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Posts Tagged ‘CPET’

Opportunity Lost

September 10th, 2013 21 comments

The CDC hosted a conference call for ME/CFS patients and advocates today. The highlight of the call was a presentation from Dr. Ian Lipkin about his pathogen and immunology work in ME/CFS. But we received an important update on the CDC multisite study, and it remains to be seen whether advocates will accept what we were given.

You may recall that at the May 2013 CFSAC meeting, advocates were aghast at Dr. Unger’s statement that the CDC multisite study would not use two-day cardiopulmonary exercise testing (CPET) despite the research showing that this protocol produces evidence of post-exertional malaise, metabolic dysfunction, and is a potential diagnostic marker for ME/CFS. When questioned, Dr. Unger said she had not discussed the protocol with Dr. Chris Snell or Staci Stevens (who created it). This seemed like yet another example of CDC having an opportunity to do good science and intentionally choosing not to do so.

On July 22, 2013, eleven groups and thirty-one individuals sent a letter to CDC requesting, among other things, that the multisite study use the two-day protocol. Here’s what they said:

The two-day CPET regimen known as the Stevens Protocol provides gas exchange and other objective and measurable results “which can’t be faked.” With properly trained personnel in place, this test can be done using technology which has been used in hospitals and other facilities for decades. Having CPET testing performed by trained personnel on subjects involved in the multi-site clinical assessment should be considered a TOP PRIORITY in order to maximize standardized data and take advantage of the opportunity provided by this important CDC-initiated study.

We cannot over-emphasize the importance of measuring and understanding post-exertional malaise (PEM) in this study. PEM is most often the largest obstacle to activities of daily living, gainful employment, exercise, and more. A combination of data from the two-day CPET test and the on-line cognitive test that is already planned will provide the data needed for effective analysis of this debilitating symptom.

Dr. Unger responded in writing on August 30th, but for unknown reasons the advocates did not receive her response until today. Both the letter and Dr. Unger’s comments on the call today explain why CDC has chosen to do one day of maximal effort testing, followed by 48 hours of cognitive testing and symptom measurements. Especially important (and highlighted in the excerpt below) is Dr. Unger’s representation of Dr. Snell’s opinion on the protocol:

To address concerns regarding the cardio-pulmonary exercise testing (CPET) in the second stage of the study, I would like to share additional details, and the rationale that we used to select the one-day maximal exercise test. Our primary objective is to measure the exercise capacity in as many of the enrolled patients as possible using a standardized protocol, and to monitor the post-exertional response for 48 hours with online cognitive testing and visual analogue scales of fatigue, pain, and symptoms. Maximal CPET with one day of testing and 48-hour follow-up of cognition was developed in consultation with Dr. Gudrun Lang (cognition) and Dr. Dane Cook and Connie Sol (exercise). The exercise protocol was discussed also with Dr. Chris Snell. Dr. Snell favors the two-day test because it gives more information, however he believes the one-day maximal CPET will provide useful information. We chose the one-day test so that more patients could be tested. The two-day test would require an additional overnight stay for those patients who travel long distances to attend clinic and excludes those who are most severely affected because of the heavy physical toll. In developing the protocol, we strived to find a balance between testing that would yield meaningful data in the broadest representation without placing an unnecessary burden on the patients.

I immediately asked Dr. Snell if this was an accurate representation of his comments, and he said it was. He commented:

As you know, we believe that the 2 day test provides important metabolic data as well as potential to objectively document fatigue following physical exertion. I do believe, for most patients, a single max test will elicit PEM which should affect the post-test cognitive scores and fatigue scale scores. The CPET data however may not be a true reflection of physiological function post exertion for all patients.

On balance, I am happy that the CDC chose to use a validated protocol for functional assessment that does incorporate objective measures of effort. This is infinitely preferable to dubious “sub-maximal” tests. I did indicate that the study was still worthwhile even absent the second test. On what may be a selfish note, I am disappointed that the study does nothing to validate the diagnostic value of repeated CPET testing for ME/CFS. It was briefly mentioned that this might be part of subsequent studies.

So is this CDC protocol a reasonable compromise? I’m sure it was influenced by budget, to some degree. CPET testing is expensive (as I can personally attest), and creates a serious burden of recovery. CDC is choosing to compromise by using a single maximal test and then measuring the effect on patients. Will a one day test be sufficient to demonstrate PEM, including the cognitive and physical symptoms of a crash? Will advocates be satisfied, especially in light of Dr. Snell’s support of CDC’s protocol for this study?

I think CDC will capture good data this way, but it won’t be a complete demonstration of PEM and the metabolic dysfunction that characterizes ME/CFS. The second day of testing captures the significant drop in VO2max, oxygen consumption at the anaerobic threshold, peak workload, and workload at the anaerobic threshold. The second day results differentiate ME/CFS patients from other illness groups. It is possible that the CDC multisite results will not do so without that second day of testing. In my opinion, that is a huge missed opportunity.

 

Two Is Better Than One

July 3rd, 2013 10 comments

My confidence in two-day cardiopulmonary exercise testing (CPET) is pretty obvious on this blog. A new study from ME/CFS experts Dr. Chris Snell, Staci Stevens, Dr. Todd Davenport, and Dr. Mark VanNess supplies hard data that shows how important a two-day maximal CPET is for diagnosis and documenting ME/CFS. The Physical Therapy Journal has made the author manuscript available (behind a paywall), and so that version I review here is not necessarily the final version that will be published by the journal.

