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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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Dedication
Chris, Anna and Emily.
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
1
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
2
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
3
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,
4
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
6
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.
7
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.
8
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.
9
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-HT3 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
12
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-HT3 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-HT3 receptor
13
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
14
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 I2 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). I2 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 (I2 = 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,
I2=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: 0.59-1.22,12=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-HT3 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
Reference List
1. Gan, TJ. Risk factors for postoperative nausea and vomiting. Anesth Analg 2006;102:1884-1898.
2. Fabling JM, Gan TJ, Guy J, et al. Postoperative nausea and vomiting. A retrospective analysis in patients undergoing elective craniotomy. JNeurosurg Anesthesiol. 1997;9:308-312.
3. Irefin SA, Schubert A, Bloomfield EL, et al. The effect of craniotomy location on postoperative pain and nausea. J Anesth. 2003; 17:227-231.
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5. Domino KB, Anderson EA, Polissar NL, et al. Comparative efficacy and safety of ondansetron, droperidol, and metoclopramide for preventing postoperative nausea and vomiting: a meta-analysis. Anesth Analg. 1999; 88:1370-1379.
6. Figueredo ED, Canosa LG. Ondansetron in the prophylaxis of postoperative vomiting: a meta-analysis. J Clin Anesth. 1998; 10:211-221.
7. Loewen PS, Marra CA, Zed PJ. 5-HT3 receptor antagonists vs traditional agents for the prophylaxis of postoperative nausea and vomiting. Can JAnaesth. 2000; 47:1008-1018.
8. Tramer MR, Reynolds DJ, Moore RA, et al. Efficacy, dose-response, and safety of ondansetron in prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized placebo-controlled trials. Anesthesiology. 1997; 87:1277-1289.
9. Eberhart LH, Morin AM, Bothner U, et al. Droperidol and 5-HT3-receptor antagonists, alone or in combination, for prophylaxis of postoperative nausea and vomiting. A meta-analysis of randomized controlled trials. Acta Anaesthesiol Scand. 2000; 44:1252-1257.
10. Henzi I, Walder B, Tramer MR. Dexamethasone for the prevention of postoperative nausea and vomiting: a quantitative systematic review. Anesth Analg. 2000; 90:186-194.
11. Gan TJ, Meyer T, Apfel CC, et al. Consensus guidelines for managing postoperative nausea and vomiting. Anesth Analg. 2003; 97:62-71.
12. Audibert G, Vial V. [Postoperative nausea and vomiting after neurosurgery (infratentorial and supratentorial surgery)]. Ann Fr Anesth Reanim. 2004; 23:422-427.
23
13. Wang YJ, Cheng ZG, Guo QL. [Clinical observation of granisetron in preventing postoperative nausea and vomiting following supratentorial craniotomy]. Hunan YiKeDaXueXue. 2002; 27:545-546.
14. Samra, S. K. , Williams B., Ciarralo, C., et. al. Lack of effect of droperidol, ondansetron, and dolasetron administration on PONV in a placebo controlled trial. Anesthesiology. 2003; 99:A305.
15. Review Manager (RevMan) [computer program]. Version. 4.2 for Windows. Oxford, England: The Cochrane Collaboration 2002.
16. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17:1-12.
17. RevMan Analyses [computer program]. Version 1.0 for Windows. In: Review Manager (RevMan) 4.2. Oxford, England: The Cochrane Collaboration, 2002.
18. Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med. 2002; 21:1575-1600.
19. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986; 7:177-188.
20. 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.
21. Altman DG, Deeks JJ. Meta-analysis, Simpson's paradox, and the number needed to treat. BMC Med Res Methodol. 2002; 2:3.
22. Higgins J, Thompson S, Deeks J, et al. Statistical heterogeneity in systematic reviews of clinical trials: a critical appraisal of guidelines and practice. J Health Serv Res Policy. 2002; 7:51-61.
23. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539-1558.
24. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ. 2003; 327:557-60.
25. Pugh SC, Jones NC, Barsoum LZ. A comparison of prophylactic ondansetron and metoclopramide administration in patients undergoing major neurosurgical procedures. Anaesthesia. 1996; 51:1162-1164.
26. Furst SR, Sullivan LJ, Soriano SG, et al. Effects of ondansetron on emesis in the first 24 hours after craniotomy in children. Anesth Analg.\996\ 83:325-328.
24
27. Hartsell, T. Long, D., Kirsch JR. The efficacy of postoperative ondansetron (Zofran) orally disintegrating tablets for preventing nausea and vomiting after acoustic neuroma surgery. Anesth Analg. 2005; 101:1492-1496.
28. Sinha PK, Tripathi M, Ambesh SP. Efficacy of ondansetron in prophylaxis of postoperative nausea and vomiting in patients following infratentorial surgery: a placebo-controlled prospective double-blind study. JNeurosurg Anesthesiol. 1999; 11:6-10.
29. Fabling JM, Gan TJ, El-Moalem HE, et al. A randomized, double-blinded comparison of ondansetron, droperidol, and placebo for prevention of postoperative nausea and vomiting after supratentorial craniotomy. Anesth Analg. 2000;91:358-361.
30. Kathirvel S, Dash HH, Bhatia A, et al. Effect of prophylactic ondansetron on postoperative nausea and vomiting after elective craniotomy. J Neurosurg Anesthesiol. 2001; 13:207-212.
31. Fabling JM, Gan TJ, El-Moalem HE, et al. A randomized, double-blind comparison of ondansetron versus placebo for prevention of nausea and vomiting after infratentorial craniotomy. J Neurosurg Anesthesiol. 2002; 14:102-107.
32. El-Shobaki AM, Bondok RS, Yakoub AM. Efficacy of intravenous granisetron versus placebo in the prophylaxis of postoperative nausea and vomiting after infratentorial craniotomy: A double-blind randomised study. Egyptian Journal of Anaesthesia. 2003; 19 297-304.
33. Madenoglu H, Yildiz K, Dogru K, et al. Randomized, double-blinded comparison of tropisetron and placebo for prevention of postoperative nausea and vomiting after supratentorial craniotomy. J Neurosurg Anesthesiol. 2003; 15:82-86.
34. White PF, Watcha MF. Has the use of meta-analysis enhanced our understanding of therapies for postoperative nausea and vomiting? Anesth Analg. 1999; 88:1200-1202.
35. Macario A, Weinger M, Carney S, et al. Which clinical anesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg 1999; 89:652-658.
25
TA
BL
E 1.
1 C
hara
cter
istic
s of
the
Stud
ies
Incl
uded
in th
e Sy
stem
atic
Rev
iew
and
Met
a-A
naly
sis
Stud
y (D
ate)
C
ount
ry
Ant
iem
etic
T
n C
Age
R
ange
(y
ears
)
Surg
ery
Loc
atio
n O
utco
me
Mea
sure
men
t T
imes
In
cide
nce
Rep
orte
d Si
nha
et a
l (19
99)
(28)
In
dia
Ond
anse
tron
4m
g IV
20
20
13
-60
Infr
aten
tori
al
Nau
sea
(ret
ch)
Emes
is (v
omit
only
) <2
4hr
(em
esis
), >2
4hr
(em
esis
), 48
hr
Fabl
ing
etal
(20
00)
(29)
U
nite
d St
ates
O
ndan
setr
on
4mg
IV
20
20
18-7
5 Su
prat
ento
rial
Nau
sea
Emes
is (v
omit
or re
tch)
0,
lhr
, 4hr
, 8h
r, 12
hr,
24hr
, 48h
r
Kat
hirv
el e
t al (
2001
) (3
0)
Indi
a O
ndan
setr
on
4mg
IV
74
78
15-7
0 Su
prat
ento
rial
Infr
aten
tori
al
Nau
sea
(with
out v
omit)
Em
esis
(vom
it or
retc
h,
+/- n
ause
a)
6hr
(em
esis
), 24
hr
Fabl
ing
et a
l (20
02)
(31)
U
nite
d St
ates
O
ndan
setr
on
8mg
IV
23
23
18-7
5 In
frat
ento
rial
N
ause
a Em
esis
(vom
it or
retc
h)
0, 3
0min
, lh
r,
4hr,
8hr,
12hr
, 24
hr, 4
8hr
Wan
g et
al (
2002
) (1
3)
Chi
na
Gra
nise
tron
3m
g IV
35
35
13
-68
Supr
aten
toria
l N
ause
a E
mes
is (v
omit
or re
tch)
72
hr
El-S
hoba
ki e
t al (
2003
) (3
2)
Egyp
t G
rani
setr
on
20ng
/kg
IV
20
20
20-7
0 In
frat
ento
rial
N
ause
a Em
esis
(vom
it or
retc
h)
0, 3
0min
, lh
r,
4hr,
8hr
, 12h
r, 24
hr, 4
8hr
Mad
enog
lu e
t al (
2003
) (3
3)
Turk
ey
Trop
isetr
on
2mg
IV
30
30
18-7
6 Su
prat
ento
rial
Nau
sea
Emes
is (v
omit
or re
tch)
24
hr
FIG
UR
E 1.
1 Fo
rest
plo
t sho
win
g th
e 24
hou
r cu
mul
ativ
e in
cide
nce
of e
mes
is.
Rev
iew
: 5H
T3 R
ecep
tor
Ant
agon
ists
For
the
Pre
vent
ion
of
Pos
tope
rativ
e N
ause
a an
d V
omiti
ng F
ollo
win
g C
rani
otom
y C
ompa
rison
: 01
Cum
ulat
ive
Pos
tope
rativ
e E
mes
is
Out
com
e:
01 T
ime=
24hr
Stu
dy
or s
ub-c
ateg
ory
Trea
tmen
t n/
N
Con
trol
n/N
R
R (
rand
om)
95%
CI
Wei
ght
%
RR
(ra
ndom
) 95
% C
I
Sin
ha (
28)
Fabl
ing
(29)
K
athi
rvel
(30
) Fa
blin
g (3
1)
El S
hoba
ki (
32)
Mad
enog
lu (
33)
2/20
8/
20
18
/74
6/2
3 4
/20
8/3
0
Tota
l (9
5% C
I) 18
7 To
tal
even
ts:
46 (
Trea
tmen
t),
98 (
Con
trol)
Test
for
het
erog
enei
ty:
Chi
2 = 3
.88,
df =
5 (
P =
0.57
), lz =
0%
Te
st f
or o
vera
ll ef
fect
: Z
= 4.
78 (
P <
0.00
001)
10/2
0 11
/20
34
/78
14
/23
11/2
0 1
8/3
0
191
4.2
3 1
8.2
7 3
6.1
1 1
4.0
1 8
.79
18
.59
100.00
20
73
56
43
36
44
[0.0
5,
[0.3
7,
[0.3
5,
[0.2
0,
[0.1
4,
[0.2
3,
0.8
0]
1.4
2]
0.9
0]
0.9
2]
0.9
5]
0.86]
0.5
0 [0
.38
, 0
.66
]
0.01
0.
1 1
10
100
Favo
urs
trea
tmen
t Fa
vour
s co
ntro
l
Figu
re 1
.1: T
rials
are
in o
rder
of p
ublic
atio
n ye
ar. T
he ri
sk f
or 2
4 ho
ur p
ost-o
pera
tive
emes
is in
the
treat
men
t and
con
trol g
roup
s fo
r ea
ch s
tudy
are
foun
d in
the
first
two
colu
mns
. (n=
num
ber
of p
eopl
e ex
perie
ncin
g th
e ev
ent,
N=t
otal
of p
eopl
e in
the
grou
p). T
he b
lack
sq
uare
s an
d bl
ack
lines
cor
resp
ond
to th
e re
lativ
e ris
k an
d 95
% c
onfid
ence
inte
rval
(C
I) o
f the
indi
vidu
al s
tudi
es (
corr
espo
ndin
g to
the
num
bers
in th
e fin
al c
olum
n). T
he s
ize
of e
ach
blac
k sq
uare
repr
esen
ts th
e w
eigh
t tha
t the
tria
l con
tribu
tes
to th
e m
eta-
anal
ysis
(c
orre
spon
ding
to th
e pe
rcen
tage
wei
ght i
n th
e ne
xt c
olum
n). T
he b
lack
dia
mon
d sh
ows
the
com
bine
d re
lativ
e ris
k an
d 95
% C
I. Th
e co
mbi
ned
rela
tive
risk
and
95%
CI a
re a
lso
repo
rted
in th
e bo
ttom
row
of t
he f
inal
col
umn
(17)
.
to
-o
FIG
UR
E 1.
