SELECTED READINGS

IN

ORAL AND

MAXILLOFACIAL SURGERY

THE PUMP VS. THE “BUMP” —WHICH IS BETTER?

Richard C. Robert, DDS, MS Mark F. Sosovicka, DMD

Volume 21, Number 4 September, 2013 THE PUMP VS. THE “BUMP” – WHICH IS BETTER?

Richard C. Robert, DDS, MS and Mark F. Sosovicka, DMD

INTRODUCTION

For nearly three-quarters of a century oral and maxillofacial surgeons have delivered intravenous anesthesia with an intermittent (incremental) bolus technique. The technique was popularized in the 1940s and 1950s by Dr. Adrian Hubbell and Harold Krough for the delivery of sodium pentothal anesthesia. Ultimately the agent utilized for intravenous anesthesia would change from sodium pentothal to methohexital and finally from methohexital to propofol. However, the method of delivery has varied little, with the possible exception of the use of somewhat smaller and more frequently administered increments of propofol as compared to methohexital. During the same time frame, medical anesthesiologists found that a constant infusion with an infusion pump provided better working conditions, hemodynamic stability, and safety with the same level of patient satisfaction. However, as in their delay in adopting new anesthetic drugs, oral and maxillofacial surgeons have not been quick to adopt the newer method of anesthetic delivery used by their medical colleagues. In this review we will explore the pros and cons of the traditional intermittent bolus technique (Part I) versus constant infusions with an infusion pump (Part II) for office-based anesthesia in oral and maxillofacial surgery. The reader is encouraged to consult the original articles referenced to develop a more thorough understanding of the issues involved. PART I: Intermittent-Bolus return to physiologic and functional baseline, Anesthesia and acceptable costs are all attainable with the intermittent-bolus technique. by Mark F. Sosovicka, DMD Any selected anesthetic technique should, first and foremost, be safe for the patient, of an appropriate duration to INTRODUCTION ­facilitate the surgical procedure, acceptable to the ­patient, and cost effective. For oral and Intermittent-bolus anesthesia for oral and maxillofacial surgeons intermittent-bolus maxillofacial surgery evolved in the 1930s anesthesia is effective for both the patient and and remains a simple, safe, and ­effective surgeon for a number of reasons. Relevantly, anesthesia technique. The overall ­anesthetic the duration of the majority (93.3%) of goals of patient safety, anxiolysis, hypnosis or oral and maxillofacial surgical procedures sleep, amnesia and analgesia are fulfilled by is ­under 60 minutes and most (63.8%) are the intermittent-bolus technique. Additional completed in less than 30 minutes.1 The anesthetic goals, including immobility/ brief ­nature of most procedures affords the muscle relaxation, inhibition of nociceptive oral and maxillofacial surgeon the ability to and autonomic reflexes, antiemesis, a rapid provide a safe and effective anesthetic, most

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commonly utilizing an operator anesthetist The mid-1950s saw a transition from model (90.9% of all OMFS providers), with conscious sedation to light general anesthetic a very low overall complication rate (0.7%).2 techniques, and intermittent methohexital We are fortunate as oral and maxillofacial became the most commonly utilized IV surgeons to continue to provide safe and ­anesthetic agent in the 1960s. In 1963, efficient ­anesthesia and surgical services to diazepam was introduced, and in 1970 our patients, the result of our comprehensive fentanyl and ketamine were first used in an training and our maintenance of high IV multi-drug regimen.The water soluble standards through continuing education and benzodiazepine, midazolam, was introduced self-imposed peer review and inspection of in 1985, and propofol ­became available our offices. in 1989, ushering in the present day use of intermittent anesthetic agents for deep HISTORY sedation/general anesthesia .3

Intermittent Bolus Goals Lundy first utilized intermittent intravenous thiopental for general anesthesia at the Mayo Clinic in the early 1930s. The goals of intermittent anesthesia are Adrian Hubbell completed his oral surgical to obtain a rapid induction of anesthesia and to training at the Mayo Clinic and subsequently maintain the anesthetic level with intermittent completed a 1-year anesthesia fellowship doses of anesthetic agent. Untoward side under Lundy before beginning to utilize IV effects should be minimized, and the dosing thiopental for oral surgical procedures. The is based on clinical parameters. The overall use of intermittent IV thiopental by Hubbell effects are dependent upon the patient’s age, replaced the nitrous oxide hypoxic anesthetic sex, health status, and body composition. technique that previously was a commonly The effects are also altered by the baseline utilized technique. level of sedation set by the administration of narcotics, benzodiazepines, and possibly The use of intermittent IV anesthesia ketamine or other agents. Once a baseline techniques by Hubbell and Krough in the level of sedation is established, sedative- 1940s and 1950s began to develop. Jorgensen hypnotic agents are utilized to maintain a at Loma Linda introduced a multi-drug state of deep sedation/general anesthesia. technique of pentobarbital, meperidine, and scopolamine for anxious dental patients The sedative hypnotic agents utilized to in 1945 and became the “father of IV establish the deep sedation/general anesthesia conscious sedation.”3 Hubbell and Krogh in generally have a rapid onset (20-60 secs.) and the 1950s presented courses throughout the a similar metabolism (80-90% hepatic).4 The United States on the use of IV thiopental for choice of agent is determined by a variety of dental patients. Hubble utilized a so-called factors, including drug effects (desired and intermittent pump technique. The “Hubbell adverse), patient profile, provider preference, Bubble” technique delivered a fixed dose of cost and availability. Availability of drugs has intermittent methohexital via a foot pump.

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recently been a factor in anesthetic technique Untoward excitatory side effects due to shortages of drug supplies. Drug of methohexital include hiccoughs, shortages have been caused by manufacturing myoclonic movements, and possible seizure shortages, contamination with metal or glass activity. Other untoward effects include particles, and drug companies’ discontinuing tachycardia (usually 30% from baseline) production due to medicolegal issues. due to baroreceptor-mediated sympathetic Lawsuits have been brought against several stimulation, dose-related hypotension, and drug manufacturers due to unsafe injection overall cardiac depression. Arrythmias may practices related to the use of multidose vials also arise in pediatric­ patients. Respiratory resulting in the spread of hepatitis and HIV.5 depression ­occurs and is dose-dependent; brief apnea following the induction dose is Sedative Hypnotic Induction Agents common. There is also a higher incidence of The most often utilized sedative laryngospasm with the use of methohexital hypnotic induction agents include than with the use of propofol. Many of propofol, methohexital, ketamine, and these side effects­ can be minimized by slow dexmedetomidine. Thiopental was also injection and an adequate baseline level of 6 previously used but is no longer available sedation with narcotics and benzodiazepines. in the United States. This discussion will center on the induction agents propofol and Methohexital is epileptogenic and methohexital. Ketamine can also be utilized is utilized in the induction of psychiatric as both and induction and maintenance agent, patients undergoing electroshock or 7 and dexmedetomidine, an alpha agonist with electroconvulsive therapy. Bariturates in antihypertensive and sedative effects, has general can have a “hangover” effect due also been utilized as an induction agent. to their slow ­metabolism with repeated doses and they will cause pain on injection. Methohexital is an ultrashort barbiturate The use of a 1% solution limits the pain, induction agent. Methohexital was first but higher concentrations of methohexital utilized in the 1960s with twice the result in more pain with vascular injection, potency and half the duration of thiopental. a greater possibility of tissue necrosis with Methohexital is prepared as a 1% solution arterial injection, and increased undesirable 6 (10mg/ml) and has a rapid onset of 1 arm- muscle activity. Advantages of methohexital brain circulation time of 40 seconds. This include its use for induction, maintenance ultrashort duration is based on redistribution of total intravenous anaesthesia (TIVA) from the vessel-rich brain to muscle and fat, for short diagnostic or surgical procedures, with little overall accumulation in fat tissue. and the short duration of action that ­allows Methohexital ­anesthesia lasts 5-7 minutes manipulation of anesthetic depth as dictated after injection and has a long elimination by the needs of the surgeon or patient. phase due to its slow metabolism in muscle and fat. Recently, there has been a resurgence Once reconstituted, methohexital in the use of methohexiatal due to intermittent is stable as a 1% solution and has a very propofol shortages.6 basic pH of 10. Vials of methohexital are

