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*Department of Anesthesia, University of Iowa, Iowa City, Iowa; Department of Anesthesiology, Fuqua School of Business, Duke University, Durham, North Carolina
Address correspondence to Franklin Dexter, Department of Anesthesia, University of Iowa, Iowa City, IA 52242. Address e-mail to franklin-dexter{at}uiowa.edu
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Abstract |
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Implications: The true cost of succinylcholine is more than 20 times the acquisition cost of the drug. The estimated cost is very sensitive to the risk and cost of patients dying or sustaining brain injury from anaphylactic or anaphylactoid reactions to succinylcholine.
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Introduction |
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Methods |
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Butyrylcholinsterase Deficiency
We considered patients who have 50% or less of the average normal activity of butyrylcholinsterase to be "deficient" (6) The frequency of the atypical A gene was 102 of 5480 genes, yielding a population incidence of the AA genotype of 1:2886 (6). Other genotypes have much lower incidence rates (6). The lower and upper limits (95% confidence interval) on the incidence of butyrylcholinesterase deficiency equaled 1:4327 and 1:1967, respectively (6).
The mean time for patients with the AA genotype to resume spontaneous respiratory activity after the administration of 100 mg of succinylcholine was 1 h (n = 3) (7). This represents a lower limit on the duration of paralysis. The mean time for patients to regain a train-of-four ratio of 0.7 was 2.4 h (n = 2; 2.3 and 2.5 h, respectively) (8). We used 2.4 h in our calculations, with lower and upper limits of 1 and 3 h, respectively. Based on the mean duration of surgical cases in the United States of 1.82 h (9), 72%, 33%, and 85% of surgical cases would be expected to have durations shorter than 2.4, 1, and 3 h, respectively (10). We used the mean duration of cases nationwide, because we calculated costs from society’s perspective.
The estimated cost of caring for a patient with butyrylcholinesterase deficiency who received a dose of succinylcholine was $169.28. This included the costs of an adult ventilator circuit, 5 mg of midazolam, 2.4 h of a postanesthesia care unit nurse’s time, and 1 h of an anesthesiologist’s time (Table 1). We included the anesthesiologist’s time because of the need for family, patient, and staff education. For lower and upper limits, we used 1 and 3 h in the postanesthesia care unit, giving $135.81 and $186.83, respectively.
We assumed that human plasma cholinesterase would not be administered for treatment, because human plasma cholinesterase is not kept at some hospitals’ pharmacies (11), and its use would increase costs because of the drug’s costs (11,12).
The overall expected cost per dose of succinylcholine for butyrylcholinesterase deficiency then equaled $0.04, where $0.04 = (1/2,886) x 72% x $169.28. The lower and upper limits are $0.02 and $0.05, respectively. These are the smallest and largest values for the cost as would be expected to be reasonable, based on the published literature.
Malignant Hyperthermia
The incidence of fulminant malignant hyperthermia when succinylcholine was used with volatile drugs was 1:61,961, where 61,961 = (6.5 yr x 76,260 anesthetics ÷ 8 episodes of fulminant malignant hyperthermia) (13). The incidence when volatile anesthetics were used without succinylcholine was 1:174,597, where 174,597 = (6.5 yr x 53,722 anesthetics ÷ 2 episodes of fulminant malignant hyperthermia). There were no episodes when succinylcholine was used without volatile drugs. The incremental risk of malignant hyperthermia from using succinylcholine was then 1:96,046, where 96,046 = (1/61,961 - 1/174,597)-1. The 95% confidence interval was -1:302,755 to 1:41,442. We used lower and upper limits of 0 and 1:41,442.
The estimated treatment cost was $4970.67 (Table 1). We included supplies for treatment. We considered two anesthesiologists, the surgeon, and the two operating room nurses to work for three hours during treatment. We considered the patient to stay one day in an intensive care unit (ICU) and 1 day on a ward, and included the value of the patient’s time (i.e., his or her opportunity cost). For lower and upper limits, we used zero and 3 days on a ward, giving $4337.47 and $6237.07, respectively.
The contribution of treating malignant hyperthermia on the cost per dose of succinylcholine, when administered to adults, then equaled approximately $0.05, where $0.05 = (1/96,046) x ($4,970.67). The lower and upper limits were $0 and $0.12, respectively.
Succinylcholine was used in all five cases of death reported to the North American Malignant Hyperthermia registry between 1996 and March 1999 (14). The estimated risk of dying from an episode of malignant hyperthermia in 1997 was 4% (15). The lower and upper limits (95% confidence interval) were approximately 1.9% and 7.2%, respectively.
