Bariatric surgery: the role of dexmedetomidine

Seminars in Anesthesia, Perioperative Medicine and Pain (2006) 25, 51-56

Bariatric surgery: the role of dexmedetomidine Michael A. Ramsay, MD, FRCA From the Department of Anesthesiology and Pain Management, Baylor University Medical Center, Dallas, Texas. KEYWORDS: Bariatric surgery; Morbid obesity; Acute postoperative analgesia; Dexmedetomidine sedation

Bariatric surgery has become a popular treatment for morbid obesity. The type of surgery could be either a gastric resection with Roux-en-Y construction or an adjustable gastric banding. Although still performed as an open procedure, bariatric surgery is now usually performed laparoscopically. The pathophysiology of morbid obesity puts the patient at risk for major respiratory and cardiovascular adverse events. To ameliorate these risks, the ␣2-adrenoreceptor agonist dexmedetomidine was introduced for the anesthetic and postoperative management of these patients. In one center, over 2000 bariatric procedures have now been performed safely using the perioperative administration of dexmedetomidine. Dexmedetomidine has little effect on ventilation is cardioprotective and neuroprotective and allows for a hemodynamically very stable course, while reducing the need for opioids and inhalational agents. This results in less respiratory depression and airway compromise, less nausea and vomiting, better intestinal function, and potentially, a day surgery (less than 24 hour admission) procedure. © 2006 Elsevier Inc. All rights reserved.

In the United States, over 67% of adults are overweight or obese and 2.3% of the population is morbidly obese.1,2 Obesity is defined in terms of the body mass index (BMI). The BMI is calculated by dividing the body weight in kilograms by the height in meters squared. The healthy adult has a BMI of 18.5—25, and people who range between 25 and 30 are considered overweight. A BMI of 30 –35 is diagnosed as obesity, 35– 40 as severe obesity, and greater than 40 as morbid obesity. The number of persons being considered overweight and/or obese is increasing worldwide, and this condition is associated with an increasing mortality and risk for cardiovascular events.3 In the United States alone, obesity is estimated to be responsible for approximately 400,000 deaths per year.4 Diseases associated with obesity include the insulinresistant syndrome. In this case, the patient will present with at least three of the following indicators: abdominal obesity

Address reprint requests and correspondence: Michael A. Ramsay, MD, FRCA, Department of Anesthesiology and Pain Management, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246. E-mail: [email protected].

0277-0326/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.sane.2006.02.004

(girth ⬎ 102 cm in men and ⬎88 cm in women), triglycerides ⬎ 150 mg/dL, low level of high-density lipoprotein cholesterol (⬍40 mg/dL in men, and ⬍50 mg/dL in women), hypertension (⬎135/85 mm Hg), and hyperglycemia (⬎110 mg/dL). Comorbidities that have a direct bearing on the management of anesthesia for these obese patients are those that affect the major organ systems. The respiratory system may be compromised by restrictive lung disease, obstructive sleep apnea, obesity hypoventilation syndrome and Pickwickian syndrome, pulmonary hypertension, hypoxia, and respiratory failure. The cardiovascular system may be affected by hypertension, coronary artery disease, congestive heart failure, cardiomegaly, peripheral vascular disease, thromboembolism, and sudden death syndrome. The endocrine system may be dysfunctional with diabetes mellitus and its associated pathologies, hypothyroidism, hyperlipidemia, and Cushing’s syndrome. The gastrointestinal system may be affected adversely by the presence of reflux, hernias, gall stones, and a fatty liver. Physically, the morbidly obese patient has impaired mobility. These comorbidities associated with obesity result in

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these patients frequently presenting for surgery and anesthesia at an increased risk. Bariatric surgery is now being performed at an increasing frequency as an effective therapy for morbid obesity.