The purpose of this study was to establish whether the objective measurements in CPET could distinguish patients with CFS from healthy controls. The study enrolled 51 female CFS patients and 10 female sedentary controls. The CFS patients were diagnosed using the Fukuda criteria, and they also reported symptom exacerbation after activity. All subjects completed two maximal effort CPETs conducted 24 hours apart. Unfortunately, the study did not include testing for post-exercise gene expression (like the Light study). No evaluation or follow up is reported, so we do not know how long it took the subjects to recover from the testing.

In Test 1, the CFS patients did not perform as well as controls. Multiple measurements were lower in the CFS group, including VO2max, peak workload, and workload at the anaerobic threshold. However, only the peak workload difference was statistically significant. In Test 2, the differences were quite dramatic. The controls performed the same or even better on the second test. But the CFS patients demonstrated a drop in VO2max, oxygen consumption at the anaerobic threshold, peak workload, and workload at the anaerobic threshold. The mean for the last value – workload at the anaerobic threshold – dropped by more than 50%. Respiratory measurements prove that all subjects gave a maximal effort in both tests, so the reduction is not due to lack of effort.

So what does this mean? The inability of people with CFS to reproduce their CPET results on day two is extraordinary. The authors state that it “could be utilized diagnostically as an objective indicator of abnormal post-exertional response, and possibly even a biomarker for this condition.” In fact, statistical analysis of the results correctly classified CFS patients and controls with 95.1% accuracy.

Healthy individuals stay below the anaerobic threshold most of the time. But this study showed that for many CFS patients, even activities of daily living require them to push past their anaerobic thresholds. My own test results demonstrated the same impairment. This could explain not only our limitations on good days, but why those limitations shrink during post-exertional malaise.

This study demonstrates the importance of using a two-day test protocol. While there were differences between patients and controls on the first day, only the CFS patients demonstrated a dramatic drop in performance on the second day. This significant reduction in performance appears to be unique to CFS. A recent study in patients with sarcoidosis (an inflammatory condition) failed to find any difference in CPET results between patients and controls, despite using a two day protocol.

One of the questions this paper cannot answer is: why? What do these results tell us about the underlying cause? The authors say, “It is very possible that a synergy of small effects across multiple systems is responsible for the poor exercise performance of the individuals with CFS in this study.” The results are consistent with reduced oxygen carrying capacity, possibly due to low blood volume, cardiac abnormalities, or autonomic dysfunction.

The conclusion of the paper is worth quoting at length:

In conclusion, a serial CPET protocol with measurement of expired gases demonstrates efficacy in distinguishing between individuals with CFS and sedentary, but otherwise healthy controls. As in the only other studies identified employing a dual CPET paradigm with measurement of expired gases, individuals with CFS showed a decrease in performance on the second test that was not seen in controls. This functional deficit may provide an objective indication of PEM. Despite considerable patient heterogeneity with respect to illness duration and type of onset, analysis of data from the second test was able to correctly classify 49 out of 51 individuals with CFS and 9 out of 10 controls. Non-invasive biomarkers for CFS do not currently exist. Physical therapists may consider the use of CPET performance measures to differentiate between individuals with CFS and otherwise non-disabled sedentary persons. Work efficiency (i.e. oxygen consumption and work output) at the ventilatory/anaerobic threshold appears to have diagnostic potential for CFS. (emphasis added)

This paper had a long journey to publication. The manuscript was submitted in October 2011, but was not accepted until June 2013. I hope its publication will lead to wider use of the two day maximal CPET protocol, particularly in research like the CDC’s multisite study. The suffering and agony of a two day test can be severe, as my own experience shows. But an objective way to diagnose CFS has held this field back for thirty years. If the two day CPET can provide objective diagnosis, then I say let’s go full speed ahead.

 

Heart Rate and Beta Blockers

July 2nd, 2013 4 comments

Beta blockers are routinely prescribed to ME/CFS patients who have orthostatic intolerance. But because of the medication’s effects on heart rate, it can be challenging to incorporate heart rate monitoring into the picture. After some uncertainty, I have managed to do it and would like to share what I learned.

I’ve blogged extensively about using a heart rate monitor to help me pace my activities. For many months, I kept the monitor set at 95 beats per minute, my anaerobic threshold on the second day of my exercise test. By wearing the monitor constantly, I captured multiple episodes of elevated heart rate accompanied by dizziness, nausea and sweating. And I was frustrated that my alarm would sound when I climbed a single flight of stairs or took a shower.

I received conflicting advice from two ME/CFS experts. One advised reducing my activity level further in order to avoid setting off the alarm. The other suggested taking beta blockers to steady and lower my heart rate. The first expert’s concern with beta blockers is that it would lower my heart rate, but not affect my anaerobic threshold. That expert was worried that if my heart rate monitor did not go off as frequently, I would naturally increase my activity level and risk overdoing it.

After thinking about it, and listening to other patients’ experiences, I decided to give beta blockers a try. I kept my heart rate monitor set for 95 beats per minute, and knew I would have to be very cognizant of my perceived level of exertion in order to avoid overdoing it. Several months later, I give two thumbs up to beta blockers!

The first thing I noticed on the beta blocker was that my heart rate dropped, as expected. Before the medication, I would exceed 95 beats per minute every time I climbed a flight of stairs. On the medication, I rarely exceed 90 bpm. After showering, my heart rate dropped from 98 bpm to 80 bpm. On average, I think my heart rate is about 10 beats per minute lower on the medication.