A synthesis of contingent valuation studies for unforeseen instant death found the median financial value to be $2.5 million (16). The lower and upper limits of reported values were $1.25 million and $6.5 million, respectively (16). These three values were adjusted to 1999 dollars by using the United States’ annual consumer price index. Contingent valuation studies directly elicit the willingness of a group of people to pay to reduce mortality risks sufficiently that one life is expected to be saved (16).
The contribution of death from succinylcholine-induced malignant hyperthermia on the estimated cost per dose then equaled $1.04, where $1.04 = (1/96,046) x 4% x $2.5 million. The lower and upper limits are $0 and $2.71, respectively.
Cardiac Arrest from Bradycardia and/or Hyperkalemia
We excluded from consideration reports of cardiac arrests in children, adolescents, and patients who sustained paraplegia or burns weeks before receiving succinylcholine (17,18). Problems in these groups did not fit our criteria of analyzing the cost per dose of succinylcholine administered per manufacturers’ guidelines.
Succinylcholine was used in 45% of anesthetics in 1983 in Denmark (13). The lower and upper limits (95% confidence interval) were 44% and 45%, respectively.
There were three observational studies of cardiac arrest during anesthesia with data from this period: 1967 to 1984 (17), 1969 to 1984 (19), and 1983 to 1987 (20). There were 21 cardiac arrests from succinylcholine in these studies’ 457,609 anesthetics, with no deaths. All cardiac arrests from succinylcholine (bradycardia and/or hyperkalemia reported together) occurred in the earliest of the studies (21 cardiac arrests in 250,541 cases or 1:11,930) (17). We therefore used lower and upper limits of 0 and 1:11,930.
Cost per treatment was estimated to equal $2,137.38 (Table 1). We considered two anesthesiologists, the surgeon, and the two operating room nurses to work 2 h during treatment. Then, we considered the patient to stay overnight (1/2 day) in an ICU and 1 day on a ward, and included the value of the patient’s time (i.e., his or her opportunity cost). For lower and upper limits, we used zero and three days on a ward, giving $1,504.18 and $3,403.78, respectively.
The cost per dose of succinylcholine from cardiac arrest then equaled $0.22, where $0.22 = (1/0.45) x (21/457,609) x ($2,137.38). The lower and upper limits are $0 and $0.40, respectively.
Masseter Muscle Rigidity
Masseter muscle spasm occurred infrequently in children receiving succinylcholine after halothane induction (3 of 607 (21) and 1 of 500 (22)). However, we excluded from consideration succinylcholine administered to children because we limited consideration to the use of the drug for nonemergency purposes according to manufacturers’ guidelines. Masseter muscle rigidity can occur in adults as a sign heralding the onset of malignant hyperthermia (23), the cost of which was considered above.
Myalgia
When patients received 0.1 mg/kg rocuronium to prevent myalgia, the incidence of myalgia from succinylcholine was <14.2% on postoperative Day 1, 7.1% on Day 2, and 0% on Day 7 (24). Without rocuronium, the incidence of myalgia was 78.2%, 78.5%, and 0%, respectively (24). In another study, with a dose of 6 mg of rocuronium, the incidence on postoperative Day 1 was 20% versus 70% without rocuronium (25). Given the decreased incidence, we included $1.38 for preventing myalgia with 6 mg of rocuronium (Table 1). We chose rocuronium because it decreased the incidence of myalgia more than atracurium (24). For lower and upper limits, we used the costs of 5 mg and 10 mg of rocuronium, $1.15 and $2.27.
The average cost of treating myalgia with 1.2 g per day of ibuprofen equaled $0.06 per dose of succinylcholine, where $0.06 = 14.2% x $0.10 + 7.1% x 6 days x $0.10, and $0.10 is the cost of the ibuprofen (Table 1). For lower and upper limits, we used no treatment and 7 days of treatment, $0 and $0.70.
We did not include the cost of myalgia’s preventing timely return to work, as explained in the Discussion.