2 Fo
rest
plo
t sho
win
g 48
+ ho
ur c
umul
ativ
e in
cide
nce
of e
mes
is
Rev
iew
: 5H
T3 R
ecep
tor
Ant
agon
ists
For
the
Pre
vent
ion
of
Pos
tope
rativ
e N
ause
a an
d V
omiti
ng F
ollo
win
g C
rani
otom
y C
ompa
rison
: 01
Cum
ulat
ive
Pos
tope
rativ
e E
mes
is
Out
com
e:
02 T
ime=
48+h
r
Stu
dy
Trea
tmen
t C
ontro
l R
R (
rand
om)
Wei
ght
RR
(ra
ndom
) or
sub
-cat
egor
y n/
N
n/N
95
% C
I %
95
% C
I
Sin
ha (
28)
3/2
0 1
3/2
0 10
10
0
23
[0
08
, 0
69]
Fabl
ing
(29)
9
/20
11
/20
—1
21
21
0 82
[0
4
4,
1 53
] Fa
blin
g (3
1)
8/2
3 1
5/2
3 23
78
0
53
[0
28
, 1
01]
Wan
g (1
3)
6/3
5 1
7/3
5 —
a—
16
75
0
35
[0
16,
0 79
] E
l Sho
baki
(32
) 8
/20
14
/20
25
16
0 57
[0
3
1,
1 05
]
Tota
l (9
5% C
I) 11
8 11
8 4
100
00
0 52
[0
3
6,
0 75
] To
tal
even
ts:
34 (
Trea
tmen
t),
70 (
Con
trol)
Test
for
het
erog
enei
ty:
Chi
2 = 5
.41,
df =
4 (
P =
0.25
), I2 =
26.
1%
Test
for
ove
rall
effe
ct:
Z =
3.48
(P
= 0.
0005
)
0.01
0.
1 1
10
100
Favo
urs
trea
tmen
t Fa
vour
s co
ntro
l
Figu
re 1
.2: T
rials
are
in o
rder
of p
ublic
atio
n ye
ar. T
he ri
sk f
or 4
8+ h
our e
mes
is in
the
treat
men
t and
con
trol g
roup
s in
eac
h st
udy
are
foun
d in
the
first
two
colu
mns
. (n=
num
ber
of p
eopl
e ex
perie
ncin
g th
e ev
ent,
N=t
otal
of p
eopl
e in
the
grou
p). T
he b
lack
squ
ares
and
bl
ack
lines
cor
resp
ond
to th
e re
lativ
e ris
k an
d 95
% c
onfid
ence
inte
rval
(C
I) o
f the
indi
vidu
al s
tudi
es (
corr
espo
ndin
g to
the
num
bers
in
the
final
col
umn)
. The
siz
e of
eac
h bl
ack
squa
re re
pres
ents
the
wei
ght t
hat t
he tr
ial c
ontri
bute
s to
the
met
a-an
alys
is (
corr
espo
ndin
g to
th
e pe
rcen
tage
wei
ght i
n th
e ne
xt c
olum
n). T
he b
lack
dia
mon
d sh
ows
the
com
bine
d re
lativ
e ris
k an
d 95
% C
I. Th
e co
mbi
ned
rela
tive
risk
and
95%
CI a
re a
lso
repo
rted
in th
e bo
ttom
row
of t
he fi
nal c
olum
n (1
7).
to
oo
FIG
UR
E 1.
3 Fo
rest
plo
t sho
win
g 24
hou
r cum
ulat
ive
inci
denc
e of
nau
sea
Rev
iew
: 5H
T3 R
ecep
tor
Ant
agon
ists
For
the
Pre
vent
ion
of
Pos
tope
rativ
e N
ause
a an
d V
omiti
ng F
ollo
win
g C
rani
otom
y C
ompa
rison
: 02
Cum
ulat
ive
Pos
tope
rativ
e N
ause
a O
utco
me:
03
Tim
e=24
hr
Stu
dy
or s
ub-c
ateg
ory
Trea
tmen
t n/
N
Con
trol
n/N
R
R (
rand
om)
95%
CI
Wei
ght
%
RR
(ra
ndom
) 95
% C
I
Fabl
ing
(29)
K
athi
rvel
(30
) Fa
blin
g (3
1)
El
Sho
baki
(32
) M
aden
oglu
(33
)
7/2
0 1
0/7
4 1
7/2
3 1
1/2
0 9
/30
14
/20
4/7
8 2
0/2
3 1
7/2
0 1
4/3
0
—•—
HB-
16
.53
7.
67
33 .
75
25
. 68
1
6.3
8
0.5
0 [0
.26
, 0
.97
] 2
.64
[0.8
6,
8.0
4]
0.8
5 [0
.64
, 1
.14
] 0
.65
[0.4
2,
1.0
0]
0.6
4 [0
.33
, 1
.25
]
Tota
l (9
5% C
I) 16
7 17
1 <•
• 1
00
.00
0.7
6 [0
.54
, 1
.06
] To
tal
even
ts:
54 (
Trea
tmen
t),
69 (
Con
trol)
Test
for
het
erog
enei
ty:
Chi
2 = 7
.71,
df =
4 (
P =
0.10
), I2 =
48.
1%
Test
for
ove
rall
effe
ct:
Z =
1.61
(P
= 0.
11)
0.01
0.
1 1
10
100
Favo
urs
trea
tmen
t Fa
vour
s co
ntro
l
Figu
re 1
.3: T
rials
are
in o
rder
of p
ublic
atio
n ye
ar. T
he ri
sk f
or 2
4 ho
ur n
ause
a in
the
treat
men
t and
con
trol g
roup
s fo
r eac
h st
udy
are
foun
d in
the
first
two
colu
mns
. (n=
num
ber
of p
eopl
e ex
perie
ncin
g th
e ev
ent,
N=t
otal
of p
eopl
e in
the
grou
p). T
he b
lack
squ
ares
and
bl
ack
lines
cor
resp
ond
to th
e re
lativ
e ris
k an
d 95
% c
onfi
denc
e in
terv
al (
CI)
of t
he in
divi
dual
stu
dies
(co
rres
pond
ing
to th
e nu
mbe
rs in
th
e fin
al c
olum
n). T
he s
ize
of e
ach
blac
k sq
uare
repr
esen
ts th
e w
eigh
t tha
t the
tria
l con
tribu
tes
to th
e m
eta-
anal
ysis
(co
rres
pond
ing
to
the
perc
enta
ge w
eigh
t in
the
next
col
umn)
. The
bla
ck d
iam
ond
show
s th
e co
mbi
ned
rela
tive
risk
and
95%
CI.
The
com
bine
d re
lativ
e ris
k an
d 95
% C
I are
als
o re
porte
d in
the
botto
m r
ow o
f the
fin
al c
olum
n (1
7).
to
FIG
UR
E 1.
4 Fo
rest
plo
t sho
win
g 48
+ ho
ur c
umul
ativ
e in
cide
nce
of n
ause
a
Rev
iew
: 5H
T3 R
ecep
tor
Ant
agon
ists
For
the
Pre
vent
ion
of
Pos
tope
rativ
e N
ause
a an
d V
omiti
ng F
ollo
win
g C
rani
otom
y C
ompa
rison
: 02
Cum
ulat
ive
Pos
tope
rativ
e N
ause
a O
utco
me:
04
Tim
e=48
+hr
Stu
dy
Trea
tmen
t C
ontro
l R
R (
rand
om)
Wei
ght
RR
(ra
ndom
) or
sub
-cat
egor
y n/
N
n/N
95
% C
I %
95
% C
I
Sin
ha (
28)
Fabl
ing
(29)
Fa
blin
g (3
1)
Wan
g (1
3)
El
Sho
baki
(32
)
4/2
0 8/
20
18
/23
3/3
5 16
/20
10
/20
14
/20
20
/23
3/3
5 1
7/2
0
Tota
l (9
5% C
I) 11
8 To
tal
even
ts:
49 (
Trea
tmen
t),
64 (
Con
trol)
Test
for
het
erog
enei
ty:
Chi
2 = 6
.10,
df =
4 (
P =
0.19
), I2 =
34.
4%
Test
for
ove
rall
effe
ct:
Z =
1.52
(P
= 0.
13)
118
6.6
5 1
4.7
8 3
8.8
9 2
.91
3 6
.78
100.00
0.4
0 0
.57
0.9
0 1.
00
[0.1
5,
[0.3
1,
[0.6
9,
[0.22,
0.9
4 [0
.71
,
1.0
7]
1.0
5]
1.18
] 4
. 62
] 1
.25
]
0.81
[0.62,
1.06]
0.01
0.
1 1
10
100
Favo
urs
trea
tmen
t Fa
vour
s co
ntro
l
Figu
res
1.4:
Tria
ls a
re in
ord
er o
f pub
licat
ion
year
. The
risk
for
48+
hou
r nau
sea
in th
e tre
atm
ent a
nd c
ontro
l gro
ups
for e
ach
stud
y ar
e fo
und
in th
e fir
st tw
o co
lum
ns. (
n=nu
mbe
r of
peo
ple
expe
rienc
ing
the
even
t, N
=tot
al o
f peo
ple
in th
e gr
oup)
. The
bla
ck s
quar
es a
nd
blac
k lin
es c
orre
spon
d to
the
rela
tive
risk
and
95%
con
fiden
ce in
terv
al (
CI)
of t
he in
divi
dual
stu
dies
(co
rres
pond
ing
to th
e nu
mbe
rs in
th
e fin
al c
olum
n). T
he s
ize
of e
ach
blac
k sq
uare
repr
esen
ts th
e w
eigh
t tha
t the
tria
l con
tribu
tes
to th
e m
eta-
anal
ysis
(co
rres
pond
ing
to
the
perc
enta
ge w
eigh
t in
the
next
col
umn)
. The
bla
ck d
iam
ond
show
s th
e co
mbi
ned
rela
tive
risk
and
95%
CI.
The
com
bine
d re
lativ
e ris
k an
d 95
% C
I are
als
o re
porte
d in
the
botto
m r
ow o
f the
fin
al c
olum
n (1
7).
FIG
UR
E 1.
5 Fu
nnel
Plo
t to
Exam
ine
Publ
icat
ion
Bia
s
Rev
iew
: 5H
T3 R
ecep
tor
Ant
agon
ists
For
the
Pre
vent
ion
of P
osto
pera
tive
Nau
sea
and
Vom
iting
Fol
low
ing
Cra
niot
c C
ompa
riso
n02
Cum
ulat
ive
Pos
tope
rativ
e E
mes
is
Out
com
e:
01 T
ime=
24hr
-i-O
.O
SE(lo
gRR)
--0
.2
--0.
4
--0
.6
--0.
8
0.01
«
H
0.1
10
100
RR (
fixed
}
Figu
re 5
: The
fix
ed e
ffec
t rel
ativ
e ris
k of
eac
h st
udy
is p
lotte
d on
the
x-ax
is a
nd th
e st
anda
rd e
rror
of t
he v
aria
nce
of th
e lo
g R
R o
n th
e y-
axis
(16
). A
n as
ymm
etric
al a
ppea
ranc
e in
dica
tes
pote
ntia
l bia
s (2
0).
u>
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 version of this paper has been accepted for publication as:
Neufeld, S.M. & Newburn-Cook, C.V. The Efficacy of 5-HT3 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 I2 statistic, which
describes the percentage of total variation across studies due to heterogeneity as opposed
to chance (11). The I2 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 (I2=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
TA
BL
E 2.
