Medical and Pediatric Oncology 19:499-504 (1991)

Midazolam premedication for Pediatric Bone Marrow Aspiration and Lumbar Puncture Alice C. Friedman, PhD, Raymond K. Mulhern, PhD, Diane Fairclough, Dr PH, Pamela M. Ward, MA Ed., Donald Baker, Pharm D, Joseph Mirro, MD, and Caston K. Rivera, MD The ability of midazolam, a benzodiazepine, to reduce the distress associatedwith lumbar puncture and bone marrow aspiration was examined in 23 children with acute lymphocytic leukemia. Patients were randomized to receive 0.2 mgkg midazolam HCI or placebo intravenously 3-5 min before the procedures, under double-blind conditions. Based on prior experiences, children in both groups anticipated severe pain from these procedures. Postprocedure pain ratings by patients were markedly reduced in the midazolam but not the placebo group. Both physicians and parents judged the midazolam group as significantly less distressed than controls during and after the

procedures. Trained observers recorded significantly fewer pain: and anxiety-related behaviors in the midazolam group immediately before and after, but not during the procedures. The amnestic effects of midazolam, confirmed in a visual recall/ recognition test, appear to account for the decreased pain ratings since the behavioral manifestations were similar in the two groups. There were no adverse drug reactions or significant changes in vital signs. Midazolam warrants further investigation as a premedication for painful diagnostic and treatment procedures in children with cancer.

Key words: pain, benzodiazepine, cancer

INTRODUCTION

of toxicity or oversedation with the use of potent systemic medications [ 111. Also, children have shown paradoxic The distress experiencedby children with cancer, even responses to some drugs that decrease the discomfort of those with advanced disease, is more often related to their adults during cancer therapy [12]. treatment than to the disease itself [l]. Knowledge of In a survey conducted at St. Jude Children’s Research effective methods to control pain and alleviate anxiety Hospital (SJCRH), practitioners rated current premedihas not kept pace with the development of increasingly cations for BMA and LP with local anesthesia and oral effective, and often more aggressive, therapeutic interdiazepam or meperidine, promethazine, and chlorproventions. Invasive diagnostic procedures are major mazine in combination as only modestly effective. Fursources of apprehension, particularly when they must be ther, there were reports of children remaining uncooperrepeated routinely to assess disease status [2,3]. Prime ative even with heavy sedation. We therefore undertook examples are bone marrow aspiration (BMA) and lumbar a double-blind pilot trial of midazolam, a benzodiazepine puncture (LP) in children being treated for leukemia. The distress associated with these procedures is typically severe and tends to increase with successive experiences. From the Divisions of Psychology (A.G.F., R.K.M., P.M.W.) and ~41. Biostatistics and Information Services (D.F.), the Department of Existing pain control practices for children are incon- Hematology-Oncology (J.M., G.K.R.), and the PharmaceuticalDivisistent and generally inadequate [l]. Children are less sion (D.B.), St. Jude Children’s Research Hospital, Memphis, Tenlikely than adults with similar diagnoses to receive pain nessee; and the Department of Pediatrics, the University of Tennessee medication [5,6]. When analgesics are prescribed, they College of Medicine, Memphis, Tennessee. are often given inconsistently, infrequently, and in inad- Received July 18, 1990; accepted April 3, 1991. equate doses [7]. Possible explanations for this include Address reprint requests to Alice G . Friedman, PhD, Department of the dearth of empiric studies in pediatric pharmacology, Psychology, State University of New York at Binghamton, Binghamespecially regarding pain medications [8-101 and the fear ton. New York 13902-6000. 0 1991 Wiley-Liss, Inc.

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that has shown promise as a preanesthetic agent in observing the treatment response, declined to further children [ 13-1 51. We compared midazolam to placebo enroll patients who might be randomized to the placebo because there is no generally accepted, consistently treatment. effective premedication suitable for comparison in this clinical setting. PROCEDURE

METHOD Patients

Children aged 3-16 years with acute lymphocytic leukemia (ALL) in complete remission were eligible for study unless they had known sensitivity to benzodiazepines or had been routinely sedated in the past for BMNLP. Children who had been previously sedated with midazolam for bone marrow biopsy were not excluded. All children had an existing central venous catheter with adequate access or were already scheduled to receive a catheter i.v. for chemotherapy later the same day. All children were scheduled to receive both BMA and LP. The study was approved by the institution’s clinical trials review committee, and informed consent was obtained from parents, and assent from children, according to institutional guidelines. Study Design

