Treatment of Low Metabolic Rate Following Bariatric Surgery
Treatment of Low Metabolic Rate Following Bariatric Surgery
Purpose is to determine the effect of ephedrine and caffeine, on metabolic rate and weight
 loss after bariatric surgery. Approximately 40% of patients struggle with their weight loss
 rate, or metabolic rate, after bariatric surgery, and at least 30% previously had or develop
 a low metabolic rate after surgery. Metabolic rate is the speed at which calories are burned.
 The fewer the calories eaten and the more calories burned, the more rapidly weight is lost.
 It is possible that despite a very low calorie intake following bariatric surgery metabolic
 rate will decrease so much so that weight does not decrease even if intake is reduced to 1000
 calories per day. Ephedrine is a medicine used commonly to treat asthma, difficulty
 breathing, and wheezing. However, 40 years ago it was reported in scientific studies that
 ephedrine increases weight loss in patients on low calorie diets by increase the amount of
 calories that are burned. Combining caffeine with ephedrine makes ephedrine work more
 efficiently (more weight loss over time). Many studies show the effect of ephedrine on weight
 loss that began in 1974 with patients on food diets. Ephedrine used in various strengths and
 with a number of different combinations has shown to be effective and safe, especially when
 directed by a physician. There is only one study where ephedrine has been used in patients
 after bariatric surgery. In that study, both the patient and medical staff knew they were
 taking ephedrine (i.e., they were not "blinded"). The patients who were not losing weight or
 had measured low metabolic rates were treated with ephedrine. The patients taking ephedrine
 lost more weight after surgery than those not taking ephedrine. While this is a significant
 finding, the study was not designed to be the best test of the effects of ephedrine. The best
 test is where neither the patients nor the medical staff know if the patient is taking the
 active drug (double blind). All patients enrolled into the Research Study will receive
 capsules that contain either ephedrine and caffeine (the active drug) or identical capsules
 with no active ingredient (called a "placebo"). Neither group of patients will know which set
 of capsules they receive. The expected duration of treatment in the Study is 7 months from
 the day of surgery. This is a single site study. All patients will have their gastric bypass
 performed through Oregon Weight Loss Surgery at Legacy Good Samaritan Hospital. The
 investigators expect to study 200 patients with 100 receiving the study drugs (ephedrine and
 caffeine in a capsule) and 100 receiving placebo (inactive ingredients in an identical
 capsule) over approximately 6 months.
Research Objectives:

 The primary objective is to apply an effective medical weight loss treatment to post
 bariatric surgery patients to enhance their weight loss through stimulation of thermogenesis
 and lipolysis and retention of lean body mass. This treatment using ephedrine with
 phosphodiesterase inhibitor (caffeine or theophylline) has been extensively documented as
 safe and effective in the medical weight loss setting but has not been applied to
 post-bariatric surgery patients in a placebo controlled, double blind, randomized study. From
 preliminary studies this treatment should be effective, especially in the treatment of
 post-surgical patients who continue to have difficulty losing weight despite good activity
 levels and significant calorie restriction.

 Clinical Relevance:

 Raum and others have been treating patients presenting with low metabolic rates during
 medical and bariatric surgery induced weight loss for many years with ephedrine in
 combination with caffeine and/or theophylline. All the literature outlined below for the last
 40 years have been conducted only during medical weight loss. There are no randomized trials
 in surgical patients. Abstracts and expert opinion papers have been published but without
 randomization or blinding.

 Ephedrine has become controversial despite considerable evidence of its safe and effective
 treatment of airway resistance (asthma) for 50 years, and its use for medical weight loss (to
 stimulate REE and prevent loss of lean body mass) since 1974. An association with a
 non-regulated food additive, ephedra sparked the initial problems with inappropriate dosing,
 lack of physician supervision for patient selection and sensationalism in the lay press
 unsupported by peer-reviewed studies to contradict previous favorable studies. Secondly,
 using ephedrine and pseudoephedrine as substrate for the illegal manufacture of
 methamphetamine, caused an aura of further unreasoned apprehension. Because ephedrine with
 caffeine or theophylline is one of the few drug combinations that can potentially reverse a
 low REE and allow a successful weight loss following bariatric surgery, a randomized,
 controlled study is needed to determine if this effect is statistically and clinically
 significant in patients having bariatric surgery.

 SPECIFIC AIMS Background and Current Research Following bariatric surgery, metabolic rate
 decreases secondary to a decrease in sympathetic activity and lean body mass preventing
 optimal weight loss (1-3). Patients reaching this "plateau" during weight loss be it medical
 or surgical is well recognized. The plateau is reached when there is no longer a significant
 difference between calories burned and calories consumed. The equation can be modified at
 either end. High calorie intake is, by far, the most common reason given for lack of weight
 loss. The advice provided is to decrease calorie intake. However, there is a large subgroup
 of individuals whose metabolic rate (measured as Resting Energy Expenditure - REE or Resting
 Metabolic Rate - RMR) decreases while caloric intake has remained low. Raum (3) has routinely
 measured REE in bariatric surgery patients for 10 years. A low REE is commonly associated
 with a reduced weight loss rate. Hundreds of patients have been found to have REEs
 significantly depressed from normal (90-s100%) to a range of 45% to 80% and a mean of 65%.
 These patients have a deficit of 500 to more than 1000 kcal per day that they would be
 burning with a normal REE. Some patients must consume less than 700 to 1000 kcal/day just to
 maintain their weight.