2 C
hara
cter
istic
s of
the
Stud
ies
Incl
uded
in th
e Sy
stem
atic
Rev
iew
and
Met
a-A
naly
sis
Age
Su
rger
y O
utco
me
Tim
es
Stud
y (D
ate)
C
ount
ry
Ant
iem
etic
n
Ran
ge
Mea
sure
men
t In
cide
nce
T C
(y
ears
) R
epor
ted
Furs
t eta
l. (1
996)
U
nite
d O
ndan
setro
n 28
32
2-
18
Infra
tent
oria
l Em
esis
= ex
pulsi
on o
f gas
tric
8 an
d 24
St
ates
. 1
5mg/
kg at
an
d co
nten
ts ov
er 1
-2 m
inut
es.
hour
s be
fore
su
prat
ento
rial
Retc
hing
not
con
sider
ed a
n su
rgic
al
sche
dule
d ev
ent.
inci
sion
and
cran
ioto
my
for
at su
rgic
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n tu
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r, cl
osur
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Chia
ri m
alfo
rmat
ions
, or
seiz
ures
.
Subr
aman
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l. In
dia
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tron
51
24
2-20
In
frate
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ial
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is= v
omiti
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etch
ing
6 an
d 24
(2
007)
. 1
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an
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1 m
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d gr
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r at
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for
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note
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old
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l clo
sure
br
ain
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our.
child
ren
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repo
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if an
d 6
hour
s oc
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abse
nce
of
post-
vom
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erat
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reat
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ate)
R
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6)
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5
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and
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V
arie
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disc
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neur
osur
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. 5/
5
U>
FIGURE 2.1 Search Results
FIG
UR
E 2.
2 Fo
rest
Plo
t of 2
4 H
our
Emes
is
Rev
iew
: 5H
T3 R
ecep
tor
Ant
agon
ists
for
the
Pre
vent
ion
of P
osto
pera
tive
Em
esis
in
Chi
ldre
n Fo
llow
ing
Cra
niot
omy
Com
paris
on:
01 T
reat
men
t vs
. C
ontr
ol a
t 24
Hou
rs
Out
com
e:
01 P
osto
pera
tive
Em
esis
in
Chi
ldre
n
Stu
dy
or s
ub-c
ateg
ory
Trea
tmen
t n/
N
Con
trol
n/N
R
R (
rand
om)
95%
CI
Wei
ght
%
RR
(ra
ndom
) 95
% C
I
Furs
t, 19
96
Sub
ram
ania
m 2
007
16
/28
9/5
1 2
1/3
2 8
/24
• 7
4.8
7 2
5.1
3 0
.87
[0.5
8,
1.3
1]
0.5
3 [0
.23
, 1
.20
]
Tota
l (9
5% C
I) 79
56
1
00
.00
0.7
7 [0
.50
, 1
.19
] To
tal
even
ts:
25 (
Trea
tmen
t),
29 (
Con
trol)
Test
for
het
erog
enei
ty:
Chi
2 = 1
.21,
df=
1 (
P =
0.27
), I2 =
17.
7%
Test
for
ove
rall
effe
ct:
Z =
1.18
(P
= 0.
24)
0.1
0.2
0.5
1 2
5 10
Fa
vour
s tr
eatm
ent
Favo
urs
cont
rol
Figu
re 2
.2: T
rials
are
in o
rder
of p
ublic
atio
n ye
ar. T
he ri
sk o
f em
esis
in th
e tre
atm
ent a
nd c
ontro
l gro
ups
for e
ach
stud
y ar
e fo
und
in
the
first
two
colu
mns
. (n=
num
ber o
f peo
ple
expe
rienc
ing
the
even
t, N
=tot
al o
f peo
ple
in th
e gr
oup)
. The
bla
ck s
quar
es a
nd b
lack
line
s co
rres
pond
to th
e re
lativ
e ris
k an
d 95
% c
onfid
ence
inte
rval
(C
I) o
f the
indi
vidu
al s
tudi
es (
corr
espo
ndin
g to
the
num
bers
in th
e fin
al
colu
mn)
. The
siz
e of
eac
h bl
ack
squa
re re
pres
ents
the
wei
ght t
hat t
he tr
ial c
ontri
bute
s to
the
met
a-an
alys
is (
corr
espo
ndin
g to
the
perc
enta
ge w
eigh
t in
the
next
col
umn)
. The
bla
ck d
iam
ond
show
s th
e co
mbi
ned
rela
tive
risk
and
95%
CI.
The
com
bine
d re
lativ
e ris
k an
d 95
% C
I are
als
o re
porte
d in
the
botto
m r
ow o
f the
fin
al c
olum
n.
Ul
FIG
UR
E 2.
3 Fo
rest
Plo
t of R
escu
e A
ntie
met
ic U
se
Rev
iew
: 5H
T3 R
ecep
tor
Ant
agon
ists
for
the
Pre
vent
ion
of P
osto
pera
tive
Em
esis
in
Chi
ldre
n Fo
llow
ing
Cra
niot
omy
Com
paris
on:
01 T
reat
men
t vs
. C
ontr
ol a
t 24
Hou
rs
Out
com
e:
02 R
escu
e A
ntie
met
ic U
se
Stu
dy
or s
ub-c
ateg
ory
Trea
tmen
t n/
N
Con
trol
n/N
R
R (
rand
om)
95%
CI
Wei
ght
%
RR
(ra
ndom
) 95
% C
I
Furs
t. 19
96
Sub
ram
ania
m 2
007
6/2
8 5
/51
10
/32
3/2
4 H
- u-7
0.2
7 2
9.7
3 0
.69
[0.2
9,
1.6
5]
0.7
8 [0
.20
, 3
.02
]
Tota
l (9
5% C
I) 79
56
1
00
.00
0.7
1 [0
.34
, 1
.49
] To
tal
even
ts:
11 (
Trea
tmen
t),
13 (
Con
trol)
Test
for
het
erog
enei
ty:
Chi
2 = 0
.03,
df =
1 (
P =
0.87
), l2
= 0%
Te
st f
or o
vera
ll ef
fect
: Z
= 0.
90 (
P =
0.37
)
0.1
0.2
0.5
1 2
5 10
Fa
vour
s tr
eatm
ent
Favo
urs
cont
rol
Figu
re 2
.3: T
rials
are
in o
rder
of p
ublic
atio
n ye
ar. T
he ri
sk f
or re
scue
ant
i-em
etic
use
in th
e tre
atm
ent a
nd c
ontro
l gro
ups
for e
ach
stud
y ar
e fo
und
in th
e fir
st tw
o co
lum
ns. (
n=nu
mbe
r of p
eopl
e ex
perie
ncin
g th
e ev
ent,
N=t
otal
of p
eopl
e in
the
grou
p). T
he b
lack
sq
uare
s an
d bl
ack
lines
cor
resp
ond
to th
e re
lativ
e ris
k an
d 95
% c
onfid
ence
inte
rval
(C
I) o
f the
indi
vidu
al s
tudi
es (
corr
espo
ndin
g to
the
num
bers
in th
e fin
al c
olum
n). T
he s
ize
of e
ach
blac
k sq
uare
repr
esen
ts th
e w
eigh
t tha
t the
tria
l con
tribu
tes
to th
e m
eta-
anal
ysis
(c
orre
spon
ding
to th
e pe
rcen
tage
wei
ght i
n th
e ne
xt c
olum
n). T
he b
lack
dia
mon
d sh
ows
the
com
bine
d re
lativ
e ris
k an
d 95
% C
I. Th
e co
mbi
ned
rela
tive
risk
and
95%
CI a
re a
lso
repo
rted
in th
e bo
ttom
row
of t
he f
inal
col
umn.
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
TA
BL
E 3.
1 D
escr
iptio
n of
Stu
dies
Ref
eren
ce
Loca
tion
of
Stud
y Ta
rget
Pop
ulat
ion
Stud
y D
esig
n Sa
mpl
e
Size
Le
ngth
of
Stud
y In
clus
ion
Crit
eria
Ex
clus
ion
Crit
eria
K
ram
er e
t al
. (19
94)
Uni
ted
Stat
es
Adu
lt an
d pe
diat
ric
intra
cran
ial
mon
itorin
g
Ret
rosp
ectiv
e st
udy
of
cons
ecut
ive
patie
nts.
56
3 ye
ars
Adu
lts a
nd c
hild
ren
afte
r ins
ertio
n of
in
tracr
ania
l el
ectro
des
(incl
udin
g de
pth
elec
trode
s, su
bdur
al
grid
s, su
bdur
al s
trips
or
bot
h)
Non
e sp
ecifi
ed
Qui
ney
et
al. (
1995
) U
nite
d K
ingd
om
Adu
lt an
d pe
diat
ric
cran
ioto
my
Pros
pect
ive
stud
y of
co
nsec
utiv
e pa
tient
s.
52
3 m
onth
s A
ll pa
tient
s (a
dults
an
d ch
ildre
n)
unde
rgoi
ng e
lect
ive
cran
ioto
my
who
wer
e fu
lly c
onsc
ious
, co
oper
ativ
e, a
nd
orie
nted
at 3
0 m
inut
es
post
oper
ativ
ely.
Non
e sp
ecifi
ed.
Fabl
ing
et
al. (
1997
) U
nite
d St
ates
A
dult
Cra
niot
omy
Ret
rosp
ectiv
e st
udy
of
cons
ecut
ive
patie
nts.
199
18 M
onth
s A
ge 1
8-70
yea
rs
Elec
tive
Cra
niot
omy
ASA
Sta
tus
1-4
Bur
r hol
es
Man
nine
n et
al. (
1999
) C
anad
a A
dult
neur
osur
gery
Pr
ospe
ctiv
e st
udy
of
cons
ecut
ive
patie
nts.
431
4 m
onth
s A
ge_>
18
year
s N
euro
surg
ery
Func
tiona
l su
rger
y C
hron
ic p
ain
surg
ery
ON
Tabl
e 3.
1 (C
ontin
ued)
Man
nine
n an
d Ta
n (2
002)
Can
ada
Adu
lt cr
anio
tom
y fo
r tum
our
Pros
pect
ive
stud
y of
co
nsec
utiv
e pa
tient
s.
187
(tota
l) 1
year
C
rani
otom
y fo
r tu
mou
r re
sect
ion
In fi
nal r
isk
fact
or a
naly
sis,
proc
edur
es >
6
hour
s w
ere
excl
uded
. Ir
efin
et a
l. (2
003)
U
nite
d St
ates
A
dult
cran
ioto
my
for t
umou
r an
d sp
inal
sur
gery
> 3
ho
urs.
Pros
pect
ive
stud
y of
co
nsec
utiv
e pa
tient
s.
128
Not
sp
ecifi
ed
Elec
tive
cran
ioto
my
for t
umou
r or
spin
al
surg
ery
>3ho
urs
dura
tion.
Bra
in b
iops
y
Lesl
ie e
t al.
(200
3)
Aus
tralia
A
dult
Neu
rosu
rger
y Pr
ospe
ctiv
e st
udy
of
cons
ecut
ive
patie
nts.
200
Not
sp
ecifi
ed
Ag
e8
year
s El
ectiv
e ne
uros
urge
ry
unde
r ge
nera
l an
esth
etic
A
dmitt
ed a
t lea
st 1
po
stop
erat
ive
nigh
t
Emer
genc
y su
rger
y Li
mite
d En
glis
h N
ot e
xpec
ted
to c
oope
rate
Ex
pect
ed
intu
batio
n A
SA IV
or V
K
urita
et a
l. (2
004)
Ja
pan
Adu
lt cr
anio
tom
y fo
r tum
our
Ret
rosp
ectiv
e st
udy
of
cons
ecut
ive
patie
nts.
178
Not
sp
ecifi
ed
Age
>18
yea
rs
Cra
niot
omy
for
tum
our.
Non
e sp
ecifi
ed
Stie
glitz
et
al. (
2005
) G
erm
any
Adu
lt ve
stib
ular
sc
hwan
nom
a su
rger
y
Ret
rosp
ectiv
e st
udy
of
cons
ecut
ive
patie
nts
97
2 ye
ars
Adu
lts a
ged
18-7
3 ye
ars
Ves
tibul
ar
Schw
anno
ma
surg
ery
Neu
rofib
ro-
mat
osis
Typ
e 2
Rec
urre
nt
tum
our
ON
O
N
Tabl
e 3.
