General anesthesia complicated by unexpected hypertension and tachycardia

CASE CONFE~CW=E Alan Jay Schwartz, MD, MSEd Frederick A. Hen&y, Jr, MD

CASE 3-1992 General Anesthesia Complicated by Unexpected Hypertension and Tachycardia David L. Reich, MD, John L. Bucek, BA, Nelson M. Wolf, MD, David B. Klumpe, Pharm D, and David J. Cullen, MD, MS

Case Presentation

A 33-year-old, 63-kg man with systemic lupus erythematosus, mild diastolic hypertension, coronary artery disease (CAD), and severe mitral regurgitation (MR) was admitted for elective myocardial revascularization and mitral valve replacement. His chronic preoperative medications included prednisone, isosorbide dinitrate, enalapril, and furosemide. Physical examination was remarkable for a loud holosystolic murmur radiating to the axilla and stigmata of systemic lupus erythematosus. The patient received his usual medications on the morning of surgery, plus 100 mg of intravenous (IV) hydrocortisone. In addition to standard monitoring (electrocardigraphic [ECG] leads II and Vs, and digital pulse oximetry), invasive hemodynamic monitoring was established using local anesthesia, and included radial arterial and pulmonary artery catheters (PAC). Upon induction of anesthesia using fentanyl, 4,000 pg, midazolam, 2 mg, and metocurine, 20 mg, the heart rate (HR) rapidly increased from 80 to 140 beats/min, mean arterial pressure (MAP) increased from 90 to 135 mm Hg (Fig l), and mean pulmonary arterial pressure (PAP) increased from 27 to 53 mm Hg. A Berman-type oral airway was placed to facilitate mask ventilation, but controlled ventilation by mask was extremely difficult due to truncal rigidity. Upper extremity rigidity and cutaneous pallor were also noted. IV esmolol, 150 mg, labetalol, 20 mg, and nitroprusside, 40 ug, were administered during the next 1.5 minutes, and a nitroglycerin infusion (1.6 pg/kg/min) was begun. The MAP returned to an acceptable level in approximately 10 minutes. Pancuronium, 5 mg, was admin-

David L. Reich, MD, and John L. Bucek, BA, Department of Anesthesiologv Mount Sinai Medical Center, New York, NY; Nelson M. Wolf MD, Cardiac Catheterization Laboratory, Medical College of Pennsylvania, Philadelphia, PA; David B. Klumpe, Pharm D, Depatiment of Pharmacy Services, Medical College of Pennsylvania, Philadelphia, PA; David .I. Cullen, MD, MS, Department of Anesthesia, Massachusetts General Hospital, Boston, MA. Address reprint requests to David L. Reich, MD, Department of Anesthesiology, Mount Sinai Medical Center, 1 Gustave L. Levy Place, PO Box 1010, New York, NY10029-6574. Copyright o 1992 by W B. Saunders Company 1053-0770192/0603-0023$3.00/O Kqy words: medication errors, cardiac surgery, dobutamine, metocurine 360

istered 9 minutes after induction and the chest wall rigidity resolved. There were no atria1 or ventricular premature contractions. Tracheal intubation was performed 12 minutes after induction. The HR and PAP returned to baseline values in approximately 20 minutes. A 12-lead ECG showed no signs of ischemia or infarction. Surgery was begun 30 minutes later and was performed as planned. After the procedure, the patient was taken to the intensive care unit with the endotracheal tube in place. His trachea was extubated the following day. The patient had no complications and was discharged on the tenth postoperative day. Postoperatively, it was determined that undiluted dobutamine, 12.5 mg/mL, had been inadvertently drawn into a 10 mL syringe, and labeled as metocurine, 2 mg/mL. Thus. instead of metocurine, 20 mg, the patient had actually received an IV bolus of dobutamine of 125 mg. DISCUSSION

