Invasive diagnostic or therapeutic procedures, such as lumbar punctures and bone marrow aspirations and biopsies, are required for the management of most children with cancer and serious hematologic disorders. The physical and emotional distress caused by these procedures are notable and have been well documented in behavioral studies of children with cancer.¹ Because procedure-related discomfort has been identified by children as the most negative aspect of their cancer treatment, efforts to improve their quality of life have included minimizing the acute distress associated with the procedures.⁴ One such approach has been the use of brief sedation or anesthesia to reduce the anticipation and actual experience of pain during the invasive procedures.

The selection of a sedation agent appropriate for that purpose is dependent upon several factors. These include the procedures, which vary in type, combination, duration, invasiveness, and frequency; the patients, who have variable coping capabilities; and the treatment setting, which is typically a busy outpatient clinic. Accordingly, desirable characteristics in a sedation agent for this patient population include rapid onset, predictable efficacy, controllable duration, and short recovery time, as well as convenient administration, manageable side effects, and feasibility relative to institutional resources.

With the above in mind, since 1991 we have operated a joint sedation program staffed by our Divisions of Hematology/Oncology and Critical Care Medicine, in which children are routinely offered brief, unconscious sedation while undergoing their invasive outpatient procedures. In our institution, the agent used almost exclusively for this purpose has been methohexital sodium for intravenous use (MHX; Brevital, Lilly). MHX is an ultrashort-acting barbiturate which results in rapid induction of sleep with fewer cumulative effects and more rapid recovery than with other barbiturates.⁵ MHX was selected for use in our program because its properties appeared consistent with those of a desirable sedation agent described above, as suggested by the prior experience of our pediatric intensivists using MHX for invasive procedures in critically ill children. Our preliminary experience using MHX for the sedation of pediatric oncology outpatients was recently reported in a retrospective study.⁶

Because of limitations related to its retrospective design, however, we undertook this larger, prospective study in which we sought to confirm the apparent safety and efficacy of MHX for pediatric oncology outpatients undergoing invasive procedures. The specific aims of this study were: 1) to characterize in greater detail the physiologic responses of children receiving MHX sedation while undergoing invasive procedures; 2) to determine more accurately the types and incidences of adverse reactions in children receiving MHX sedation; and 3) to measure the levels of behavioral distress exhibited by children undergoing invasive procedures while receiving MHX sedation.

MATERIALS AND METHODS

Sedation Procedure

Physiologic Response Assessments

Behavioral Distress Assessments

RESULTS

Patients and Procedures: Characteristics

Table 1. Patient Characteristics [View Table]

Table 2. Outpatient Procedures Performed [View Table]

Procedural Data

Table 3. Summary of Procedural Data From 233 Outpatient Procedures [View Table]

Physiologic Responses

Also for each procedure, SaO₂ was measured continuously and recorded at 3-minute intervals. Of the 233 procedures, seven (3.0%) were associated with measured but clinically insignificant decreases of SaO₂ below 94%, which responded to the simple addition or increase of low-flow supplemental oxygen.

Adverse Reactions

Table 4. Number of Adverse Reactions Among 233 Outpatient Procedures [View Table]

Two (0.9%) procedures were associated with transient airway obstruction: one in a 14.6-year-old child with acute myelogenous leukemia who vomited thick gastric secretions but responded promptly to suctioning, airway positioning, and increasing supplemental oxygen; the other in a 3.7-year-old child with acute lymphoblastic leukemia who had copious oropharyngeal secretions and possible incomplete laryngospasm, and responded rapidly to suctioning and brief (<30 seconds) positive-pressure assistance with a bag-mask device. None of the 233 procedures was associated with apnea, intubation, or early termination for any reason. All invasive procedures were completed with a satisfactory level of sedation.

Behavioral Distress Responses

Table 5. Number of Invasive Procedures Associated With Behavioral Distress During MHX Sedation (n = 49)* [View Table]

DISCUSSION

Methohexital is an ultrashort-acting oxybarbiturate available as a monosodium salt for intravenous administration.⁵ The drug is highly lipid soluble and, after infusion, undergoes rapid uptake by gray matter in the central nervous system.⁹ Accordingly, the onset of its sedative effect is nearly immediate (within 30 seconds).⁵ The drug then undergoes redistribution into less vascular areas of the brain and other tissues with a distribution half-life of approximately 6 minutes.¹⁰ It is believed that this rapid redistribution phase of MHX is primarily responsible for its short duration of sedative effect. However, MHX is also extensively extracted and metabolized by the liver and subsequently excreted by the kidney with an elimination half-life of 3.5 hours.^10,11 Therefore, it tends not to accumulate in body tissues as extensively as other highly fat soluble barbiturates, such as thiopental.⁵