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commonly stored with refrigeration for up to of 7-8, undergoes oxidative degradation once 1 month with no bacterial growth. In contrast, a vial is opened, and does support bacterial propofol must be utilized within 6 hours once growth due to its lipid emulsion of soya, opened. However, the FDA does recommend glycerol, and egg lecithin. Therefore, it must that methohexital be utilized within 24 hours be used within 6 hours of opening the vial.6 once reconstituted. Although the cost per mg of methohexital is greater than propofol, the Propofol demonstrates first-order common practice of storing methohexital for pharmacokinetics with a fast redistribution utilization for multiple anesthetic cases over t1/2 α of 2-4 minutes, a slow redistribution t1/2 an extended period of time can be a potential β of 30-60 minutes, and an elimination t1/2 δ source of cost containment.6 of 3-12 hours. Propofol’s pharmacokinetics are not affected by gender, hepatic cirrhosis, Propofol is currently the most utilized or renal failure.7 Propofol plasma level sedative hypnotic induction agent due to rapid can be increased by the administration induction and recovery with minimal central of other anesthetic agents. Propofol nervous system effects. Di-isopropophenol pharmacodynamically induces rapid sedation, (propofol) was introduced in 1985 and has hypnosis, and ­amnesia. Propofol induces become a standard induction agent both in the β subunit of the GABAA receptor, with the operating room and for ambulatory deep possible inhibition of acetylcholine release in sedation/general anesthesia cases. Propofol the hypocampus and pre-frontal cortex and can also be utilized as a maintenance agent possible inhibition of NMDA receptors. for TIVA cases. Undesirable propofol effects include Propofol does have the drawback of possible short-term hypotension, i.e., a 15% having no analgesic properties. The drug to 30% decrease in blood pressure. The has a rapid onset of 20-50 seconds and ­degree of hypotension is related to the total is short-acting with no clinical effects 30 dose and rate of propofol injection. Propofol- minutes after discontinuing the drug due to related hypotension is rarely a problem its rapid redistribution, similar to what was ­except in the elderly, hypovolemic patients, described above for barbiturates.7 Propofol or patients with impaired left ventricular is highly lipophilic and has a large volume function. Propofol-related neurologic effects of distribution. Propofol has no active can result in excitatory phenomenon, such as metabolites, has a rapid hepatic metabolism, muscle twitching or spontaneous movement and may also exhibit extrahepatic metabolism in 14% of adults and 30% to 90% of pediatric through the lung. Propofol does cause pain patients. This increased muscle activity may upon ­intravenous injection but this can be resemble a seizure, including opisthotonus or reduced by injection in a larger arm vein back-arching rigidity, and has been termed instead of a dorsal hand vein. The pain upon propofol-related seizure-like phenomenon. injection can also be reduced by administering Propofol-related infusion syndrome (PRIS) is lidocaine prior to the propofol or a fluid bolus rare and possibly fatal. It results in metabolic following the propofol. Propofol has a pH acidosis and rhabdomyolysis that is related

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to long infusions, especially in pediatric supplies are utilized for each case, representing patients.8 Propofol exhibits antiemetic operating costs only with no initial capital properties and decreases the chance of post- costs. In contrast, the continuous-infusion operative nausea and vomiting with deep technique requires initial purchase of the ­sedation/general anesthesia.7 ­infusion pump, the cost for pump inspection and maintenance, and in some cases use of Propofol dosing is usually 1-3 mg/ ­additional administration lines or syringes kg for induction and 20-100 ug/kg/min via that may be specific to the pump utilized. infusion, and bolus dosing of 25-50 mg Costs of infusion pumps generally range followed by additional 10-20 mg bolus doses from $1,500 to $4,000, depending on the as required by the patient’s vital signs or brand and features of the pump. Additionally, signs of light anesthesia.9,10 Propofol costs there is an increased cost-per-use associated have increased over the last several years due with 1.7 ml to 7 ml of waste drug left in the to manufacturing and distribution shortages tubing following the case. The lifespan of an limiting availability of the drug.5 Some infusion pump has been estimated to be 5-7 practitioners have recently utilized propofol- years, requiring replacement of the pumps sparing techniques by administering other following this time span adding to the capital agents, such as greater doses of narcotics, costs. benzodiazepines, and ketamine. Armamentarium and Setup The use of continuous-infusion pumps also has other drawbacks. Specific tubing The armamentarium and set-up for the and syringe brands may be necessary for intermittent-bolus technique are minimal. the ­accurate use of specific infusion pumps. The set-up includes a basic IV administration Different syringe manufacturers use different set, 10-50cc syringes, and the desired drugs. bore sizes for the same general size of The simple set-up usually requires no more syringe, and volumetric pump accuracy is than 1-2 minutes. In contrast, the set-up for sensitive to the internal diameter of syringe a continuous infusion requires an infusion tubing. Neff, et al. have shown that small pump or pumps, an administration line in ­syringes, low flow rates, and compressibility ­addition to the IV administration set, specific of the syringe plunger affect the flow rate of 11 syringe brands and sizes in some cases based infusion pumps. on the infusion pump utilized and a 3-way stopcock to refill the syringe in the infusion Another factor is compliance, i.e., the pump. The set-up time for the continuous change in volume with a change in applied ­infusion method is obviously greater because pressure in the non-rigid components of the the syringes have to be loaded in the pump, pump, such as the plunger or infusion line. the pump programmed and the administration Compliance has resulted in inadvertent line primed prior to use. overdoses when compression of the syringe plunger or infusion line blocked outflow, The costs of the intermittent-bolus for example, someone standing on or technique are relatively minimal. The same compressing the infusion line attached to

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the pump. When the occlusion is released INTERMITTENT-BOLUS TECHNIQUE the patient can receive an unintended bolus of drug, ­resulting in a change in depth of The intermittent-bolus technique for sedation or vital signs of the patient.8 propofol or methohexital relies upon a baseline anesthesia level which is established Specific companies report approximately with opioids and benzodiazepines. Most a 1% flow rate variation in the infusion pump commonly fentanyl is administered at 1µg/ and approximately a 3% variation when the kg and midazolam is administered at 0.05 infusion pump accuracy and the ­accuracy to 0.1 mg/kg for adult patients. These drugs of the syringe attached to the pump are are titrated­ by weight and clinical effect combined. These levels of variation are not to provide anxiolysis and analgesia. Often generally a safety factor unless a pediatric ketamine is administered at 1-2 mg/kg as a or geriatric patient has increased sensitivity neuroleptic agent to deepen the anesthetic to medications that result in potential over- level. Once the baseline level of anesthesia sedation or other untoward effects related to is established, the sedative-hypnotic agents 9 an overdose. (propofol or methohexital) are administered at 0.5-1 mg/kg by a bolus technique to induce Infusion pump maintenance and general anesthesia; doses are based both on calibration is another cost factor with the weight and on clinical effect. These agents use of infusion pumps that is not required place the patient in a state of deep sedation/ with the intermittent-bolus technique. The general ­anesthesia ­requiring mandatory Joint Commission on Hospital Accreditation maintenance of the airway due to loss of and the FDA have specific written standards protective reflexes. regarding the maintenance and calibration of automated equipment. Formal and Throughout the clinical procedure the documented maintenance and calibration desired level of anesthesia can be adjusted programs must be implemented to ensure depending on the needs of the surgeon or the patient safety and should be performed every amount of clinical stimulation through the use one to two years as a minimum. of additional 10-30 mg boluses of propofol or methohexital. Dosage of all agents may In 2010, the FDA published a paper on have to be adjusted for age, sex, and body errors or injuries during the use of automated composition of the patient. Elderly patients devices, including infusion pumps. Most generally are treated with a “low and slow” ­often, these were due to human error or approach of drug administration due to their from electronic or software malfunction. increased drug sensitivity and decreased drug Obviously, the use of infusion pumps is clearance times whereas younger patients not trouble-free or infallible, and their use may require greater overall drug doses on a has resulted in patient-related safety issues mg/kg basis. not encountered with the intermittent bolus technique.10

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The intermittent-bolus technique surgeon and two observers rated the overall generally utilizes higher doses of the anesthetic by a visual analog scale. The sedative- hypnotic agents during the surgeon and observers were not blinded to the initial administration of local anesthesia. anesthetic technique utilized. In the 16 cases Once adequate local anesthesia has been evaluated the mean total dose of propofol by established, the intermittent doses of the intermittent bolus was 6.03 mg/kg/hr and by sedative-hypnotic agent are decreased and are continuous infusion was 7.93 mg/kg/hr. The usually administered in response­ to changes number of boluses required were 3.6 per in vital signs or other clinical signs (e.g., eye 10-minute interval by the intermittent-bolus opening or vocalization) of an inadequate technique and 1.1 per 10-minute interval depth of anesthesia. Ultimately, the patient with the continuous-infusion technique. should ­experience ­intraoperative anxiolysis, Seventy-five percent of the continuous- amnesia, and analgesia while maintaining infusion cases required bolus administration spontaneous ventilation. of propofol. Recovery time was slightly faster in the intermittent-bolus group than in Is the intermittent-bolus technique a the continuous-infusion group. safe and effective technique? Bennet and Shaffer, et al. compared the intermittent The surgeons and observers rated the bolus versus continuous infusion propofol continuous-infusion technique superior, for dentoalveolar surgery. The hypothesis ­although the technique used was not blinded. evaluated was that propofol by continuous Both anesthetic procedures were rated infusion would result in lower propofol satisfactory and all patients were amnestic to doses, a better surgical environment, and the surgery. The overall results did not support more rapid patient recovery than propofol by the initial hypothesis. The intermittent-bolus intermittent bolus. The study evaluated ASA group used less propofol and had faster I and II patients undergoing dentoalveolar ­recovery times than the continuous-infusion procedures. All patients received baseline group. More importantly, the continuous- fentanyl and midazolam by weight and infusion group required additional boluses general anesthesia was induced by propofol of propofol, showing the technique is not “a administration of 1 mg/kg. Deep sedation/ hands-free technique” once the continuous general anesthesia was maintained by either infusion has been started.12 intermittent bolus or continuous infusion propofol. The intermittent-bolus group Other studies had similar results. As received additional propofol boluses of 10- recently as 2012 a Cochrane collaboration 30 mg. and the continuous-infusion group study evaluated target-controlled infusion received a propofol infusion of 6 mg/kg/hr versus manually-controlled infusion of with additional boluses of propofol as needed propofol for general anesthesia or sedation based on the anesthetist’s observations in adults. The study reviewed 20 trials of vital signs, movement, lacrimation, or involving 1,759 patients to evaluate whether vocalization.12 a target-controlled infusion is as effective as Recovery time was recorded and the a manually-controlled infusion of propofol