Immediate tachycardia and hypertension on induction of anesthesia are typically associated with sympathomimetic agents, such as ketamine, or vagolytic agents, such as pancuronium. Other causes include the noxious stimulation of laryngoscopy and tracheal intubation, hypoxia, hypercarbia, and preexisting labile hypertension. Undiagnosed pheochromocytoma, idiosyncratic drug reactions, malignant hyperthermia, and drug administration errors are rare, but potentially fatal, possibilities. Initially, it was not clear what caused the tachycardia and hypertension in this patient. The two possible etiologies that were immediately excluded were hypercarbia and hypoxemia. Hypoxemia was ruled out by digital pulse oximetry monitoring. Hypercarbia was also considered unlikely, because capnometry demonstrated an end-tidal COz within the normal range both during induction, and following tracheal intubation. Hypercarbia usually develops over several minutes, but the hemodynamic changes occurred seconds after induction in this case. Hypertensive patients may have an exaggerated hemodynamic response to noxious stimuli, including airway manipulations. The high-dose opioid anesthetic given in this case should have been sufficient to block the noxious stimulus of oral airway placement. In addition, the onset of the hemodynamic changes preceded the loss of consciousness and the placement of the oral airway, implicating the administration of the induction medications as a cause of the changes.

Journal of Cardiothoracic and VascularAnesthesia, Vol6, No 3 (June), 1992: pp 360-365

CASE 3-1992

361

Time

0740

0750

cex

0810

oam

0830

o&M

P

V Systolic

V V

z

0 $ Induction

+ lntubation

$ Incision

Fig 1. The anesthetic recordingof vital signs.

anesthetized but paralyzed patient could also have this type of hemodynamic reaction if he were aware enough to trigger a massive catecholamine response due to anxiety. However, this scenario was unlikely, because the patient appeared to be inadequately paralyzed. If the patient had an immediate hypersensitivity or anaphylactoid reaction to one of the medications, an episode of hypotension rather than hypertension should have occurred. While it is unlikely, hypertension and tachycardia may have been early signs of an idiosyncratic drug reaction or malignant hyperthermia. A previously undetected pheochromocytoma could also have caused this type of reaction at any time during the stresses of the perioperative period.

An inadequately

As noted above, it was determined that instead of 20 mg of metocurine, the patient had been given approximately 125 mg of dobutamine. The anesthesiologist had mistakenly taken a bottle of undiluted dobutamine from the drawer above the one containing the metocurine. Both medications are in the same size bottles, manufactured by the same company (Eli Lilly Pharmaceutical, Eli Lilly & Co, Indianapolis, IN), and the bottle labels are similar in layout, coloring, and type (Fig 2). The dobutamine was drawn into a syringe and was labeled as metocurine, 2 mg/mL. Dobutamine is a sympathomimetic amine with activity at both (Y- and B-adrenergic receptors. The clinically used formulation is a racemic mixture of enantiomeric structures.* The (-)isomer is a potent ol- and P-adrenergic agonist. The (+) form is about 10 times more potent as a P-adrenergic agonist than the (-)isomer. At clinically recommended doses, dobutamine is relatively more inotropic than chronotropic when compared with dopamine and isoproterenol, possibly due to action on cardiac oradrenergic receptors. Doses less than 20 ug/kg/min cause only a modest increase in HR. This may be because the peripheral resistance is left relatively unchanged by simultaneous cxl- and l$-adrenergic receptor stimulation.2 Dobutamine increases the automaticity of the sinus node less than isoproterenol at doses that cause an equal increase in cardiac output. Clinically useful dobutamine doses are in the range of 2.5 to 10 ug/kg/min.3 In the present case, a 63-kg man was given a 125mg dose of dobutamine IV over approximately 3 minutes. This dose of roughly 2,000 kg/kg is between 70 and 250 times the usual infusion dose of 2.5 to 10 pg/kg/min and it resulted in marked tachycardia and hypertension. Dobutamine has an

s

Fig 2. The drug bottle labels.