Those awful tachycardia episodes of elevated heart rate, nausea, etc have virtually disappeared. And it is so much easier to get up in the morning. Every day it was a struggle for me to get up, think clearly, and start moving around. I frequently felt a little nauseous, and I always felt like I was carrying 50 pounds on my shoulders just to get up and to the bathroom. With the beta blockers, that has become much easier. I don’t feel good in the morning, but I can get up without nausea and can start thinking about the day ahead. It is not the huge act of will and stubbornness that it used to be to just get out of bed.

Am I overdoing it? Am I crashing more as a result of masking the measure of my anaerobic threshold? That is more difficult to say. I am still crashing, and still ending the day (crash or not) in a puddle of pain and exhaustion. But there have been some unusual circumstances. Illnesses in my family have taken a severe physical and emotional toll on me. At the same time, I’ve been unusually active in this blog, advocacy efforts and FDA-related activities. So of course I am crashing, and that’s never pretty. I really can’t say for certain if the beta blockers have helped extend my capacity (like they did for Sue Jackson) or made me made me more vulnerable to overdoing it. But the worst-case scenario that Expert One worried about – that artificially lowering my heart rate would lead to more crashes – also does not seem to have occurred.

Beta blockers, like all medications, are not side effect free. I was concerned about some symptoms I have been experiencing and whether they might be a result of the beta blockers. Under my doctor’s advice, I stopped the beta blockers for a week. My heart rate shot back up within a day, and the “side effect” did not dissipate. I was happy to restart the medication after that week-long experiment.

For me, beta blockers have helped with the tachycardia and orthostatic intolerance symptoms. I’m not sure it has extended my limitations, but it hasn’t really hurt either. As with everything in ME/CFS, your individual experience may differ from mine. But it is possible to use a heart rate monitor while on beta blockers. Just remember that your anaerobic threshold hasn’t changed, so you will have to rely on your perceived exertion as well as the monitor alarm to pace your activities.

 

Meeting METS

June 21st, 2013 5 comments

It has been more than a year since I had a two-day exercise test. My exercise test report was full of all kinds of jargon, and over the last year I have been trying to decode and apply it to my pacing. One of these concepts is “METS,” a measurement of the effort needed to do an activity, and correlating my results to the real world has been nothing short of shocking.

METS is the Metabolic Equivalent of Task, and is a measure that expresses the relative energy cost of activities, with a MET of 1 equal to sitting quietly. Walking at a slow pace has a MET of 2, meaning that walking slowly costs twice as much energy as sitting quietly. In exercise testing, METS is calculated from the maximum amount of oxygen consumed (VO2max), although it is not intended to perfectly correlate to an individual’s metabolism. But for purposes of understanding the relative costs of different activities, and estimating parameters of an individual’s functional capacity, METS is used as a standard measure.

In my exercise testing, my VO2max (which is the maximum amount of oxygen I consumed) correlated to 5.9 METS. This means I can’t do any activity that requires more work than 5.9 METS because my body can’t perform that level of work. My anaerobic threshold (as I’ve previously explained) was very low. A healthy person with a maximum METS of 5.9 should cross the anaerobic threshold between 3.0 and 4.425 METS. In the first test, I switched to anaerobic energy at 1.9 METS. In the second test, my anaerobic threshold occurred at 0.92 METS. Needless to say, this is abnormally low!

The real value of METS is in understanding the energy cost of activities relative to each other. The Compendium of Physical Activities is a list of the METS of numerous activities, and provides a way to look at the intensity or work capacity needed for those activities. When I took the METS results from my test and applied it to the Compendium, I was shocked to see the kinds of activities that are outside my functional capacity.

As I said, my absolute maximum capacity is 5.9 METS. This means I should not attempt any activity over that limit. Examples of activities out of my reach include scrubbing a bathroom with vigorous effort (6.5 METS), moving household items upstairs (9.0 METS), carrying 16-24 pounds up stairs (6.0 METS), or shoveling snow (6.0 METS). Many of the activities are things that I have long since given up on ever doing again, such as hiking (7.8 METS) or swimming slow laps (6.0 METS).

It is more shocking (devastating?) to see the activities over my functional capacity at my anaerobic threshold. On the first test, my AT occurred at a METS of 1.9. This means that any activity over 1.9 METS requires me to rely on anaerobic metabolism. As a result, I can’t sustain those activities for very long and I experience severe and disproportional fatigue afterwards. So I have to be very cautious with those activities, even on non-crash days. What kinds of activities are over the 1.9 limit?

  • mild stretching (2.3 METS)
  • Hatha yoga (2.5 METS)
  • general kitchen activity (3.3 METS)
  • light cleaning (2.5 METS)
  • washing dishes (2.5 METS)
  • cooking, moderate effort (3.5 METS)
  • changing bed linens (3.3 METS)
  • container gardening (2.3 METS)
  • light weeding (3.5 METS)
  • playing piano (2.3 METS)
  • showering (2.0 METS)
  • walking at a slow pace (2.8 METS)

These are basic tasks of living. Some of these I don’t have to attempt (like changing bed linens) because I am fortunate to live with a helpful husband. But if I lived alone? I know so many patients who live alone and have to expend all their energy just doing the basic chores of daily living, and then spend time recovering from them. The METS limit also helps explain why walking at a slow pace has been so difficult for me. I can do it for a short time, but with caution and the risk of crashing. Now I know that it is over my AT limit of 1.9 METS, so OF COURSE it is difficult for me.

Not surprisingly, the activities I spend the most time on are under the 1.9 METS limit. Sitting and watching tv (1.3 METS), reclining while reading (1.3 METS), and knitting (1.3 METS) are all in that safe zone. But as my exercise report noted, when I am crashed my AT occurred at < 1.o METS, which means lying down and doing nothing, or even sleeping, is at or above my limit. The other important thing to note is that METS and the Compendium are both focused on physical activities. I have found no way to measure cognitive load or capacity.