To avoid unnecessary exposure of children to the placebo condition, interim analyses were planned after 20,40, and 60 patients had been evaluated. As specified in the protocol, interim analyses involved two measures: the total score for the Observational Scale of Behavioral Distress-Revised (OSBD-R) and the practitioner’s rating of patient distress after the procedure. If the differences between the two groups on both measures were significant (a= 0.01) then patient accrual was to be terminated. When the first analysis was performed, the practitioner’s rating of patient distress was highly significant ( P < 0.0001) but the total OSBD-R scores barely failed to meet the statistical criterion ( P = 0.015). The study was nevertheless terminated when physicians,

Upon enrollment in the study, patients were randomly assigned to receive midazolam or placebo. A stratified block randomization, with block size of 2, was used to balance treatment assignment by age ( I 2 years) and gender because these characteristicshave been shown to influence children’s behavioral responses to BMA and LP [3]. Characteristics of the 23 patients enrolled are given in Table I. Children underwent BMNLP during regularly scheduled clinic visits. Midazolam HC1 (0.2 mg/kg, to a maximum of 8 mg) and placebo (0.9% sodium chloride USP) were prepared in identical syringes. Practitioners (physicians, nurses, and physician’s assistants), parents, and patients were blinded to the contents of syringes. Injections were administered by slow i.v. push, 3-5 min before BMNLP. The children were continuously monitored by cutaneous oximetry, and a nurse recorded blood pressure, respiration, and pulse rates at regular intervals. Supplemental oxygen, resuscitative equipment, and personnel trained in cardiac support were immediately available. ASSESSMENTS

On the morning of scheduled BMNLP, children rated the distress they expected to experience on a visual analog scale shaped like a thermometer which is numbered from 0 (no pain) to 100 (extremely severe pain) marked in intervals of 10. When the procedures were completed, children used this pain thermometer to indicate the pain they had actually experienced. Parents and practitioners completed 10-point Likert-type scales after BMNLP to rate the child’s distress (0 = none, 10 =

TABLE I. Demographic Characteristics of Patient Sample* Midazolarn (N = 11) Median Range Age at study (yr) Age at diagnosis (yr) Days since last BMA/LP Number of previous BMA/LP Race (% white) Sex (% male) Previous midazolarn

5.8 3.5 105 9.0

3.1-15.3 1.9- 12.5 39-163 5-37 Percent 91 54 20

*There were no significant differences between groups (P > .25).

Placebo (N = 12) Median Range 4.8-15.4 2.2-14.0 112 48-273 8.5 5-3 1 Percent 83 42 17 6.5 5.4

Midazolam Prernedication

extreme) and cooperativeness (0 = extremely cooperative, 10 = highly uncooperative). All ratings were completed individually with respondents blind to all other respondent’s ratings. Each child’s behavioral manifestations of fear and anxiety (e.g., crying, verbal resistance, flailing) were recorded throughout the study period by one of three trained observers who were also blind to group assignment. Ratings were based on the Observational Scale of Behavioral Distress-Revised (OSBD-R) [16], with the exclusion of the items related to the need for restraint since all children were restrained for these procedures. Behaviors were recorded in continuous 15sec intervals during four phases of the procedures: Phase 1 (Anticipatory p e r i o d 4 5 sec preceding site cleansing), Phase 2 (Site preparation-the first 90 sec of site cleansing), Phase 3 (Procedures-an average of the first 90 sec from needle insertion for BMA and for LP), Phase 4 (After BMNLP-the first 90 sec following needle withdrawal after the second procedure). A minimum interobserver agreement [(agreemenuagreement + disagreement) X 1001 of 80% for five consecutive procedures was obtained prior to the trial. A visual recall/recognition test was used to evaluate the effects of midazolam on memory. Each patient was shown two different cards depicting familiar cartoon and storybook characters, one immediately before the injection and the other between BMA and LP. An hour after BMNLP, children were asked to name these characters (recall) or, if they could not do so, to select the appropriate card from a group that included others not seen previously (recognition).