Introduced for clinical use in the early 1960s, MHX has continued to be used primarily for preoperative induction of anesthesia in children via the rectal¹² or intravenous^11,15 routes. Before the initiation of our MHX sedation program in 1991, published applications of single-agent MHX for brief pediatric sedation were limited to diagnostic or therapeutic radiology (by the intramuscular route)^16,17 and dentistry (by the rectal route).¹⁸ Given its nearly immediate onset and short duration of effect, MHX given intravenously offered the possibility of rapidly achieving an adequate level of sedation which could then be maintained in highly individualized fashion through the frequent titration of additional small amounts of MHX. Such dosing flexibility seemed well suited for pediatric oncology outpatients, where consistent sedation efficacy and short recovery times are desirable despite varying duration and invasiveness of procedures.

The results of our study appear to confirm these characteristics. As measured from the onset of sedation, the mean time to patient alertness was only 22 minutes, which included performance of the invasive procedures themselves (Table 3). This time is shorter than the 30 minutes to patient alertness noted in our previous study, a difference probably accounted for by the 20% reduction in the cumulative MHX dose used in this study. Because the patient populations, invasive procedures, and loading MHX dose were comparable between our two studies, this reduction in cumulative dose may reflect further refinement of our dose titration technique. Despite the lower MHX dose, the level of sedation provided continues to be effective, as suggested by the favorable behavioral response data discussed below. Few pediatric oncology sedation studies report the time required for either sedation onset or recovery. Defined differently between studies, recovery from sedation appears to have ranged between approximately 1 and 4 hours as reported for oral midazolam,¹⁹ oral ketamine,²⁰ and a combination of intravenous midazolam/ketamine or etomidate/fentanyl.²¹ Relative to these studies, the total time per patient required for completion of procedures and sedation appear to be substantially less with intravenous MHX. This characteristic is not only beneficial for patients, but also promotes efficiency for our pediatric intensivists, by allowing five to seven sedations to be performed sequentially on each of two clinic days per week.

Two specific aims of this prospective study were to characterize in further detail the physiologic responses and adverse reactions to MHX sedation in this patient population. Both the heart and respiratory rates increased transiently by approximately 10 to 20% during the time coinciding with the painful stimulus. In contrast, for the MAP there was a gradual 10 to 15% decrease below baseline during sedation, a change which could represent the normal response of a sleeping child, possibly magnified by mild preprocedure anxiety elevating the baseline measurement. As with our previous experience, these measured physiologic responses to sedation, including the decreased MAP, were clinically insignificant and needed no intervention.

Adverse reactions encountered in this study were similar to our previous experience in type, overall lack of severity, and minimal need for intervention. Because of their importance, respiratory complications were monitored carefully. The most frequent of these was increased oropharyngeal secretions easily managed with simple suctioning. While this may well be considered an expected occurrence in deep pediatric sedation, we elected to track oral secretions to provide a more complete description of typical management required for safe sedation using MHX. Isolated, nonobstructive stridor of mild to moderate severity was noted in 2.6% of procedures and was managed with simple airway repositioning. Rare, but of importance, were two episodes of transient upper airway obstruction, as described in Results. Neither of these patients had any interval history of upper respiratory symptoms before sedation. Both patients had received previous MHX without difficulty, and MHX was given subsequently to the first child without complication. Combining our two studies of MHX sedation involving 365 procedures in 109 children, there have been four (1.1%) episodes of transient upper airway obstruction. No patients have required intubation, experienced apnea, or needed premature termination of their procedure for any reason. These data suggest the incidence of these complications is very low under the conditions utilized here, though the need for expert airway management during deep sedation remains.⁷ Other sedation agents utilized in the pediatric oncology population have been associated with varied side effects including decreased blood pressure,^19,22,23 hypoxemia,^19,21 behavioral reactions,^18,25,26 laryngospasm,²⁵ emesis,^21,22,24 pruritis,^22,24 cough,²⁵ arrhythmias,²⁷ and respiratory arrest.²⁸ Thus, the adverse reactions with MHX encountered here appear less serious than many reported for similar types of pediatric sedation. Overall, our procedural experience compares favorably with published applications of MHX in other patient populations, which we have summarized elsewhere.⁶

