The pharmacoeconomics of neuromuscular blocking drugs.

Abstract

The recent availability of shorter-acting neuromuscular blocking agents (NMBAs) with more favorable side-effect profiles (e.g., rocuronium, mivacurium, cisatracurium) has enhanced the conduct of safer anesthesia and promoted a prompt return to “street fitness” in patients after undergoing ambulatory surgery (1–3). However, the introduction of these newer drugs has coincided with the advent of managed care, case-mix and capitated payments, characterized by a movement away from indemnity-based reimbursements to a system in which fees remain fixed regardless of the number of services provided. The success of these new market-based programs in reducing health care costs have rendered them appealing to both employers and third-party payers and has rapidly revolutionized the manner of health care provision in the United States. In the current cost-conscious health care environment, clinical departments with high resource utilization, namely the operating rooms (OR), intensive care units (ICU), postanesthesia care units (PACU), and emergency rooms, are no longer considered profit centers but cost centers. The movement toward ambulatory surgery is in part an attempt to contain the spiraling costs of surgical care and to reduce the length of hospital stay but also to increase the number of procedures done on a same-day discharge basis. The present challenge facing the practitioner is to continue delivering the same high-quality patient care while consuming fewer resources (“value-based anesthesia care”) (4). Although the costs of drugs used for anesthesia constitute <6% of the total costs of perioperative care (5), they are highly visible and represent an easy target for scrutiny in cost-control programs (6). As limits are imposed on the total resources available for health care, it behooves anesthesia caregivers to carefully consider the fiscal as well as the clinical consequences of replacing current NMBAs with newer, more costly pharmaceuticals. Models of Economic Analysis The study of the relationship of drug therapy costs to health care systems has been termed “pharmacoeconomics,” in which four types of cost-analysis methodologies are commonly used: cost-minimization, cost-benefit, cost-effectiveness, and cost-utility analyses (1,2). Most of the recent emphasis in anesthesia has been placed on cost containment or cost minimization, where the goal is to provide a service at the least cost without regard to patient outcome (7–11). This model is often assumed by hospital administrators and insurance companies because up-front costs can be conveniently reduced. Cost-benefit, cost-effectiveness, and cost-utility analyses are applied in the evaluation of interventions that result in quantitatively definable outcomes. Cost-benefit analysis assigns a monetary value to both pertinent costs and consequences and is the most relevant model from the societal standpoint, because it determines the optimum utilization of overall health care resources for a given population. In contrast, cost-effectiveness analysis ascribes a monetary value only to the intervention and not to a specific outcome, e.g., the costs per patient free from a particular complication. This point of view is often adopted by health care providers as it attempts to discern the optimal balance between cost containment and quality improvement in patient care plans and because of the inherent difficulty in monetizing various patient outcomes. A cost-utility analysis incorporates patient preference and satisfaction factors, and defines economic costs in terms of patient-oriented outcomes, such as dollars per quality adjusted life year saved or health equivalent life year saved. Unfortunately, these terms are often misused in pharmacoeconomic studies (12). Dynamics of Anesthesia Costs The costs of a therapeutic regimen will depend on the perspective of whoever is making the assessment. The patient’s perspective of total costs would include nonmedical “out-of-pocket” expenses (e.g., transportation, lodging for caretakers, domiciliary care, insurance premiums), along with the indirect cost from lost wages (2). From an institutional perspective, the true costs of using a particular drug are not limited to the acquisition cost of the amount administered, but also include the costs for storing, dispensing, and administering the drug, drug wastage, as well as the labor and material costs to treat side effects (13). Many studies of anesthetic drugs have used charges as a substitute for costs; however, the cost-to-charge ratio is lower for anesthesia services compared with that for other departments of the hospital, and the use of charges as a substitute for costs leads to over-estimates of resource