1 (C
ontin
ued)
Flyn
n an
d N
umer
gut
(200
6)
Uni
ted
Stat
es
Adu
lt En
dona
sal
trans
sphe
noid
al
surg
ery
Ret
rosp
ectiv
e st
udy
of
cons
ecut
ive
patie
nts.
877
6 ye
ars
5mon
ths
Sam
e su
rgeo
n En
dona
sal
trans
sphe
noid
al
tech
niqu
e
Non
e sp
ecifi
ed
Men
g an
d Q
uinl
an
(200
6)
Uni
ted
Stat
es
Adu
lt re
trom
asto
id
cran
iect
omy
with
M
icro
vasc
ular
de
com
pres
sion
of
cran
ial n
erve
s
Ret
rosp
ectiv
e st
udy
of
cons
ecut
ive
patie
nts.
185
5 ye
ars
Age
18-
65 y
ears
R
etro
mas
toid
cr
anie
ctom
y w
ith
mic
rova
scul
ar
deco
mpr
essi
on o
f cr
ania
l ner
ves
ASA
Sta
tus
1-3
Mor
e th
an o
ne
cran
ioto
my
proc
edur
e
Men
g,
Lasi
ca e
t al.
(200
6)
Uni
ted
Stat
es
Min
imal
ly in
vasi
ve
cran
ial s
urge
ry
Ret
rosp
ectiv
e st
udy
of
cons
ecut
ive
patie
nts.
258
5 ye
ars
All
patie
nts
unde
rgoi
ng m
inim
ally
in
vasi
ve c
rani
al
surg
ery
(tran
s-na
sal
proc
edur
es f
or
hypo
phys
ectio
n an
d sk
ull b
ase
tum
our
rese
ctio
n).
Non
e sp
ecifi
ed.
Won
g et
al.
(200
6)
Chi
na
Adu
lt ne
uros
urge
ry
with
tota
l in
trave
nous
an
aest
hesi
a
Pros
pect
ive
stud
y of
co
nsec
utiv
e pa
tient
s.
145
1 ye
ar
Adu
lts
Elec
tive
neur
osur
gery
To
tal i
ntra
veno
us
anae
sthe
sia
Non
e sp
ecifi
ed.
ASA
Sta
tus:
Am
eric
an S
ocie
ty o
f Ane
sthe
siol
ogis
ts' P
hysi
cal S
tatu
s C
lass
ifica
tion
Syst
em.
ON
—
]
TA
BL
E 3.
2
Mea
sure
men
t of O
utco
me
Var
iabl
es
Ref
eren
ce
Tim
e Pe
riod
Out
com
e an
d re
porte
d m
easu
rem
ent
Leve
l of A
naly
sis
Kra
mer
et a
l. (1
994)
D
urat
ion
of e
lect
rode
m
onito
ring
afte
r 24
hour
s po
stop
erat
ivel
y.
Nau
sea:
Nau
sea
char
ted
in m
edic
al r
ecor
ds.
Vom
iting
: Vom
iting
cha
rted
in m
edic
al r
ecor
ds
and
com
bine
d w
ith n
ause
a in
the
anal
ysis
.
Biv
aria
te.
Qui
ney
et a
l. (1
995)
Fi
rst 2
4 ho
urs
afte
r su
rger
y.
PON
V: P
atie
nt r
atin
g ev
ery
two
hour
s. Th
ree
poin
t sc
orin
g sy
stem
: l=N
o na
usea
2=
Mod
erat
e na
usea
3=
Seve
re n
ause
a or
vom
iting
. Th
e m
axim
um s
core
ove
r tw
o co
nsec
utiv
e tim
e pe
riods
was
re
cord
ed.
Ord
inal
Fabl
ing
et a
l. (1
997)
Fi
rst 4
8 ho
urs
post
oper
ativ
ely.
N
ause
a: A
n ep
isod
e of
nau
sea
if ch
arte
d in
the
nurs
ing
note
s. Em
esis
: An
epis
ode
of re
tchi
ng if
cha
rted
in th
e nu
rsin
g no
tes
or v
omiti
ng if
cha
rted
in th
e flu
id b
alan
ce r
ecor
ds.
Res
cue
Ant
iem
etic
s: A
dmin
istra
tion
of a
n an
tiem
etic
if c
harte
d on
the
med
icat
ion
reco
rds.
Biv
aria
te
Man
nine
n et
al.
(199
9)
Firs
t 4 h
ours
po
stop
erat
ivel
y N
ause
a: D
ocum
ente
d on
a s
tand
ardi
zed
form
. V
omiti
ng: D
ocum
ente
d on
a s
tand
ardi
zed
form
. B
ivar
iate
Man
nine
n an
d Ta
n (2
002)
Fi
rst 4
hou
rs, 4
-24
hour
s an
d >2
4 ho
urs
post
oper
ativ
ely.
Nau
sea:
Fre
quen
cy o
f nau
sea
from
obs
erva
tion
and
docu
men
tatio
n fr
om c
hart
revi
ew.
Vom
iting
: Fre
quen
cy o
f vom
iting
fro
m o
bser
vatio
n an
d do
cum
enta
tion
from
cha
rt re
view
. R
escu
e A
ntie
met
ics:
Fre
quen
cy o
f adm
inis
tratio
n of
an
tiem
etic
s.
Biv
aria
te
ON
oo
Tabl
e 3.
1 (C
ontin
ued)
Ir
efin
et a
l. (2
003)
R
epor
t res
ults
onl
y th
e fir
st 2
hou
rs
post
oper
ativ
ely.
Nau
sea:
Fre
quen
cy o
f nau
sea
in 1
5 m
inut
e in
terv
als.
Emes
is: N
ot c
lear
if f
requ
ency
of e
mes
is is
mea
sure
d or
w
heth
er o
r not
it is
con
side
red
toge
ther
with
nau
sea
in th
e an
alys
is.
Biv
aria
te
Lesl
ie e
t al.
(200
3)
Post
oper
ativ
e da
y on
e.
Nau
sea:
Pat
ient
repo
rt of
nau
sea
in q
uest
ionn
aire
. V
omiti
ng: P
atie
nt re
port
of v
omiti
ng in
que
stio
nnai
re.
Biv
aria
te
Kur
ita e
t al.
(200
4)
Firs
t 24
hour
s po
stop
erat
ivel
y PO
NV
: Nau
sea
and
vom
iting
com
bine
d in
to o
ne v
aria
ble.
B
ivar
iate
Stie
glitz
et a
l. (2
005)
En
tire
post
oper
ativ
e ho
spita
lizat
ion
Nau
sea:
Sub
ject
ive
naus
ea (n
ot s
peci
fied
how
mea
sure
d).
Vom
iting
: Vom
iting
(not
spe
cifie
d an
d in
clud
ed/in
terc
hang
ed
with
nau
sea)
. R
escu
e A
ntie
met
ics:
Pos
tope
rativ
e am
ount
of u
ptak
e of
m
edic
atio
n (n
ot s
peci
fied
how
mea
sure
d).
Con
tinuo
us
(leng
th o
f tim
e sy
mpt
oms
wer
e ex
perie
nced
)
Flyn
n an
d N
emer
gut (
2006
) U
ntil
disc
harg
ed f
rom
th
e po
stop
erat
ive
reco
very
uni
t adm
issi
on
(PA
CU
).
Vom
iting
: For
cefu
l exp
ulsi
on o
f gas
tric
cont
ents
in th
e op
erat
ing
room
or P
AC
U.
Res
cue
Ant
iem
etic
s: A
dmin
istra
tion
of a
n an
tiem
etic
follo
win
g em
erge
nce
from
ana
esth
esia
, afte
r vom
iting
or n
ause
a.
Biv
aria
te
Men
g an
d Q
uinl
an (
2006
) Fi
rst 2
4 ho
urs
post
oper
ativ
ely.
N
ause
a: C
onsi
dere
d pr
esen
t if n
oted
in n
ursi
ng r
ecor
ds.
Emes
is: R
etch
ing
or v
omitu
s no
ted
by n
ursi
ng s
taff
. R
escu
e A
ntie
met
ics:
Cha
rted
in th
e m
edic
al a
dmin
istra
tion
reco
rds.
Biv
aria
te
Men
g, L
asic
a et
al
. (20
06)
Firs
t 12
and
24
hour
s af
ter s
urge
ry.
PON
V/R
escu
e an
tiem
etic
s: R
evie
w o
f rec
over
y ro
om r
ecor
ds,
anes
thes
ia re
cord
s, nu
rsin
g re
cord
s an
d m
edic
atio
n ad
min
istra
tion
reco
rds.
Biv
aria
te.
Won
g et
al.
(200
6)
Firs
t hou
r afte
r sur
gery
or
whe
n di
scha
rged
fr
om th
e po
stan
aest
hetic
re
cove
ry ro
om,
whi
chev
er w
as s
oone
r.
PON
V: P
osto
pera
tive
naus
ea a
nd/o
r vom
iting
on
chec
ks e
very
15
min
utes
. B
ivar
iate
.
TA
BL
E 3.
3
Ris
k fa
ctor
s ide
ntifi
ed th
ough
uni
varia
te a
naly
sis
Ref
eren
ce
Kra
mer
eta
l. (1
994)
PO
NV
Inci
denc
e 50
%
Ris
k fa
ctor
s (p
<.05
) N
one.
N
on-s
igni
fican
t fac
tors
C
hild
ren
vs. a
dults
, typ
e of
reco
rdin
g te
chni
que
used
. Q
uine
y et
al. (
1995
) PO
NV
Inci
denc
e N
one:
29%
, Mod
erat
e na
usea
: 35%
, Sev
ere
naus
ea o
r vom
iting
: 37
%
Ris
k fa
ctor
s (p
<.05
) N
one
iden
tifie
d N
on-s
igni
fican
t fac
tors
Si
te o
f ope
ratio
n (te
mpo
ral,
parie
tal,
fron
tal,
or o
ccip
ital).
Fa
blin
g et
al.
(199
7)
Nau
sea In
cide
nce
50%
R
isk
fact
ors
(p<.
05)
Fem
ales
(61
%) v
s. m
ales
(37
% p
=.00
1)
Infr
aten
toria
l sur
gery
(65
%) v
s. su
prat
ento
rial s
urge
ry (4
3% p
=.03
8)
Non
-sig
nific
ant f
acto
rs
Posto
pera
tive o
pioi
d us
e, A
naes
thet
ic te
chni
que (
gene
ral v
s. aw
ake)
, and
Intra
oper
ativ
e an
tiem
etic
s Em
esis
Inci
denc
e 39
%
Ris
k fa
ctor
s (p
<.05
) Fe
mal
es (
46%
) vs.
mal
es (
31%
p=.
029)
N
on-s
igni
fican
t fac
tors
Su
rger
y si
te (i
nfra
tent
oria
l sur
gery
vs.
supr
aten
toria
l), P
osto
pera
tive
opio
id u
se, A
naes
thet
ic
tech
niqu
e (g
ener
al v
s. aw
ake)
, and
Int
raop
erat
ive
antie
met
ics
Res
cue
Ant
iem
etic
s In
cide
nce
61%
R
isk
fact
ors
(p<.
05)
Fem
ales
(69
%) v
s. m
ales
(51
% p
=.01
3)
Non
-sig
nific
ant f
acto
rs
Infr
aten
toria
l Sur
gery
, Pos
tope
rativ
e O
pioi
d us
e, A
naes
thet
ic te
chni
que
(gen
eral
vs.
awak
e),
Intra
oper
ativ
e an
tiem
etic
s
Tabl
e 3.
1 (C
ontin
ued)
Man
nine
n et
al.
(199
9)
PON
V In
cide
nce
38.7
%
Ris
k fa
ctor
s (p
<.05
) Sp
ine
(50%
) com
pare
d to
bra
in tu
mou
r (28
%),
vasc
ular
(38
%) a
nd o
ther
(34%
, p<.
05).
Non
-sig
nific
ant f
acto
rs
No
othe
r ris
k fa
ctor
s ex
amin
ed.