(Extreme) 10

Statistical Analyses

Comparisons of the two treatment groups were based on the Wilcoxon rank sum test or, for dichotomous variables, Fisher’s exact test. The level of significance for the two variables used in the interim analysis was set at 01 = .01. For the remaining variables the level of statistical significance was set at 01 = .05. RESULTS

The midazolam and placebo groups did not differ on any of the clinical characteristicsthat might have affected children’s perception or expression of pain (see Table I). All 23 children had undergone numerous prior BMAs and LPs and there were no significant differences in number of previous procedures in the two groups. Prior to the procedures, the majority of patients rated their degree of expected pain as extreme with no significant difference noted between those randomized to the two groups (medians = 100, P > 0.25). Following the procedures, the children who received midazolam rated the actual pain of BMNLP as minimal, whereas children given placebo rated the BMNLP as extremely painful (medians = 0 vs. loo, P < 0.01). Practitioners rated the midazolam group as significantly less distressed than the placebo controls before (medians = 5.0 vs. 8.0, P < 0.05), during (medians = 4.5 vs. 8.0, P < 0.05), and after (medians = 0.0 vs. 4.0, P < 0.01) the BMAlLP (Fig. 1). Parents’ ratings were similar to those of practitioners but did not differ significantly between the midazolam and placebo groups

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Fig. 1. Distress ratings for children given midazolam (open bars) or placebo (hatched bars) pre-, during, and post-BMNLP. Dark horizontal lines represent median values. Top and bottom of the boxes outline the 25th-75th percentiles.

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for the preprocedure interval. There were no differences between the midazolam and placebo groups in practitioners’ (medians = 8.0 vs. 6.5, P > .25) or parents’ (medians = 6.0 vs. 6.5, P > .25) ratings of cooperativeness during the BMNLP. Scores on the OSBD-R (Table 11) indicated that painand anxiety-related behaviors were significantly less frequent in the midazolam group during preparation of the site and after the procedures were completed. The frequency of observed distress behaviors did not differ between groups during BMNLP. Children in the midazolam and placebo groups exhibited equivalent recall and recognition of the memory test cards (Fig. 2) they had been shown before injection (P > .25). However, compared to the placebo group, the

TABLE 11. Median Scores (and Ranges)on the Observational Scale of Behavioral Distress* Group Before BMAlLP Site preparation During BMA/LPb After BMAlLP

Midazolam

Placebo

P-Value

0 (0-6.0)’ 2.2 (0-5.2) 3.3 (0.3-8.8) 1.6 (0-3.5)

2.3 (0-6.5) 4.8 (0-9.0) 5.3 (1.0-9.8) 3.4 (0-4.8)

.02 1 .017 .29 .016

*Lower scores indicate less distress. aL~w scores probably reflect the rapid onset of sedative effects, as this scoring phase continued after injection. bRatings are based on summed means for the time periods of bone marrow aspiration and lumbar punctures.

children given midazolam had significantly impaired recall (88% vs. 9%, P < .001) and recognition (100% vs. 18%’ P < 0.001) of the cards that were presented during the interval between BMA and LP. No overt signs of psychologic or physiologic toxicity were observed, and all children recovered uneventfully from the procedures. There were no significant differences between the midazolam and placebo groups on measures of blood pressure, pulse or respiration rates at any assessment interval (P > .25). DISCUSSION

Midazolam significantly reduced the perceived pain of lumbar puncture and bone marrow aspiration in children who had numerous prior experiences with these procedures and considered them extremely painful. Children’s self-reports were paralleled by parent and practitioner ratings indicating significantly less distress in the midazolam than the placebo group during and after BMA/LP. This study extends previous findings of midazolam’s efficacy as a preanesthetic for pediatric orthopedic or otolaryngologic surgery [ 14-16] by suggesting its usefulness as a premedication for painful, invasive diagnostic procedures. Because the use of a placebo in this setting raises humanitarian concerns, we limited our sample to the number of patients required to demonstrate significant drug effects. The patients who received placebo in this study can serve as historical controls for future studies, thus avoiding unnecessary exposure of children to painful procedures without premedication.

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Fig. 2. Recall and recognition of memory cards presented pre- and postinjection with placebo (hatched bars) or midazolam (solid bars). Differences between groups are significant only for memory cards shown after injection (P < 0.001).