A healthy person spends most of her time under the anaerobic threshold, even while exercising. When she finally crosses her AT, she experiences the rapid onset of fatigue and will stop the activity and rest. And even if she reaches her maximum oxygen consumption and bonks, she will recover to normal within a day or two.

My exercise test shows that my entire energy system is broken all along these stages. I spend most of my time over my anaerobic threshold, except for when I am sitting and reading or knitting. Because I spend so much time over my AT, I have become accustomed, even immune, to increasing fatigue and the signals to stop and recover. And I bonk on a regular basis, without ever approaching my VO2max.

In the last year, I have had to examine all of my activities and modify where I could to try and accommodate these limits. But I don’t live in a world where I can stop washing dishes and cooking and showering. I don’t want to give up slow walking or baking or light gardening just because it is over my AT. Over many months, I have used the heart rate monitor, METS Compendium and a perceived exertion rating of “somewhat hard” to control my physical activity levels. I know it is not practical (or desirable) for me to live below the AT/1.9 METS limit. But I have really struggled to find the right balance between the two extremes of never getting off the couch and cooking/gardening/walking until I bonk. It seems like there should be a big slushy middle ground, but I have struggled to find it.

 

Moving On Up

May 1st, 2013 1 comment

For years, the Pacific Fatigue Lab at the University of the Pacific has done the best research on exercise and ME/CFS. Staci Stevens, Dr. Chris Snell, and their collaborators perfected the use of two-day cardio-pulmonary exercise testing (CPET) in people with ME/CFS. Last week, Dr. Snell announced at the FDA meeting that the University had closed the Lab but that the work will continue at new locations.

Snell and colleagues have done more research documenting abnormal CPET results in ME/CFS than anyone else in the field. Beyond documenting abnormal results, the group has also proposed physical therapy regimens based on the metabolic dysfunction revealed in the tests. The Pacific group understands ME/CFS. They do not believe we can exercise our way out of the disease, but they do recommend staying as active as possible within limitations. Stevens was the first to recommend using a heart rate monitor for pacing, and her method is still one of the best out there. When I sought my own exercise testing, I relied on the protocol devised by this group.

So why would the Lab close when it has been such a successful pioneer in this area? Dr. Snell did not elaborate at the FDA meeting, but Stevens says the answer lies in patient services. The Lab has provided exercise testing and disability evaluation to ME/CFS patients for years. I personally know several people who succeeded in disability claims because of the assessments they received in the Lab. Stevens told me that University constraints would no longer allow the Lab to provide this essential service to patients. In order to continue the disability evaluation practice, the Lab had to leave the University.

Stevens created the Workwell Foundation fifteen years ago, and it was structurally meshed with the Fatigue Lab at the University. When the decision was made to close the Lab, Workwell became the backbone of the new effort. Disability evaluation and exercise testing will now be performed in two locations: the XCEL Physical Therapy Clinic in Ripon, California and Sierra Internal Medicine in Incline Village, Nevada (Dr. Dan Peterson’s clinic). Stevens says that the relocation actually enhances the quality of care that Workwell can provide patients. Working in Dr. Peterson’s office will not only offer patients access to his expertise in ME/CFS, but patients can receive IV saline to help them recover from the CPET. That’s an option I wish I had immediate access to last year. At the XCEL clinic, patients will have access to massage therapy to help with recovery, and there is the potential for rehab services in the future. Working with the XCEL Clinic also creates the opportunity for educating rehabilitation professionals, something that Stevens has been doing for years. Stevens says that leaving the University will improve the quality of Workwell’s services because “our new partnerships bring greater diversity, more experience, enhanced services and additional professionals to help with patient care.”

Beyond the disability evaluations, Stevens says that research will continue as well. To me, this is a critical priority. Stevens, Snell and the rest of the team have done excellent work in this area and it needs to continue. Research funding has been and remains a challenge, but Workwell is pursuing grants and other funding in order to continue this research. The research team remains intact. Snell, Dr. Todd Davenport, Dr. Mark Van Ness, and others from the University of the Pacific are staying involved in Workwell. Stevens has also added a Scientific Advisory Committee to Workwell’s structure. Separating from the University may create new challenges for Workwell in terms of grant and research administration, but Stevens says that the team is committed to continuing research in this important area. Several manuscripts are in progress, and members of the team continue to speak at conferences and meetings, including Snell’s presentation at the FDA last week.

Workwell’s goal is “to facilitate an understanding of the biological basis for fatigue and provide objectively determined therapeutic interventions that will improve quality of life” for people with ME/CFS. Fee-for-service exercise testing will provide the basis for disability evaluations, and will help fund more research. Workwell will also continue to educate researchers, health care providers, and policy makers about evaluating and treating people with ME/CFS. Stevens told me that, “We have the same personnel with the same services at nicer facilities.” This change is a new chapter for Stevens and her team, and new challenges will certainly arise, but the core team remains committed to helping people with ME/CFS.

 

Comparing Exercise Advice

January 18th, 2013 44 comments

Exercise is an issue for every CFS patient, and there is no shortage of advice on whether and how to do it. On January 14th, the CDC hosted a conference call as part of its Patient Centered Outreach and Communication Activity (PCOCA) efforts. Dr. Nancy Klimas and Dr. Connie Sol presented their exercise advice for people with ME/CFS. I’ve seen some sharp criticism of the presentation, so I thought it would be helpful to compare their advice to the recommendations from Dr. Christopher Snell’s group at the Pacific Fatigue Lab. Dr. Snell and his collaborators (Staci Stevens, Todd Davenport, Mark Van Ness) have done the most work on exercise capacity in CFS, and published a conceptual model for safe exercise in 2010. You can learn more about their work in this webinar they gave last year.