consumption by the anesthesia department (5). Moreover, a comparison of charges and costs among and within institutions over different time periods is difficult because of disparities in bulk-purchasing discounts and dispensing policies. The up-front purchase costs of NMBAs can compose a significant portion of a hospital’s pharmacy budget (8,9), and several new NMBAs have recently been added to hospital formularies in part because of aggressive sales efforts of the pharmaceutical industry (14). Many OR managers and administrators tend to adopt the simplistic view that the drug with the lowest acquisition price is the preferred drug, and that there are no cost consequences associated with differences in the duration of action or side effects of drugs in the same class (1,2). Recent studies (7–11) advocating the preferential use of older and less expensive NMBAs (succinylcholine versus rocuronium or mivacurium, pancuronium versus vecuronium or atracurium) have not fully elucidated the savings (3,15). Educational programs, pharmaceutical practice guidelines, departmental policies, price-labeling, and formulary restrictions have been adopted in these studies to promote cost containment, but they have met with mixed results as physicians tend to revert to their former practice patterns (16–20). Suggestions that cost reduction could be achieved through synergistically combining NMBAs have not addressed concerns of altered drug biodisposition (21). Carefully conceived and administered guidelines based on cost and outcome data gleaned from computerized records could help the anesthesiologist make more informed drug selection choices (22). Comparative cost analyses between “old” and new drugs should encompass direct and indirect costs and factor in benefits to both the patient and practitioner. There could well be an indirect cost-related boon to having a “peace of mind” from avoidance of adverse events caused by the older drugs, as well as the ease of administration, improved titratability, and better predictability of drug action conferred by the newer NMBAs. Research has shown that not all practitioners attain the same desired patient outcome after anesthesia, and the best outcome would probably result from familiarity with a particular drug or technique. To resurrect older, long-acting drugs that most anesthesiologists have since stopped using in their clinical practice would reduce the total hospitalization cost by no more than 3% (5) yet may lead to more adverse sequela. The cost-versus-quality debate would probably rage on as physician autonomy (in drug selection) becomes subsumed by fiscal tightening measures. Succinylcholine is still the “gold standard” for facilitating rapid airway control and is the only approved drug with both an ultra-rapid onset and short duration of action. However, its plethora of well known adverse effects (myalgia, increased pressures, dysrhythmias, hyperkalemia, prolonged neuromuscular blockade in pseudochlinesterase-deficiency states, sustained muscle contractures in patients with myotonic conditions, masseter spasm, and malignant hyperthermia) may make its use based on low acquisition cost a “penny wise, pound foolish” proposition. Older, long-acting relaxants such as pancuronium and d-tubocurarine are cheaper (metocurine, however, is costly) but are associated with a more frequent incidence of residual neuromuscular blockade in the postoperative period (23,24) and ensuing morbidity related to the inadequate return of airway reflexes (25). Ballantyne and Chang (26) demonstrated that the longer recovery time associated with the use of such drugs resulted in recovery room charges which outstripped the larger acquisition costs of the newer drugs. The potential costs for reintubation, short-term mechanical ventilation and anesthetic supervision (which could delay the OR schedule), plus the “cost” of patient distress and discomfort should be factored in as well. New drugs with a rapid and smooth onset are desirable because the risks of aspiration and hypoxemia can be reduced. They also have a lower propensity for inadequate reversal because of their rapid and predictable recovery profile (which may render the need for reversal superfluous). If antagonism of neuromuscular blockade is not required, not only are the costs of reversal drugs saved, but their associated side effects (e.g., nausea, vomiting, dysrhythmias, and dry mouth) can be prevented as well. Thus, it is no surprise that these new NMBAs appeal to the anesthesiologist, especially in the ambulatory setting and in elderly/ill patients in whom organ dysfunction may limit drug clearances. Decisions based solely on the acquisition costs of drugs without considering personnel costs may fail to achieve the desired financial