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for general anesthesia and sedation with used in the future.14 respect to anesthesia quality, adverse events, and overall propofol drug costs. The target- Candelaria and Smith also evaluated controlled infusion was associated with the use of a propofol infusion technique greater overall propofol doses and costs than for out-patient general anesthesia during manual infusion and there were no clinically dentoalveolar surgery.15 Their study evaluated significant differences in the number of the use of alfentanyl 10µg/kg, nitrous oxide, adverse evbents between techniques. Clinical and propofol at 1 mg/kg for induction followed anesthetic quality did not differ significantly by continuous infusion of propofol at 150 in terms of bispectral index values, recovery µg/kg/min. No midazolam was used. Any time, and patient, surgeon, and anesthetist movement to surgical stimulus was treated satisfaction. The authors concluded that with a propofol bolus of 10 mg. All patients overall results of the systematic review were induced under general anesthesia did not provide significant evidence to in less than 1 minute and all patients had recommend target-controlled infusion versus anterograde ­amnesia. No excitation, tremors, manual-controlled infusion of propofol for or hypotonus were noted and the vital signs 13 clinical anesthesia. were stable. The average case was 22 minutes in length for induction and completion of the Klein, et al. compared propofol surgical procedure.15 The optimal infusion administered by continuous infusion versus rate was 150 ug/kg/min and the average total bolus in pediatric patients undergoing propofol dose was 350 mg. Patients received ambulatory ­oncologic procedures such as an average of 2 propofol bolus doses, with a bone marrow biopsy or line insertion.14 range of 0 to 5. All patients received an induction bolus of propofol at a dose of 0.5 mg/kg; this was The overall assumptions that continuous followed either by a continuous infusion variable-rate infusions decreased the amount of 0.1 mg/kg/min. (increased by 20% until of propofol administered and that using a induction) or additional intermittent boluses pump for continuous infusion allows the of 0.5mg/kg until achievement of deep surgeon to direct attention to the surgical sedation/GA. There were no differences in field without repeat interruptions to provide induction doses or induction time, recovery additional boluses with the bump technique time, or adverse events. As expected, more were not supported. Obviously the total boluses were delivered in the bolus group overall propofol dose was rather high and (8.5) than in the continuous-infusion group the procedure was not completely hands-free (5.4). However, the total propofol dose was once the infusion was started; an average higher in the continuous-infusion group of two additional propofol doses were than the bolus group (8 mg/kg versus 5.8 administered to the patients in this study.15 mg/kg). Both the continuous infusion and bolus techniques were satisfactory to the HOW DEEP IS DEEP ENOUGH? patient and surgeons. Ultimately physician preference will dictate which method will be

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Questions often arises concerning the surgery. overall depth of anesthesia and whether all patients require a continuous infusion to The overall satisfaction rate was maintain a deep anesthetic state. The depth 95.8%, leaving little room for improvement. of anesthesia is determined by the needs of Interestingly, when patients received deep the patient and the surgeon. Most surgical sedation/general anesthesia with local procedures can be performed in a safe and anesthesia, a narcotic, and a benzodiazepine efficient manner under deep sedation, and but no propofol, methohexital, or ketamine some movement is generally tolerable with they had greater overall satisfaction than when most dentoalveolar procedures based on propofol, methohexital, and ketamine were the surgeon’s overall skills and experience. utilized (96.4% versus 95.6% satisfaction). An excellent study of factors that influence Unexpectedly, providing a deeper anesthetic ­patient satisfaction or dissatisfaction with level did not improve the overall patient office-based deep sedation/general anesthesia satisfaction with the anesthetic procedure. were evaluated by Coyle, et al.16 The study The ­addition of nitrous oxide to the deep evaluated over 14,000 patients who had deep sedation/general anesthesia with local sedation/general anesthesia for dentoalveolar anesthetic, a narcotic, and a benzodiazepine ______Table 1: Comparison of Anesthetic Techniques

Intermittent Bolus Continuous Infusion Technique Set up time: Minimal Longer Overall armamentarium: Minimal Greater Initial equipment start-up costs: None High Specific syringes or IV tubing No Yes needed: Periodic equipment calibration or No Yes maintenance Need for periodic equipment No Yes replacement: Opportunity for human error: Minimal Greater Opportunity for equipment malfunc- No Yes tion: Totally hands-free anesthesia tech- No No nique: Lower overall drug use: Yes No Overall anesthetic costs: Minimal Greater Acceptable overall anesthetic Yes Yes quality:

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did improve overall patient satisfaction PART II: CONTINUOUS INFUSION (96.3% versus 95.8%). Additionally, the use WITH AN INFUSION PUMP FOR of steroids with the sedation had no effect on OFFICE-BASED SURGERY IN OMS overall patient satisfaction.16 by Richard C. Robert, DDS MS Placing the patient in a deeper anesthetic state did not improve overall patient INTRODUCTION satisfaction and was possibly performed to comply with the desires or expectations of the operating surgeon rather than the desires The Early Years or expectations of the patient because most patients had no recall of the procedure. Certain The inestimable contributions of factors were predictors of dissatisfaction, dentists to the history of anesthesia are including patient age less than 10 years, undeniable. The very foundation of surgical vomiting during recovery, remembering pain anesthesia can be traced to dentists Horace during the procedure, and a memory of ­being Wells and William T.G. Morton, who in the awake with inability to communicate. The 1840s discovered the anesthetic properties of result that the use of propofol, methohexital, nitrous oxide and ether respectively. These or ketamine did not improve overall patient inhaled gases were to remain the principal satisfaction reinforces the belief that agents in anesthesia for the next century.17 anesthetic depth is not a predictor of patient However, “anesthesia” based on anoxic 16 satisfaction. levels of nitrous oxide anesthesia would ultimately be toppled by two other dental CONCLUSIONS anesthesia pioneers: Californian Adrian Hubbell and his East Coast colleague, Harold The intermittent-bolus anesthesia Krough, promoted sodium pentothal-based technique is simple, with minimal equipment, intravenous anesthesia in the mid-twentieth no______equipment maintenance, low overall century.3 Sodium pentothal also began to gain costs, quick set-up, and low potential for considerable attention in medical anesthesia mistakes due to dosing or set-up errors. The during and after the Second World War. intermittent-bolus technique has been and remains an effective anesthetic technique for Interestingly these early pioneers out-patient oral and maxillofacial surgical realized that the intermittent-bolus technique procedures. prevented the maintenance of a constant plasma level of anesthetic and hence a smoother anesthetic course. Indeed, in an attempt to circumvent loading and delivering drugs with syringes, Hubbell invented the “Hubbell Bubble”, a rubber bulb that could be frequently activated by a “human pump” (the operator’s foot) in order to achieve as