Why Do It?

It’s common knowledge that exercise is an important part of preventing heart disease, diabetes, and osteoporosis. And I think most CFS patients would be eager to exercise if it did not make us sick. On Monday, Dr. Klimas said that deconditioning explains much of the dysautonomia seen in CFS. I think she may have overstated it because there are physically fit people who develop POTS, NMH or other orthostatic conditions, but deconditioning certainly wouldn’t help. Dr. Klimas described herself as the “perfect advocate to talk about exercise” because of her decades of research and clinical experience focused on biomarkers and immune function. She does not believe exercise is the only possible treatment for the disease (unlike proponents of the psychosocial model), but she also does not think it should be ignored.

I should note that while Drs. Klimas and Sol use exercise to provoke PEM so they can measure the gene expression cascade that follows, they have published no papers on exercise physiology in CFS. Snell and his group have published multiple papers on the topic, including a study that shows deconditioning is not the cause of PEM. Despite showing that there is metabolic dysfunction unique to CFS, Snell and many other experts recommend being as active as is safely tolerated. Stronger muscles will lead to less pain. Being as physical fit as possible will improve our chances with heart disease and other long-term consequences. If we can safely tolerate a certain kind or level of activity, we should do it. The emphasis must be on the word SAFE, and activity should be tailored to each individual patient’s capacity.

Identifying a Target Heart Rate

My articles on PEM and exercise explain the body’s energy systems and the importance of heart rate in detail. For purposes of this post, I can say that both Klimas and Snell agree that heart rate at the anaerobic threshold is the limit for safe activity in CFS. So how do we identify the correct heart rate?

Dr. Sol uses a single test in which the patient exercises to exhaustion. Multiple measurements help identify the heart rate at the anaerobic threshold, and then that heart rate is used to design an individualized exercise protocol. Dr. Snell and Staci Stevens use a two day maximum exercise test to do the same thing. That second test is critical because CFS patients’ metabolic function declines significantly after the first test. In my own case, my heart rate at the anaerobic threshold went from 105 on day one to 95 on day two. Under Sol’s system, 105 beats per minute would be my maximum heart rate, but that would be too high on any day that I was not well rested. My personal view is that by skipping the second test, Sol and Klimas are at risk for setting the safety limits too high for most patients.

Not everyone can take a two-day exercise test (for a variety of reasons), so there is a simple calculation for guessing at your heart rate at the AT. Klimas and Sol recommended: 220 minus your age times 60%. In my case, (220 – 44) x 60% = 105.6 bpm (matching my AT on day one).  Stevens recommends 50%, or (220 – 44) x 50% = 88bpm (lower than my AT on day two). Here’s the problem with the calculation: a bedridden patient would not have the same limit as me (housebound) or a friend of mine (who can leave the house every day). We’re all sick with CFS; we all have metabolic dysfunction. But it’s unlikely that our heart rate limits are identical.  Patients must be cautioned that the calculation is a guess only; careful experimentation is necessary to establish your safe level.

Defining Safe Activity

Both Sol and Stevens agree that the safe level of activity is the level that does not produce symptoms. Dr. Sol said that she knows she has prescribed the right level of activity when the patient reports that he/she feels no difference. Stevens has said that any symptom flare that lasts more than a few hours is too much and that activity must be scaled back.

What qualifies as exercise? Both Sol and Stevens agree that activities of daily living should be seen as exercise. The effort required to cook a meal or shower can raise your heart rate too high, and may need to by modified to stay in the safe zone. They both agree patients should examine the activities that make them tired, and try to adapt and pace those activities. Dr. Klimas said that these methods will lead to a more even, reliable supply of energy; Dr. Snell has said the same thing.

Beyond activities of daily living, Sol suggested yoga or non-weight bearing activities such as water exercises. She recommended starting with a minute or two of activity followed by a few minutes of rest, repeated five times once a week to start. In contrast, Stevens recommends a more modest starting point of stretching and range of motion exercises. Patients should advance to low intensity, short duration activity only if the stretching is well tolerated. For Snell and Stevens, heart rate is not the only indicator of capacity. Patients must pay attention to their perceived level of effort, and avoid activities (or activity duration) that feels “somewhat hard.”

Severely Ill

There is no question that there are CFS patients who are too sick to come to a lab and pedal a bike for eight minutes. Accordingly, these patients have not been studied for metabolic dysfunction and exercise capacity. Drs. Klimas and Sol made no comment on Monday about what these patients could or should do. I interviewed Staci Stevens as part of the research for my article on exercise, and based on her advice I wrote:

A bed bound patient may need assistance to turn in bed or complete basic activities such as showering, but heart rate biofeedback can help identify the appropriate pace and duration of these activities. Bed bound patients can also try deep diaphragmatic breathing, perhaps six deep breaths at a time. Deep breathing will lower heart rate, and also work the large muscles of the diaphragm. Severely ill patients might begin with passive stretching, where a physical therapist or caregiver moves the patient’s limbs slowly and carefully to gently stretch muscles and try to improve flexibility.

This must be done very cautiously. There is simply no published data that investigates the metabolic dysfunction in bedridden CFS patients or that explains what they can do safely. The cost of trial and error can be high, so patients should be very careful.