 The methods to increase REE, sympathetic activity, brown adipose tissue activity include
 exercise, and several drugs including catechins (green tea), caffeine or theophylline with
 ephedrine, and capsaicin (1). Many clinical trials have demonstrated the effect of ephedrine
 on weight loss (4-7). A significant effect of ephedrine on increasing metabolism is thought
 to be one of the mechanisms for weight loss. Stimulation of brown adipose tissue was thought
 to contribute to 15% of the increase in thermogenesis and the remainder due to thermogenesis
 in muscle (8). Combinations of ephedrine with methylxanthines (caffeine and/or theophylline)
 are noted to be even more effective in raising metabolic rates. These effects were most
 notable in post-obese patients who had some lost some weight, and had depressed metabolic
 rates. REE increased 8% in the post-obese but had no effect in lean subjects. In the
 previously obese subjects, the ephedrine-methylxanthine combination normalized the defective
 thermogenic response to a meal (9). In a 24-week trial with 20 mg of ephedrine and 200 mg of
 caffeine tid were randomized with placebo. The ephedrine/caffeine group lost 17.5% of body
 weight with 25% of the weight loss attributed to thermogenesis (10). The thermogenic effect
 of ephedrine may be lost early in treatment but is restored with the addition of
 aminophylline (11).

 The effect of ephedrine on body composition has been studied. Two groups were given a very
 low calorie diet. Placebo or Ephedrine in combinations with or without methylxanthines and/or
 aspirin (110 mg tid) in an 8 week trial demonstrated no side effects. The ephedrine groups
 lost 4.5 kg more fat and 2.5 kg less lean than the placebo, significant differences. REE fell
 13% in the placebo group, but only 8% in the ephedrine groups (18).

 A few examples of the literature were highlighted above that reflect similar studies that can
 be found in extensive reviews of ephedrine on weight loss (19-26), energy balance and
 thermogenesis (27,28).

 Considerable recent controversy about the safety of ephedrine has come to pass due to the
 widespread use of an herbal food additive, ephedra, being marketed widely beginning in the
 late 1990s. Ephedrine had been used without controversy from the 1960s until this time. Many
 anecdotal reports were circulated, including over 18,000 case reports. These and 550 trials
 were reviewed in a meta-analysis (30). Of these reports less than 10% of the trials could be
 scientifically assessed and of these only 22 consisted of a placebo with some combination of
 ephedrine, ephedra, caffeine or other herbs. These remaining studies demonstrated a 2.2 to
 3.6 fold increase in one or more of the following grouped subjective complaints,
 psychological, gastrointestinal, autonomic symptoms, and/or palpitations. Presumably the
 other 90% of actual trials did not test or did not highlight these symptoms. Other papers
 (31-33) which were reviews of various types of reports (not designed studies) described
 instances of acute intoxication resulting in strokes, heart attacks, seizure and even death.
 Because of the uncontrolled nature of the data in the reports, doses, combinations with other
 drugs, and frequency or duration of exposure were unknown, they could only state whether the
 associations with ephedra were possible or probable.

 Other research observed no significant adverse effects or only temporary minor effects with
 ephedra, ephedrine and caffeine (13, 14, 34-37). These studies were double-blind placebo
 controlled in selected populations. Multiple clinical weight loss trials have measured the
 chronic and acute effects of combinations of ephedrine (30, 60 and 150 mg per day) with
 caffeine (300 to 600 mg per day) up to 180 subjects over 24 weeks (10, 12-15). Acutely, mean
 arterial pressure is increased by 9 mm/Hg and pulse by 7 beats per minute. By 8 weeks the
 side effects of tremor, insomnia, dizziness and blood pressure initially noted with ephedrine
 were equal to placebo. In some studies side effects were only seen at the highest dose of 50
 mg tid (16). No adverse effects were noted with a dose of ephedrine 25 mg and caffeine 200 mg
 tid for 10 days on cardiovascular function as measured by thoracic bio-impedance, automatic
 sphygmomanometry, continuous electrocardiographic recording or ergometric exercise (17).

 The difference between these two contrasting sets of data demonstrates that the unregulated
 use of ephedrine-containing compounds in unknown and potentially lethal doses in susceptible
 populations is not to be encouraged. But in preparations where dosage is known and
 controlled, given in appropriately selected populations, ephedrine with caffeine is safe and
 effective.

 References available on request.