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constant a plasma concentration as possible.18 Although each of the advances of the Similarly, medical anesthesiologists utilized latter decades of the last century were warmly “piggy-back” micro-drips of anesthetic embraced by medical anesthesiologists, for agents in an attempt to maintain a constant inexplicable reasons the pioneering spirit of infusion.19 oral and maxillofacial surgeons (and dentists in general) appeared to wane. They clung Although oral and maxillofacial to meperidine, diazepam and methohexital surgery offices were the predominant venue even as newer shorter-acting agents became for office-based anesthesia at mid-century, well entrenched in the armamentarium our medical colleagues were ultimately of anesthesiologists in outpatient surgery to appreciate the advantages of providing centers and office-based anesthesia. anesthesia on an outpatient basis without the need for lengthy, expensive hospital stays. By It was not until the first decade of the latter decades of the century, 75% of what the present century that the shorter-acting had been formerly predominantly hospital agents began to make definitive inroads inpatient surgery found a home in a variety into oral and maxillofacial surgery offices. of ­ambulatory venues, including outpatient Perhaps the most dramatic change was surgery centers and surgeons’ offices.20 prompted by the so-called “Brevital Crisis” when methohexital production came to a As medical anesthesiologists developed halt because of contamination at its major their appreciation for the outpatient setting, production facility.24 With methohexital they realized that the intravenous and no longer available oral and maxillofacial inhalation agents at their disposal would be surgeons were forced to turn to propofol. a primary limiting factor. Pharmaceutical This lead to a “Eureka experience”, which companies, sensing new and profitable prompted most surgeons to continue to use markets, poured R&D funds into the their new found anesthetic ally even when development of new agents that would methohexital came back on the market. allow the patient to become “street-ready” as rapidly as possible. The longer-acting A similar reluctance to embrace newer benzodiazepine diazepam would soon be shorter-acting agents is seen when one looks at replaced by a shorter-acting water-soluble the method of delivery most commonly used benzodiazepine, midazolam.21 Similarly, the by oral and maxillofacial surgeons versus longer-acting but well established synthetic their medical colleagues. The same scientific phenylpiperidine opioid meperidine approach that enabled medicinal chemists was soon replaced by the shorter-acting to develop new short-acting agents laid the anilidopiperidine fentanyl.22 Then in the final foundation for use of constant-infusion decade of the century, the ultra-short-acting technology for anesthetic delivery. Yet oral barbiturates thiopental and methohexital and maxillofacial surgeons continue to hold were eclipsed by an even ­shorter-acting tightly to the intermittent-bolus technique, major hypnotic agent, propofol.23 which was developed three-quarters of a century ago, long after scientific discoveries

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prompted medical anesthesiologists to century events took place that would largely abandon the bolus technique in favor ultimately change the entire foundation of constant-infusion technology that could of the field of pharmacology. Langley and capitalize on the most desirable attributes of Elliot’s laboratories at Cambridge University the newer drugs. In this section I will explore in the United Kingdom , as well as Ehrlich’s their reasons for their making the change laboratory in Frankfurt, Germany, established and examine a number of the factors that that the ­action of most drugs is due to the prompted their decision,including: binding of the drug molecules to protein molecules within the host (“receptors”).25 1. The foundation in scientific Although this concept formed the basis for ­research that supports one vs. the other. countless pharmacologic investigations during the next three-quarters of a century, 2. The quality of operating the receptor concept did not become conditions afforded by using the commonly accepted in anesthesia circles different techniques. until the 1980s. Up until that time the theory 3. Patient satisfaction with the of “lipoid solubility”, propounded by Myer technique utilized. and Overton was ­regarded as the overriding mechanism of anesthetic agents. This theory 4. The hemodynamic stability was based on the concept that the action of provided by the technique. anesthetic agents was due to their dissolution 5. The safety afforded the patient in the membrane of neurons that prompted by use of the technique. a physical change such as thickening of the membrane, which in turn altered the 6. The convenience and expense permeability of the membrane to ions. It associated with the technique. was postulated that this permeability change SCIENCE LEADS THE WAY produced the anesthetic effect.26

Ultimately, in the 1990s, this theory was In the latter part of the twentieth century, overturned by the work of Franks and Lieb while oral and maxillofacial surgeons became showing that the action of anesthetic agents complacent with their methohexital-based is based upon the binding of anesthetic ­intermittent bolus technique, considerable molecules to host receptors.27 This revelation scientific investigation prompted facilitated investigation of rapidly-acting anesthesiologists to begin using constant agents with short duration such as propofol. infusions with infusion pumps for their It was demonstrated that propofol had an ambulatory surgery procedures. ­affinity for a site on a chloride ion channel, i.e., the same gamma-aminobutyric acid The Receptor Concept (GABAA)receptor ion channel targeted by benzodiazepines.28 (Fig. 1, P. 14) In At the beginning of the twentieth turn, the short duration of the bond with

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Figure 1: A number of anesthetic agents have receptor

sites on the GABAA receptor. There are sites for the benzodiazepines, barbiturates, propofol, and inhala- tion agents. Figure 2: The GABA receptor contains 2 α subunits, Redrawn from Evers SA and Maze M. Anesthetic A 2 β subunits, and 1 γ subunit. Note: the 3 β subtypes β , Pharmacology: Physiologic Principles and Clinical 1 β , and β , as described in the text. Practice. Philadelphia: Churchill Livingstone; 2004; 2 3 with permission. Page 418. Redrawn from Miller RD. Miller’s Anesthesia. 6th edition. Philadelphia: Churchill Livingstone/Elsevier, ______Philadelphia; 2005. Page 337. rapid redistribution of the agent meant ______that sustaining the effect would be most ­effectively achieved by constant “bathing” for both the induction and maintenance of 30 of the receptor with the agent, something ­anesthesia, as well as sedation. only accomplished with a constant infusion. In the latter setting it has found Frequent intermittent boluses could approach application for management of the elderly, but never duplicate this effect. the medically compromised, patients with A particularly fascinating characteristic obesity and obstructive sleep apnea and of propofol is the unusual manner in which patients who undergo longer procedures for it reacts with the different GABA receptor which a lighter level of sedation is required, A such as complex implant cases. This lighter subtypes. Classic GABAA receptors contain five subunits: two α-subunits, two β-subunits, level of sedation is much more practically and one γ-subunit. (Fig. 2) At least three achieved with a low-level, continuous subtypes of the β-subunit have been identified infusion than with very small intermittent boluses timed appropriately to maintain the and they are designated as β1, β2 and β3. When propofol is given at higher doses, it induces level of minimal to moderate sedation. a level of deep hypnosis and immobilization through its binding to receptor sites on The Blood-brain Barrier

those GABAA receptors that contain the β3- subtype.29 However, at lower doses propofol Investigations into the nature of the

targets receptors containing β1 and β2 blood-brain barrier during the latter decades of subtypes, facilitating the action of GABA in the twentieth century pointed to two primary a manner somewhat similar to that seen with factors determining passage of drugs through benzodiazepines. Thus, propofol can be used the barrier to exert anesthetic effects on the

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Figure 4: Conceptualization of a three compartment model which takes into account the complex pharma- cokinetics of highly lipid soluble drugs such as propo- fol ketamine and remifentanil. Source: 33, Page 26 Fig.3 ______Figure 3: The endothelium of the blood brain barrier has tight junctions which allow paracellular passage As more highly lipophilic, rapidly-­ of only small molecules such as those of propofol and redistributing drugs became available, it methohexital. In addition, the end feet of the astrocytes was realized that some of the parameters cover much of the circumference of the capillary. previously utilized in pharmacokinetics were ______inadequate to describe the complexities of brain. The first of these is the membrane’s the fate of anesthetic agents in the body. In tight junctions, which limit paracellular particular, the concept of elimination half- permeability and thereby limit passage of life did not take into account the dynamic many compounds on the basis of molecular relationship between redistribution and size alone.31 (Fig. 3, P. 15) Small molecules drug clearance. It became apparent that such as those of propofol and methohexital redistribution was largely dependent upon pass rapidly through the membrane. circulation differences in various types of the body’s tissue. Investigators divided the The second factor is lipophilicity and various tissues into artificially designated the pKa of the agent. Drugs with a pKa “compartments” based on vascularity. A ­approaching physiologic, such as remifentanil, model for drug distribution was developed tend to pass very rapidly through the barrier.32 based on a vascular-rich group, a vascular- Because the drugs also pass rapidly out of the poor group and an ­intermediate group.33 As brain following the short duration of the bond drug molecules were differentially distributed with the receptor site, drug ­effect can “wear through the various groups, they would off” rapidly if there is not a constant serum ultimately return to the central compartment level of the agent, something best provided at different times and then be subject to by a constant infusion with an infusion pump. biotransformation and elimination. (Fig. 4)

Compartments and Distribution To adequately describe this dynamic ­interplay between the agents and the body’s

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Figure 5. A. The context-sensitive half-times of sev- eral intravenous and opiod anesthetics. The low, flat plot for propofol correlates closely with rapid recov- ery and readiness for discharge. Note the low, flat plot for remifentanil which is similar to that of propofol. Redrawn from: Springman S: Ambulatory Anesthesia: the Requisites in Anesthesiology. 1st edition. Phila- delphia: Mosby; 2006; redrawn from original in Egan TD. Pharmacokinetics and rational intravenous drug selection and administration in anesthesia. IN: Lake CI, Rice I, Sperry RJ, (eds.) Advances in Anesthe- sia. vol. 12. St Louis (MO): Mosby; 1995. p. 363e88; ______and Barash PG: Clinical Anesthesia. Sixth ed. Phila- delphia: Wolters – Kluwer, Lippincott, Williams and tissues a new parameter, the “context-sensitive Wilkins ; 2009. P. xviii, 1640; Page 492 half-time”, was introduced. Calculated with ______mathematic models based on pharmacokinetic studies, it represents the time required for the The newer lipophilic and rapidly-­ plasma concentration of the drug in question redistributing drugs developed in the latter to decline by 50% once the infusion has been decades of the 20th century also tended terminated.34 This is an important parameter to undergo rapid biotransformation and because it provides uniform comparison of elimination. Hepatic biotransformation of the behavior of different drugs that affect propofol is rapid but it is also accompanied their clinical attributes (Fig. 5). For ­example, by biotransformation in other body tissues, 35 it explains why recovery from a propofol- ­especially the lungs. based anesthetic is more rapid than that from methohexital and dramatically more rapid In addition, medicinal chemists than that from thiopental. developed a new approach to drug biotransformation. It was found that However, capitalizing on this parameter incorporation of certain forms of chemical is more likely if a constant level of agent is linkage could enable drug biotransformation ­being introduced into the system by a constant in tissues other than the liver. For example, in infusion, clinically manifested by a “smooth” the case of remifentanil the anilidopiperidine anesthetic course with minimal tendency base is linked to a side chain with an ester ­toward patient movement and ­response linkage, and biotransformation takes place to surgical stimulation. With intermittent through enzymatic cleavage of the ester link. delivery the dynamic interplay discussed (Fig. 6, P. 17) Because esterases are present in above would tend to accentuate peaks and virtually all body tissues, biotransformation troughs of agent concentration in the serum. takes place much more rapidly than that of other opioids, for which the biotransformation 36 Biotransformation and Elimination takes place only in the liver.