Bariatric surgery Bariatric surgery may be performed as an open procedure through an approximately 10-inch incision in the upper abdomen, or more frequently, as a laparoscopic procedure. The types of procedures offered include an adjustable gastric banding and the more complex Roux-en-Y gastric bypass. The adjustable gastric banding procedure reduces the size of the opening between the esophagus and the stomach thereby reducing the amount of food that can comfortably be eaten at one session. The size of the opening may be adjusted by inflating or deflating the band with saline via a port placed subcutaneously in the abdominal wall. The Roux-en-Y gastric bypass is the most common procedure performed surgically for the treatment of morbid obesity in the United States.5 In this procedure, the stomach is transected and a 30 mL gastric pouch is created. A Roux limb length of 100 cm for patients with a BMI ⬍ 50 kg/m2 and a limb of 150 cm for BMI ⬎ 50 kg/m2 are constructed with a circular gastrojejunostomy and a linear jejunojejunostomy for creation of the Roux limb including closure of the resultant jejunostomy. This procedure, when performed laparoscopically with good perioperative pain management that includes the administration of dexmedetomidine, may be done on a day surgery (less than 24 hour admission) basis.6 In an analysis of 2000 consecutive patients at a single center who underwent laparoscopic Roux-en-Y gastric bypass in a 3-year period, the demographics reported were as follows: The average BMI was 49 kg/m2 with a range from 35 to 77 kg/m2; the mean age was 42 years and seven times as many females underwent the surgery as males. The comorbid conditions in this series included degenerative joint disease 62%, gastroesophageal reflux 55%, hypertension 50%, urinary stress incontinence 40%, sleep apnea 31%, and diabetes mellitus 25%. Over 29% of the patients had 4 or more of these comorbid factors. The operative time ranged from 54 to 115 minutes, and of the 2000 patients, 84% were discharged from the hospital within 23 hours. The most common types of early surgical complications were anastomotic strictures 0.8%, gastrointestinal bleeding 0.3%, anastomotic leak 0.2%, and pulmonary embolism 0.1%. Following bariatric surgery, patients generally achieve an approximate loss of 70% excess body weight over the next 7 to 10 years. The correction of comorbidities after bariatric surgery has been reported as 83% for diabetes mellitus, 69% for hypertension, and 100% for gastric reflux.7,8 In addition to a reduction in long-term morbidity and mortality from the complications of obesity, bariatric sur-

gery has been clearly demonstrated to improve the quality of life for patients.9,10 As a result of these very impressive outcomes, bariatric surgery is being performed in increasing numbers and in patients at higher risk from associated medical conditions and increasing age.11 Medicare reimburses for bariatric surgery in many states. A review of early mortality among 16,000 Medicare beneficiaries who underwent bariatric surgery revealed 2% mortality at 30 days and 4.6% mortality at 1 year.12 The mortality rate is associated with advancing age, male sex, and lower surgeon volume of bariatric procedures. Patients aged 65 years or older have a 3-fold increase in the risk of early mortality (4.8% within 30 days) than younger patients. Cardiovascular disease is a significant risk factor for obese patients undergoing surgery, yet weight loss is a key goal in the treatment of patients with coronary artery disease who are overweight.13 Therefore bariatric surgery is being recommended for obese patients with coronary artery disease who cannot lose weight by more conservative measures.14 Bariatric surgery induces a major improvement in metabolic risk factors associated with cardiovascular disease. However, these patients are at increased risk for a perioperative cardiovascular event, and the anesthetic management has to be directed at avoiding this complication. Dexmedetomidine as a cardioprotective agent can play a major role with these patients.

