Treatment of Low Metabolic Rate Following Bariatric Surgery
Condition: Morbid Obesity
MeSH terms: Obesity, Morbid
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Ephedrine sulfate with caffeine; cellulose
Intervention type(s): Drug; Drug
Intervention description(s): Ephedrine sulfate 25-mg with caffeine 200-mg combination capsule to start 5 weeks after gastric bypass surgery at 3 times per day 4 hours apart.; sufficient cellulose to fill a placebo capsule identical to the active drug to be taken 3 times per day 4 hours apart for 6 months after gastric bypass surgery
Intervention MeSH terms: Ephedrine; Pseudoephedrine; Caffeine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: resting energy expenditure; fat free mass; lean body mass; bariatric surgery; morbid obesity; ephedrine; caffeine; Low metabolic rate; Low lean body mass; Weight loss rate