The rapid metabolic pathways of drugs

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and office based anesthesia, three stand out: propofol, remifentanil and ketamine. (Fig. 5, P. 16) In medical anesthesia, all three of these agents have been successfully used and enjoy­ wide popularity. In oral and maxillofacial surgery, propofol is the primary agent used in the vast majority of offices, with ketamine finding an ever-increasing role. Remifentanil Figure 6: Comparison of the chemical structures of has piqued interest in some practitioners but fentanyl and remifentanil. The ester linkage illus- 38 trated enables biotransformation by esterases found is still infrequently utilized. throughout the body. Redrawn from Morgan GE, et al: Clinical Anesthesi- As pointed out above, propofol interacts ology, 4th ed. New York: McGraw-Hill; 2006. Page with the GABAA receptor in two different 193 Fig. 8-6 ways such that it can be utilized for both ______­sedation as well as induction and general ­anesthesia. Soon after its introduction in the such as propofol and remifentanil worked United Kingdom, studies began to emerge hand-in-hand with rapid redistribution to about the successful use of propofol for create very low, flat plots of context-sensitive sedation. In 1987, Mackenzie and Grant half-time (Fig. 5). This, in turn, is ­reflected reported that “recovery is impressively rapid, in the rapidity and completeness of recovery even in elderly patients, and devoid of side with these agents. effects.”39

The Agents Although the “gold standard” for amnesia ­associated with anesthetic agents is the benzodiazepines, it appears that propofol Obviously a primary requisite of office- may have some amnestic properties as well. In based or ambulatory anesthesia is the ability 1997, Veselis concluded that when the agents to render the patient street-ready as rapidly as are used for sedation, propofol produces possible so that recovery at home can continue the same degree of amnesia as midazolam both comfortably and safely. The quantitative while thiopental provides very little and parameter that comes closest to equating fentanyl no amnesia at all.40 Furthermore, with rapid, yet safe, patient discharge is the Tesniere found that when propofol was used context-sensitive half-time discussed above. in low concentrations, its respiratory effects A low, flat plot suggests that the drug’s effects were moderate, and it allowed spontaneous (especially untoward ones such as respiratory ventilation throughout maintenance of depression) dissipate rapidly and do not sedation.41 Thus, there is good support for return, even after protracted infusion.37 use of propofol for sedation in the elderly, the medically compromised and for patients When one views the plots of the various undergoing longer procedures. Administering agents that have been used for ambulatory it in low concentrations is challenging without

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the use of an infusion pump to provide a Over the last several decades, as consistently low serum level of the agent. ­advancements in medicinal chemistry brought newer, more desirable drugs to Because each of the agents propofol, the marketplace, technology based on ketamine and remifentanil produce a microchips advanced even more rapidly. This desirable low, flat context-sensitive half- ­explosion of technologic advancement made time plot, the possibility of using them in possible computer-driven server mechanisms combination was too great for investigators that allow various pieces of apparatus to be to resist. Rama-Maceiras, et al. found that controlled by computers. This technologic using remifentanil with propofol significantly advancement soon found its way into the decreased the incidence of post-operative field of anesthesia with the introduction of nausea and vomiting compared to fentanyl.42 much improved infusion pumps. Although Numerous studies have reported good results large cumbersome infusions pumps had been with the propofol-remifentanil combination, available during previous decades, the new and in 2009, Eikaas and Raeder concluded devices incorporating microchip technology that propofol with remifentanil was emerging supplanted their predecessors rapidly. as the most popular technique for total intravenous anesthesia.43 The caveat was that One of the first of these devices, each of the drugs must be administered by originally developed by Bard (C.R. Bard, continuous infusion. Inc., Murray Hill, New Jersey) in the late 1980s, was sold to Baxter (Baxter Another intriguing combination of International Deerfield, Illinois) in the early the new agents has been the simultaneous 1990s and became­ the Baxter Infuse O.R. ­administration of propofol and ketamine, pump that was to dominate infusion pump capitalizing on the complementary effects of technology over the next couple of decades. the two drugs. For instance, the hypotension It was a hybrid­ analog-digital device with that accompanies administration of propofol an internal drive mechanism that relied on is counter-balanced by the increase in blood separate electromagnet templates to control pressure and pulse from the admixed ketamine. the individual drugs. Setting the parameters Similarly the tendency for dysphoria, often for medication delivery was accomplished associated with ketamine administration with a simple and exceedingly intuitive when it is given alone, is largely overcome programming panel containing four dials.45 by the euphoria imparted to the mixture by (Fig. 7 on P. 19) propofol. The admixture is most commonly administered by infusion pumps in medical Although Baxter ultimately discontinued anesthesia and in some studies in the oral and manufacture of the Infuse O.R. pump, its maxillofacial surgery literature as well.44 popularity has remained unabated. The unit continues to be in high demand in hospitals, Providing Ease of Administration - outpatient surgery centers and in oral and Technology maxillofacial surgery offices as well. As the demand persisted, refurbished units returned

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Figure 8: The Aitecs Pro SP-12S infusion pump. An electronically controlled advancement screw enables delivery of a constant infusion. The pump is equipped with “smart technology” which makes it possible for the pump to “sense” the brand and size of the syringe which is placed in the carriage. Source: Courtesy of Richard C. Robert, DDS, MS, South San Francisco, CA ______Figure 7: The Baxter Infuse O.R. infusion pump, a hy- syringe through which the drug will be brid analog-digital device popular for many years but no longer in production. Refurbished units continue to administered. Newer pumps also have a be used widely in ambulatory surgery and office-based confirmation mode such that the settings for anesthesia. each patient must be confirmed, assuring that Source: Courtesy of Richard C. Robert, DDS, MS, settings used for a previous patient are not South San Francisco, CA. inadvertently used for the current one.38 ______to the market at a price nearly twice that of Because computer modeling can the original units. be successfully utilized in assessing the pharmacokinetic properties of various Newer-design pumps incorporate agents with the context-sensitive half-time, ­extensive “smart technology” based on investigators attempted to take the process microprocessor technology. The syringes one step further. Computer models were continue to be driven by a screw mechanism, developed for the maintenance of a continuous with the control of the servo-motor directed serum concentration of drug, a so-called by extensive drug libraries containing “target-controlled infusion” system. The TCI settings for large numbers of agents and concept took hold in countries throughout administration parameters. (Fig. 8 ) The Europe.13,46-53 However, both the FDA in the pumps can even “sense” the type of syringe United States and the Canadian authorities in the pump cradle to assure that the drug- found that TCI ­devices were not sufficiently administration settings match those of the advantageous to ­approve their commercial

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use.54 Providing Surgeon Satisfaction

