21(4), 230-250.
149
Appendix 8
Data Extraction Tool:
5HT3 Receptor Antagonists in the Prevention of
Postoperative Nausea and Vomiting of Neurosurgical Patients
(Used for Papers 1 and 2)
Reviewer
Authors
Country
Publication Year
Setting = Acute Care Hospital
Population
Clearly Stated (at least 2 of age, sex, disease stage)
Partially Stated
Unclear
Location of surgery:
Supra-tentorial
Infra-tentorial
Both supratentorial and infratentorial
Spinal cord
Patient Make-up:
Consecutive Patients
Random Sample
Convenience Sample (day of week, time, etc.)
Other
Unknown
Inclusion Criteria Exclusion Criteria
150
Demographics
N= Number
Enrolled
Number
Complete
Age
Range
Age
Mean
Age
SD
Sex
M/F
Treatment
Control
Other drug
Total
Surgery Type
N= Supra-
tentorial
Infra-
tentorial
Neoplasm Vascular
Treatment
Control
Other drug
Total
151
Description of withdrawals & drop outs
Treatment:
Control:
Other drug arm:
Other population issues.
Intervention
Medication Dose Route Timing
Total Doses
Treatment Pre-op
Dural Closure
Skin Closure
Reversal
Other
Control Pre-op
Dural Closure
Skin Closure
Reversal
Other
Other drug Pre-op
Dural Closure
Skin Closure
Reversal
Other
152
Co-Interventions
Medication Dose Route Timing
Total
Doses
Dexamethasone Pre-operatively q h
Intra-operatively q h
Post-operatively q h
Other steroid Pre-operatively q h
Intra-operatively q h
Post-operatively q h
Anxiolytic
Analgesic
Standardized anaesthesia protocal:
Yes
No
Unclear
Drug Dose Route Time
Induction Induction Induction
Neuromuscular
Blockade
Maintenance Maintenance Maintenance
Reversal Reversal Reversal Reversal
Length of Anaesthetic (mean, SD)
Treatment Control
153
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Adverse Events
Event Treatment Control Not measured
Protracted PONV
Hemorrhage
CSF Leak
Decreased LOC
Diarrhoea
Constipation
Headache
Elevated liver enzymes
Extrapyramidal Effects
Other
Other
156
Trial Methodology
Concealment of treatment allocation: Adequate
Inadequate
Unclear
Adequate: e.g. central randomization; numbered/coded containers; drugs prepared
by pharmacy; serially numbered, opaque, sealed envelopes
Inadequate e.g. alternation, use of case record numbers, dates of birth or day of
: week; open lists
Unclear: Allocation concealment approach not reported or fits neither above
category
Part 2 Jadad Scale (Jadad et al. (1996).
Score
1. Was the study described as randomized (this includes the use of words
such as randomly, random and randomization)?
Yes = 1 No = 0
2. Was the study described as double-blind?
Yes = 1 No = 0
3. Was there a description of withdrawals and drop-outs?
Yes = 1 No = 0
Additional points: Add 1 point if:
Method to generate the sequence of randomization was described and
was appropriate (e.g. table of random numbers, computer generated,
coin tossing, etc.)
Method of double-blinding described and appropriate (identical
placebo, active placebo, dummy)
Point deduction: Subtract 1 point if:
Method of randomization described and it was inappropriate
(allocated alternately, according to date of birth, hospital number, etc.) "
Method of double-blinding described but it was inappropriate
(comparison of tablet vs injection with no double dummy) "
OVERALL SCORE (Maximum 5)
Note. From: Jadad, A.R., Moore, R.A., Carroll, D. et al. (1996). Assessing the quality of
reports of randomized clinical trials: is blinding necessary? Controlled Clinical
Trials 17, 1-12. Copyright 1996. Reprinted with permission from Elsevier.
157
Source of Funding
Industry
Investigator controlled
Industry controlled
Peer review - External
Peer review - Internal
Non-peer review - Internal
Combination: explain
Other
Additional Comments:
Appendix 8
Data Extraction Risk Factors for PONV (Paper 3)
STUDY REVI EWER
COUNTRY Author PUBLICATION YEAR:...