Anesthetic considerations Obesity is a common presentation in patients for all types of surgery. The morbidly obese and severely obese patients are being referred for bariatric surgery in increasing numbers as the success of the outcomes continues to be sustained. It is not uncommon for some facilities to have up to 20 bariatric surgery procedures scheduled in 1 day. This presents logistical challenges to the health care team. Rapid turnover of cases with minimal delays in anesthesia care and early recovery of patients so that the recovery room is not overcrowded are essential criteria if this high volume of cases is to be sustained. The comorbid factors associated with this patient group present significant reason to slow this process down unless absolute attention to detail is provided by the anesthesiologist and measures are put in place to prevent complications. The preoperative assessment of the patient is crucial in identifying potential risk factors that might lead to perioperative adverse events. The cardiac evaluation should contain an assessment of cardiac function that includes echocardiography if there are indicators of cardiomegaly, cardiac failure, coronary artery disease, or pulmonary hypertension.15 The cardiac state should be optimized preoperatively. In the morbidly and severely obese patient, the airway and respiratory system are frequently compromised. The extra adipose tissue can make airway management very

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difficult, and in some incidences, awake fiberoptic intubation may be necessary. Obstructive sleep apnea is probably underdiagnosed in this patient group. Heavy snoring is a very common finding in the preoperative history. Some patients will present with biphasic airway pressure delivery systems or continuous positive airway pressure devices that they use routinely at night to enable them to get proper sleep. Obese patients experience oxygen desaturation more rapidly than normal patients when they are made apneic on induction of anesthesia.16 Morbid obesity results in reductions in all lung volumes, including functional residual capacity, forced vital capacity, and expiratory reserve volume.17,18 The management of the airway should be handled very carefully as loss of the airway and hypoxia can occur rapidly with conventional sedation, induction, and anesthetic agents. Similarly, postoperatively, the airway may be severely compromised, and respiratory depression occurs easily in response to routine sedatives, analgesics, and residual postanesthetic effects. Correct positioning of the patient is critical to facilitate airway management and to prevent rapid onset of hypoxia caused by atelectasis of the lower lobes of the lungs, which is caused by the mass effect of the abdominal contents on the diaphragms. Proper positioning with the use of an elevation pillow to produce the head-elevated laryngoscopy position can facilitate endotracheal intubation.19 The “back up” position at induction of anesthesia and also for recovery from anesthesia, especially when extubating the trachea, can prevent severe respiratory compromise and hypoxia. The goal of the anesthetic technique has to focus on protection of the airway and preservation of ventilation and oxygenation in combination with cardioprotection in the perioperative period. The inclusion of the ␣2-adrenoceptor agonist dexmedetomidine as the major anesthetic and postoperative agent addresses these concerns and provides increased airway protection and cardiovascular protection.

Dexmedetomidine in bariatric surgery Dexmedetomidine is a lipophilic imidazole derivative that is a highly selective ␣2-adrenoceptor agonist which has sedative and analgesic effects with minimal effects on ventilation.20 Supramaximal plasma concentrations of dexmedetomidine in healthy volunteers do not cause respiratory acidosis and do not cause prolonged apnea leading to desaturation.21 The administration of high doses of dexmedetomidine (10 ␮g/kg/h) to patients undergoing surgery in the vicinity of the airway has been demonstrated to maintain ventilatory drive but may cause obstructive apnea.22 The bariatric surgery patient may require an awake intubation because of the potential of being not only unable to intubate by direct laryngoscopy but the potential for not being able to bag-mask-ventilate. Dexmedetomidine together with topical anesthesia may provide optimal conditions for a fiberoptic awake intubation with a cooperative