Anaphylactic and Anaphylactoid Reactions
During the 2.5 yr between July 1994 and December 1996, there were 106 documented cases of anaphylaxis to succinylcholine in France (26). Sixty percent of suspected cases of anaphylaxis in France were investigated by follow-up skin testing of patients for allergic reactions (27). In 1996, there were approximately 2,395,704 anesthetics performed with neuromuscular blockers (28). Succinylcholine had a 5% units sold market share of neuromuscular blockers in France during this time period (26). The incidence of anaphylactic or anaphylactoid reactions to succinylcholine was approximately one case in 1695 doses, where 1695 = (2,395,704 anesthetics per year) x (5% use of succinylcholine) ÷ [(106 cases ÷ 2.5 yr) ÷ 60% reported]. If half of the succinylcholine purchased was drawn up for emergency use but not administered, the incidence of anaphylactic or anaphylactoid reactions to succinylcholine would have been one case in 869 doses, where 869 = (2,395,704 anesthetics per year) x [0.05/(2-0.05)] ÷ [(106 cases of anaphylaxis ÷ 2.5 yr) ÷ 60% reported]. Alternatively, if all succinylcholine drawn up was administered, and for each anesthetic with a neuromuscular blocker either one vial of succinylcholine (e.g., for short procedures) or three vials of a nondepolarizing neuromuscular blocker (e.g., for long procedures) were used, the incidence of anaphylaxis from succinylcholine would have been one event in 4,623 doses, where 4,623 = (2,395,704 anesthetics per year) x [3 x 0.05/(1 + 2 x 0.05)] ÷ [(106 cases of anaphylaxis ÷ 2.5 yr) ÷ 60% reported]. The use of three vials of a nondepolarizing neuromuscular blocker was chosen as a deliberately high value for this sensitivity analysis in that the median duration of anesthesia for patients receiving general anesthesia in France was 80 min (28). The lower and upper limits we used were one event in 4,623 and 869 doses, respectively.
The cost per treatment was estimated, from the values in Table 1, to equal $2,278.15. We used the average time of 2.4 h to restore blood pressure (29) as the time the surgeon, two anesthesiologists, and two operating room nurses resuscitated the patient. We considered the patient to stay overnight (1/2 day) in an ICU and 1 day on a ward. For lower and upper limits, we used zero and 3 days on a ward, giving $1644.95 and $3544.55, respectively.
The estimated cost for treating anaphylaxis from succinylcholine was $1.34 per dose, where $1.34 = (1/1,695) x $2,278.15. The lower and upper limits are $0.49 and $2.62, respectively.
Studies of anaphylactic or anaphylactoid reactions reported 7 cases of permanent brain damage or death in 116 Australian cases (29), 1 death in 100 French cases (30), and 0 cases of death or brain injury in 154 French cases (but 1 case of adult respiratory distress syndrome, 2 cases of disseminated intravascular coagulation, and one case of hepatic failure) (31). The incidence of death or brain injury from anaphylactic or anaphylactoid reactions under anesthesia was approximately 2.2%, where 2.2% = (1 + 0 + 7) ÷ (100 + 154 + 116). For the lower bound, the value of 0.5% was used based on the two French studies. To estimate the upper bound, we considered that succinylcholine reactions generally are classic Type 1 anaphylaxis requiring extensive and prolonged management including epinephrine (32). The mortality rate was estimated to be 3% to 9% among hospitalized patients in the United States sustaining a severe allergic reaction (33). Death occurred in 4.7% of cases of intraoperative anaphylactic or anaphylactoid reactions reported in Japanese anesthesiology journals from 1952 to 1990 (34). A survey of Japanese hospitals found the mortality rate to be 4.8% (35). The value of 5% was used as the upper limit for the incidence of death or severe morbidity.
As explained above in the malignant hyperthermia section, the median financial value, in 1999 dollars, among contingent valuation studies for unforeseen death was $2.5 million (16). The lower and upper limits of reported values were $1.25 million and $6.5 million, respectively (16).
The contribution of death or brain injury from succinylcholine-induced anaphylactic or anaphylactoid reactions to the cost per dose equaled approximately $32.45, where $32.45 = (1/1,695) x 2.2% x $2.5 million. The lower and upper limits are $7.37 and $84.36, respectively.
Succinylcholine accounts for a disproportionately large number of anaphylactic and anaphylactoid reactions relative to its use in anesthetics (26,29–32,36,37). We took advantage of this consistent finding among epidemiological studies from three countries [France (24,30,31) Australia (29), and United Kingdom (32,36,37)] to further evaluate the sensitivity of the cost per dose of succinylcholine to the incidence of anaphylactic or anaphylactoid reactions. This finding means that the incidence of anaphylactic and anaphylactoid reactions to a dose of succinylcholine is more frequent than the incidence of anaphylactic or anaphylactoid reactions per anesthetic (i.e., to all anesthetics). Even if succinylcholine were no more likely than other anesthetics to cause anaphylactic and anaphylactoid reactions, because it is not used for many anesthetic cases, the incidence of anaphylactic and anaphylactoid reactions to a dose of succinylcholine would likely be at least as frequent as the average incidence of reactions per anesthetic.