Setting:
Hospital ICU [ ]
PARR [ ]
Gen. Ward [ ]
Other specify)
Multi site [ ] Single site [ ]
POPULATION:
[ ] Clearly stated (at least 2 of age, sex, diagnosis, type of surgery)
[ ] Partially stated (one of above only)
[ ] Not mentioned
Number of patients enrolled:
Number of patients completing the study:
Description of drop outs and withdrawals:
Drop-outs:
Withdrawals:
COHORT:
Data Collection:
Prospective
Retrospective
Data Extraction/Outcome measure:
Blinded
Describe
Other issues
159
INCLUSION CRITERIA EXCLUSION CRITERIA
PATIENT MAKE-UP
[ ] Consecutive patients
[ ] Random sample
[ ] Convenience Sample (by day of week, time, etc.)
[ ] Other (volunteers)
[ ] Unknown
Source of funding:
Industry:
If industry: Investigator controlled [ ]
Industry controlled [ ]
Peer Review - External [ ]
Peer Review - Internal [ ]
Non-peer review - Internal [ ]
Combination: explain:
ASSESSMENT OF Adverse OUTCOMES
Outcomes
Adverse effects (Name)
1:
2:
3:
4:
160
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Quality Assessment (Hayden, Cote, & Bombardier, (2006).
Potential Bias
Items to consider for assessment of potential opportunity for bias
1) Study Participation: The study sample represents the
population of interest
• The source population or population of interest is adequately
described for key characteristics
• The sampling frame and recruitment are adequately described
including period and place of recruitment
• There is adequate participation in the study by eligible
individuals
• The baseline study sample is adequately described for key
characteristics
€ Yes
€ Partly
€ No
€ Unsure
Yes No
Yes No
Yes No
Yes No
2) Study Attrition: Loss to Follow-up is not associated with
key characteristics
• Proportion of the study sample completing and providing
outcome data is adequate
• Information on non-completers is provided
• Reasons for non-completion are provided
• There are no important differences between completers and
non-completers
€ Yes
€ Partly
€ No
€ Unsure
Yes No
Yes No
Yes No
Yes No
163
3) Prognostic Factor Measurement: The prognostic factor of
interest is adequately measured in study participants to
sufficiently limit potential bias.
• A clear description of the prognostic factor measured is
provided
• Continuous variables are reported or appropriate cut-points
are used
• The prognostic factor measure and method are adequately
valid and reliable to prevent misclassification bias
• Adequate proportion of the study sample has complete data
for prognostic factors.
• The method and setting of measurement are the same for all
study participants.
• Appropriate methods are used if imputation is used for
missing prognostic factor data
€ Yes
€ Partly
€ No
€ Unsure
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No n/a
4) Outcome Measurement: The outcome of interest id
adequately measured in study participants to sufficiently limit
potential bias.
• A clear definition of the outcome of interest is provided
including duration of follow-up and level and extent of the
outcome construct
• The outcome measure ant method used are adequately valid
and reliable to limit misclassification bias
• The method and setting of measurement are the same for all
study participants.
€ Yes
€ Partly
€ No
€ Unsure
Yes No
Yes No
Yes No
164
5) Confounding measurement and account: Important
potential confounders are appropriately accounted for,
limiting potential bias with respect to the prognostic factor (s)
of interest.
• Theoretically and clinically important confounders including
treatments are measured
• Clear definitions of the confounders are provided
• Measurement of important confounders is adequately valid
and reliable
• The method and setting of confounding measurement are the
same for all study participants
• Important potential confounders are accounted for in the study
design (matching for key variables, stratification or initial
assemble of comparable groups.
• Important potential confounders are accounted for in the
analysis (i.e. appropriate adjustment)
€ Yes
€ Partly
€ No
€ Unsure
Yes No
Yes No
Yes No
Yes No
Yes No
Yes No
6) Analysis: The statistical analysis is appropriate for the
design of the study, limiting potential for presentation of
invalid results
• There is sufficient presentation of data to assess the adequacy
of the analysis
• The strategy for model building (i.e. inclusion of variables) is
appropriate and is based on a conceptual framework or model.