53 patient and no risk of respiratory depression or airway obstruction at doses of 0.7 ␮g/kg/h or less.23 Dexmedetomidine causes sedation and analgesia by its actions on the ␣2-adrenergic receptors in the locus coeruleus in the brain and receptors in the spinal cord. The quality of sedation is different from the more common gabaminergic drugs in that it acts through the endogenous sleep pathways. ␣2-Adrenoreceptors may be found in presynaptic, postsynaptic, and extrasynaptic sites. Presynaptic ␣2-adrenoreceptors regulate the release of norepinephrine through a negative feedback mechanism. Receptors for ␣2 are found in the peripheral and central nervous systems and in a variety of organ systems. The ␣2-adrenoreceptor mediates its effects by activating guanine–nucleotide regulatory binding proteins (G proteins). The ␣2-adrenoreceptor agonist generates clinical effects by binding to an ␣2-adrenergic receptor, of which there are three subtypes: ␣2A, ␣2B, and ␣2C. All of these subtypes produce an effect by signaling through a G-protein. The ␣2A adrenoreceptor is responsible for the anesthetic, sedative, and analgesic properties of dexmedetomidine. The locus coeruleus, the predominant noradrenergic nucleus in the brain and an important modulator of vigilance, has one of the highest densities of ␣2-adrenoreceptors in the brain. The locus coeruleus releases norepinephrine that activates the thalamocortical– corticothalamic reverbrating circuits that arouse the brain and may be the source of consciousness. Sensory event-related potentials have a major importance in the study of the cognitive process. The most studied component of sensory event related potentials is the P3 nucleus located in the locus coeruleus. The P3 reflects the information processing and decision-making function of the locus coeruleus/norepinephrine system.24 A discrete stroke in the locus coeruleus results in a comatose vegetative mental state. Dexmedetomidine modulates the release of norepinephrine from the locus coeruleus and in this manner prevents activation of the central nervous system, allowing the patient to fall into a sedated state where the sleep pattern appears to be like natural sleep. Dexmedetomidine also stimulates ␣2-receptors directly in the spinal cord, thus inhibiting the firing of nociceptive neurons. The activation of the G-protein results in regulation of the calcium entry into the cell, preventing propagation of a signal. Potassium entry into the cell decreases the firing rate of excitable cells and prevents the generation of a signal. In this manner, nociceptive neurons are inhibited. There are studies performed in animals that would suggest that dexmedetomidine may also reduce the inflammatory response and the hyperalgesia resulting from inflammation.25 The effect on the cardiovascular system of low-dose infusions of dexmedetomidine is to reduce heart rate and blood pressure as a result of modulating the release of norepinephrine thereby reducing beta receptor activation. The perioperative administration of ␣2-adrenoreceptor ago-

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nists has been demonstrated to reduce perioperative myocardial ischemia and also significantly reduce postoperative mortality over 2 years.26 The sympatholytic effect of dexmedetomidine may result in a severe bradycardia in the vagotonic patient. During laparoscopic procedures, as the peritoneum is distended, vagal stimulation may occur, potentially causing a transient sinus arrest. This can easily be prevented or treated with the administration of vagolytic drugs.27 The enhancement of the effects of the vagus nerve is a function of the ␣2A-adrenosubreceptor stimulation.28 If a loading dose of dexmedetomidine (1 ␮g/kg) is administered, transient hypertension may be seen, and this is the result of ␣2B-adrenoreceptor stimulation. Dexmedetomidine, following intravenous administration, has a rapid distribution phase with a distribution halflife of approximately 6 minutes. The terminal elimination half-life is approximately 2 hours. However, dexmedetomidine is extremely lipophilic and it is likely that, in the morbidly obese patients, it will be taken up by the fat tissues and have a more prolonged elimination. This could be an advantage in providing prolonged postoperative analgesia. Metabolism is undergone in the liver by almost complete biotransformation via glucuronidation and cytochrome P450 hydroxylation into inactive metabolites. Dexmedetomidine exhibits linear kinetics in the recommended dosing of 0.2-0.7 ␮g/kg/h. Dexmedetomidine exhibits potent neuroprotective effects in experimental animal models.29,30 It exerts preconditioning effects toward preventing brain ischemic injury in clinically relevant doses in the animal model and has an anti-apoptotic effect on brain neurons. Postsurgical delirium is one of the most common psychiatric syndromes found in a general hospital setting. Delirium can lead to prolonged postoperative hospitalization and an increase in morbidity and mortality.31 Dexmedetomidine may be associated with a lower incidence of postoperative delirium when compared with the use of more traditional forms of sedation. This may be due to its unique pharmacological profile, a significant decrease in adjuvant opioid requirement, the absence of anticholinergic side effects, and its potential neuroprotective properties.32 These exciting properties of dexmedetomidine suggest that it may play a significant role in the maintenance of patient mental wellbeing. Dexmedetomidine has been used in a single center series of over 2000 bariatric surgery procedures.6 It was introduced into the practice because of the high incidence of postoperative respiratory complications associated with conventional opioid pain management. In the immediate postoperative period, morbidly obese patients are prone to develop pulmonary atelectasis that does not resolve rapidly.33 Postoperative analgesia provided by opioids carries the risk of respiratory depression, airway obstruction, hypoxia, and the frequent need for airway intervention. Patients with obstructive sleep apnea are more sensitive to the sedative effects of opioids and most gabaminergic sedative agents.34