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elimination half-life of approximately 2 minutes. Thus, the serum concentration would not fall to the usual therapeutic levels for approximately 10 half-lives, or 20 minutes. This would explain why this patient’s HR remained elevated for this period of time despite esmolol and labetalol therapy. One published case history reported that a dobutamine dose of 70 Fg/kg/min caused a lo-minute period of supraventricular tachycardia (140/min).4 What is most remarkable in the present case is that the hemodynamic reaction was relatively mild, and no life-threatening dysrhythmias were present. Several patient factors may have attenuated the cardiovascular response to the dobutamine. The patient’s chronic medications included isosorbide dinitrate and enalapril. These may have blunted the hypertensive response to some degree. Beta-adrenergic receptor blockade, such as the administration of esmolol and labetalol, has been shown to decrease the inotropic effect of dobutamine, and results in an increased pressor effect of dobutamine.5 Although patients with a history of hypertension may be at greater risk of having an exaggerated pressor response to therapeutic levels of dobutamine,3 it is difficult to predict the vascular response to a dose this large in the presence of these underlying medications. The inotropic response to dobutamine is also significantly less in patients with moderate to severe congestive heart failure.6,’ Denniss et al demonstrated that sarcolemma1 p-adrenergic receptors are reduced in number and p-adrenergic transmembrane signaling is impaired in patients with congestive heart fai1ure.s This may be due to the chronically increased sympathetic activity associated with decreased cardiac output states. In this case, the patient had MR and congestive heart failure. It may be that impaired or submaximal response of p-adrenergic receptors due to “downregulation” also attenuated this patient’s response to dobutamine. Medication errors can be errors of prescription, dosage, container labeling, “syringe swap,” or, as in this case, mistaken identity.9J0 Mistaken identity of a medication due to packaging similarity is not uncommon, and has been well described.*1x12A related, but more common, error is when the wrong drug is given because prepackaged syringes are confused.13 Efforts to encourage manufacturers to change package labeling have not been completely effective. Clinical Pharmacology and Management of a Dobutamine Overdose *

The authors describe a case of accidental dobutamine overdosage in a patient with known coronary and mitral valvular disease. The resultant sinus tachycardia and pulmonary and systemic hypertension were relatively mild and reverted to normal in about 20 minutes. No ischemia was noted. Dobutamine is a synthetic cardioactive sympathomimetic agent that stimulates p:-, p2-, and ol-adrenoreceptors (Tables 1 and 2). Betal-action predominates over p2, and (~1

Table 1. Receptor Actions of

Pl

Action

Myocardium

increase atrial and ventricular

Sinoatrial node

Increase heart rate

Atrioventricular

Enhance atrioventricular

contractility

conduction

conduction P2

Arterioles

Vasodilation

Lungs

Bronchodilation

Peripheral arterioles

Vasoconstriction

a

Reprinted with permission?3

predominates over CQ. The agent has no dopaminergic activity and does not release norepinephrine from adrenergic nerve endings. The stimulation of the P,-receptors results in acceleration of spontaneous sinoatrial cell depolarization, speeding atrio-ventricular (AV) node conduction and shortening the refractory period of both atria1 and ventricular muscle. The agent has been associated with significant reductions of plasma potassium concentration most likely secondary to activation of the sodium-potassiumadenosine triphosphatase (ATPase) system. All of these factors could result in dysrhythmias; sinus tachycardia and supraventricular or ventricular dysrhythmias can be seen with this drug. The patient presented with sinus tachycardia as his dysrhythmia. Paulman et all4 presented the case of a 47-year-old woman who was mistakenly given dobutamine instead of IV antibiotics. Her dose was a 130 pg/kg/min for approximately 30 minutes. She also had sinus tachycardia as her presenting dysrhythmia. There was no mention of potassium levels in the case presentation of either of these patients. The potential for myocardial ischemia exists with a dobutamine overdosage, secondary to increasing myocardial oxygen needs. This agent, through B, activity, increases contractility and HR. It also increases systemic BP. There is little effect on the peripheral vasculature due to the stimulation of both (Y-and p-receptors. Neither of the two patients described appeared to have ischemic symptoms or signs. In contrast, epinephrine stimulates both a- and p-receptors. The p2 stimulation results in inotropic and chronotropic cardiac effects, and the (Yeffect results in vasoconstriction. Epinephrine in low dose may cause a reduction of BP due to pz stimulation and vasodilatation. In moderate doses, increases in systolic pressure with a decrease in diastolic pressure occurs. At high dose, both systolic and diastolic pressures increase. Karch, in 1988,15 described a Table 2. Adrenergic-Receptor