The Bottom Line Even before propofol became available in the US, investigators were exploring the By the middle of 1990s, with excellent differences between incremental bolus and short-acting drugs available, a better continuous infusion techniques. In 1983, in understanding of how the drugs worked, and a cohort of 100 patients, White compared compact “user-friendly” infusion pumps, intermittent bolus administration to a medical anesthesiologists set out to document continuous infusion utilizing ketamine-based the superiority of operating conditions, street and fentanyl-based intravenous anesthetics.55 readiness of their patients and satisfaction of He concluded that “continuous infusion... the patients with their anesthetic experience. improves intra-operative conditions, and Miller summarized the rationale for use of a decreases recovery­ time compared with a continuous infusion: traditional ­intermittent bolus technique.” In a study comparing the two approaches for “Administration of IV anesthetic drugs opioid-based anesthetics utilizing fentanyl by infusion provides for greater stability of and alfentanil, White, et al. concluded “the drug concentration within the plasma and use of a continuous infusion (vs. intermittent hence at effector sites, than can be achieved injection) of alfentanil allows the anesthetist with an incremental bolus technique... to titrate the dose of drug with greater Infusion techniques thus tend to provide a precision...”56 smooth intra-operative course characterized by enhanced cardiovascular stability, and From studies conducted in Europe in with appropriate titration, facilitate rapid the mid 1980s, it became apparent that a ­total and uneventful emergence from general intravenous anesthetic based on propofol anesthesia...Other potential advantages could be used for ambulatory anesthesia. In include a lower incidence of side effects, 1988, Price, et al. compared a total intravenous shorter recovery times, and decreased drugs anesthetic utilizing a propofol infusion to 45 costs.” an inhalation technique with enflurane.57 Their decision to use a constant infusion MAXIMIZING OPERATING was based on their previous experience with CONDITIONS ­intermittent bolus infusion. They concluded: “Infusion rather than intermittent bolus For an anesthetic experience to be ­administration of intravenous anesthetics is successful, the surgeon must be satisfied the logical choice if smooth anesthesia is to with the operating conditions and the be obtained.” patient satisfied that he was as comfortable as possible under the circumstances. In this By the mid 1990s, propofol had become section we will ­address the former and in the the preferred agent for ambulatory anesthesia next section the latter. in medicine. Studies continued to assess differences between anesthetics delivered

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by intermittent­ bolus techniques versus a was associated with an anesthesia level that constant infusion. In 1995, Newson, et al. was statistically superior in both minimizing summarized their conclusions in comparing patient movement and providing a more the two techniques indicating that the “The optimal overall quality of anesthesia.” anesthesiologist had to intervene more frequently in the intermittent bolus injection By the end of the 1990s and the beginning group rather than in the two infusion groups. of the first decade of the 21st century, the We conclude the use of the infusion technique evidence was mounting that the incremental may allow the anesthesiologist more time bolus technique could not provide the same for monitoring the patient by decreasing optimal surgical conditions that could the number of interventions necessary to be achieved with a pump-administered administer supplemental doses of sedative continuous infusion. In fact, it even appeared medication during the operation.”58 that a continuous infusion of a propofol-based anesthetic could provide surgical conditions During the 1990s, oral and maxillofacial equal to or superior to those provided surgeons also began to explore the possibility by a traditional balanced anesthetic with of using propofol for office-based anesthesia. isoflurane and alfentanil. In 2003, Everhart, Candeleria and Smith noted wide fluctuations et al. reported on such a comparison in a in cardiorespiratory and psychomotor cohort of 90 consecutive patients undergoing activity in intravenous techniques utilizing microscopic and endoscopic sinus surgery. the incremental bolus technique.15 In a They concluded: “Intravenous anesthesia study of 21 ASA I patients undergoing using propofol-remifentanil provides short-duration OMS procedures in an office better surgical conditions compared with setting they concluded that “using a pump a traditional balanced anesthetic technique 59 for continuous infusion allows the surgeon to utilizing isoflurane-alfentanil. direct ­attention to the surgical field without repeated interruptions to administer the drug Providing Patient Satisfaction bolus required with the bump technique” and “... an infusion pump enables achievement of Interestingly, there has been little in a sustained sedative-hypnotic effect without the way of investigation comparing patient oscillations between peak and trough levels satisfaction with one anesthetic technique in the blood and brain, producing varying versus another. In White’s 1983 study, an 15 levels of anesthetic depths.” intravenous bolus technique was compared to an infusion technique for both a fentanyl- In 1998, Bennett, et al. compared an based and a ketamine-based anesthetic, and ­incremental bolus technique to a continuous satisfaction among the various groups was infusion technique of propofol in a cohort virtually indistinguishable. The largest study of 39 ASA I and II patients.12 Although comparing patient satisfaction with anesthesia both techniques were found to provide was published by Perrott, et al. in 2003. In “satisfactory conditions,” they concluded a sample of over 34,000 patients, patient that “The continuous infusion of propofol satisfaction approached 95% overall with no

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significant difference in satisfaction between surgery, had concluded that the newer the conscious sedation group (94.4%) and agents such as propofol and remifentanil the general anesthesia/deep sedation group are best delivered via continuous infusion. (94.9%).1 Interestingly, virtually all of In a multicenter evaluation with a cohort of ­patients who received general anesthesia or 161 patients who received total intravenous deep sedation first received a pre-induction ­anesthesia with remifentanil and propofol dose of midazolam, the same primary via continuous infusion Hogue, et al. ­sedating agent used in the conscious sedation concluded that “remifentanil 0.25-4.0 µg/ category. Consequently, when a patient kg/ min. ­effectively controlled intraoperative receives a few milligrams of midazolam as responses while allowing for rapid emergence a pre-induction agent, it appears to make from anesthesia.”60 little difference in his or her satisfaction with the anesthetic, regardless of the subsequent Further studies have tended to be anesthetic technique. conducted with this administration modality. In 2002, Gansberg, et al. reported that In another article from the same large remifentanil used for conscious sedation study a table was compiled comparing all of administered by constant infusion allowed less the various combinations of the intravenous fluctuation in cardiovascular parameters.61 agents utilized in a wide range of anesthetic Although these studies pointed to the distinct techniques. It was found that all techniques advantages of adding remifentanil to the mix relied upon a pre-induction dose of with a continuous infusion, doing so with an benzodiazepine (usually midazolam). 16 The ­intermittent bolus technique was found to be satisfaction rate for all of the combination fraught with difficulties. In 2003, a study of categories was 95% to 96%.Respondents 64 subjects who received remifentanil with an in the study were not asked to indicate intermittent-bolus approach found that “the whether their anesthetics­ were delivered older cohort (and some younger subjects) by an intermittent bolus or by an infusion experienced…substantial respiratory pump. However, ­because no difference in depression at lower doses.”62 satisfaction was noted among the various combinations of agents, it is exceedingly In 2012, Kramer, et al. compared a unlikely that attempting to distinguish combination of propofol with fentanyl to a between those anesthetics delivered with combination of propofol and ketamine for the bolus technique or by an infusion-pump deep sedation for third molar surgery.63 Each technique would have made any difference. of the combinations was delivered with an ­infusion pump, and both groups demonstrated MAINTAINING HEMODYNAMIC excellent hemodynamic and respiratory STABILITY stability. In the propofol-ketamine group there was an overall slight increase in heart By the closing decade of the 20th century rate, but this was not clinically significant. most investigators in medical anesthesia and anesthesia for oral and maxillofacial Also in 2012, Cillo reported on propofol

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with low dose ketamine admixtures for their impact. dentoalveolar surgery.44 The admixtures ranged from a ratio of 10:1 propofol to If one wishes to take a detailed look at ketamine to 3.3:1, and all were delivered the setting for adverse events associated with with an infusion pump. There was excellent infusion pump reviews, it is difficult to find hemodynamic stability in the 10:1 and 5:1 studies from the United States. Because the ratio groups, which had been previously United States does not have a national health studied. Only in the higher ketamine care system, data has usually been generated concentration group, with a ratio of 3.3:1, was from small groups of hospitals as opposed there a significant increase in cardiovascular to the nation as a whole. One such study, parameters. ­involving three U.S. hospitals, disclosed that approximately 92% of infusion pump-related ASSURING PATIENT SAFETY errors occurred in the intensive care unit.64

Infusion Pump Safety Because data collection from a large U.S. patient population is not possible, one must turn to countries that have national The safety of any method of drug healthcare systems to obtain data generated ­delivery is obviously essential. Today there from relatively large patient samples. Much is a wide range of infusion devices used of the data has been generated in the United in medicine. They are used in intensive Kingdom, Australia and New Zealand. care, for patient controlled analgesia, for administration of nutrients, hormones, Obviously, pump-related medication antibiotics, chemotherapy drugs and insulin, ­errors are a part of an overall problem of among others. Thus, when one looks at the medication errors throughout medicine incidence of adverse­ events associated with in general. Intuitively one might expect infusion pumps, all these other applications that having to deal with a piece of medical must be taken into account, as well as those equipment such as an infusion pump would that are associated with anesthesia. tend to increase the likelihood of a medication error. In actuality, it appears that exactly the Overall, the number of adverse events is opposite is the case. quite large. In 2010, the Center for Devices In a New Zealand study involving and Radiologic Health of the US Food and 8,000 anesthetics, 63% of errors involved Drug Administration mounted an Infusion intravenous boluses while only 20% involved Pump Improvement Initiative to address infusions.65 Another study in Australia 10 ­reducing the incidence of adverse events. disclosed a 2.5 times greater incidence of In it they reported that the FDA had received drug administration errors via bolus versus ­approximately 56,000 reports of adverse infusion.66 events between 2005 and 2009. The question obviously arises to how many of these events An interesting aspect of the introduction occurred during anesthesia, and what was

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of errors into medication delivery is the errors in anesthesia.69 The factors identified underlying cause. In a hospital setting 80% as being most frequently responsible included of medication errors are caused by human failure to read drug vial labels carefully, error as opposed to equipment error.67 In a distraction and inattention. The ­incidence of United Kingdom study of approximately pump failure was so low that it did not even 1,000 incidents in anesthesia, only 5 involved appear on the list of causative factors. infusion pumps and most of these were user- related.68 The greater incidence of drug errors in bolus administration, as opposed to pump In a 2013 review, Cooper and Nossaman ­administration, is due to the lack of a double- examined a number of studies from the world’s check and closed loop communication. literature to better assess the nature of drug For example, one can pick up a vial for ______

Figure 9: Operation of the Aitecs Pro 12S infusion pump: (A) The pump senses the type of syringe and displays the information on the LED screen. (B) Verification that propofol will be the drug delivered. (C) Entering the patient’s weight in kg. (D) Confirming the bolus dose which is one-third of the total induction bolus. Source: Courtesy of Richard C. Robert, DDS, MS, South San Francisco, CA.

