Treatment of Low Metabolic Rate Following Bariatric Surgery

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