Activity of Sympathomimetic ol

Peripheral

Pi Cardiac

Amines Pz

Peripheral

Norepinephrine

++++

++++

0

Epinephrine

++++

+++t

tf

Dopamine

++++

-t+++

++ ++++

lsoproterenol Dobutamine Methoxamine

*Nelson M. Wolf, MD

Catecholamines

Site

Adrenoceptor

1992

0

+++

+

++i-+

+++f

Reprinted with permission.33

0

;

CASE 3-l

992

case of epinephrine overdosage and reviewed several others. The patient received 2 mg of IV epinephrine. He developed chest pain, nausea, diaphoresis, sinus tachycardia, and hypotension. The ECG showed inferior and lateral ST elevation that eventually resolved. Of note, the patient’s serum potassium was diminished. Most of the other cases Karch reviewed had symptoms of chest pain or pulmonary edema and ECG evidence of ischemia. Many of the patients also had hyperkalemia and hyperglycemia. Fyfe et all6 described another case of epinephrine overdosage associated with shock and reversible global diminished left ventricular function. The left ventricular function reverted to normal after days of support. Hypotension frequently occurs with epinephrine overdosage and is thought to be secondary to return of (Y stimulation to normal with predominant remaining p overstimulation. Myocardial ischemia can also be implicated in some of these cases. Coronary spasm has been implicated as the cause of the ECG changes seen in epinephrine overdosage. It is thought to be due to a profound direct epinephrine effect. In one case, a myocardial infarction developed with later documentation of normal coronary anatomy.15 Beta-adrenergic blocking agents including esmolol and labetalol have been used to treat these overdosages. Other agents may be considered if coronary spasm is present, including nitrates and calcium antagonists. Antidysrhythmics may also be needed. Frequently, the inotropic overdose syndrome is short-lived and relatively easily controlled. Physiologic support of the patient often results in a good prognosis. In summary, the sympathomimetic inotropic agents are used frequently and a potential for overdosage exists. Each of the agents interacts with the (Y-and P-adrenoreceptors in a particular manner, not only for the agent, but for the dose given. The spectrum of symptoms and signs seen with overdosage will be variable from one agent to another. It appears that these overdose states are similar to the hyperadrenergic syndromes see in tetanus, cocaine excess, pheochromocytoma, and postoperative hypertension. The treatment revolves around the discontinuation of the drug, physiologic support, administration of adrenergic blocking agents, and treatment for ischemia or dysrhythmias. Medication Errors in the Operating Room: Need for Physician Involvement in Continuous Quality Improvement?

This case describes a potentially morbid medication error that occurred in the operating room. The authors state that medication errors are a rare or uncommon cause of patient morbidity and mortality during medical treatment. However, the medical literature is replete with case reports of permanently disabling or fatal medication errors resulting from a variety of therapeutic misadventures. Public concern and awareness regarding the incidence and severity of medication errors in hospitals are rising rapidly due to increasing scrutiny by the lay press. Fatal medication errors