• The selected model is adequate for the design of the study
• There is no selective reporting of results.
€ Yes
€ Partly
€ No
€ Unsure
Yes No
Yes No
Yes No
Yes No
Note. From: Hayden, J. A., Cote, P., & Bombardier, C. (2006). Evaluation of the quality
of prognosis studies in systematic reviews. Annals of Internal Medicine, 144(6),
427-437. Copyright 2006. Adapted with permission from the American College of
Physicians.
165
Additional comments:
166
Appendix 3
Nausea and Vomiting After Posterior Fossa Surgery
Case Report Form (Paper 4)
Child Demographics:
Age at surgery: years months Gender: M F Started Menses: Y N Unknown N/A
Other Health Issues Weight
Surgery Summary:
Surgery:
Surgery date: / / Discharge (from surgery) date: / /
Discharge location: Home Oncology Unit Rehabilitation Unit Other
Hospital Discharge Date / /
Pathology/Final diagnosis:
Preoperative
History:
Yes No
Other surgery (Specify
Postoperative Nausea
Postoperative Vomiting
Presenting signs and symptoms:
Yes No
Nausea (describe
Vomiting (describe_
Hydrocephalus
Syringomyelia/scoliosis
Headache
Ataxia
cranial nerve deficits (specify )
other (specify )
Antiemetics in 24 hours before surgery
Yes No
Dimehyndrinate (Gravol)
Granisetron (Kytril)
Metochlorpramide (Maxeran)
Ondansetron (Zofran)
Scopolamine
Other (Specify )
Steroids in 24 hours before surgery
Yes No
Dexamethasone
Other steroid (Specify
CSF Management
Yes NO Date Inserted
EVD
Lumbar Drain
Other (Specify
Third Ventriculostomy
VP Shunt
Intraoperative
ASA Status: I II III IV
Anaesthetic start time
Surgery start time
Pre/Intra/Post
Pre/Intra/Post
J Pre/Intra/Post
Pre/Intra/Post
Pre/Intra/Post
Anaesthetic finish time :
Surgery finish time :
Date D/C
/ /
/ /
/ /
Anaesthesia:
Induction: Theopentol Propofol N
2
0 Rocuronium Other
Maintenance: Isoflurane Desflurane Sevoflurane N
2
0 Other
Reversal: Neostigmine Atropine Glycopryyolate
Opioid: Fentanyl Morphine Remifentanil
Antiemetic: Time:
Steroids: Time:
Mannitol: Time:
Estimated size of Lesion: Preoperative/Intraoperative MRI
Location of Lesion:
€ Cerebellar vermis
€ Cerebellar hemisphere: Right Left
€ Intraventricular
€ Outside of 4th ventricle and cerebellum (i.e. Cerebello-pontine angle, undersurface of cerebellar
hemisphere)
€ Other
Degree of Resection:
Evidence of: Extensive Bleeding Cranial Nerve Damage Other
Notes on surgery:
168
Postoperative
PARR -4h 4-8h 8-24h 24-48h 48-72h
Location
Nausea Y N Y N Y N Y N Y N Y N
Vomiting
(Counts)
Retching Y N Y N Y N Y N Y N Y N
Pain
€ None noted
€ Headache
€Ne c k
€ Other
€ None noted
€ Headache
€Ne c k
e Other
€ None noted
€ Headache
€Ne c k
€ Other
€ None noted
€ Headache
€Ne c k
€ Other
€ None noted
€ Headache
€Ne c k
€ Other
€ None noted
€ Headache
€Neck
€ Other
Antiemetics
Ordered
Antiemetics
Given*
Nonpharm.