Man
nine
n an
d Ta
n (2
002)
O
vera
ll PO
NV
In
cide
nce
29%
R
isk
fact
ors (
p<.0
5)
Proc
edur
es >
6 ho
urs
(42%
) vs.
< 6
hour
s (2
2%, p
=.00
9),
Infr
aten
toria
l pro
cedu
res
(57%
) vs
. Sup
rate
ntor
ial
(21%
, p=.
001)
Pr
oced
ures
<6h
ours
(n=
107)
N
ause
a Ris
k fa
ctor
s (p<
.05)
A
wak
e an
aest
hesi
a (4
%) v
s. ge
nera
l ana
esth
esia
at 4
hou
rs (2
3% p
=.01
2)
Non
-sig
nific
ant f
acto
rs
Aw
ake
anae
sthe
sia
vs. g
ener
al a
naes
thes
ia a
t tim
e pe
riods
4-2
4 ho
urs
and
>24
hour
s. Em
esis
Ris
k fa
ctor
s (p<
.05)
A
wak
e an
aest
hesi
a at
4 h
ours
(0%
) vs.
gene
ral a
naes
thes
ia a
t 4 h
ours
(11%
, p=.
052)
. N
on-s
igni
fican
t fac
tors
A
wak
e an
aest
hesi
a vs
. gen
eral
ana
esth
esia
at t
ime
perio
ds 4
-24
hour
s an
d >2
4 ho
urs
Res
cue
Ant
iem
etic
s R
isk
fact
ors
(p<.
05)
Aw
ake
anae
sthe
sia
at 4
hou
rs (1
6%) v
s. ge
nera
l (40
%, p
val
ue n
ot r
epor
ted)
. N
on-s
igni
fican
t fac
tors
A
wak
e an
aest
hesi
a vs
. gen
eral
ana
esth
esia
at t
ime
perio
ds 4
-24
hour
s an
d >2
4 ho
urs
Iref
in e
t al.
(200
3)
Nau
sea In
cide
nce
59%
R
isk
fact
ors
(p<.
05)
Non
e N
on-s
igni
fican
t fac
tors
Lo
catio
n of
sur
gery
(inf
rate
ntor
ial v
s. su
prat
ento
rial v
s. sp
inal
) Le
slie
et a
l. (2
003)
PO
NV
Inci
denc
e 64
% d
ay 1
, 42%
day
2, 3
2% d
ay 3
, 25%
day
30,
27%
day
90.
R
isk
fact
ors
(p<.
05)
Non
e.
Non
-sig
nific
ant f
acto
rs
Cra
nial
vs.
spin
al s
urge
ry.
Tabl
e 3.
3 (C
ontin
ued)
Kur
ita e
t al.
(200
4)
PON
V In
cide
nce
49%
R
isk
fact
ors
(p<.
05)
Infr
aten
toria
l sur
gery
(75%
) vs.
supr
aten
toria
l sur
gery
(45%
, p=0
.001
) N
on-s
igni
fican
t fac
tors
G
ende
r, ag
e, w
eigh
t, he
ight
, siz
e of
bra
in tu
mou
r, an
aest
hetic
tech
niqu
e (in
hala
tion
vs
intra
veno
us w
ith n
itric
oxi
de),
intra
oper
ativ
e fe
ntan
yl d
ose,
and
intra
oper
ativ
e po
stur
e.
Stie
glitz
et a
l. (2
005)
N
ause
a Mea
n ±
SD (R
ange
) 2.
3 da
ys ±
0.2
6 (0
-16
days
) R
isk
fact
ors (
p<.0
5)
Gra
de 1
(3.5
day
s) v
s. G
rade
4b
Tum
ours
(1 d
ay, p
=.02
4), f
emal
es (3
.0 d
ays)
vs.
mal
es (1
.6 d
ays
p=.0
09).
Non
-sig
nific
ant f
acto
rs
Hei
ght,
size
of p
atie
nt, b
ody
mas
s in
dex,
age
, gra
de o
f tum
our (
othe
r tha
t gra
de 1
vs
4b),
preo
pera
tive
posi
tive
step
ping
test
. R
escu
e A
ntie
met
ics
Ris
k fa
ctor
s (p
<.05
) Fe
mal
es (3
.3 d
ays)
vs.
mal
es (1
.7 d
ays,
p=.0
04)
Non
-sig
nific
ant f
acto
rs
Hei
ght,
size
of p
atie
nt, b
ody
mas
s in
dex,
age
, gra
de o
f tum
our,
preo
pera
tive
posi
tive
step
ping
te
st.
Flyn
n an
d N
emer
gut (
2006
) Em
esis
Inci
denc
e 7.
5%
Ris
k fa
ctor
s (p
<.05
) Fa
t gra
ft fo
r cer
ebra
l spi
nal f
luid
leak
(11.
7%) v
s. no
ne (5
.4%
p<.
001)
, Int
raop
erat
ive
use
of a
lu
mba
r dra
in (1
7.1%
) vs.
none
(6.6
%, p
<.00
1), C
rani
opha
ryng
iom
a (1
8%) v
s. no
n-fu
nctio
ning
ad
enom
as (
6% p
=.00
7).
Non
-sig
nific
ant f
acto
rs
Gen
der,
age,
pre
oper
ativ
e m
idaz
olam
, per
iope
rativ
e us
e of
nitr
ic o
xide
or n
eost
igm
ine,
re-
oper
atio
n, tu
mou
r siz
e, a
ntie
met
ic tr
eatm
ent i
n th
e op
erat
ing
room
, and
Cus
hing
's di
seas
e,
acro
meg
aly,
pro
lact
inom
a, o
r rat
hke
clef
t cys
t vs.
non-
func
tioni
ng a
deno
mas
.
N>
Tabl
e 3.
3 (C
ontin
ued)
Men
g an
d Q
uinl
an (
2006
) PO
NV
Inci
denc
e 60
%
Ris
k fa
ctor
s (p<
.05)
Fe
mal
es (
OR
= 2
.3, 9
5% C
I: 1.
3-4.
0), C
rani
al N
erve
V d
ecom
pres
sion
(O
R=2
.4, 9
5% C
I: 1.
4-4.
0), R
ecei
ved
Des
flura
ne (O
R=2
.4, 9
5% C
I: 1.
4-4.
3), C
umul
ativ
e fe
ntan
yl d
ose.
>250
mcg
(O
R=
1.9,
95%
CI:
1.1-
3.3)
. Pro
tect
ive
fact
or o
f the
use
of a
tran
sder
mal
sco
pola
min
e pa
tch
(OR
=. 5,
95
% C
I: 0.
4-0.
7).
Non
-sig
nific
ant f
acto
rs
Post
oper
ativ
e op
ioid
use
. Cum
ulat
ive
intra
oper
ativ
e fe
ntan
yl d
ose
>100
meg
and
cum
ulat
ive
intra
oper
ativ
e fe
ntan
yl d
ose
>150
meg
. M
eng,
Las
ica
et a
l. (2
006)
PO
NV
Inci
denc
e 0-
12 h
ours
: 31%
and
12-
24 h
ours
: 6%
R
isk
fact
ors
(p<.
05)
0-12
hou
rs: U
se o
f sev
oflu
rane
, pro
pofo
l inf
usio
n +
fent
anyl
bol
us (4
0%) v
s. se
voflu
rane
, pr
opof
ol in
fusi
on +
rem
ifent
anil
bolu
s (2
1%, p
<.05
). N
on-s
igni
fican
t fac
tors
no
ne re
porte
d R
escu
e A
ntie
met
ics
Inci
denc
e 0-
12 h
ours
: 20%
R
isk
fact
ors
(p<.
05)
0-12
hou
rs: U
se o
f sev
oflu
rane
, pro
pofo
l inf
usio
n +
fent
anyl
bol
us (3
0%) v
s. se
voflu
rane
, pr
opof
ol in
fusi
on +
rem
ifent
anil
bolu
s (8
%).
Non
-sig
nific
ant f
acto
rs
none
repo
rted
Won
g et
al.
(200
6)
PON
V In
cide
nce
16.6
%
Ris
k fa
ctor
s (p
<.05
) N
one
Non
-sig
nific
ant f
acto
rs
Loca
tion
of s
urge
ry (s
upra
tent
oria
l, po
ster
ior
foss
a, in
tracr
ania
l vas
cula
r, tra
nsph
enoi
dal,
or
extra
cran
ial).
O
R=O
dds
Rat
io
TA
BL
E 3.
4
Qua
lity
Ass
essm
ent:
Was
Pot
entia
l Bia
s A
ddre
ssed
by
the
Stud
ies?
Ref
eren
ce
Stud
y Pa
rtici
patio
n St
udy
Attr
ition
R
isk
Fact
or
Mea
sure
men
t O
utco
me
Mea
sure
men
t C
onfo
undi
ng
Fact
ors
Add
ress
ed
App
ropr
iate
A
naly
sis
Kra
mer
eta
l. (1
994)
Y
es
n/a
Yes
Y
es
No
No
Qui
ney
etal
. (1
995)
Y
es
Yes
Y
es
Partl
y N
o Y
es
Fabl
ing
etal
. (1
997)
Y
es
n/a
Partl
y Y
es
Partl
y Pa
rtly
Man
nine
n et
al.
(199
9)
Yes
Pa
rtly
Yes
Pa
rtly
No
Yes
M
anni
nen
and
Tan
(200
2)
Yes
Y
es
Yes
Pa
rtly
Partl
y Y
es
Iref
in e
t al.
(200
3)
Partl
y N
o Y
es
Partl
y Pa
rtly
Yes
Le
slie
et a
l. (2
003)
Y
es
Yes
Y
es
Yes
N
o Y
es
Kur
ita e
t al.*
(20
04)
Yes
n/
a Y
es
Yes
N
o Y
es
Stie
glitz
et a
l. (2
005)
Y
es
n/a
Yes
N
o N
o N
o Fl
ynn
and
Nem
ergu
t (20
06)
Yes
n/
a Pa
rtly
Yes
N
o Y
es
Men
g an
d Q
uinl
an (
2006
) Y
es
n/a
Yes
Y
es
Yes
Y
es
Men
g, L
asic
a et
al.
(200
6)
Yes
n/
a Y
es
Partl
y N
o Pa
rtly
Won
g et
al.
(200
6)
Yes
Y
es
Yes
Pa
rtly
No
Yes
n/
a: D
oes
not a
pply
as
it is
a re
trosp
ectiv
e st
udy.
* M
etho
dolo
gica
l qua
lity
dete
rmin
ed w
ith th
e he
lp o
f a J
apan
ese
inte
rpre
ter.
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
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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-HT3 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.
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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),
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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.
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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
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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.
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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
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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
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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).
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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.
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. Anesth Analg, 105(6), 1615-1628, table of contents.
Gottschalk, A., Berkow, L. C., Stevens, R. D., Mirski, M., Thompson, R. E., White, E. D., et al. (2007). Prospective evaluation of pain and analgesic use following major elective intracranial surgery. J Neurosurg, 106(2), 210-216.
Hornby, P. J. (2001). Central neurocircuitry associated with emesis. Am J Med, 111 Suppl 8A, 106S-112S.
Korttila, K. (1992). The study of postoperative nausea and vomiting. Br J Anaesth, 69(1 Suppl 1), 20S-23S.
Kovac, A. L. (2007). Management of postoperative nausea and vomiting in children. Paediatr Drugs, 9(1), 47-69.
99
Kurita, N., Kawaguchi, M., Nakahashi, K., Sakamoto, N., Horiuchi, T., Takahashi, M., et al. Retrospective Analysis of Postoperative Nausea and Vomiting after Craniotomy. Masui - Japanese Journal of Anesthesiology. Vol. 53(2)(pp 150-155), 2004.
Lenth, R. V. (2006). Piface (Version 1.64).
Lerman, J. (2007). Inhalation agents in pediatric anaesthesia - an update. Curr Opin Anaesthesiol, 20(3), 221-226.