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in hospitals have become front-page and evening television news. An important concern about this case is consideration of steps to reduce the possibility that this error or other possible similar errors could reoccur. Although this case involved human error, systems or procedures may need to be changed to lessen the risk of similar errors in the future. This case may serve as an example of what the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) will soon expect hospitals and physicians to do following serious, isolated patient events. The JCAHO will soon promulgate new hospital and medical staff standards, which emphasize the need for continuous quality improvement (CQI). These new standards will require hospitals and physicians to provide evidence of continuous, incremental improvements in the quality of care provided to patients. The JCAHO will expect that a sentinel patient event, such as the serious medication error described in this case, leads to a documented corrective action plan to prevent such an error from occurring in the future. CQI techniques focus on progressively improving the processes used to perform tasks or to provide services with the goal of reducing errors or deviations from good medical practice to zero. In the case described, the JCAHO would expect that the hospital documented their efforts to prevent this error from occurring again in the future. Merely attributing this incident to human error and providing evidence that the anesthesiologist involved was counseled would overlook the fact that an underlying system problem may exist, which must be addressed. Correcting this problem could include reorganizing the anesthesia medication cart, switching product manufacturers, implementing a double-check system before all drugs are administered, or involving pharmacy personnel to prepare and double-check all necessary doses. All health care professionals involved in the prescription, preparation, and administration of drug products must take responsibility for improving systems for their use. We owe it to our patients. Drug-Related Adverse Events in Anesthesiology $

A drug-related adverse event with the potential for serious, if not lethal, patient injury occurred as a result of an error reported in this case. Although critical incidents such as this were first described by Cooper et al in 1978,‘O much progress has been made in understanding and preventing anesthesia-related adverse events. Compared with other medical specialties, anesthesiology is far ahead of its time. The recently completed Medical Practice Study, performed by a team from the Harvard Medical School and the Harvard School of Public Health, estimated that 98,000 patients hospitalized in New York state in 1984 suffered a disabling injury as a result of medical therapy-3.7% of all New York patients hospitalized during that year.19-21Extrapolated nationwide, more than 1 million patients are injured in hospitals each year, 180,000 of whom die annually as a result of these injuries. Drug-related problems

$David J. Cullen, MD, MS

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were the single most common cause of adverse events (19.4%) were responsible for a disabling injury in 0.7% of hospitalized patients, and were the most frequent cause of injury leading to a malpractice claim.*9-22 Studies evaluating human errors in anesthesia note that environmental factors such as fatigue, boredom, excessive work load, production pressure, and communication failures are associated with errors.23,24These studies and many others stimulated system changes, particularly in monitoring and setting of standards, which have dramatically lowered the risk of anesthetic death and brain damage.25,26 Doctors, being as human as nuclear engineers and pilots, make errors while performing difficult tasks in lifethreatening situations. The underlying cause of human errors must be identified to change the system and reduce human errors to a minimum. The production process itself contributes to accidents.27,28 While a “human” error may have occurred, a defect in the design of the system permits a relatively minor operator error to result in an accident. Such is the case described herein. Clearly, the physician in this case should have read the drug bottle’s label. However, wouldn’t the system have served the patient better had the two bottles or their labels differed in size, layout, color, and type? In a similar instance, Solomon et alzg reported that nearly identical packaging led to several premature infants receiving epinephrine and suffering severe medical consequences. The problem occurred not because of disregard for the usual dispensing procedures, but rather due to weaknesses in the system of marketing and dispensing pharmaceuticals. 3o Once the hospital changed its pharmaceutical dispensing system to a unit-dosing system, this problem ceased. Unit dosing was shown to reduce medication errors by 82% in one study.31 However, anesthesiologists draw up medication doses as needed on a stat and/or PRN basis in the operating room, and are less likely to be affected by a central pharmacy providing unit doses for every potential drug used. On the other hand, Shafer et al described the establishment of an operating room satellite pharmacy, a system that would have prevented the drug error reported here.32 To prevent future drug-related adverse events, it is important to not only identify the error, but also understand why, in this instance, dobutamine was drawn up instead of metocurine. Both medications were provided in the same size bottles, manufactured by the same company, and were similarly labeled. One factor was the complexity of the case, since the patient had several medical problems and received numerous medications to induce cardiac anesthesia. Another factor may have been the physician’s