Strategies
Opioids Given
EVD
€ Op e n @
€ Clamped
€ d / c
€ n / a
€ Op e n @
€ Clamped
€ d / c
€ n / a
€ Op e n @
€ Clamped
€ d/c
€ n/a
€ Open @
€ Clamped
€ d/c
€ n / a
€ Open @
€ Clamped
€ d/c
€ n/a
€ Open @
€ Clamped
€ d/c
€n/ a
Evidence of
Hydrocephalus
Y N
CT MRI
Y N
CTMRI
Y N
CTMRI
Y N
CTMRI
Y N
CTMRI
Y N
CTMRI
Notes:
Yes No
Postoperative Dexamethasone/Steroid (Number of days until d/c )
Postoperative anti-emetic given BEFORE first episode of vomiting/retching (answer
yes even if no episodes reported and antiemetics given for prevention)
Hours to first documented oral/gastric intake
169
Postoperative
72-96 96-120 120-144 144-168 168-192 192-216 216-240
Location
Nausea Y N Y N Y N Y N Y N Y N Y N
Vomiting
(Counts)
Retching Y N Y N Y N Y N Y N Y N Y N
Pain
€ None noted
€ Headache
€Neck
€ Other
€ None noted
€ Headache
€Neck
€ Other
€ None noted
€ Headache
€Neck
€ Other
€ None noted
€ Headache
€Neck
€ Other
€ None noted
€ Headache
€Neck
€ Other
€ None noted
€ Headache
€Neck
€ Other
€ None noted
€ Headache
€Neck
€ Other
Antiemetics
Ordered
Antiemetics
Given*
Nonpharm.
Strategies
Opioids
Given
EVD
€ Open
€ Clamped
€ d / c
€n/ a
€ Open
€ Clamped
€<f c
€n/ a
€ Open
€ Clamped
€d<c
€n/ a
€Open
€ Clamped
€d/c
€n/ a
€ Open
€ Clamped
€d!c
€ n/a
€Open
€ Clamped
€d/ c
€n/ a
€ Open
€ Clamped
€d/ c
€n/ a
Evidence of
Hydrocepha
lus
Y N
CTMRI
Y N
CTMRI
Y N
CTMRI
Y N
CTMRI
Y N
CTMRI
Y N
CTMRI
Y N
CT MRI
Notes:
170
Outcomes
Rating of vomiting and/or retching:
None Mild Moderate Severe
No documented
retching or vomiting
1-3 Episodes
Responsive to
treatment
>3 Episodes
Responsive to
treatment
>3 Episodes
Not responsive to
treatment
Limits Activity
Rating of nausea
None Mild Moderate Severe
No documented nausea <48 Hours
Responsive to
treatment
< 48 hours
Responsive to
treatment
>48 hours
Refractory to treatment
Yes NO
Wound failure
CSF Leak
Pseudomeningocele (Clinically noted OR MRI/CT noted only)
Infection
Cerebellar mutism / Posterior Fossa Syndrome
Cranial Nerve Deficits (Describe )
Other
Other
Readmission within 30 Days? Yes No
Reason for readmission
Notes:
Appendix 8
Nausea and Vomiting After Posterior Fossa Surgery
Data Collection Notes
Child Demographics:
• History, admission record
• Menses started: Circle Y if LMP noted.
Surgery Summary:
• OR records and discharge summary.
• Pathology report.
Preoperative
History:
• Anaesthesia history
• History of PONV - check charts of previous surgery if not on anaesthesia history
• Presenting symptoms - admission record, physical exam record
Antiemetics/Steroid
• Admission record
• If admitted, medication administration record
CSF Management
• OR records
• Progress notes
Intraoperative
• Anaesthesia flow sheet
• Surgical summary
• Location of Lesion: Preoperative MRI report and operative report. If conflicting (i.e. vermis vs.
fourth ventricular, use operative report). If both the vermis and cerebellar hemisphere involved,
check both locations.
• Size of lesion. Preoperative MRI. Note that we will use the largest diameter reported in the
analysis.

Postoperative
Nausea
Vomiting
Retching
Pain
Recovery room record
Nurses notes
Note time of documentation
Recovery room record
Counts from in & out flow sheet (after reviewing flow sheet, go to nurse's
notes& note each separately charted episode, if it corresponds to the flow sheet
do not count again)
Note time of documentation
Recovery room record
Nurses notes
Nurses notes, pain flow sheet, progress notes
Note headache, neck/back of head/incision, and other
172
Antiemetics Ordered
Antiemetics Given*
Nonpharm. Strategies
<
Opioids Given
Order sheets and medication administration records. Note changes to orders
(usually intermittent changed to prn and vice versa).