Macario, A., Weinger, M., Carney, S., & Kim, A. (1999). Which clinical anesthesia outcomes are important to avoid? The perspective of patients. Anesth Analg, 89(3), 652-658.
Manninen, P. H., & Tan, T. K. (2002). Postoperative nausea and vomiting after craniotomy for tumor surgery: a comparison between awake craniotomy and general anesthesia. J Clin Anesth, 14(4), 279-283.
Meng, L., & Quinlan, J. J. (2006). Assessing risk factors for postoperative nausea and vomiting: a retrospective study in patients undergoing retromastoid craniectomy with microvascular decompression of cranial nerves. J Neurosurg Anesthesiol, 18(4), 235-239.
Miller, A. D. (1999). Central mechanisms of vomiting. DigDis Sci, 44(8 Suppl), 39S-43S.
Miller, A. D., Nonaka, S., Jakus, J., & Yates, B. J. (1996). Modulation of vomiting by the medullary midline. Brain Res, 737(1-2), 51-58.
Neufeld, S. M., Drummond, J. Newburn-Cook, C.V. (2008). Prognostic models and risk scores: Can we accurately predict postoperative vomiting for children after craniotomy. Journal of Perianesthesia Nursing, in press.
Ou, C.H.K, Kent, S.K., Hammond, A.M., Warren, D., Bowen-Roberts, T. & Warren, D.T. (2008). Morphine infusions after cranial surgery in children: A retrospective analysis of safety and efficacy. Canadian Journal of Neuroscience Nursing, 30(3), 14-20.
Peduzzi, P., Concato, J., Kemper, E., Holford, T. R., & Feinstein, A. R. (1996). A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol, 49(12), 1373-1379.
Rose, J. B., & Watcha, M. F. (1999). Postoperative nausea and vomiting in paediatric patients. BrJAnaesth, 53(1), 104-117.
100
Rowley, M. P., & Brown, T. C. (1982). Postoperative vomiting in children. Anaesth Intensive Care, 10(4), 309-313.
Scuderi, P. E., & Conlay, L. A. (2003). Postoperative nausea and vomiting and outcome. Int Anesthesiol Clin, 41(4), 165-174.
Stieglitz, L. H., Samii, A., Kaminsky, J., Gharabaghi, A., Samii, M., & Ludemann, W. O. (2005). Nausea and dizziness after vestibular schwannoma surgery: a multivariate analysis of preoperative symptoms. Neurosurgery, 57(5), 887-890; discussion 887-890.
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(1), 615-619.
Tramer, M. R. (2007). [Prevention and treatment of postoperative nausea and vomiting in children. An evidence-based approach]. Ann Fr Anesth Reanim, 26(6), 529-534.
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
TA
BL
E 4.
2
Cum
ulat
ive
inci
denc
e of
retc
hing
/vom
iting
, nau
sea
and
PON
V
Hou
rs f
rom
ana
esth
etic
fin
ish
time
Tota
l num
ber o
f chi
ldre
n w
ith le
ast o
ne e
vent
reco
rded
(C
umul
ativ
e Pe
rcen
t) 0-
4 0-
8 0-
24
0-48
0-
72
0-96
0-
120
0-14
4 0-
168
0-19
2 0-
216*
R
etch
ing/
V om
iting
59
(2
3.7%
) 75
(3
0.1%
) 11
9 (4
7.8%
) 15
3 (6
1.4%
) 16
4 (6
5.9%
) 17
4 (6
9.9%
) 18
1 (7
2.7%
) 18
6 (7
4.7%
) 18
7 (7
5.1%
) 19
0 (7
6.3%
) 19
1 (7
6.7%
) N
ause
a 24
(1
0%)
32
(13%
) 59
(2
4%)
84
(34%
) 93
(3
7%)
98
(39%
) 10
3 (4
2%)
105
(43%
) 10
5 (4
3%)
106
(43%
) 10
7 (4
4%)
PON
V
69
(28%
) 81
(3
3%)
134
(54%
) 16
2 (6
5%)
172
(69%
) 18
2 (7
3%)
189
(76%
) 19
0 (7
6%)
191
(77%
) 19
4 (7
8%)
195
(79%
) PO
NV
: Firs
t rec
orde
d na
usea
, ret
chin
g or
vom
iting
.
TA
BL
E 4.
3 U
niva
riate
ana
lysi
s V
aria
ble
POV
by
120
Hou
rs
Odd
s R
atio
(95
% C
I)
Early
(< 2
4 ho
urs)
vs.
Late
PO
V1
Odd
s R
atio
(95
% C
I)
1. S
ite
Stol
lery
Chi
ldre
n's
Hos
pita
l 1.
00
1.00
H
ospi
tal f
or S
ick
Chi
ldre
n 1.
74 (
0.92
-3.2
9)
1.71
(0.
73-4
.03)
2.
Chi
ld C
hara
cter
istic
s A
ge 0
to <
4 ye
ars
1.00
1.
00
4 to
<6
year
s 1.
10(0
.48-
2.49
) 0.
26 (
0.11
-0.6
4)**
7
to <
12 y
ears
0.
90 (
0.42
-1.9
2)
0.30
(0.
13-0
.69)
**
12 to
<17
year
s 0.
54 (
0.24
-1.2
3)
0.41
(0.
16-1
.08)
Fe
mal
e G
ende
r 0.
79 (
0.45
-1.3
8)
1.39
(0.7
4- 2
.62)
R
equi
red
Surg
ery
Bra
in T
umou
r 1.
00
1.00
C
hiar
i I M
alfo
rmat
ion
2.32
(1.1
7-4.
60)*
0.
60 (
0.30
-1.1
9)
Oth
er
0.39
(0.1
3-1.
13)
4.86
(0.
90-2
6.30
) 3.
Pre
sent
ing
Sym
ptom
Pr
esen
ting
with
Vom
iting
0.
95(0
.55-
1.67
) 1.
09 (
0.58
-2.0
5)
4. In
traop
erat
ive
Car
e A
dmin
istra
tion
of O
ndan
setro
n 1.
78(1
.00-
3.15
) 0.
74 (
0.39
-1.3
8)
Adm
inis
tratio
n of
Dex
amet
haso
ne
0.65
(0.
37-1
.15)
1.
62 (
0.86
-3.0
5)
Leng
th o
f su
rger
y 1.
00 (
0.98
-1.0
1)
1.00
(0.
98-1
.01)
U
se o
f Des
flura
ne
1.32
(0.
66-2
.64)
0.
34(0
.14-
0.83
)*
5. P
osto
pera
tive
Car
e Pr
ophy
lact
ic P
osto
pera
tive
Ant
iem
etic
0.
77 (
0.43
-1.3
7)
0.87
(0.
45-1
.70)
O
pioi
d in
firs
t 24
hour
s 0.
42 (
0.12
-1.4
7)
0.53
(0.
20-1
.44)
1.
Ear
ly v
omiti
ng c
oded
as
0 an
d la
te a
s 1.
*p
<.05
**
p<.0
1 C
I=C
onfid
ence
Int
erva
l o
TAB
LE 4
.4
Mul
tivar
iabl
e A
naly
sis:
PO
V b
y 12
0 H
ours
M
odel
Num
ber
5 4
3 2
1
Var
iabl
e A
djus
ted
Odd
s Rat
io
Adj
uste
d O
dds
Rat
io
Adj
uste
d O
dds R
atio
A
djus
ted
Odd
s Rat
io
Odd
s Rat
io
(95%
CI)
(9
5% C
I)
(95%
CI)
(9
5% C
I)
(95%
CI)
1.
Site
St
olle
ry C
hild
ren'
s H
ospi
tal
1.00
1.
00
1.00
1.
00
1.00
H
ospi
tal f
or S
ick
Chi
ldre
n 4.
26(1
.61-
11.2
9)**
4.
25 (
1.62
-11.
12)"
**
1.78
(0.
90-3
.51)
1.
78(0
.90-
3.50
) 1.
74 (
0.92
-3.2
9)
2. C
hild
Cha
ract
erist
ics
Age
in q
uart
iles%
0
to <
4 ye
ars
1.00
1.
00
1.00
1.
00
4 to
<7
year
s 0.
84(0
.33-
2.10
) 0.
84 (
0.34
-2.0
6)
0.96
(0.
41-2
.27)
1.
00(0
.43-
2.35
) 7
to <
12 y
ears
0.
62(0
.26-
1.47
) 0.
56 (
0.24
-1.3
1)
0.72
(0.3
2-1.
61)
0.74
(0.3
3-1.
64)
12 to
<17
year
s 0.
34 (
0.13
-0.8
6)*
0.33
(0.
13-0
.82)
"*
0.48
(0.2
0-1.
12)
0.47
(0.2
0-1.
11)
Fem
ale
Gen
der
0.61
(0.
33-1
.15)
0.
66 (
0.35
-1.2
1)
0.71
(0.
39-1
.27)
0.
69(0
.39-
1.25
) Su
rger
y Brai
n Tu
mou
r 1.
00
1.00
1.
00
1.00
C
hiar
i I M
alfo
rmat
ion
2.58
(0.
96-6
.94)
2.
43 (
0.91
-6.4
8)a
3.46
(1.
48-8
.10)
a **
2.80
(1.3
7-5.
71)*
* O
ther
0.
45 (
0.11
-1.7
9)
0.53
(0.
14-1
.99)
0.
54 (
0.17
-1.7
9)
0.44
(0.
15-1
.35)
3.
Pre
sent
ing
Sym
ptom
s Pr
esen
ting
with
Vom
iting
1.
68 (
0.75
-3.7
4)
1.63
(0.
75-3
.54)
1.
40(0
.67-
2.90
) 4.
Int
raop
erat
ive
Car
e A
dmin
istra
tion
of O
ndan
setr
on
2.27
(1.1
6-4.
47)*
2.
22(1
.14-
4.33
)*
Adm
inist
ratio
n of
Dex
amet
haso
ne
0.53
(0.2
5-1.
10)
0.58
(0.2
8-1.
19)
Leng
th o
f sur
gery
0.
92 (
0.78
-1.0
9)
0.91
(0.
78-1
.08)
U
se o
f Des
flura
ne
3.57
(1.2
6-10
.08)
* 3.
11 (
1.13
-8.6
2)*
5. P
osto
pera
tive
Car
e Pr
ophy
lact
ic A
ntie
met
ic
0.60
(0.
32-1
.15)
O
pioi
d in
firs
t 24
hour
s 0.
33 (
0.09
-1.2
8)
*p<.
05
**p<
.01
a C
hang
e >
15%
in a
stat
istic
ally
sig
nific
ant v
aria
ble
or >
15%
mak
ing
a va
riabl
e st
atis
tical
ly s
igni
fican
t C
I=C
onfid
ence
Inte
rval
Tabl
e 4.
4 C
ontin
ued
Mod
el N
umbe
r 6
Fina
l Mod
el w
ith I
nter
actio
n V
aria
ble
Adj
uste
d O
dds
Rat
io
(95%
CI)
1.
Site
St
olle
ry C
hild
ren'
s H
ospi
tal
1.00
Hos
pita
l for
Sic
k C
hild
ren
3.77
(1.3
9-10
.27)
**
2. C
hild
Cha
ract
erist
ics
Age
in q
uart
iles
0 to
<4
year
s 1.0
0 4
to <
7 ye
ars
0.86
(0.
34-2
.19)
7
to <
12 y
ears
0.
56 (
0.23
-1.3
8)
12 to
<17
year
s 0.
35 (
0.14
-0.9
2)*
Fem
ale
Gen
der
0.59
(0.
31-1
.12)
Su
rger
y Brai
n Tu
mou
r 1.0
0 C
hiar
i I M
alfo
rmat
ion
2.96
(1.0
8-8.
11)"
**
Oth
er
0.48
(0.
12-1
.94)
3.
Pre
sent
ing
Sym
ptom
s Pr
esen
ting
with
Vom
iting
1.
80 (
0.79
-4.1
2)
4. I
ntra
oper
ativ
e C
are
Adm
inis
trat
ion
of O
ndan
setr
on
3.66
(1.6
8-8.
00)*
* A
dmin
istra
tion
of D
exam
etha
sone
0.