Expectations

Reasonable and realistic expectations are an important part of any rehabilitation effort. Snell and his group describe the goal as being as active as possible within toleration, and hopefully this will lead to a more predictable energy supply (eliminating the push-crash cycle). In contrast, Dr. Klimas said on Monday that patients will show improvement if they follow the program, and that when they stay below the AT they feel “much better.” Then Dr. Klimas claimed that some patients have been able to return to work or athletics. This is an extraordinary claim, especially in the absence of published data. How impaired were these patients to start with? How long did they follow the program, and was the program standardized across patients? Did these patients show objective improvement on subsequent exercise testing? How long did their improvement last?

Personally, I was very surprised to hear Dr. Klimas make this claim. She is quite familiar with the severity of the disease, the dearth of treatments, and the danger of false hope. In my opinion, claiming that pacing with a heart rate monitor and slowly progressing exercise is curative in the absence of published data is misleading, at best. The notion that exercise will make us all better is pervasive and potentially harmful to patients. Show me the data.

The Comparison

There are many similarities between the advice of Klimas and Sol on the one hand and Snell and Stevens on the other. Both sides agree that patients should be as active as they can safely tolerate. They agree that activities of daily living should be seen as exercise. Both recommend using a heart rate monitor to pace activity by staying under the anaerobic threshold. Both recommend starting very slow with exercise, and avoiding exercise that increases symptoms.

There are also some differences. The two groups calculate the safe zone differently, with Klimas and Sol potentially setting limits higher than patients’ anaerobic thresholds. Klimas and Sol offered no advice to bedridden or other severely incapacitated patients, while Snell and Stevens offer at least a little guidance. Finally, Snell and Stevens do not suggest that their program is curative in any way. They suggest a cautious but realistic goal of eliminating the push-crash cycle. In contrast, Dr. Klimas was quite expansive in her claim that her program had helped some patients return to work.

Despite their differences, both groups give the same basic advice to CFS patients: use a heart rate monitor to help you recognize when you are doing too much; ensure adequate rest; be as active as you can without triggering symptom flares or post-exertional malaise. This is a good starting point, but I hope that one day we will have access to physical therapists and others trained to help us navigate these limits. From my own experience, trying to apply this expert advice on my own has been unnecessarily frustrating.

Speeding Things Up

December 10th, 2012 1 comment

In my previous post, I explained the definitions FDA used to determine that CFS is a serious or life-threatening condition. But the true significance of FDA’s decision is that it makes CFS treatments eligible for programs that speed up the process of getting those treatments to patients. To understand these programs, you first have to understand the drug approval process.

The Pipeline: A Hypothetical

Let’s say that XYZ drug company has created a drug called PemX to treat CFS, and has tested that drug in animals to show that it is not toxic. XYZ then files an Investigative New Drug (IND) application with FDA and includes information on the drug and the plans for clinical trials in humans. XYZ conducts a Phase 1 clinical trial in 75 patients to test the safety of PemX. The results show PemX is safe, so XYZ conducts a Phase 2 clinical trial in 300 patients. The Phase 2 trial is designed to test whether PemX is effective in treating CFS, so half of the patients get PemX and half receive placebo. Since Phase 2 was a success, XYZ and the FDA discuss the design of Phase 3 trials. Phase 3 trials typically involve thousands of patients, and are designed to test appropriate dosages, side effects and drug interactions.

XYZ believes that the Phase 3 trials are a success, and files a New Drug Application (NDA). This is a request to FDA to approve PemX for sale in the United States, and the application includes all the data from all the studies. FDA has 60 days to decide whether to file the NDA for review. If the NDA is filed for review, then an FDA review team is appointed to examine all the data, the proposed labeling, and the manufacturing facility. FDA may also ask an advisory committee to examine the data. After all the reviews, FDA decides whether to approve PemX, including what dosages should be available.

Fast Track

Fast Track is an expedited process for drugs that treat serious diseases and fill an unmet medical need. Serious diseases include cancer, heart disease, AIDS, and now includes CFS as well. An unmet medical need is a condition for which there are no approved treatments (like CFS) or when the proposed drug is potentially superior to existing drugs.

Fast Track designation must be requested by the drug company, and the request can be made at any point in the drug review process. In our hypothetical, XYZ requests Fast Track status after the Phase 2 trials, and FDA has 60 days to make that determination. FDA approves Fast Track for PemX, and so now XYZ will have more meetings and more correspondence with FDA about the clinical trials. PemX is now eligible for rolling review, meaning that XYZ can submit portions of the NDA as they are completed rather than waiting to the end and submitting all at once. PemX is also now eligible for Accelerated Approval.

Accelerated Approval

There are many potential treatments that can take years to show true effectiveness. For example, a chemotherapy drug may be intended to extend the lives of cancer patients but it could take a decade or more to prove that the drug does in fact do so. To address these situations, FDA uses Accelerated Approval to base review on a surrogate endpoint. For cancer, that endpoint might be tumor shrinkage. The chemotherapy drug could be approved because it successfully shrinks tumors, and FDA would require post-approval studies to verify that the drug does in fact extend the lives of the cancer patients.

In my example, PemX is intended to treat CFS, but it could take years to be certain that patients experience long-lasting benefits that make it possible to return to work or normal life. In the Accelerated Approval process, XYZ proposes that exercise testing be used as a surrogate endpoint. Patients are put through two-day exercise challenges before treatment and then at six and twelve months post-treatment. Improvement in exercise capacity and reduction in recovery time are used as surrogate endpoints, and longer term studies would be needed to prove that PemX really did enable patients to return to work. If PemX is approved in the accelerated process, then FDA can require post-approval studies and restrictions on use of the drug.