Medication administration records, effectiveness charted in nurses notes. Note
time of administration if prn.
Nurses notes - directly following any charting of nausea or vomiting
Medication administration records
Note type of drug: Morphine/Codeine etc.
EVD @
• EVD flow sheet, nurses notes
Evidence of Hydrocephalus
• CT/MRI report
Notes:
• Any significant changes as noted on progress notes or nurses' notes. For
example, intubation (<48 hours), surgery for vp shunt, IV started for
dehydration.
Dexamethasone: Note postoperative administration (also if ordered after emesis note this as well)
First Oral Intake: Note time to first oral intake (including oral meds administered). This should be found on
the flow sheets/in and out records and sometimes first sips are in the PARR report.
Notes: Last recorded vomit or retch/nausea: If > 10 days, follow nurses notes and in and out flow sheets
until resolved (may also show in progress notes and discharge summary if severe and refractory)
Outcomes
Rating of vomiting and/or retching/rating of nausea: This rating is the subjective impression of the data
collector with some quantitative guidelines. When data has been collected and initial analysis complete, the
categories may be further refined. Include rationale in notes section.
Wound failure
CSF Leak
Pseudomeningocele
Infection
• Note location: CSF (progress notes) Wound (progress notes, nurses notes).
Cerebellar mutism / Posterior Fossa Syndrome:
• Progress notes, speech/language notes, nurses notes)
Cranial Nerve Deficits
• Progress notes, opthamology consults, ENT consults, physiotherapy notes,
speech language notes.
Other
• Any other outcomes indicated on the progress notes
This is failure at the surgical site. Progress notes and nurses notes.
This is a CSF fluid leak through the skin
Note location (surgical site, shunt site, EVD exit site, etc.). Progress notes and
nurses notes.
Present if "pseudomeningocele" or "bulging" noted in clinical records or if a
fluid collection is present superficial to the craniotomy flap on postoperative CT
scan or MR scan (even if not clinically noted).
173
Appendix 8
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Elsevier
Controlled Clinical Trials
Assessing the reports of
randomized clinical trials: Is
blinding necessary.
Alejandro R. Jadad, R. Andrew
Moore, Dawn Carroll, Crispin
Jenkinson, D. John M. Reynolds,
David J. Gavaghan and Henry J.
McQuay
February 1996
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177
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vl. 2
21. Other conditions:
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178
Appendix 8
Permission to use Quality of Prognostic Studies (Appendix 2)
ACP
AMERI CAN COLLEGE OF PHYSICIANS
I NTERNAL MEDI CI NE I Doctors for Adults
R O A 0 8 1 5 9 8 8
March 18, 2009
Susan Neufeld
8919-117st
Edmonton, AB, Canada T6G 1R8
Dear Susan Neufeld:
Thank you for your request to print the following from Annals of Internal Medicine:
Table 3: Hayden JA, Cote P, Bombardier C. Evaluation of the quality of prognosis
studies in systematic reviews. Ann Intern Med 2006; 144:
Permission is granted to republish the preceding material with the understanding that you will
give appropriate credit to Annals of Internal Medicine as the original source of the material. Any
translated version must carry a disclaimer stating that the American College of Physicians
is not responsible for the accuracy of the translation. This permission grants non-exclusive,
worldwide rights for this edition in print only. ACP does not grant permission to reproduce entire
articles or chapters on the Internet. This letter represents the agreement between ACP and Susan
Neufeld for request ROAO815988 and supersedes all prior terms from the requestor.
Thank you for your interest in Annals of Internal Medicine. If you have any further questions or
would like to discuss the matter further, please contact me at 856-489-8555 or fax 856-489-4999.