60 (
0.28
-1.2
6)
Leng
th o
f su
rger
y 0.
90(0
.76-
1.08
) U
se o
f Des
flura
ne
16.4
2 (2
.89-
92.9
9)**
5.
Pos
tope
rativ
e C
are
Prop
hyla
ctic
Ant
iem
etic
0.
61 (
0.31
-1.1
6)
Opi
oid
in fi
rst 2
4 ho
urs
0.27
(0.
08-1
.17)
6.
Sig
nific
ant I
nter
actio
n U
se o
f Des
flura
ne X
In
trao
pera
tive
Adm
inist
ratio
n of
Ond
anse
tron
0.
08 (
0.01
-0.5
0)**
*p<.
05
**p<
.01
a C
hang
e >
15%
in a
stat
istic
ally
sig
nific
ant v
aria
ble
or >
15%
mak
ing
a va
riab
le s
tatis
tical
ly s
igni
fican
t C
I=C
onfid
ence
Int
erva
l
TA
BL
E 4.
5 M
ultiv
aria
ble
Ana
lysi
s: E
arly
vs.
Late
PO
V (
POV
in th
e fir
st 2
4 ho
urs
vs. a
fter
24
hour
s to
120
hou
rs)1
Mod
el N
umbe
r 5
4 3
2 1
Var
iabl
e A
djus
ted
Odd
s R
atio
(9
5% C
I)
Adj
uste
d O
dds
Rat
io
(95%
CI)
A
djus
ted
Odd
s R
atio
(9
5% C
I)
Adj
uste
d O
dds
Rat
io
(95%
CI)
O
dds
Rat
io
(95%
CI)
1. S
ite
Stol
lery
Chi
ldre
n's
Hos
pita
l 1.
00
1.00
1.
00
1.00
1.
00
Hos
pita
l for
Sic
k C
hild
ren
0.72
(0.
22-2
.33)
0.
72(0
.22-
2.19
) 1.
80(0
.72-
4.52
) 1.
80 (
0.72
-4.5
0)
1.71
(0.
72-4
.03)
2.
Chi
ld C
hara
cter
istic
s A
ge in
qua
rtile
s%
0 to
<4
year
s 1.
00
1.00
1.
00
1.00
4
to <
7 ye
ars
0.30
(0.
11-0
.79)
* 0.
30(0
.11-
0.79
)*
0.31
(0.
12-0
.79)
* 0.
31 (
0.12
-0.7
8)*
7 to
<12
yea
rs
0.31
(0.
12-0
.79)
* 0.
31 (
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0.32
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0.
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0.13
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12 to
<17
year
s 0.
50(0
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) 0.
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) 0.
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) 0.
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Fem
ale
Gen
der
1.91
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uire
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rger
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ther
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3.
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sent
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ptom
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esen
ting
with
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(0.
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0.
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7)
4. I
ntra
oper
ativ
e C
are
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inist
ratio
n of
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anse
tron
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0.40
-1.8
0)
0.85
(0.
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.80)
A
dmin
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tion
of D
exam
etha
sone
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-4.8
3)
2.02
(0.
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.68)
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ngth
of
surg
ery
1.00
(0.9
8-1.
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1.00
(0.
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se o
f Des
flura
ne
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(0.
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* 0.
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0.07
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3)*
5. P
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tive
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e Pr
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oid
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rst 2
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urs
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1.
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ly v
omiti
ng c
oded
as
0 an
d la
te c
oded
as
1.
*p<.
05
**p<
01
a C
hang
e >
15%
in a
stat
istic
ally
sig
nific
ant v
aria
ble
or >
15%
mak
ing
a va
riab
le s
tatis
tical
ly s
igni
fican
t C
I=C
onfid
ence
Int
erva
l
TA
BL
E 4.
6 C
orre
latio
ns a
mon
g in
depe
nden
t var
iabl
es in
the
mod
el
Var
iabl
e 1
2 3
4 5
6 7
8 9
10
11
12
13
14
Site
1
1.00
4 to
<6
year
s1 2
-.06
1.00
7 to
<12
yea
rs1
3 .1
6 -
1.00
12 to
<17
year
s1 4
-.08
--
1.00
Fem
ale
Gen
der
5 -.0
3 -.0
3 .0
3 .0
3 1.
00
Chi
ari I
M
alfo
rmat
ion
6 -.0
4 -.0
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0 .1
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00
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er2
7 -.0
7 -.0
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9 -.0
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1.00
Pres
entin
g w
ith
Vom
iting
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0*
1.00
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inis
tratio
n of
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ndan
setro
n 9
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.03
1.00
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inis
tratio
n of
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exam
etha
sone
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8 .0
9 -.0
1 -.0
9 -.0
3 -.4
6*
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.40*
.1
4 1.
00
Leng
th o
f su
rger
y 11
.0
8 .0
9 -.0
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9 -.0
2 .4
5*
-.10
-.39*
.1
4 .3
0*
1.00
Use
of D
esfl
uran
e 12
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9 .0
1 -.1
2 -.1
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7 .0
4 -.0
2 -.0
8 .1
9 .0
3 .0
0 1.
00
Prop
hyla
ctic
Po
stop
erat
ive
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iem
etic
13
-.01
-.07
.10
-.06
-.05
-.01
-.01
.07
.01
-.01
-.03
.07
1.00
Opi
oid
in fi
rst 2
4 ho
urs
14
-.13
.01
.04
.08
.01
.12
-.11
-.10
.08
-.11
-.11
.03
-.01
1.00
1 R
efer
ence
cat
egor
y 0-
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2 R
efer
ence
cat
egor
y br
ain
tum
our
surg
ery
Two
taile
d pc
.Ol
TA
BL
E 4.
7 R
elat
ions
hip
of P
OV
by
120
hour
s to
adv
erse
out
com
es
Vom
iting
by
120
hour
s Ph
i St
atis
tic
n (%
tota
l) (S
igni
fican
ce)
Tota
l (n=
249)
N
o Y
es
Pseu
dom
enin
goce
le
No
49 (
19.7
) 12
4 (4
9.8)
Y
es
19(7
.6)
57 (
22.9
) .0
3 (p
=.59
) W
ould
Fai
lure
/CSF
Lea
k N
o 55
(22
.1)
158
(63.
5)
Yes
13
(5.2
) 23
(9.
2)
-.08
(p=.
20)
Wou
nd I
nfec
tion
No
63 (
25.3
) 17
5 (7
0.3)
Y
es
5 (2
.0)
6(2.
4)
-.09
(p=.
17)
Bra
in T
umou
r (n
=153
)
Post
erio
r Fo
ssa
Synd
rom
e N
o 34
(22
.2)
82 (
53.6
) Y
es
13 (8
.5)
24(1
5.7)
-.0
5 (p
=.50
)
FIG
UR
E 4.
1
Hie
rarc
hica
l Mod
el f
or D
ata
Entry
into
Mul
tivar
iabl
e A
naly
sis
1.
Site
2.
Chi
ld C
hara
cter
istic
s •
Age
•
Gen
der
• R
equi
red
Surg
ery
3.
Pres
entin
g Sy
mpt
oms
(Vom
iting
)
4.
Intra
oper
ativ
e C
are
• U
se o
f Des
flur
ane
• A
dmin
istra
tion
of D
exam
etha
sone
•
Adm
inis
tratio
n of
Ond
anse
tron
• Le
ngth
of
Surg
ery
5.
Post
oper
ativ
e C
are
• O
pioi
d in
itiat
ed b
y th
e fir
st 2
4 H
ours
•
Prop
hyla
ctic
use
of a
n A
nti-e
met
ic
FIG
UR
E 4.
2 H
ours
fro
m fi
rst r
ecor
ded
retc
hing
or v
omiti
ng to
last
in th
e 24
0 ho
ur p
erio
d
20.0
18.0
16.0
14.0
12.0
110.
0 .c
•5
8.
0 w
01
.a E
6.0
3 C T5
z 4.
0 **
o S 2.
0 Si «
0.0
I I
FIG
UR
E 4.
3 N
umbe
r of
reco
rded
ret
chin
g or
vom
iting
eve
nts
over
the
stud
y pe
riod
0 1
2 3
4 5
6 7
8 9
10
11
12
13
14
15
16
17
18
19
20
>20
Cou
nts
of v
omiti
ng u
p to
240
hou
rs
Paper 5
Strengths and limitations of currently proposed clinical practice guidelines for preventing
and treating nausea and vomiting in children after posterior fossa craniotomy
114
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
115
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
116
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,
117
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
118
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
119
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,
120
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).
121
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
122
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, &
123
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
124
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
125
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
126
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.
128
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.
129
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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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)
Droperidol1 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 Risk Moderate Risk Severe Risk Very Severe Risk % chance of P O N V 10-20% 4 0 % 60% 8 0 %
# 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 NSAIDS
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 P O N V on admission, discharge & more frequently as needed
NO
C o n t i n u e t o mon i to r
Nausea/vomiting?
Y E S 1
I If nausea is present, quantify severity using a VDS or VAS
Did patient receive prophylactic anti-emetic agent(s)
Verify adequate hydration
N O
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 w i 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
Out
com
es
Mea
sure
men
t (D
escr
ibe
how
mea
sure
d):
Vom
iting
Nau
sea
Inci
denc
e of
PO
NV
Om
in
T=
3 Om
in
T=
lhr
T=
2hr-
6hr
T=
6-8h
r T=
9h
r-12
hr
T=
13-2
4hr
T=
25-4
8hr
T=
49-7
2hr
T=
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Vom
iting
+/-
naus
ea
Nau
sea
Res
cue
Ant
i-em
etic
*If m
ore
than
one
mea
sure
for
a ti
me
perio
d, ta
ke la
test
tim
e pe
riod.
Cum
ulat
ive
Inci
denc
e of
PO
NV
Om
in
T=
3 Om
in
T=
lhr
T=
2hr-
6hr
T=
6-8h
r T=
9h
r-12
hr
T=
13-2
4hr
T=
25-4
8hr
T=
49-7
2hr
T=
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Tx
C
Vom
iting
+/-
naus
ea
Nau
sea
Res
cue
Ant
i-em
etic
Patie
nt S
atis
fact
ion
with
trea
tmen
t for
PO
NV
: Tr
eatm
ent
Con
trol
Not
mea
sure
d
Leng
th o
f St
ay:
Trea
tmen
t C
ontro
l N
ot m
easu
red
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 REVIEWER
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
OU
TC
OM
ES
: U
niva
riab
le A
naly
sis
Mea
sure
men
t St
atis
tics
Sign
ifica
nt
Pred
icto
r 1
Sign
ifica
nt
Pred
icto
r 2
Sign
ifica
nt
Pred
icto
r 3
Sign
ifica
nt
Pred
icto
r 4
Sign
ifica
nt
Pred
icto
r 5
Excl
uded
Pr
edic
tors
N
ause
a
Vom
iting
Res
cue
Ant
iem
etic
Oth
er
OU
TCO
ME
S:
Mul
tivar
iabl
e A
naly
sis
Out
com
es
Mea
sure
men
t St
atis
tics
Mod
el
Excl
uded
Var
iabl
es
Nau
sea
Vom
iting
Res
cue
Ant
iem
etic
Oth
er
Mod
el D
iagn
ostic
s us
ed (
Spec
ify s
tatis
tics
and
resu
lts):
For
prog
nost
ic m
odel
s:
How
was
ext
erna
l val
idat
ion
expl
ored
: sp
lit s
ampl
e bo
otst
rapp
ing
new
sam
ple
othe
r W
hat
wer
e th
e fin
ding
s fo
r ex
tern
al v
alid
atio
n?