Priority Review

Normally, FDA has a goal of ten months to review an NDA for approval. But a drug company can request Priority Review for a treatment that offers a major advance over existing therapies or where no treatment exists. If FDA assigns Priority Review for a drug, the goal timeline for review is six months. Priority Review does not change the requirements for clinical trials or drug safety and effectiveness. In our hypothetical, XYZ requests Priority Review for PemX because there are no existing therapies for CFS. FDA grants the request and the review process for the PemX NDA is now six months.

On Speed

Because FDA has determined that CFS is a serious or life-threatening condition, my hypothetical drug PemX gets to market faster. First, XYZ requests Fast Track status and this means that FDA has more contact with XYZ during the trials process, and XYZ can submit sections of its final NDA as they are completed. PemX also becomes eligible for Accelerated Approval, meaning that exercise testing is used as a surrogate endpoint for treatment success. As a result, clinical trial data can be collected for 12 months instead of many years. XYZ also requests and is granted Priority Review for PemX, and the final NDA review process takes only six months instead of ten. These three programs shorten the time it takes for PemX to move from “bench to bedside,” and it all happens because FDA determined CFS is a serious or life-threatening condition.

Note: PemX is a drug invented in my imagination, and all the examples in this post are purely hypothetical. The FDA website has an incredible amount of information on the drug approval process, and I relied heavily on the FDA’s descriptions of these programs in writing this post.

 

Insufficient Data

December 4th, 2012 21 comments

One of the most frustrating aspects of coping with CFS is the lack of definitive data. A PubMed search for “chronic fatigue syndrome” yields 4,877 results (as of today), but as a patient on the front lines I have to make treatment decisions based on theory, supposition, and anecdotal evidence.

Case in point: I’m wearing a heart rate monitor and reducing my activity to stay below my anaerobic threshold based on a few studies that show CFS patients have disruptions in their energy metabolism. There is even a published case study showing that following this pacing method and short duration exercise leads to improvement in functional capacity and activity recovery. But because my anaerobic threshold is so low, I exceed my heart rate limit just by climbing 12 steps. An expert advised me to reduce my activity to stay below the heart rate limit, even if it meant stopping halfway up the steps to rest or using a shower chair. Another expert endorsed the use of beta blockers to lower my heart rate. That topic is worthy of a separate post, but there are patients who have benefited from this approach. Sue Jackson has written excellent posts about her experience doing just that, and she credits beta blockers with drastically improving her functional capacity. When I asked the first expert about beta blockers, the expert responded that beta blockers would not change my actual anaerobic threshold but would mask when I was exceeding my limit by lowering my heart rate.

So how do I decide what to do? Expert One advises significantly reducing my activity to obey the heart rate limit, and not using medication to lower the heart rate. Expert Two advises using the medication to lower heart rate in order to increase my activity levels. There is no research that definitively answers this question. There have been no case control studies or systematic long-term follow up. Both experts can support their theories with anecdotal patient data. Both experts can support their theories with sound reasoning. There is simply no data that answers the question: which method is better for my health?

Large treatment trials, longitudinal studies, and sophisticated research into etiology and disease course drive treatment decisions for many diseases and conditions. If I had breast cancer, detailed analysis of the tumor would tell my doctor which chemotherapy regimen to use and for how long. If I had a broken hip and a heart condition, a physical therapist would be able to prescribe a rehab program suitable for both conditions. If I was HIV positive, triple therapy would be prescribed and tightly monitored to make frequent adjustments.

But those of us with CFS are left flapping in the wind. I think even the best CFS expert doctors in the country would acknowledge that treating people with CFS involves a lot of trial and error, educated guesses, and fine-tuning. The CFIDS Association recently stated that CFS patients on Patients Like Me report trying over 800 different treatments. This is insane! It’s like throwing spaghetti at the wall to see how much will stick.

Making CFS treatment decisions should be like playing sudoku – there might be some trial and error, but there is inherent logic to the puzzle. Instead, making these decisions feels like the Sunday New York Times crossword on steroids, with incomprehensible clues and multiple right answers. No one can get all the right answers based on insufficient data. Should I take the beta-blockers, or should I buy a shower chair? Your guess is as good as mine. Literally.

Rest Medicine

November 28th, 2012 6 comments

I have been working really hard at resting. That probably doesn’t make sense, but I have been struggling to incorporate preemptive rest into my routine and it feels like a lot of work. The rationale for preemptive rest is that scheduled breaks help your body restore its energy capacity because you are not pushing to the point of exhaustion. Bruce Campbell explains preemptive rest very well, and credits it as a key component of his own recovery.

I was very resistant to trying it. My functional window of opportunity is so small and fleeting. Why should I interrupt an activity to rest, especially when I feel like I can keep going? I’ve always been a power-through-it kind of person, and I’ve approached CFS the same way. Taking two scheduled breaks a day to lie down and rest, regardless of how I feel, has been a huge emotional disruption. I hate this daily reminder that I am weak. I hate feeling like a sick person who has to lie down after an hour on the computer. I don’t want to need this rest. I shouldn’t have to need it. I should be able to overcome these limitations, not feed them or cater to them. When I started taking these rest breaks, I hated it so much I would lie on my bed and fume about it (and yes, that defeats part of the purpose of resting).