savings. Because personnel costs are a major proportion of costs in the operating and recovery room suites, anesthetic techniques associated with a greater need for nursing services may be more expensive (22). Time-and-motion studies have been used to identify personnel costs, but it may be inappropriate to assume that there is a linear relationship between labor costs and the time spent in providing a clinical service. Even if a patient spends an additional 15–30 minutes in the PACU or step-down unit, institutional costs may not be affected unless overtime costs are incurred, increased patient throughput is achieved with the same shift of staff, or the PACU can be closed earlier after discharge of the last patient (27). In addition, more rapid recovery in the OR suites may not be translated into earlier discharge readiness if patients require more sedation, analgesia, or antiernetic therapy in the PACU. Even if the times to discharge of all patients undergoing general anesthesia were decreased, there may not be a substantial decrease in PACU costs in tertiary care centers (27). Dexter and Tinker (27) used computer simulations to show that the peak number of patients in the PACU had a greater effect on PACU economics than the choice of anesthetic drugs because personnel costs accounted for 98% of the total costs. These investigators concluded that a greater effect would be achieved by arranging an OR schedule to optimize the distribution of admission rates to the PACU. If the use of short-acting drugs would permit a safe transfer of patients directly from the OR suites to the less labor intensive Phase II recovery area, major cost savings to the institution could be achieved (28). Bypassing of Phase I recovery (i.e., the PACU) has been termed “fast tracking” in ambulatory surgery. With a more rapid recovery, as fewer patients remain deeply sedated in the PACU, the duration of time they are “at risk” for airway compromise may be decreased, along with the need for highly skilled “one-on-one” nursing care. Cost savings may also be realized through changing the mix of nurses to (less expensive) aides in the PACU, cross-training perioperative nurses to function in both the OR and PACU, and arranging flexible work schedules to match the supply and demand of personnel. Structural changes in facilities (e.g., constructing a Phase II PACU wherein family members can aid in patient care) may also alleviate costs by promoting more efficient deployment of personnel. However, even greater overall savings could be achieved if nursing policies eliminate the need for a mandatory stay in the PACU, and if the economic structure of the OR/PACU facility favors a higher variable:fixed (overhead) cost ratio. The ICU is a high-acuity area where pharmaceutical and personnel costs are correspondingly high. NMBAs are routinely used herein to facilitate diagnostic investigations and therapeutic interventions and are administered as repeated boluses or continuous infusions, usually over a relatively long period of time. The protracted use of continuous infusions has been implicated in prolonged paralysis and muscle atrophy in the ICU, with the attendant high cost accruement from extended ventilatory support, rehabilitation, and hospitalization times. Infusion regimens have been based on the pharmacokinetics/dynamics of short-term OR and animal studies and take little account of overdosing, metabolite accumulation, tachyphylaxis, organ dysfunction, and drug interactions. There is, as yet, no consensus as to whether bolus dosing (constituting short “drug holidays”) or drug rotation (using different NMBAs) should be recommended (29). There have been only a few cost-analysis studies of NMBAs done in the ICU setting; Tobias et al. (30) advocated the use of pancuronium over atracurium or vecuronium based on less expensive daily acquisition costs of $5.88 vs $91.20 and $113.01, respectively. However, Murray et al. (31) calculated that the cost of a typical course of treatment (based on average wholesale prices), was less for doxacurium, a newer, more potent drug, than for pancuronium ($86.30 vs $106.40). However, the niche for newer, shorter-acting NMBAs that do not depend on end-organ function for elimination is undefined. Although use in critically ill patients with multi-organ failure syndrome would seem appropriate, the intensivist should balance this “advantage” against the added costs of apparatus for infusion and neuromuscular blockade monitoring, as well as increased nursing interventions. Nevertheless, optimal attempts to facilitate effective mechanical ventilation with a combination of sedatives and opioids should be made before the use of NMBAs is considered. Rapacuronium Rapacuronium (Org 9487) is a, nondepolarizing