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PEDIATRICS Vol. 105 No. 1 January 2000, pp. 73-78
,
From the * Unit for Pediatric Oncology and Hematology,
Department of Women's and Children's Health, Uppsala University
Children's Hospital, Uppsala, Sweden; Department of Pediatric
Anesthesia and Intensive Care, Sahlgrenska University Hospital,
Sahlgrenska, Sweden; § Multidisciplinary Center for Pain Treatment,
Department of Anesthesiology and Intensive Care, University Hospital,
Uppsala, Sweden; and the Department of Research, Central Hospital,
Västerås, Sweden.
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ABSTRACT |
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Top
Abstract
Results
Discussion
Conclusion
References
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Objective. Anxiety and pain even in minor procedures are still great problems in pediatrics, not least in pediatric oncology. Conscious sedation is indicated when other means to overcome a child's fear fail. The aim of this study was to investigate whether intranasal administration of midazolam given before insertion of a needle in a subcutaneously implanted central venous port could reduce anxiety, discomfort, pain, and procedure problems.
Method. Forty-three children with cancer participated in this randomized, double-blind, placebo-controlled, crossover study in which nasal administration of midazolam spray, .2 mg/kg body weight, was compared with placebo. Children, parents, and nurses completed a visual analog scale questionnaire to evaluate efficacy.
Results. Parents and nurses reported reduced anxiety,
discomfort, and procedure problems for children in the midazolam group
and would prefer the same medication at next procedure. They
also reported pain reduction. Children reported reduced anxiety and
procedure problems but reduction of pain and discomfort was not
significant. No serious or unexpected side effects occurred. Nasal
discomfort was the most common side effect (17/38
45%) and
the primary reason for dropouts (8/4319%).Anxiety varied with age but not with gender. When anxiety increased,
the differences between midazolam and placebo increased.
Conclusion. Nasal midazolam spray offers relief to children anxious about procedures, such as insertion of a needle in a subcutaneously implanted intravenous port, venous blood sampling, venous cannulation, etc. Its use, however, may be limited by nasal discomfort in some patients for whom rectal and oral routes might be alternatives. Key words: pediatric procedure sedation, anxiety, procedure, midazolam, administration, intranasal.
Many studies show that pain in children is underestimated
and, therefore, inadequately treated.1-3 Anxiety and pain
even in minor procedures is a common and often overlooked problem, not
least in pediatric oncology,4,5 where long
treatment-periods and repeated procedures are common.
Thirty years ago nearly all children with cancer died. Therefore, the
primary issue in pediatric oncology has been to increase survival.
Today, when about two thirds of these children
survive,6-9 there is a need to increase knowledge in
different areas of supportive care. In pediatric oncology, pain has
been reported to be the symptom most feared by children.10
Studies have revealed that procedure- and treatment-related pain are
greater problems than cancer pain.411-13 Therefore, introduction of subcutaneously implanted intravenous (IV) ports and
central venous catheters was a relief. However, many children are
anxious and afraid of pain when a needle is to be inserted through the
skin into the port, even though they are pretreated with eutectic
mixture of local anesthetics (EMLA; ASTRA Pain Control, Södertälje, Sweden). Conscious sedation in a pediatric
setting is indicated when other means to overcome a child's fears
fail, but a major problem in this situation is that there is no route for quick sedation. Traditionally oral and rectal routes have been used
for drugs like chloral hydrate or diazepam, but these drugs are not
ideal primarily because of the slow onset of action, long effect, and a
variable uptake. An ideal sedative drug should provide rapid onset,
short recovery time, a minimum of side effects, and it should be safe
and easy to administer.
Midazolam is a benzodiazepine that can be administered orally, nasally,
rectally, intramuscularly, or intravenously because of water-soluble
properties. It has a short onset time,14 a relatively
rapid redistribution phase, and a plasma half-life of ~2 hours in all
age groups except neonates for whom it is longer.15,16 Midazolam is not considered to have analgesic properties by itself and,
therefore, should not be the sole means for sedation for children
undergoing procedures in which a significant amount of pain could be
expected. Respiratory and circulatory depression are unlikely when
midazolam is used as a single drug,17,18 but when combined
with opioids or other sedatives the risk for respiratory depression
increases.19,20 In a monitored setting according to
guidelines for conscious sedation,21 however, these risks
can be handled, and for more painful procedures a combination of
opioid- and benzodiazepine-sedation or even general anesthesia is more
appropriate. Attributable to pharmacokinetic properties and a wide
therapeutic window, midazolam is well suited for use in children. Oral
and rectal routes are not ideal alternatives primarily because uptake
is very variable, onset is slow, and recovery is
delayed.20 Furthermore, some children, especially older
children, dislike rectal administration.22 Intranasally administered midazolam fulfill many criteria of an ideal sedative drug14,15,17 and nasal spray is preferable to nasal
drops.17 However, nasal discomfort may reduce
tolerability.22,23
The primary aim of the present study was to test whether intranasal
spray administration of midazolam could reduce anxiety, discomfort,
pain, and procedure problems if given before insertion of a needle in a
subcutaneously implanted central venous port. Furthermore, tolerability
and side effects were investigated.