But I wanted to give this method a fair trial. I knew I had to change the way I think about the rest breaks in order to get any benefit from it. I thought about treatments for other diseases and how those patients probably don’t enjoy the process either. If I had cancer, I would hate chemotherapy but I would do it. In fact, I think I would attack chemotherapy with a “let’s do this!” attitude. Cancer? Screw cancer, give me the chemo – I’ll take it and kick cancer’s ass. Rather than seeing preemptive rest as a burdensome imposition, would it help me to treat it as a daily medicine?

I don’t get pissy about taking my medications; I need them, so I take them on schedule every day. But I am still struggling to feel that way about preemptive rest. For example, I should lie down right now but I want to finish this blog post before lunch. I’m at war with myself every day because my expectations and desires are always bigger than my energy capacity. No matter how short my list is, no matter how much I have reduced my expectations, I never accomplish everything on my list. Taking rest breaks feels like a disruption and waste of time.

Would I resent chemo like this? All the horrible side effects and agony of chemo have a purpose: to rid you of cancer. I see my medications the same way: I take pain medication and it helps my pain. I am trying to bring the same attitude to preemptive rest. The rest breaks are necessary, just like my pain medication, and I should embrace it as another part of my arsenal. I realize that it might take months to see benefits from any treatment, whether it’s chemo or a new pain medication or rest breaks. I know I have to stick with it, and part of that process is adopting a positive attitude towards a method designed to help me. I am working hard, every day, to give rest breaks a fair chance.

Update (11/30/12): After I published this post, ME/CFS Self-Help Guru posted about reframing challenges in a positive way.

 

This. Is. Why.

October 17th, 2012 27 comments

I’m on the verge of tearing my hair out, and I suspect I’m not the only one. The American Academy of Family Physicians published a review article about CFS (paywall) on Monday, accompanied by a patient information sheet. From the very first sentence, this information sheet is a disaster. It packages harmful misinformation for family doctors to share with patients. Let’s take a look:

Chronic fatigue syndrome (CFS) is a disorder that causes you to be very tired.

NO! No it does not! A person with sleep apnea is tired. A nursing mother is tired. A perfectly healthy person studying for the bar exam is tired (ask me how I know). CFS does not make me tired. CFS causes prostration, a medical term that means a collapse from complete physical or mental exhaustion. Using the word “tired” is not only medically inaccurate, it falsely minimizes the severity of my disease and my experience.

People with CFS may have other symptoms, such as poor sleep, trouble with remembering things, pain, sore throat, tender lymph nodes, or headaches.

Can you spot what’s missing? Post-exertional malaise! The generally accepted hallmark symptom of this disease is not on the list. It is the first symptom on the Fukuda criteria list of accompanying symptoms. But it’s not listed here and not explained to the patient.

Not everyone with CFS has all of these symptoms.

I know hundreds of CFS patients. Every single one of us has experienced these symptoms for extended periods of time, if not daily, over the course of years. While it is technically correct that the Fukuda criteria do not require all of those symptoms, it is an oversimplification to simply say we don’t have all the symptoms. And of course all the other symptoms and overlapping conditions are not mentioned at all.

Childhood trauma (for example, physical or sexual abuse) may raise the risk of getting it.

I am aware of two studies that showed a higher prevalence of childhood trauma among CFS cases compared to healthy controls (this one and this one). Here’s the problem: childhood trauma may raise the risk of many disorders later in life. Without comparing the prevalence rate of trauma among other illness groups, there is no way to know if the association with CFS is unique. Are there studies comparing the incidence of childhood trauma among people who develop multiple sclerosis, rheumatoid arthritis, cancer, hepatitis, heart disease or  . . . oh, that’s right. Doing that kind of study in those illnesses might be offensive because those illnesses are real. But we can do those studies in CFS with no problem.

Two treatments can help with CFS: cognitive behavior therapy (CBT) and graded exercise therapy. With CBT, a therapist teaches you about how your thinking affects how you feel and act. With graded exercise therapy, you slowly increase your physical activity, which hopefully increases your function.

You know where this is going, right? Setting aside the arguments about whether CBT and GET studies actually show a benefit, and setting aside how this sort of statement plays right into the mental illness meme, let’s talk about GET. Will GET increase CFS patients’ functional ability? Maybe some patients, but it should be pursued with extreme caution and prejudice. As the work of the Pacific Fatigue Lab and my own exercise testing results show, the energy metabolism systems of CFS patients are severely impaired. We do not make or use energy, or recover from activity, the way other people (including other illness groups) do. Graded exercise must be undertaken very carefully because it takes very little activity to push a patient into a severe crash.

I shudder to think about how family doctors will use this information sheet, and what it will do to the patients who receive it. What is truly remarkable about it is that it bears only a passing resemblance to the full review article and the AAFP’s patient education page on CFS. But this watered down, oversimplified summary of misinformation about CFS will undoubtedly be used, and it is likely to make things worse for patients, not better.

So does anyone – journalists, doctors, policymakers, or other observers – wonder why the CFS Advisory Committee and patient advocates have been begging CDC to fully revise its website and remove the harmful content that filtered into this information sheet?

This is why.

Does anyone wonder why the CFSAC  recommended that the CDC remove its Toolkit from the CDC website?

This is why.

Does anyone wonder why an alliance of organizations and patients wrote a lengthy and heavily referenced position paper in support of that recommendation?

This is why.

Does anyone wonder why there was such vigorous disagreement at the CFSAC meeting about whether professional societies like the AAFP should be invited to participate in revising the CFS case definition?

THIS. IS. WHY.

 

 

Update November 2, 2012: Author Toni Bernhard published a great article about the AAFP patient information sheet.

Update October 31, 2012: I’ve also published a detailed analysis of the AAFP review article on CFS.