Sincerely,
Gina Brown
Permissions Coordinator
179
Appendix 8
Permission to use Figures 5.1, 5.2 and 5.3
ELSEVIER LICENSE
TERMS AND CONDI TI ONS
Nov 11, 2008
This is a License Agreement between Susan M Neufeld ("You") and Elsevier
("Elsevier"). The license consists of your order details, the terms and conditions
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Nov 11, 2008
Elsevier
Journal of PeriAnesthesia Nursing
ASPAN's Evidence-Based Clinical
Practice Guideline for the
Prevention and/or Management of
PONV/PDNV Algorithms
December 2006
21
6
3
Thesis / Dissertation
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of chapter, Pages No., Copyright (Year), with permission from Elsevier [OR
APPLICABLE SOCIETY COPYRIGHT OWNER]." Also Lancet special credit -
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Copyright (Year), with permission from Elsevier."
4. Reproduction of this material is confined to the purpose and/or media for which
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GENERAL TERMS
181
deletions and/or any other alterations shall be made only with prior written authorization
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182
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no event will Elsevier or Copyright Clearance Center be responsible or liable for any
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This license was made in connection with a course,
This permission is granted for 1 year only. You may obtain a license for future website
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All content posted to the web site must maintain the copyright information line on the
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A hyper-text must be included to the Homepage of the journal from which you are
licensing at http ://www. sciencedirect. com/science/i ournal/xxxxx or the Elsevier
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Central Storage: This license does not include permission for a scanned version of the
material to be stored in a central repository such as that provided by Heron/XanEdu.
17. Author website for journals with the following additional clauses:
This permission is granted for 1 year only. You may obtain a license for future website
posting,
All content posted to the web site must maintain the copyright information line on the
bottom of each image, and
183
The permission granted is limited to the personal version of your paper. You are not
allowed to download and post the published electronic version of your article (whether
PDF or HTML, proof or final version), nor may you scan the printed edition to create an
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A hyper-text must be included to the Homepage of the journal from which you are
licensing at http://www.sciencedirect.com/science/iournal/xxxxx , or the Elsevier
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Central Storage: This license does not include permission for a scanned version of the
material to be stored in a central repository such as that provided by Heron/XanEdu.
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Authors are permitted to place a brief summary of their work online only.
A hyper-text must be included to the Elsevier homepage at http://www.elsevier.com
This permission is granted for 1 year only. You may obtain a license for future website
posting,
All content posted to the web site must maintain the copyright information line on the
bottom of each image, and
The permission granted is limited to the personal version of your paper. You are not
allowed to download and post the published electronic version of your article (whether
PDF or HTML, proof or final version), nor may you scan the printed edition to create an
electronic version,
A hyper-text must be included to the Homepage of the journal from which you are
licensing at http ://www. sciencedirect. com/science/i ournal/xxxxx , or the Elsevier
homepage for books at http://www.elsevier.com and
Central Storage: This license does not include permission for a scanned version of the
material to be stored in a central repository such as that provided by Heron/XanEdu.
19. Website (regular and for author): "A hyper-text must be included to the Homepage
of the journal from which you are licensing at
http://www.sciencedirect.com/science/iournal/xxxxx."
20. Thesis/Dissertation: If your license is for use in a thesis/dissertation your thesis
may be submitted to your institution in either print or electronic form. Should your
thesis be published commercially, please reapply for permission. These requirements
include permission for the Library and Archives of Canada to supply single copies, on
demand, of the complete thesis and include permission for UMI to supply single copies,
on demand, of the complete thesis. Should your thesis be published commercially,
please reapply for permission.
vl.2
21. Other conditions:
Other
184
Appendix 8
Permission for Tables 5.1 and 5.2
s
x \ i | , t i ppi ncot t Wi l l i ams & Wilkii
•.. > W o l t e r s K l u w e r s i - r ^
6
'
Health
DATE: 11/21/08
Susan M. Neufeld
Doctoral Student
University of Alberta
Faculty of Nursing
8919-117st
Edmonton, AB, Canada
T6G 1R8
Fee: $0.00
Re: Anesthesia and Analgesia
Spec Mat: ANE, 105(6): 1615-1628, Tab. 4 &5
Doctoral Dissertation
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