Another specific aim of this study, unable to be addressed in our retrospective study, was confirmation of the efficacy of MHX sedation through formal behavioral distress assessments. In all but a few procedures, observed distress was rated mild, very mild, or absent altogether (Table 5). The maximal distress response noted across all procedural phases consisted of transient muscular withdrawal movements during the invasive procedure itself. We regard this as evidence that MHX sedation is effective in reducing procedure-related behavioral distress, inasmuch as the endpoint for dose titration was not the elimination of all pain responses but their reduction to mild levels, as an indication of adequate, but not excessive, sedation. It is difficult to exclude any possibility of bias inherent in observational assessments of behavioral distress. In this study, we attempted to maximize their reliability by utilizing in prospective fashion an established, standardized, relatively simple checklist of clearly defined behavioral items appropriate for detecting anxiety in children.⁸ Further, we limited our study's behavioral observers to two: a research project physician with pediatric anesthesiology training and experience (M.T.N.), and an experienced pediatric hematology registered nurse, both of whom observed several sedation procedures and were familiar with the Procedure Behavioral Checklist before performing assessments for this study. Although for ethical reasons this study did not evaluate a comparable control group of unsedated children undergoing painful procedures, we believe the observed levels of distress were far below those expected without MHX sedation, based upon our own historical observations of children before its regular use, as well as behavioral studies documenting the extreme anxiety and physical discomfort caused by these invasive procedures for children with cancer.¹ This study did not specifically evaluate whether children had any substantial, unpleasant, immediate or remote recall of the invasive procedures performed while they were sedated with MHX. However, the minimal levels of any distress measured preprocedure and at end of monitoring suggest they did not.

This study indicates the several characteristics of MHX sedation which are advantageous for pediatric oncology outpatients. Our success with this approach has led us to extend its use to children needing similar sedation for other procedures, eg, radiation therapy treatment for infants and toddlers, tunneled central venous catheter placement, and gastrointestinal endoscopy. However, it is also appropriate to recognize conditions required for its safe administration which may influence patient convenience, costs of sedation, and institutional feasibility. Regarding patient convenience, MHX and similar intravenous agents require restriction of oral intake for several hours before procedures, as well as procurement of venous access. To minimize the time in which oral intake must be actively restricted, we limit procedures to morning hours and schedule the youngest children first. This study suggests that venous access via an existing central venous catheter will be available in approximately 75% of patients. In the remainder, insertion of a peripheral venous angiocatheter must be accomplished. We consider the transient distress associated with that maneuver to be justified by the excellent quality of pain prevention during the more invasive procedures(s) subsequently performed during sedation. The use of oral sedatives will not eliminate this source of discomfort for all patients, because many need peripheral venous access for other reasons. Moreover, many oral agents pose their own inconveniences and limitations compared with MHX, including typically slower onset of effect, variable absorption, inability to be titrated rapidly and precisely according to individual need, prolonged somnolence, and patient refusal to ingest the medication. Our study did not include a longer term assessment of patient or parent satisfaction with various aspects of their experience with MHX sedation. As further sedation alternatives continue to become available, such information could aid in selecting from among them and should be sought in future studies.

The cost of deep sedation with MHX or similar agents is influenced by the need for appropriate personnel and equipment to ensure safety of the child at all times. Because much of the same equipment, facilities, and ancillary staff must also be available for safe conscious sedation, an important cost difference for deep sedation relates to the need for a "competent individual" whose sole responsibility is monitoring and managing the deeply sedated child, as recommended in current guidelines published by the American Academy of Pediatrics.⁷ In our approach, this individual is a pediatric intensivist who typically charges the standard fee for a comprehensive consultation for each sedation event. This consultation encompasses patient evaluation before sedation, direct management of the sedation itself, and patient supervision through recovery from sedation. Although not specifically measured in this study, reimbursement for this consultative service appears to be comparable to other pediatric intensive care procedures at our institution and varies somewhat with the specific third party payor. In other institutions, specific figures can be expected to vary according to geographic region, institutional billing practices, and prevailing reimbursement systems.

Finally, the requirements for safe conduct of deep pediatric sedation may also affect its feasibility relative to resources available within specific institutions. Sedation of pediatric oncology outpatients using MHX is a realistic option for institutions capable of adhering to current American Academy of Pediatrics guidelines for elective use of deep sedation.⁷ Most operational sedation programs, including ours, represent adaptations to circumstances and opportunities unique to their particular institutions. Because the safety of sedated children must remain paramount, one of several alternatives for conscious sedation may be substituted where the use of MHX is deemed impractical.

Reduction of pain during invasive procedures has been identified by the American Academy of Pediatrics as an important goal for children with cancer.²⁹ To achieve this, it is necessary to acknowledge that all approaches to pain management, even those which are exclusively behavioral, engender some degree of patient inconvenience, added expense, and institutional burden when compared with the historical practice of providing none whatsoever. In our experience reported here, we have determined that the considerable benefits of MHX sedation outweigh its few, relative disadvantages described above. With the recent development of this and other successful regimens, it may be important for future pediatric sedation studies to include well-designed, prospective comparisons of the cost and convenience, as well as safety and efficacy, of different agents and approaches.