AU
RO
CC
G
oodn
ess
of fi
t (S
peci
fy s
tatis
tic)
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 € N e c k € Other
€ None noted € Headache € N e c k e Other
€ None noted € Headache € N e c k € Other
€ None noted € Headache € N e c k € Other
€ None noted € Headache € N e c k € Other
€ None noted € Headache €Neck € Other
Antiemetics Ordered
Antiemetics Given*
Nonpharm. Strategies
Opioids Given
EVD € O p e n @ € Clamped € d / c € n / a
€ O p e n @ € Clamped € d / c € n / a
€ O p 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 €<fc € 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
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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
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INTRODUCTION
1. The publisher for this copyrighted material is Elsevier. By clicking "accept" in connection with completing this licensing transaction, you agree that the following terms and conditions apply to this transaction (along with the Billing and Payment terms and conditions established by Copyright Clearance Center, Inc. ("CCC"), at the time that you opened your Rightslink account and that are available at any time at <http ://myaccount.copyright.com>).
2. Elsevier hereby grants you permission to reproduce the aforementioned material subject to the terms and conditions indicated.
3. Acknowledgement: If any part of the material to be used (for example, figures) has appeared in our publication with credit or acknowledgement to another source, permission must also be sought from that source. If such permission is not obtained then that material may not be included in your publication/copies. Suitable acknowledgement to the source must be made, either as a footnote or in a reference list at the end of your publication, as follows:
"Reprinted from Publication title, Vol /edition number, Author(s), Title of article / title of chapter, Pages No., Copyright (Year), with permission from Elsevier [OR APPLICABLE SOCIETY COPYRIGHT OWNER]." Also Lancet special credit - "Reprinted from The Lancet, Vol. number, Author(s), Title of article, Pages No., Copyright (Year), with permission from Elsevier."
4. Reproduction of this material is confined to the purpose and/or media for which permission is hereby given.
5. Altering/Modifying Material: Not Permitted. However figures and illustrations may be altered/adapted minimally to serve your work. Any other abbreviations, additions, deletions and/or any other alterations shall be made only with prior written authorization of Elsevier Ltd. (Please contact Elsevier at [email protected])
GENERAL TERMS
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6. If the permission fee for the requested use of our material is waived in this instance, please be advised that your future requests for Elsevier materials may attract a fee.
7. Reservation of Rights: Publisher reserves all rights not specifically granted in the combination of (i) the license details provided by you and accepted in the course of this licensing transaction, (ii) these terms and conditions and (iii) CCC's Billing and Payment terms and conditions.
8. License Contingent Upon Payment: While you may exercise the rights licensed immediately upon issuance of the license at the end of the licensing process for the transaction, provided that you have disclosed complete and accurate details of your proposed use, no license is finally effective unless and until full payment is received from you (either by publisher or by CCC) as provided in CCC's Billing and Payment terms and conditions. If full payment is not received on a timely basis, then any license preliminarily granted shall be deemed automatically revoked and shall be void as if never granted. Further, in the event that you breach any of these terms and conditions or any of CCC's Billing and Payment terms and conditions, the license is automatically revoked and shall be void as if never granted. Use of materials as described in a revoked license, as well as any use of the materials beyond the scope of an unrevoked license, may constitute copyright infringement and publisher reserves the right to take any and all action to protect its copyright in the materials.
9. Warranties: Publisher makes no representations or warranties with respect to the licensed material.
10. Indemnity: You hereby indemnify and agree to hold harmless publisher and CCC, and their respective officers, directors, employees and agents, from and against any and all claims arising out of your use of the licensed material other than as specifically authorized pursuant to this license.
11. No Transfer of License: This license is personal to you and may not be sublicensed, assigned, or transferred by you to any other person without publisher's written permission.
12. No Amendment Except in Writing: This license may not be amended except in a writing signed by both parties (or, in the case of publisher, by CCC on publisher's behalf).
13. Objection to Contrary Terms: Publisher hereby objects to any terms contained in any purchase order, acknowledgment, check endorsement or other writing prepared by you, which terms are inconsistent with these terms and conditions or CCC's Billing and Payment terms and conditions. These terms and conditions, together with CCC's Billing and Payment terms and conditions (which are incorporated herein), comprise the entire agreement between you and publisher (and CCC) concerning this licensing transaction. In the event of any conflict between your obligations established by these terms and conditions and those established by CCC's Billing and Payment terms and conditions, these terms and conditions shall control.
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14. Revocation: Elsevier or Copyright Clearance Center may deny the permissions described in this License at their sole discretion, for any reason or no reason, with a full refund payable to you. Notice of such denial will be made using the contact information provided by you. Failure to receive such notice will not alter or invalidate the denial. In no event will Elsevier or Copyright Clearance Center be responsible or liable for any costs, expenses or damage incurred by you as a result of a denial of your permission request, other than a refund of the amount(s) paid by you to Elsevier and/or Copyright Clearance Center for denied permissions.
LIMITED LICENSE
The following terms and conditions apply to specific license types:
15. Translation: This permission is granted for non-exclusive world English rights only unless your license was granted for translation rights. If you licensed translation rights you may only translate this content into the languages you requested. A professional translator must perform all translations and reproduce the content word for word preserving the integrity of the article. If this license is to re-use 1 or 2 figures then permission is granted for non-exclusive world rights in all languages.
16. Website: The following terms and conditions apply to electronic reserve and author websites: Electronic reserve: If licensed material is to be posted to website, the web site is to be password-protected and made available only to bona fide students registered on a relevant course if: 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 posting, All content posted to the web site must maintain the copyright information line on the bottom of each image, 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.
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 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
177
licensing at http://www.sciencedirect.com/science/iournal/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.
18. Author website for books with the following additional clauses: 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/iournal/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:
None
178
Appendix 8
Permission to use Quality of Prognostic Studies (Appendix 2)
ACP A M E R I C A N COLLEGE OF PHYSICIANS INTERNAL MEDICINE 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 CONDITIONS
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 provided by Elsevier, and the payment terms and conditions.
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Elsevier Limited The Boulevard,Langford Lane Kidlington,Oxford,0X5 1GB,UK
1982084
Susan M Neufeld
8919-117st
Edmonton, AB T6G1R8
2066220982858
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
Figures/table/illustration/abstracts
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You are an author of the Elsevier article No
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No
Expected publication date
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Total 0.00 USD
Terms and Conditions
INTRODUCTION
1. The publisher for this copyrighted material is Elsevier. By clicking "accept" in connection with completing this licensing transaction, you agree that the following terms and conditions apply to this transaction (along with the Billing and Payment terms and conditions established by Copyright Clearance Center, Inc. ("CCC"), at the time that you opened your Rightslink account and that are available at any time at <http ://myaccount. copyright. com>).
2. Elsevier hereby grants you permission to reproduce the aforementioned material subject to the terms and conditions indicated.
3. Acknowledgement: If any part of the material to be used (for example, figures) has appeared in our publication with credit or acknowledgement to another source, permission must also be sought from that source. If such permission is not obtained then that material may not be included in your publication/copies. Suitable acknowledgement to the source must be made, either as a footnote or in a reference list at the end of your publication, as follows:
"Reprinted from Publication title, Vol /edition number, Author(s), Title of article / title of chapter, Pages No., Copyright (Year), with permission from Elsevier [OR APPLICABLE SOCIETY COPYRIGHT OWNER]." Also Lancet special credit -"Reprinted from The Lancet, Vol. number, Author(s), Title of article, Pages No., Copyright (Year), with permission from Elsevier."
4. Reproduction of this material is confined to the purpose and/or media for which permission is hereby given.
5. Altering/Modifying Material: Not Permitted. However figures and illustrations may be altered/adapted minimally to serve your work. Any other abbreviations, additions,
GENERAL TERMS
181
deletions and/or any other alterations shall be made only with prior written authorization of Elsevier Ltd. (Please contact Elsevier at [email protected])
6. If the permission fee for the requested use of our material is waived in this instance, please be advised that your future requests for Elsevier materials may attract a fee.
7. Reservation of Rights: Publisher reserves all rights not specifically granted in the combination of (i) the license details provided by you and accepted in the course of this licensing transaction, (ii) these terms and conditions and (iii) CCC's Billing and Payment terms and conditions.
8. License Contingent Upon Payment: While you may exercise the rights licensed immediately upon issuance of the license at the end of the licensing process for the transaction, provided that you have disclosed complete and accurate details of your proposed use, no license is finally effective unless and until full payment is received from you (either by publisher or by CCC) as provided in CCC's Billing and Payment terms and conditions. If full payment is not received on a timely basis, then any license preliminarily granted shall be deemed automatically revoked and shall be void as if never granted. Further, in the event that you breach any of these terms and conditions or any of CCC's Billing and Payment terms and conditions, the license is automatically revoked and shall be void as if never granted. Use of materials as described in a revoked license, as well as any use of the materials beyond the scope of an unrevoked license, may constitute copyright infringement and publisher reserves the right to take any and all action to protect its copyright in the materials.
9. Warranties: Publisher makes no representations or warranties with respect to the licensed material.
10. Indemnity: You hereby indemnify and agree to hold harmless publisher and CCC, and their respective officers, directors, employees and agents, from and against any and all claims arising out of your use of the licensed material other than as specifically authorized pursuant to this license.
11. No Transfer of License: This license is personal to you and may not be sublicensed, assigned, or transferred by you to any other person without publisher's written permission.
12. No Amendment Except in Writing: This license may not be amended except in a writing signed by both parties (or, in the case of publisher, by CCC on publisher's behalf).
13. Objection to Contrary Terms: Publisher hereby objects to any terms contained in any purchase order, acknowledgment, check endorsement or other writing prepared by you, which terms are inconsistent with these terms and conditions or CCC's Billing and Payment terms and conditions. These terms and conditions, together with CCC's Billing and Payment terms and conditions (which are incorporated herein), comprise the entire
182
agreement between you and publisher (and CCC) concerning this licensing transaction. In the event of any conflict between your obligations established by these terms and conditions and those established by CCC's Billing and Payment terms and conditions, these terms and conditions shall control.
14. Revocation: Elsevier or Copyright Clearance Center may deny the permissions described in this License at their sole discretion, for any reason or no reason, with a full refund payable to you. Notice of such denial will be made using the contact information provided by you. Failure to receive such notice will not alter or invalidate the denial. In no event will Elsevier or Copyright Clearance Center be responsible or liable for any costs, expenses or damage incurred by you as a result of a denial of your permission request, other than a refund of the amount(s) paid by you to Elsevier and/or Copyright Clearance Center for denied permissions.
LIMITED LICENSE
The following terms and conditions apply to specific license types:
15. Translation: This permission is granted for non-exclusive world English rights only unless your license was granted for translation rights. If you licensed translation rights you may only translate this content into the languages you requested. A professional translator must perform all translations and reproduce the content word for word preserving the integrity of the article. If this license is to re-use 1 or 2 figures then permission is granted for non-exclusive world rights in all languages.
16. Website: The following terms and conditions apply to electronic reserve and author websites: Electronic reserve: If licensed material is to be posted to website, the web site is to be password-protected and made available only to bona fide students registered on a relevant course if: 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 posting, All content posted to the web site must maintain the copyright information line on the bottom of each image, 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.
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 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/iournal/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.
18. Author website for books with the following additional clauses: 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 ippincottWil l iams & 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
CONDITIONS
Permission is granted for your requested use. Retain this copy for your records. This permission is subject to the following conditions:
1) A credit line will be prominently placed and included: for books - the author(s), title of book, editor, copyright holder, year of publication; for journals - the author(s), title of article, title of journal, volume number, issue number and inclusive pages.
2) The requestor warrants that the material shall not be used in any manner which may be considered derogatory to the title, content, or author(s) of the material or to Wolters Kluwer Health.
3) Permission is granted for one time use only as specified in your correspondence. Rights herein do not apply to future reproductions, editions, revisions, or other derivative works.
4) Permission granted is non-exclusive, and is valid throughout the world in the English language only.
5) Wolters Kluwer Health cannot supply the requestor with the original artwork or a "clean copy."
6) The requestor agrees to secure written permission from the author (for book material only).
410 528 4000 tel www.LWW.com
185
Permission is valid if the borrowed material is original to a Wolters Kluwer Health imprint (Lippincott, Williams & Wilkins, Lippincott-Raven Publishers, Williams & Wilkins, Lea & Febiger, Harwal, Igaku-Shoin, Rapid Science, Little Brown and Company, Harper & Row Medical American Journal of Nursing Co, and Urban & Schwarzenberg - English Language).