3-1992

state-of-mind; that is, what behavioral factors contributed to the medication being drawn from the wrong bottle? Human errors result from inadequate information or data, faulty decision making, or flawed performance. The operator may suffer from physiological deficits such as lack of sleep, illness, emotional stress, or distractions, or the operator may be overwhelmed by the patient’s illness, medication requirement, and induction of anesthesia. Or. perhaps the operator was not properly motivated and. therefore, did not try or care enough to do the job well. Perhaps the operator had a momentary lapse of attention or simply followed a mindless habit of drawing up a drug from a familiar bottle without bothering to read the label. Knowledge deficit can be ruled out, because metocurine and dobutamine are such different drugs, both of which would be well known to an anesthesiologist. No complex technology malfunctioned, no computer failed, and, presumably, sufficient staff and/or resources existed to conduct this anesthetic. The authors are to be commended for investigating and reporting the immediate cause of this drug-related adverse event. Considering that the unexpected nature of the event in this case at the time of induction was so bizarre. it should have been strongly considered that the wrong drug was administered and an immediate investigation could have been conducted. Quality improvement programs aim to reduce the probability of events such as described here. Many such programs focus exclusively on individual outliers, rather than evaluating the environment in which they work, based on the premise that quality can best be improved by singling out or punishing “bad apples” who fail to provide acceptable care.27 Quality programs based on the threat of punishment have a limited ability to improve the quality of health care. because the overall level of quality is determined by the system in place, not by its outliers. Total or continuous quality improvement principles suggest that the system should be improved, because changing the system improves quality for everyone continuously, rather than limiting improvements to those who are outside the normal limits of the system.27q30In this case, the human error could conceivably have been obviated by a system change, such as obtaining all drugs from a central operating room pharmacy station. Had the manufacturer used a different color-coding system, vial size, or print labeling, perhaps the error could also have been avoided. If further in-depth evaluation determined why the anesthesiologist misread or failed to read the label in the first place, other systems-related problems could be identified and improvement could avoid further mistakes in drug administration.

REFERENCES 1. Ruffulo RR, Spradlin TA, Pollock GD, et al: Alpha- and beta-adrenergic effects of the stereoisomers of dobutamine. J Pharmacol Exp Ther 219:447-452,198l 2. Ruffulo RR: The pharmacology of dobutamine. Am J Med Sci 294:244-248, 1987 3. Hoffman BB, Lefkowitz RJ: Catecholamines and sympathomimetic drugs, in Gilman AG, Rail TW, Nies AS, Taylor P (eds): The Pharmacological Basis of Therapeutics. New York, NY, Pergamon, 1990, pp 202-203

4. Goethals M, Demey H: Massive dobutamine overdose in a cardiovascular compromised patient. Acta Cardiol 39:373-378. 1984 5. Tarnow J, Komar K: Altered response to dobutamine in relation to the degree of preoperative beta-adrenoreceptor blockade. Anesthesiology 68:912-919,1988 6. Colucci WS, Denniss AR, Leatherman GF, et al: Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure. Dose-response relationships, correlation