Midazolam Premedication

Other premedications used for BMNLP can render children even less cooperative during the procedures [2]. In this study, children who received midazolam were no more or less cooperative than those who received placebo. The fact that patient cooperativeness was not improved in the midazolam group even though selfreported pain was diminished probably reflects druginduced amnesia for the experience [ 131. Children given midazolam remained alert and responsive to physical and verbal stimuli, and showed behaviors indicative of distress during BMNLP. Yet they did not remember the procedures as painful; in fact, 1 hr later, some children did not realize that the BMA/LP had even been completed. The amnestic properties of midazolam were strongly confirmed by the visual recallhecognition test. Only one of the children given the active drug could recall the memory card shown after injection, whereas all but one of the children given placebo described the card accurately. Although the duration of anterogradeamnesia was not assessed, previous studies with adults suggest it can endure for periods of up to 2 hr [ 171. The selective anterograde nature of the drug-induced amnesia is illustrated by the children’s ability to recall the cards shown prior to injection. Anecdotal reports from clinicians involved in the study suggest that children who had received midazolam were less apprehensive regarding subsequentprocedures; some requested that they be given “the same shot.’’ This observation suggests that midazolam may be useful in reducing anticipatory anxiety associated with repeated procedures. Midazolam, a CNS depressant, is typically used as a hypnotic agent and for anesthesia induction. Several pharmacologic properties of midazolam offer advantages over many sedatives in current use. It is water soluble, has rapid onset of effect, short duration of action, and a short elimination half-life [ 181. In adults, sedation is achieved within 3 to 5 min after i.v. injection [17]. Its elimination half-life averages 2.3 hr and ranges from 1.3 to 3.2 hr. In children, unconscious sedation can be achieved in fewer than 30 sec [15]. Midazolam has been associated with briefer recovery room stays and less frequent vomiting compared to morphine in children undergoing outpatient surgery [ 14,151. The most commonly reported adverse effects of i.v. administration of midazolam include hiccough, nausea, vomiting, coughing, oversedation, headache and drowsiness; each of which are reported in fewer than 4% of patients [21]. In our study, there were no adverse reactions to midazolam, and vital signs did not differ significantly between the placebo and midazolam groups after injection. There is currently no information available about the frequency of midazolam adverse reactions in children. However, there have been rare reports of respira-

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tory depression [ 191, dysrhythmia 1201, and cardiac arrest [21] in adults given injectable midazolam in clinical settings. As emphasized in the manufacturer’s prescribing information [ 191, midazolam should be administered slowly (rather than as a bolus), and use of the injectable form to achieve sedation requires careful monitoring and the availability of appropriate emergency equipment and personnel. Reducing treatment-related distress experienced by children with cancer is an important goal. Yet research in this area has been limited, and the safety and efficacy of the oral and systemic premedications most often used for BMA and LP have not been clearly demonstrated in children. As shown in this study, midazolam is a promising premedication for BMNLP in children being treated for leukemia. The anterograde amnesia produced by the drug may alleviate the intense anticipatory anxiety and fear of children who must undergo these procedures on a routine basis. Local anesthesia used in conjunction with midazolam may further reduce perceived pain and distress. Further studies are needed to extend the findings of this small controlled trial to the investigation of the efficacy of other sedative and analgesic premedications for BMA and LP. ACKNOWLEDGMENTS

This work was supported by National Cancer Institute Grants CA 20180, CA 21765, and CA 23099 and by the American Lebanese Syrian Associated Charities (ALSAC). We gratefully acknowledge the assistance of Bruce Smith and Laurie Leigh in data collection; Andi Wood, Ruth Greer, and the nurses and staff of our outpatient clinic for the clinical care of the patients; Christy Wright for editorial advice; and Vicki Gray for manuscript preparation. REFERENCES 1. Miser AW, Dothage JA, Wesley RA, Miser JS: The prevalence of pain in a pediatric and young adult cancer population. Pain 29:73-83, 1987. 2. Jay SM, Elliott CH, Katz E, Siegel SE: Cognitive-behavioraland pharmacologic interventions for chifdren’s distress during painful medical procedures. J Consult Clin Psychol 55:86&865, 1987. 3. Katz ER, Kellerman J, Siegel SE: Behavioral distress in children with cancer undergoing medical procedures: Developmental considerations. J Consult Clin Psychol 48:356365, 1980. 4. Zeltzer L, LeBaron S: Hypnosis and nonhypnotic techniques for reduction of pain and anxiety during painful procedures in children and adolescents with cancer. J Pediatr 101:1032-1035, 1980. 5. Beyer JE, DeGood DE, Ashley LC, Russel GA: Patterns of postoperative analgesic use with adults and children following cardiac surgery. Pain 17:71-81, 1983.

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