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bolus administration without carefully reading the label, draw up the medication and administer it without any double-check whatsoever. Multiple studies point to the importance of a double-check and closed- loop communication.70,71

In keeping with these principles, modern digital infusion pumps have incorporated the confirmation mode discussed in the technology section above (on P. 19). Once a drug administration parameter has been entered into the pump, the entry must be confirmed ­before the pump will administer the drug. (Fig. 9, p. 24) Thus, there is essentially closed- loop communication between the pump and anesthesia­ provider. This layer of safe practice can be doubled by have two well- trained personnel review the pump settings before the infusion is delivered. The assistant can do the initial settings and the operator Figure 10: The infusion pump can be mounted on the can go back through the settings to assure light column of the operating chair. This eliminates the that they are correct and finally activate the need for a separate IV stand and enables easy access­ for the operator for pump adjustments. confirmation mode to assure yet a third check. Source: Courtesy of Richard C. Robert, DDS, MS, South San Francisco, When pump-related drug errors do CA. ­occur, two factors are frequently implicated. ______The first of these is associated with occlusion A second source of pump-induced of the infusion line. If the line becomes medication error is related to changing occluded and then the occlusion rapidly the vertical height of the pump relative to ­released, an inadvertent bolus of medication the patient. This can alter the rate of drug can be administered. This is most frequently delivery, leading to significant complications encountered when long, small-caliber lines for certain drugs such as vasoactive agents.73 from the pump are at some distance from The problem is most often encountered in the patient.8,72 There are multiple sources of intensive care and hospital-based anesthesia pressure that can occlude the line. However, when the patient is being moved from one in oral and maxillofacial surgery this problem location to another while the infusion is in can easily be circumvented by using a short, progress. In the oral an maxillofacial surgery larger caliber line kept in plain view. (Fig.10) office, the patient and pump are in static locations, making it exceedingly unlikely that this source of error would be encountered.

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Overall, it has been demonstrated that available, propofol entered the market and most medication errors can be prevented by ­innumerable scientific studies enforced the systems that incorporate tiers of protection. concept of the maintenance of the constant These include, double-checks, closed-loop serum level for optimal expression of communication and checklists for personnel drug attributes. By the end of the 1980s, involved in the administration of drugs.74 Paul White, then with the department of The incorporation of an infusion pump into anesthesiology at the Washington University drug delivery is in keeping with these system School of Medicine and a major contributor modifications to assure prevention rather to the literature for ambulatory anesthesia, than causation of drug administration errors. opined “in the near future infusion will likely ­become standard equipment on all anesthesia CONVENIENCE AND COST machines and anesthesiologists should find these techniques easier to use in their The evidence base discussed in the clinical practice.”76 A review of the literature sections above suggests that delivery of suggests that many share Dr. White’s opinion. an intravenous anesthetic via an infusion During the 1990s and thereafter fewer and pump provides better surgical conditions, fewer reports of studies conducted with the maximal hemodynamic stability, a higher intermittent-bolus technique were published. level of safety along with patient acceptance comparable to the traditional intermittent As the new millennium arrived, the bolus technique. The two remaining issues evidence base discussed above convinced in comparing the two approaches are not the majority of anesthesiologists worldwide scientific but practical ones–the ease and cost that providing intravenous anesthesia with of administration. a constant infusion provided by an infusion pump was the only prudent course for them Both ease of administration and cost of to follow. Investigators in the field of dental infusion pumps have been topics of concern and oral and maxillofacial surgery anesthesia for several decades. In the early 1980s have unquestionably followed the lead of a survey of 2,000 anesthesiologists was their medical anesthesia colleagues.44,61,63 conducted in Great Britain and Ireland to determine why so many anesthesia providers However, it is apparent that oral and had failed to adopt infusion pumps, even maxillofacial surgeons in a private practice though technologic advancements had made setting have remained unconvinced. Although them much more practical alternatives than infusion pumps have become relatively the previously available bulky, expensive standard components of anesthetic studies pumps.75 The two primary reasons cited were and university-based oral and maxillofacial the time to set up the infusion and the cost of surgery anesthesia training, private practice the equipment. surgeons have been slow to come to the realization that most of the previous problems As the decade progressed, newer, with pump usage have been largely overcome. simpler, easy-to-program pumps became

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Earlier we described the two primary into the IV line and the procedure can be arguments against pump usage: ease of completed without the expense of opening up ­administration and pump cost. The ease of a new vial of anesthetic.38 ­administration issue has very simple solutions for the office-based surgeon. State-of-the-art The final cost impediment is obviously infusion pumps are compact and exceedingly the cost of the pump itself. Several decades easy to program. They can be easily attached ago medical anesthesiologists were also to the operating chair and no longer require ­reluctant to adopt infusion pumps because of any special lines or attachment devices. their expense. They obviously found that the (Fig. 10, P. 25) They take standard syringes enumerable advantages of using an infusion of various sizes from 10 mL to 60 mL. In pump (discussed earlier in this section) ­addition, these new smart pumps actually outweighed the cost saving issue. In addition, flawlessly detect both the brand and volume in most settings the infusion pump actually of the syringe when it is attached to the pays for itself. pump. This information is then displayed on a LED screen for the operator to confirm In a recent study, Kramer, et al. alluded to (Fig. 9A, P. 24). Because the syringes and an important cost saving that can accompany connectors are the same ones used for the pump utilization.63 With the newer short average intermittent bolus technique, there is duration-of-action anesthetic agents such as no longer any appreciable difference in the propofol and remifentanil, a combination convenience and expense of the “plumbing.” ­approach can be quite efficacious. They found For the same cost and investment of time, that the propofol-remifentanil combination the anesthesia provider also gets the added provided more rapid recovery and earlier safety feature of confirmation mode to assure return to “street readiness” than a propofol- that the appropriate dosage of drug will be ketamine approach. The shorter recovery delivered and at the appropriate rate. time could reduce the cost of office personnel required for recovering patients. Trying to Another “plumbing” issue is the small maintain a relatively constant serum level of volume of anesthetic agent with which the anesthetic consisting of both propofol and pump is primed. The connecting tubing remifentanil is difficult using an intermittent usually holds a few mL’s of anesthetic that bolus technique. However, with an infusion would potentially go unused when the pump the two drugs can be delivered plunger of the syringe reaches zero. However, concomitantly at a constant rate. if just ­another 20-30 mg (2-3 mL) of agent is needed at the end of the case, there is no need Although oral and maxillofacial to open a new vial. One merely places a 10 surgeons seem to balk at the $2,000-$3,000 cc syringe filled with IV fluid obtained from ­expense of the infusion pump, they appear to the patient’s IV bag to replace the syringe be quite willing to spend $50,000 on a new used for the agent. The IV fluid propels the digital panograph or well over a $100,000 for remaining several cc’s of anesthetic solution a cone-beam CT machine. They do so because