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with circulating catecholamines, and effect of phosphodiesterase inhibition. J Clin Invest 81:1103-1110,1988 7. Colucci WS, Leatherman GF, Ludmer PL, Gauthier DF: Beta-adrenergic inotropic responsiveness of patients with heart failure: Studies with intracoronary dobutamine infusion. Circ Res 61:182-186,1987 8. Denniss AR, Colucci WS, Allen PD, Marsh JD: Distribution and function of human ventricular beta-adrenergic receptors in congestive heart failure. J Mol Cell Cardiol21:651-660,1989 9. AHSP standard definition of a medication error. Am J Hosp Pharm 39:321,1982 10. Cooper JB, Newbower RS, Long CD, McPeek B: Preventable anesthesia mishaps: A study of human factors. Anesthesiology 49:399-406, 1978 11. Cohen MR: Medication errors: Report errors caused by misleading package labels. Nursing 12:114,1982 12. Lee BL, Auerbach PS, Olson KR, et al: Cardiac arrest following direct intravenous administration of citrate anticoagulant solution. Ann Emerg Med 15:1353-1356, 1986 13. Baysinger CL, Schmidt SI: Injectable confusion. Anesth Analg 65:104-105,1986 14. Paulman PM, Cantral K, Meade JG, et al: Dopamine overdose. JAMA 264:2386-2387,199O (letter) 15. Karch SB: Coronary artery spasm induced by intravenous epinephrine overdosage. Am J Emerg Med 7:485-488, 1989 16. Fyfe AS, Daly TA, Dorian T, Tough J: Reversible cardiomyopathy after accidental adrenalin overdose. Am J Cardiol 67:318319,199o 17. Larsen LS, Larsen A. Labetalol and the treatment of epinephrine overdosage. Ann Emerg Med 19:680-682,199O 18. The nature and incidence of medical injury: Results of the medical record review, in Hiatt H, Leapel L, Brennan T, et al (eds): Patients, Doctors, and Lawyers: Medical Injury, Malpractice Litigation, and the Patient Compensation in New York (The report of the Harvard Medical Practice Study to the State of New York). Boston, MA, Harvard Medical Practice Study 19. Medical Practice Study: Patients, Doctors and Lawyers: Studies of Medical Injury in New York. Boston, MA, Harvard University, 1990 20. Brennan TA, Leape LL, Laird N, et al: Incidence of adverse

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events and negligence in hospitalized patients: Results from the Harvard Medical Practice Study I. N Engl J Med 324:370-376,199l 21. Leape LL, Brennan TA, Laird NM, et al: The nature of adverse events in hospitalized patients: Results from the Harvard Medical Practice Study II. N Engl J Med 324:377-384,199l 22. National Association of Insurance Commissioners: Medical Malpractice Closed Claims, 1975-1978, Brookfield, WI, National Association of Insurance Commissioners, 1980 23. Gaba DM, Maxwell M, DeAnda A: Anesthetic mishaps: Breaking the chain of accident evolution. Anesthesiology 66:670676,1987 24. Gaba DM: Human error in anesthetic mishaps. Int Anesth Clin 27:137-147,1989 25. Keenan RL, Boyan P: Decreasing frequency of anesthetic cardiac arrests. J Clin Anesth 3:354-357, 1991 26. Cullen DJ, Nemeskal AR, Cooper JB, et al: Effect of pulse oximetry, age, and ASA physical status on the frequency of patients admitted unexpectedly to a postoperative intensive care unit and the severity of their anesthesia-related complications (see comments). Anesth Analg 74:181-188, 1992. 27. Berwick DM: Continuous improvement as an ideal in health care. N Engl J Med 320:53-56, 1989 28. Laffel G, Blumenthal D: The case for using industrial quality management science in health care organizations. JAMA 262:28692873,1989 29. Solomon SL, Wallace EM, Ford-Jones EL, et al: Medication errors with inhalant epinephrine mimicking an epidemic of neonatal sepsis. N Engl J Med 310~166-170,1984 30. Kritchevsky SM, Simmons BP: Continuous quality improvement concepts and applications for physician care. JAMA 266:18171823,199l 31. Simborg DW, Derewicz HJ: A highly automated hospital medication system. Five years’ experience and evaluation. Ann Intern Med 83:342-346,1975 32. Shafer AL, Lisman SR, Rosenberg MB: Development of a comprehensive operating room pharmacy. J Clin Anesth 3:156-166, 1991 33. Sonneblick EH, et al: Dobutamine: A new synthetic cardioactive sympathetic amine. N Engl J Med 300:18,1979