neuromuscular blocking drug of the aminosteroid class. It has a rapid onset/offset of action that is reversible when the block is still profound (32). The onset time in the laryngeal adductors after an intubating dose of 1.5 mg/kg dose is 1.0 ± 0.2 min (33), which compares very favorably with that of succinylcholine 0.5 mg/kg (0.9 ± 0.1 min) (34) and rocuronium 0.5 mg/kg (1.4 ± 0.3 min) (35). This allows for good-to-excellent intubating conditions within 60–90 s (32,36) and would thus be useful for rapid sequence intubation in patients with a “full stomach.” The duration of action after the intubating dose is 14 ± 6 min (36), compared with 10 ± 2 min and 20 ± 6 min of succinylcholine and mivacurium, respectively (34). Because of its rapid spontaneous neuromuscular recovery rate, the duration of action of rapacuronium can be further reduced by reversal with anticholinesterases. The neostigmine-induced recovery time of approximately 10 min is similar to the spontaneous recovery time of succinylcholine (32,37). This quick dissipation of its effects would facilitate “fast tracking” in the ambulatory setting. However, recovery after a prolonged infusion or following multiple “top-up” doses of rapacuronium is more prolonged, analogous to the time-course of an intermediate-acting drug (38). If Phase III studies confirm the safety and efficacy of rapacuronium, it has the potential to become the single drug of choice in the emergency room and OR, for both rapid onset tracheal intubation and intraoperative surgical relaxation. In replacing succinylcholine, the various well known side effects of the latter could be obviated. By supplanting the long-acting drugs, the risks of “recurarization” and its attendant morbidity and ancillary costs could be reduced. Furthermore, pharmacies may realize a cost advantage by reducing or curtailing stocks of other NMBAs in their inventory. Quality of Life Issues Finally, there may be benefits to society from the use of shorter-acting drugs if patients could return to work or school earlier or if their caretakers could more readily resume their normal activities. In a study of Swedish female patients undergoing abortion procedures, despite the higher drug costs incurred in those who received a newer drug regimen (propofol/alfentanil) compared with those who received thiopental/nitrous oxide, the former patient group required less overall social insurance payouts (hence, a net savings to society), consequent to less sick leave consumed (39). In addition, patients receiving propofol/alfentanil judged they had recovered from the anesthetic earlier (better functionality) than the control group; thus drug choices should also incorporate some input from patients regarding their personal preferences. Pharmaceutical companies need to support more studies along these lines to demonstrate societal and humanistic benefits from the use of the newer, more costly drugs. It has been suggested that a new drug should not replace an existing drug unless it is shown to be more effective, associated with fewer side effects or is less expensive. Conclusion Newer anesthetic drugs provide for a faster onset, easy titration, and a more rapid recovery than the older drugs, but are more expensive. In assessing the financial consequences associated with their use, it is important to examine the total costs, and not just the acquisition costs, of new drugs. Physicians should examine marketing claims of cost savings with the same scrutiny as claims of enhanced drug efficacy and perform studies designed to demonstrate that the preferential use of the newer drugs are associated with actual decreased payments for personnel, an earlier return to normal activities by the patient and their caretakers, or the completion of an additional case in the same OR session. The safety and value of modem anesthetic care has been well documented, allowing for higher-risk patients to undergo increasingly complex surgical procedures on a routine basis (6). Anesthetic practices have advanced to the point where cost savings from variations in drug use are less than the cost reductions that can be achieved by “system-wide improvements in efficiency of resource utilization, including personnel, space, time, consumables and capital investments” (40). It is important to remember that late arrivals/scheduling errors by surgeons or the failure of OR staff to prepare the patient in a timely manner can increase OR “downtime” and thus negate any cost to savings related to the choice of anesthetic drugs. To this end, the practitioner should not be lulled into a sense of “false economy,” as even the most ardent proponents of cost-conscious practice would admit that the safety and well-being of the patient should remain our paramount concern.