This is a randomized, double-blind, placebo-controlled,
crossover study performed in a regional center for pediatric oncology at Uppsala University Children's Hospital, Sweden, during 10 months in
1997 and 1998. Children and their parents, consecutively admitted during the study period, were invited to join. Inclusion criteria were
as follows: 1) the child was over 6 months of age; 2) the child would
need to have a needle inserted 3 times during the study period; and 3)
the child was not so terrified by the procedure that a sedative had
been given on a regular basis previously (in which case it would have
been unethical to withhold sedatives in a blinded, placebo-controlled
design). Children were randomized to 1 of 2 blinded branches with
different starting points:
midazolama-placebob-placeboc
or
placeboa-midazolamb-midazolamc.
In the second step, the child crossed over to be his/her own control.
The third step, without crossover, compared with step 2, was conducted
as control for psychological carry-over effect. Forty-three children
and their families gave their consent. In the first step, 43 children
participated, and in the second and third steps, 31 and 17, respectively. Reasons for dropouts are shown in Table
1. The ethics committee at the Faculty of
Medicine, Uppsala University, and the Medical Products Agency approved
this study.
TABLE 1
PATIENTS AND METHODS
Number of Children Dropping Out for Described Reasons at Second and
Third Steps
Procedure
All children and parents were informed and prepared before the procedure according to the routines of the ward. They were informed that the intranasal spray would produce a burning sensation in the nose and have a bitter taste. All children received the EMLA patch (containing 25 mg of lidocaine and 25 mg of prilocaine) for standardization, and the needle was inserted 60 to 120 minutes after application. The nasal spray was administered when the child was calm and sitting in the lap of a parent. We gave the drug with a graded pump device providing .1 mL per puff (Apoteket AB; The National Corporation of Swedish Pharmacies, Stockholm, Sweden). Blinded ampoules contained 1.2 mL of midazolam 5 mg/mL or placebo. Each child was assigned a batch with 3 blinded ampoules (a, b, and c) with midazolama-placebob-placeboc or placeboa-midazolamb-midazolamc, respectively, according to randomization. The batches with blinded ampoules were prepared by Apoteket AB (The National Corporation of Swedish Pharmacies, Umeå, Sweden). The midazolam preparation (Dormicum/Versed; F. Hoffman-La Roche Ltd, Basel, Switzerland) was the same as that used for IV administration with a pH of 3.3. The placebo contained citric acid 7.65 mg/mL in saline with a pH of 2.22 to give a burning sensation in the nose similar to that produced by midazolam to preserve blindness as far as possible. Blinded tests were performed beforehand with 3 volunteers (medical professionals) to assure nasal discomfort was equal in the placebo and in the active substance. We chose citric acid because it is a well-studied substance without intrinsic sedative or other pharmacological activity that would interfere with our study. The ampoules were placed in the pump device and 1 or 2 puffs were made in the air to check function before use.
We gave children .04 mL/kg body weight. With active substance this equaled .2 mg/kg body weight according to earlier recommendations.17,24,25 The maximum dose was 10 puffs (ie, 1 mL = 5 mg if active substance). Children receiving >4 puffs received 2 puffs in each nostril initially, followed by another dose after 1 minute to allow absorption. No extra dose was given. The needle was inserted while the child was lying down, 10 minutes after nasal administration because time of onset has been shown to be 7.2 ± 4 minutes (mean ± standard deviation).17
The child was not allowed to eat or drink the last 30 minutes before the procedure, but otherwise there were no food restrictions because it was considered to be a very shallow type of conscious sedation. For safety, however, resuscitation equipment including a suction apparatus and a pulse oximeter were available according to guidelines for conscious sedation.21 Pulse oximetry was to be used if the child became so sedated that he/she had difficulties responding to questions. Monitoring of effects and side effects were documented on a chart used for conscious sedation at the ward. All children were observed for at least 1 hour after the sedation.