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Results |
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Discussion |
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The finding that anaphylactic or anaphylactoid reactions would account for the largest cost was expected. Past epidemiological studies of neuromuscular blockers have found the most serious adverse reactions to be immunological in nature (32,38). Previous studies found that succinylcholine was responsible for 81% of deaths from neuromuscular blockers (32,36).
We are not aware of accurate studies for the incidence of anaphylactic or anaphylactoid reactions to a dose of succinylcholine for countries other than France. Because the cost per dose of succinylcholine was sensitive to the incidence of anaphylactic or anaphylactoid reactions to succinylcholine, if the incidence were to vary among countries, then so would the results of our study (Table 3). France’s overall incidence of perioperative anaphylactic or anaphylactoid reactions (1 case in 13,000 anesthetics) (26,30,31,37) is similar to that reported in other countries. In Japan, the incidence was estimated to be 1 case in 10,000 anesthetics (35). In Australia, the incidence was estimated to be between 1:5,000 and 1:25,000 anesthetics (29). In the United Kingdom, the estimated range was 1:500 to 1:10,000 anesthetics (38).
The cost per dose of succinylcholine was insensitive to variables other than the incidence of anaphylactic or anaphylactoid reactions to succinylcholine and the financial value of unforeseen instant death or permanent brain injury. This means that inaccuracies in our estimates of the costs of these other variables (Table 1), differences in the lengths of time required for resuscitation, and differences in patients’ lengths of stay after resuscitation will have no financially important effect on our results. Improving the accuracy of our financial accounting for these costs will not substantively increase the accuracy of our estimate of the cost per dose of succinylcholine.
We performed a cost-identification analysis. This means that we tabulated the cost to society of administering a dose of succinylcholine once an anesthesia provider has decided to administer it for nonemergency purposes according to manufacturers’ guidelines. We did not evaluate the decision as to whether or not to use succinylcholine compared with alternatives, such as not using any paralysis or administering a nondepolarizing neuromuscular blocker. A pure evaluation of succinylcholine costs is a necessary building block for doing comparative analyses in the future. It may also be an important tool for operating room pharmacists who may not fully appreciate the cost of adverse clinical outcomes when professing the need to cut budgets. If the cost of another neuromuscular blocker were compared with the cost of succinylcholine from this study, it should be not just the acquisition cost of the other drug but also the cost of adverse outcomes from the drug.
We did not include the impact of myalgia on patients’ return to work, because we considered the use of succinylcholine for all types of surgical procedures. The mean time for patients to return to work was four days or longer for a wide range of procedures including laparoscopic cholecystectomy, outpatient gynecologic surgery, and liposuction (39–62). In addition, we do not know for what percentage of patients myalgia treated with ibuprofen would prevent them from returning to work as planned. If we had limited consideration to patients who planned to return to work on the second postoperative day but did not because of myalgia, the additional costs per dose for administering succinylcholine without precurarization would exceed $70, where $70 = ($108.80 per day) x (64.3% decrease in incidence of myalgia from precurarization versus placebo) [Table 1 and reference (24)].
We did not include the costs of pain and suffering, or of family members’ grief in having a patient die or sustain severe morbidity. These "intangible costs" are difficult to quantify. If we had included them, our estimated cost per dose of succinylcholine would have been larger. In addition, we did not include "direct nonmedical costs" such as lodging for a patients’ family members. Again, by limiting consideration to direct medical costs (e.g., malignant hyperthermia supplies) and indirect costs (e.g., financial value of unexpected death), we were more likely to have underestimated the actual cost per dose of succinylcholine from society’s perspective.
The cost of a dose of succinylcholine from society’s perspective equals the acquisition cost of the drug plus the cost of treating complications from succinylcholine plus the cost of adverse outcomes. Thus, whereas the acquisition cost of succinylcholine was small (e.g., $0.19, Table 1), the true cost per dose of succinylcholine from society’s perspective was many times larger. The true cost could not be determined with good precision (range, $9 to $93) because the estimate of the cost was very sensitive to the incidence of anaphylactic or anaphylactoid reactions to succinylcholine, the risk of severe injury from anaphylactic or anaphylactoid reactions, and the financial value of unforeseen instant death or permanent brain injury. Our best estimate was $37 per dose.
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Acknowledgments |
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