Clinical study results Because of the increased risks that the bariatric surgery patients present when undergoing conventional opioidbased anesthesia, dexmedetomidine was introduced into the practice protocol at one center. The rationale was to reduce the amount of opioids and inhalational anesthetic administered and obtain an awake, comfortable patient at the completion of surgery, with a safe airway, minimal respiratory depression, cardiovascular stability, and early return of intestinal function. In this manner, the recovery process could be expedited and the surgery could be performed for the majority of patients as an ambulatory (less than 24-hour admission) procedure. To assess the validity of this hypothesis, a prospective, randomized, double-blinded clinical trial was proposed comparing the effects on patient management and outcomes on a group of morbidly obese patients administered dexmedetomidine compared with a placebo saline group. The study design received institutional review board approval. The study was powered to include 80 patients, 40 in each group, but was curtailed after 25 patients and the data analyzed as there was a clear benefit to those patients administered dexmedetomidine. The dexmedetomidine solution was prepared at a concentration of 200 ␮g per 50 mL of 0.9% sodium chloride solution (4 ␮g/mL). Patients were randomized to receive either the dexmedetomidine or a placebo solution prepared in identical solution bags. The infusion was started about 1 hour before the completion of surgery and infused at a rate to deliver 0.7 ␮g/kg/h if the solution contained dexmedetomidine. The infusion rate could be adjusted between 0.4 ␮g/kg/h and 0.7 ␮g/kg/h according to the anesthesiologist’s assessment of the patient. Dosing of dexmedetomidine was based on actual body weight. This was in order to facilitate prescribing of the drug but also to take advantage of the lipophilic properties of dexmedetomidine, resulting in a prolonged postoperative analgesia action. Loading doses were not given. In the recovery room, the infusion was continued during and after extubation and adjusted to keep the patient comfortable.35,36 The improved patient care and improved patient safety in the dexmedetomidine group resulted in the cessation of the study and the introduction of dexmedetomidine into routine practice. The early analysis of data revealed that, in the 13 placebo patient group, all required an airway intervention. Every one of these patients required a chin-lift after extubation, 62% needed a nasopharyngeal airway inserted, 100% had at least one episode of hypoxia (O2 saturation less than 90%), and 23% required reintubation. No airway interventions were necessary in the 12 patient dexmedetomidine group. Postoperatively, in the recovery room, the control group exhibited tachycardia and mild hypertension compared with the dexmedetomidine group (Table 1). The postoperative pain control was significantly better in the dexmedetomidine group, and these patients required significantly less morphine (P ⬍ 0.4). The dexmedetomi-

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55

Table 1 Mean hemodynamic data in the first pre-op hour of the dexmedetomidine and control groups.28 Dexmedetomidine Control Systolic BP 115.7 ⫾ 9.4 (mm Hg) Diastolic BP 60.6 ⫾ 3.2 (mm Hg) Heart rate (bpm) 72.5 ⫾ 11.1