 EXPERIMENTAL STUDY DESIGN Patients who have been medically cleared for gastric bypass surgery
 and meet the inclusion criteria or are not eliminated by the exclusion criteria will be
 offered the opportunity to enroll in the study.

 Patients will be enrolled in the study, IRB consents obtained, and randomized to treatment or
 control groups prior to surgery. Patients will follow all usual preoperative and
 postoperative surgical and medical investigations and care. This includes a baseline resting
 energy expenditure (REE) and body composition measurement (BC) before surgery. Study visits
 will usually occur at the same times as normal follow up visits and vital signs and weights
 obtained.

 Patients will begin taking ephedrine/caffeine or placebo capsules at 5 weeks after surgery in
 a gradual tapering dose upward beginning with one capsule daily and increasing each week by
 one capsule until taking three capsules per day. For the treatment group this would be 75 mg
 of ephedrine and 600 mg of caffeine per day. At 8 weeks after surgery they will return for an
 office visit, vital signs taken, BC done, symptom checklist completed and reviewed, and if
 not experiencing any significant side effects they will be given a 6 weeks supply of
 capsules. At 14 weeks after surgery they have and office visit with vital signs taken,
 symptom checklist completed and reviewed and be given another 6 week supply of capsules. At
 20 weeks after surgery they have and office visit with vital signs taken, symptom checklist
 completed and reviewed, and an REE study will be obtained at Good Samaritan hospital and body
 composition by bioimpedance in the clinic and be given another 6 week supply of capsules. At
 26 weeks after surgery they have and office visit with vital signs taken, symptom checklist
 completed and reviewed and be given another 6 week supply of capsules. At 32 weeks after
 surgery they will return for an office visit for vital signs, a symptom checklist and an REE
 study will be obtained at Good Samaritan hospital and body composition by bioimpedance in the
 clinic. They will be given a taper pack of capsules that will be accomplished over 3 weeks.

 At the clinic visits noted above vital signs, and body weight will be obtained. Patients will
 be questioned about any side effects. They will also be encouraged to call between visits if
 they have persistent side effects, and will be given a symptom checklist to compare over the
 phone. As usual routine medical and surgical care will be provided at these visits.
 Adjustments in medications for blood pressure, diabetes, hyperlipidemia, nutritional
 deficiencies and so forth will be addressed and treated as usual. Any surgical interventions
 for wound problems, hernias, or other complications will be attended to and routine blood
 tests or any other diagnostic tests needed, will be done. If blood pressure cannot be
 controlled to < 140/80, or pulse < 100, or patient experiences excessive adrenergic side
 effects, the treatment will be stopped, but the patient will continue with usual follow up
 medical and surgical care. The investigators will continue to collect measurements on
 patients who are unable to tolerate the treatment until the end of the study. Patients may
 withdraw, however, at anytime without any repercussions and will continue to receive regular
 care.

 Body composition will be measured by body impedance analysis with a Quantum III BIA from RJL
 Systems (Michigan). This is a high quality, reproducible system using electrode placement on
 hands and feet. While DEXA body scans may provide more detailed information the research cost
 for these measurements in this study would exceed the cost of the medications alone. The
 investigators have three RJL systems in the clinic and the total body lean mass compares well
 the comparable measurements obtained with the DEXA.

 REE is measured using a Sensor Medics indirect calorimeter with O2 and CO2 measurements to
 calculate REE. This equipment is located and managed by the Respiratory Therapy Department at
 Good Samaritan Hospital and has been calibrated, tested and used in other funded research
 studies. The test is done fasting, without morning medications with minimal pretest activity
 (15 minutes at rest prior to starting the test), and normal fluid balance. The equipment is
 calibrated before each test.

 Body weights are obtained on an electronic scale, capacity 800 pounds, with shoes off and
 patients are advised to wear the same light weight clothes at each visit. The scale's
 calibration is checked quarterly (a requirement of current and prior research studies).

 The investigators use a Welch-Allyn automatic cuff for blood pressure and pulse. Two
 measurements are obtained in each arm at each visit. The investigators have multiple size
 cuffs to match upper arm diameter. Calibration checked quarterly as research protocols have
 required.

 Power analysis was performed with results from our previous studies in non-randomized
 subjects treated for 2 months.
Inclusion Criteria:

 -  Qualify for gastric bypass or sleeve gastrectomy (fertile females with negative
 pregnancy test)

 -  Willing to comply with scheduled follow up appointments

 -  Blood pressure < 140/80 and heart rate < 100 measured three times

 Exclusion Criteria:

 -  Treated hypertension with blood pressure still > 140/80

 -  Stroke or myocardial infarction within the last 12 months

 -  Angina currently requiring medical treatment

 -  On medication or a device to control arrhythmias

 -  On a beta blocker to treat hypertension

 -  On medications known to interact with ephedrine or caffeine

 -  Unable to tolerate side effects

 -  Pregnancy

 -  Fertile females unwilling to practice effective birth control