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there is a perceived benefit in improved not until the so-called “Brevital Crisis” in visualization that leads to better surgery. the early years of the first decade of the new Should not the same rationale apply to a century that oral and maxillofacial surgeons comparatively minor expense of an infusion were finally forced to adopt propofol as their pump? There is a huge mass of literature primary intravenous anesthetic. which substantiates the better working conditions, hemodynamic stability and safety Are we not now at another turning that accompanies use of an infusion pump for point in office-based anesthesia in oral and intravenous anesthesia. maxillofacial surgery? We are besieged by pressures from the outside regarding the Just as in the case of the radiographic safety and appropriateness of our anesthetic equipment discussed above, the cost are approach. Many of those leveling criticism rapidly recouped. In most states the fee for come from an anesthesia background that intravenous anesthesia is several hundred long ago ­adopted infusion pumps as their dollars per case. If the surgeon were to standard form of anesthetic delivery for make a small increase in anesthesia fee of TIVA. If we fail to adopt what is considered approximately $3.00 per case (approximately to be a standard part of ambulatory anesthesia 1%), the ­average surgeon would recoup practice, we leave ourselves far more open the expense of the pump within a single to the criticism that we are utilizing an year. Thus, it would appear that oral and antiquated approach. maxillofacial surgeons’ failure to adopt the standard practice of our medical anesthesia Without question the intermittent- colleagues is indeed “penny-wise, but pound bolus technique revolutionized office-based foolish.” anesthesia in oral and maxillofacial surgery during the middle of the last century. It has CONCLUSION been utilized safely and efficiently for the anesthesia of millions of patients for over half a century. However, during that half-century, In this section I have conducted a significant advancements in pharmacology comprehensive review of the rationale that and technology have provided an avenue has prompted medical anesthesia providers for an even better anesthetic with a solid to adopt infusion pumps for delivery of total evidence base behind it. intravenous anesthesia. I have also described the time lag between the acceptance of new It is my opinion that if Adrian Hubbell agents and techniques by anesthesiologists were alive today, he would embrace this before oral and maxillofacial surgeons follow new technology without question. When suit. Early on, anesthesiologists saw the logic methohexital became available with a shorter of replacing diazepam with midazolam, duration of action, he readily made the change meperidine with fentanyl and the barbiturate from sodium pentothal to the new agent to anesthetic agents thiopental and methohexital capitalize on its advantages. When it became with propofol, several years before their oral obvious that delivering frequent boluses and maxillofacial surgery colleagues. It was

SROMS 28 VOLUME 21.4 The Pump vs. the “Bump Richard C. Robert, DDS, MS & Mark F. Sosovicka, DMD

of anesthetics with syringes and needles pharmacology in three current textbooks. was time-consuming and cumbersome, he He is the recipient of the Committee Man of developed his human-powered pump, the the Year and Distinguished Service Awards “Hubbell Bubble.” If he could see that an even of the California Association of Oral and Maxillofacial Surgeons and the AAOMS ______Committee Person of the Year Award. Richard C. Robert, DDS, MS received Mark F. Sosovicka, DMD is currently his BS in applied biology from Georgia an Assistant Professor and Director of Institute of Technology and his DDS from Undergraduate Education within the Emory University in Atlanta Georgia. Department. of Oral and Maxillofacial He conducted bone graft research at the Surgery at the University of Pittsburgh Letterman Army Institute of Research and School of Dental Medicine. He was in private completed his M.S. in oral and maxillofacial practice oral and maxillofacial surgery for 10 surgery at the University of Michigan years prior to accepting an academic position in Ann Arbor. He is currently in private which he has maintained for the last 11 years. practice and is Clinical Professor of Oral and He completed dental school at the University Maxillofacial Surgery in the OMS residency of Pittsburgh School of Dental Medicine and program at the University of California completed an oral and maxillofacial surgery Medical Center in San Francisco. There he residency at the University of Pittsburgh directs the office anesthesia curriculum and Medical Center. He actively treats patients co-directs the curricula in surgical anatomy with both dental students and residents on and dentoalveolar surgery. He is recipient of a daily basis. ­Additionally, he maintains the Outstanding Educator of the Year Award clinical interests in the areas of dentoalveolar of the School of Dentistry at UCSF. He has surgery and out-patient deep sedation/general been active in hospital ­affairs and has chaired anesthesia and also participates in active the section of oral surgery and dentistry at facial trauma call within the University of Mt. Zion Hospital in San Francisco and Seton Pittsburgh Medical Center hospitals. Medical Center in Daly City, California.

Dr. Robert has also been active in the various committees and councils of the California Association of Oral and Maxillofacial Surgeons and the American Association of Oral and Maxillofacial Surgeons. He lectures widely for these organizations on a variety of topics including anesthesia, emergency preparedness and management of medical emergencies. He chaired the Task Force that created the AAOMS DVD on anesthesia and has authored chapters on anesthesia and

SROMS 29 VOLUME 21.4 The Pump vs. the “Bump Richard C. Robert, DDS, MS & Mark F. Sosovicka, DMD

REFERENCES 8. Murphy RS and Wilcox SJ: The link ­between intravenous multiple pump flow errors and infusion system ­mechanical 1. Perrott DH, Yuen JP, Andresen RV, et compliance. Anesth Analg 110:1297- al: Office-based ambulatory anesthesia: 1302, 2010;. outcomes of clinical practice of oral and maxillofacial surgeons. J Oral 9. Corp. Terumo. Terumo Terufusion TE Maxillofac Surg 61:983-995, 2003. 331-332 Syringe Pump Safer Daily Operation Manual. (available online via 2. Lee JS, Gonzalez ML, Chuang SK, et Treumo Corp.) 2007. al: Comparison of methohexital and propofol use in ambulatory procedures 10. US Food and Drug Administration, in oral and maxillofacial surgery. J Oral Medical Devices Section, White Paper: Maxillofac Surg 66:1996-2003, 2008. Infusion Pump Improvement Initiative. (available online via FDA)2010. 3. Finder RL: The art and science of office- based anesthesia in dentistry: a 150-year 11. Neff SB, Neff TA, Gerber S, et al: history. Int Anesthesiol Clin 41:1-12, Flow rate, syringe size and architecture 2003. are critical to start-up performance of syringe­ pumps. Eur J Anaesthesiol 4. Hemmings HC: The pharmacology 24:602-608, 2007. of intravenous asnesthetic induction agents: a primer. Anesthesiology News 12. Bennett J, Shafer DM, Efaw D, et al: 2010(11-16) Incremental bolus versus a continuous infusion of propofol for deep sedation/ 5. Fischer GE, Schaefer MK, Labus general anesthesia during dentoalveolar BJ, et al: Hepatitis C virus infections surgery. J Oral Maxillofac Surg 56:1049- from unsafe injection practices at an 1053, 1998. endoscopy clinic in Las Vegas, Nevada, 2007-2008. Clin Infect Dis 51:267-273, 13. Leslie K and Clavisi O: Target- 2010. Controlled Infusion versus Manually- Controlled Infusion of Propofol for 6. Lieblich SE: Methohexital versus General Anesthesia or Sedation in propofol for outpatient anesthesia. Adults. Cochrane Anesthesia Group. Part I: Methohexital is superior. J Oral 2012(May) Maxillofac Surg 53:811-815, 1995. 14. Klein SM, Hauser GJ, Anderson BD, 7. Dembo JB: Methohexital versus et al: Comparison of intermittent propofol for outpatient anesthesia. versus continuous infusion of propofol Part II: Propofol is superior. J Oral for elective oncology procedures in Maxillofac Surg 53:816-820, 1995. children. Pediatr Crit Care Med 4:78-82,

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48. Breslin DS, Mirakhur RK, Reid JE, 56. White PF, Coe V, Shafer A, et al: et al: Manual versus target-controlled Comparison of alfentanil with infusions of propofol. Anaesthesia fentanyl for outpatient anesthesia. 59:1059-1063, 2004. Anesthesiology 64:99-106, 1986.

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73. Weiss M, Hug MI, Neff T, et al: Syringe Outpatient Orthognathic Surgery Performed size and flow rate affect drug delivery in the Office Setting. Scott Blyer, DDS from syringe pumps. Can J Anaesth and Douglas P. Sinn, DDS. Selected 47:1031-1035, 2000. Readings in Oral and Maxillofacial Surgery, Vol. 15, #6, 2007. 74. White RE, Trbovich PL, Easty AC, et al: Checking it twice: an evaluation of Pediatric Outpatient Anesthesia and checklists for detecting medication ­errors Sedation. Vasiliki Karlis, DMD, MD, at the bedside using a chemotherapy FACS; Rachel Appelblatt, DDS; Lauren model. Qual Saf Health Care 19:562- Bourell, DDS; Robert S. Glickman, 567, 2010. DMD. Selected Readings in Oral and Maxillofacial Surgery, Vol. 18, #2, 2010 75. Wright PJ and Dundee JW Attitudes to intravenous infusion anaesthesia. Office-based Anesthesia, Mark D. Zajkowski, ­Anaesthesia 37:1209-1213, 1982. DDS, MD, Selected Readings in Oral and Maxillofacial Surgery, Vol. 20, #2, 76. White PF: Clinical uses of intravenous 2012. anesthetic and analgesic infusions. Anesth Analg 68:161-171, 1989.

RELATED ARTICLES IN SELECTED READINGS IN ORAL AND MAXILLOFACIAL SURGERY

Anesthesia Complications Associated with Ambulatory Oral and Maxillofacial Surgery. Robert L. Campbell, DDS; Jeffrey R. Campbell, DDS, Selected Readings in Oral and Maxillofacial Surgery, Vol. 9, #2, 2001.

Contemporary Ambulatory Anesthesia in Oral and Maxillofacial Surgery. William L. Chung, DDS, MD; Mark F. Sosovicka, DMD; Bernard J. Costello, DMD, MD, Selected Readings in Oral and Maxillofacial Surgery, Vol. 12, #6, 2004.

SROMS 35 VOLUME 21.4 SELECTED READINGS IN ORAL AND MAXILLOFACIAL SURGERY

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