Evaluation
Children, parents, and nurses evaluated the sedation and the procedure from their separate perspectives with a 100-mm visual analog scale (VAS) questionnaire. Children from ~7 years of age and older completed the evaluation form by themselves. Younger children and children who did not understand the questions were helped by a research nurse who did not attend the procedure to avoid inappropriate influence. The children's evaluation was performed at the earliest 1 hour after the procedure to avoid influence by the sometimes sedating medication. One of the side effects of midazolam is amnesia, which probably affected the evaluation. However, the child still had a perception of how the sedation and procedure was, and because self report is considered most appropriate when it comes to pain evaluation,26 we wanted to highlight the perspective of the child together with that of parents and nurses. Seven questions were put to children, parents, and nurses to evaluate outcome and tolerability of side effects (Table 2). We made a distinction between discomfort and pain because children at times complain of discomfort even though a procedure may not be painful. This is not uncommon when inserting a needle in an IV port after pretreatment with EMLA.
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Analysis
Analysis of the material comparing midazolama-placebob with placeboa-midazolamb showed no significant differences, indicating that starting with active substance or placebo did not affect the result. We also compared midazolamb with midazolamc and placebob with placeboc to rule out that the differences between midazolam and placebo were attributable to psychological carry-over effect. We found no differences indicative of such an effect. Thus, it was reasonable to analyze the material comparing midazolam and placebo in the first 2 steps of this crossover study.
There are reasons to believe that the most anxious children would benefit most from sedation. To investigate this, a research nurse classified children with regard to fear of the procedure in 3 groups: 1) no fear/anxiety, 2) some fear/anxiety, and 3) much fear/anxiety. This classification was based on nurses' appraisal of previous insertions of a needle in the child's IV port.
Statistical Analysis
Sample size was calculated to reach a power of .80 and 
of
<.05 for the primary outcome question, question 4 (Tables 2 and 4). In reality, the difference between midazolam and placebo was
greater than expected and power almost reached 100%.
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Nonparametric tests were generally used. For comparison of related
samples, Wilcoxon-signed ranks test was used for ordinal data and
McNemars test was used for nominal data. Tests for differences in
anxiety with age and gender were made in cross tables using the
2 test. All statistical analyses were
performed using SPSS 8.0 (SPSS Inc, Chicago, IL). P values
of <.05 were considered significant.
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RESULTS |
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Top
Abstract
Results
Discussion
Conclusion
References
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Patient and dose characteristics are shown in Table 3. With the crossover design these parameters should be about the same with each patient being his/her own control. With dropouts, however, it was important to show that the groups were still similar. We found significant differences between midazolam and placebo in most outcome measures (Table 4). Parents and nurses reported highly significant reduction of anxiety, discomfort, and procedure problems (P < .001 for all 3) in the children receiving midazolam compared with placebo, and also reported significant reduction of pain (P < .05). Children reported significant reduction of anxiety and procedure problems (P < .05 for both). This difference was not as great as for the other raters. No significant differences were found in reduction of discomfort and pain in children's reports. A dichotomous validation-control question of whether they would like the same medication again showed significant differences for parents and nurses (Table 5) but not for children.
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There were no differences in the expression of discomfort after nasal spray and in how children felt after the needle had been inserted comparing active treatment and placebo (Table 6).
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No serious or unexpected side effects were reported. All children were able to respond to questions during the procedure, thus, it was indeed conscious sedation. The most common side effect was nasal discomfort, followed by crying, bad taste, split vision, and dizziness (Table 7). The first 3 were also common in the placebo group, but not the last 2. Crying was significantly more common in the midazolam group. Severity of side effects was assessed if present, and the median rating for midazolam was 62.5 compared with 76.0 for placebo on a 100-mm VAS.
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We found significant differences in fear/anxiety of having the needle inserted in the IV port with age (P = .024), in which the younger children were more anxious than the older children, but not with gender (P = .734; Table 8). Analysis of outcome measures in the different "fear of needle groups" showed that the significant differences demonstrated in the study group as a whole were most significant in group 3, with much fear/anxiety.
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DISCUSSION |
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Top
Abstract
Results
Discussion
Conclusion
References
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In different fields of pediatrics, anxiety about pain and pain in minor procedures is a big problem. Some children require sedation, but without an IV line this requirement is often overlooked. In pediatric oncology in which many treatment protocols span over long periods of time with repeated medical procedures, there is sometimes a need for a safe and effective model for conscious sedation without IV access to preserve the child's co-operability. In pediatrics in Sweden, midazolam has been used for some years as intranasal spray on similar indications, although it is not registered for this route of administration. Therefore, it was natural to study the effects and side effects in the frame of a controlled study.