P value

143.5 ⫾ 13.2 ⬍0.001 73.8 ⫾ 6.4

⬍0.001

89.9 ⫾ 11.2 ⬍0.001

dine patients spent a mean of 34% of the time with zero pain scores compared with 5% of the time in the control group (P ⬍ 0.001). This is an indicator of an improved quality of postoperative analgesia in the dexmedetomidine group. A comparison of arterial partial pressure of carbon dioxide (PaCO2) measured prior to induction of anesthesia and 1 hour after extubation postoperatively revealed no increase in the dexmedetomidine group and a significant increase in the control group (P ⬍ 0.04). A hypercapneic response challenge was made preoperatively and 1 hour post-extubation, and the dexmedetomidine group demonstrated an improved response (P ⬍0.04). These results confirm that, at these clinical doses, dexmedetomidine does not induce respiratory depression. This study demonstrated that dexmedetomidine administered during the course of bariatric surgery and continued in the post anesthesia recovery unit after extubation significantly improved postoperative patient care in morbidly obese patients. There was no respiratory depression detected in the dexmedetomidine group, despite the effects of anesthesia and upper abdominal surgery. The morbidly obese patient has a high incidence of obstructive sleep apnea, and the respiratory depressant effects from the opioids seen in the control group may well have been accentuated by this tendency for apnea. This would account for the necessary airway interventions and hypoxic episodes seen in this group. Perioperative heart rates and blood pressure were also increased in the control group, potentially placing this high cardiac risk group of patients at an increased incidence of adverse cardiovascular events. The impressive outcomes with the dexmedetomidine patients resulted in the cessation of the clinical trial.

Clinical application The administration of intraoperative dexmedetomidine should be delivered with the strategy of reaching the end of surgery with enough dexmedetomidine infused so that the patient will awaken comfortably and be able to maintain a secure airway. In my experience for major abdominal surgery, this requires a total of 1-1.5 ␮g/kg to be infused through the procedure. Therefore, if the gastric bypass is going to take several hours of surgery time, a loading dose of dexmedetomidine is not necessary; the infusion can be

started at 0.7 ␮g/kg/h and an adequate amount of dexmedetomidine will be present at the end of the procedure to ensure a cooperative and comfortable patient. When the surgery time is shorter (in our program, the laparoscopic gastric bypass and the gastric banding procedures take less than 1 hour), the dexmedetomidine needs to be loaded with doses of 0.5-0.75 ␮g/kg. These doses may result in transient hemodynamic changes, usually a slight increase in blood pressure, and a decline in pulse rate. At the end of surgery, the dexmedetomidine infusion is reduced to 0.2 ␮g/kg/h about 5 minutes from completion, and the patient is allowed to gradually awaken. This emergence may be “fine-tuned” by monitoring cerebral cortical activity. When the patient is awake and cooperative, the back of the bed is elevated so that the weight of the abdomen is not compressing the diaphragm and the patient’s trachea is extubated. The dexmedetomidine infusion is titrated up to a maximum of 0.7 ␮g/kg/h for pain control. At the time of discharge from the recovery unit, the dexmedetomidine infusion is stopped. It is not weaned down as there is sufficient dexmedetomidine in the patient’s fat stores allowing the analgesic effects of the drug to be long lasting.

Conclusion This one bariatric surgery center now has experience of over 2000 bariatric surgery patients where dexmedetomidine has been a key part of both the intraoperative and postoperative course, and this has been a significant factor in enabling over 85% of these patients to be discharged within 24 hours of admission.6 This has had a very significant impact on patient safety and also the cost of resources utilized for this procedure. These improvements in management have allowed up to 20 patients per day to undergo surgery by a single operator and the facility to manage up to 35 procedures per day. Dexmedetomidine has now been demonstrated to be the ideal drug for managing morbidly obese patients undergoing bariatric surgery. It improves not only the quality of analgesia and sedation, but it enhances patient safety by its properties related to cardioprotection, neuroprotection, and lack of airway and ventilation compromise.

Acknowledgments Financial Disclosures: Research grants and Speaker Honoraria from Hospira Inc. Lake Forest, IL.

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