According to parents and nurses the children's anxiety, discomfort, pain, and procedure problems were all significantly reduced with midazolam, and they would like the child to use it again at next procedure. Children reported significant reduction of anxiety and procedure problems. No serious or unexpected side effects occurred, but nasal discomfort was common and for a few children a reason to drop out.
Congruence between answers to the control-question, question 5, and the other questions, especially question 4, increases the validity of the investigation.
There was a high frequency of dropouts (Table 1). This was primarily because some children did not need to have a needle inserted in their IV port as often as expected when they were included. The other important reason was nasal discomfort.
The placebo contained citric acid to preserve blindness concerning nasal discomfort and taste. We found that nasal discomfort was approximately the same in both groups, which indicated that blinding in this respect seemed adequate. Crying was significantly more common in the midazolam group; a well-known side effect attributable to reduced affect-control. Children who received midazolam did not feel worse after the procedure, compared with those who received placebo.
Pain is by definition a subjective sensation27 and the gold standard for measurement is self-report.26 The same is probably true for anxiety. Therefore, it would have been ideal if the children could have reported themselves. However, some children could not give adequate reports because of low age or amnesia attributable to midazolam, decreasing the number of respondents and power. These factors may explain why differences between midazolam and placebo are less pronounced in the reports of children than in the reports of parents and nurses in this study. This demonstrates a need to highlight the effects also from the perspectives of parents and nurses. Different studies concerning pain assessment have compared the perspectives of patients/children, parents, and medical professionals.28-34 Sometimes discrepancies between perspectives have been shown. A proposed reason for this has been inaccuracy in measurement.29,31 When a child's rating does not agree with an observer's rating, it has often been concluded that the child provides an inaccurate assessment33 or is unable to understand the required task. When the parent's rating show discrepancies compared with that of a trained observer, it has been presumed that the parents are biased.35 It has been suggested that each mode of assessment may target a different aspect of pediatric pain and that it may be more useful to understand the factors that contribute to differences among ratings, rather than to rule out data obtained from a certain individual.30,32
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CONCLUSION |
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Top
Abstract
Results
Discussion
Conclusion
References
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Nasal midazolam spray offers relief to children anxious about minor medical procedures, such as insertion of a needle in a subcutaneously implanted IV port, venous blood sampling, venous cannulation, etc. Its use, however, may be limited by nasal discomfort, especially in younger children for whom rectal and oral routes might be alternatives.
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ACKNOWLEDGMENTS |
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This investigation was supported by grants from the Children's Cancer Fund, Lions Cancer Fund at the University Hospital of Uppsala, and by Grant 9077 (to T.G.) from the Swedish Medical Research Council.
Belinda Hedberg, RN, is acknowledged for constructive administration of this study and valuable discussions. The children with cancer and their parents are acknowledged for their collaboration.
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FOOTNOTES |
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Received for publication Dec 31, 1999; accepted Jul 6, 1999.
Reprint requests to (G.L.) Unit for Pediatric Oncology and Hematology, University Children's Hospital, SE-751 85, Uppsala, Sweden. E-mail: gustaf.ljungman{at}pediatrik.uu.se
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ABBREVIATIONS |
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IV, intravenous; EMLA, eutectic mixture of local anesthetics; VAS, visual analog scale.
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REFERENCES |
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Abstract
Results
Discussion
Conclusion
References
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methods and results of a nationwide registry.
Eur J Cancer
1995;
31A:993-999 [CrossRef]preliminary report.
Pain
1987;
31:177-188 [CrossRef][Medline]
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  J. Laham Propofol: Risk vs. Benefit Clinical Pediatrics, January 1, 2002; 41(1): 5 - 7. [PDF]
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 M. E. McCann and Z. N. Kain The Management of Preoperative Anxiety in Children: An Update Anesth. Analg., July 1, 2001; 93(1): 98 - 105. [Full Text] [PDF]
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 R D W Hain, C Campbell, S SPACE, S KHARASCH, and H BAUCHNER Invasive procedures carried out in conscious children: contrast between North American and European paediatric oncology centres Arch. Dis. Child., July 1, 2001; 85(1): 12 - 15. [Abstract] [Full Text] [PDF]
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