I believe observations made in Intensive Care Units can further understanding of ME/CFS.
Indeed, following a severe injury or infection some ICU patients fail to begin recovery for unknown reasons. This condition, termed “chronic” or “prolonged critical illness,” is characterized by neuroendocrine dysfunctions perpetuated by cytokines and oxidative/nitrosative stress. Regardless of the initial injury or infection, patients experience profound muscular weakness, cognitive impairment, pain and other severe ME/CFS-like symptoms.
Given these similarities, I believe that active collaboration between critical illness and ME/CFS researchers could lead to solutions for both conditions.
Please see my brief blog post below (first published on Health Rising). Any feedback is much appreciated.
Thank you for your consideration,
Note: This blog post is based on a series of longer blog posts (see list at the bottom of this post) — references are cited in these posts.
There are generally three possible outcomes for patients admitted to Intensive Care Units (ICUs) following a severe injury or infection: some die within days, others start recovering, and yet others appear to be “neither dying, nor recovering.”
These latter patients are labeled as suffering from “chronic” or “prolonged” critical illness.It’s important to note that any severe injury or infection can lead to this condition, including head injury, severe burns, liver disease, pancreatitis, HIV infection, sepsis, cardiac surgery, etc.
Irrespective of the initial injury or infection that brought them into the ICU initially, these chronic patients generally experience fatigue, profound muscular weakness, cognitive impairment, loss of lean body mass, pain, increased vulnerability to infection, skin breakdown, etc.
Critical illness researchers have found that most of the debilitating symptoms of prolonged critical illness are due to endocrine dysfunctions – i.e. changes in the production and metabolism of hormones.
Here it is important to note that the endocrine patterns observed during the initial “acute” phase of critical illness (in the first few hours or days) differ markedly from those observed during “prolonged” critical illness (after a few days). Researchers only fully realized this distinction in the late 1990s.
Indeed, endocrine changes during the “acute” phase allow the body to prioritize certain functions (such as fighting infections and healing) over others (such as digestion or reproduction). They are thus considered adaptive and necessary responses to the stress of a severe injury or infection.
Endocrine patterns that appear during the “prolonged” phase, however, appear to inhibit recovery and are now increasingly considered maladaptive. It is the endocrine patterns that appear during the “prolonged” phase that are reminiscent of what is seen in ME/CFS and FM.
Pituitary Gland Suppression
The suppression of the pituitary gland’s pulsatile secretion of tropic hormones is central to prolonged critical illness. In other words, the signals emitted by the pituitary — in the form of specific pulses of hormones targeting the “downstream” endocrine glands (e.g. adrenal gland, thyroid gland, liver and gonads) — are disturbed.
Note that changes in these signals can only be fully captured by repeated blood tests performed day and night — as often as every 10 minutes. The failure to do this might explain why the endocrine dysfunctions in prolonged critical illness were only documented in the late 1990’s.
This suppression of the pituitary secretions has severe consequences:
- Without sufficient pulsatile stimulation by the tropic hormone ACTH the adrenal glands begin to atrophy, compromising patients’ ability to deal with all kinds of external stressors, and permits excessive inflammatory responses.
- Suppression of TSH release from the pituitary causes weakness and cognitive and organ dysfunction.
- Erratic rather than pulsatile production of growth hormone by the pituitary leads to an imbalance between catabolic and anabolic hormones – in other words, between hormones that break-down proteins and those that build proteins. This results in loss of muscle and bone mass, muscle weakness, and changes in glucose and fat metabolism.
- Finally, the suppression of FSH secretion can lead to muscle weakness and increased pain sensitivity.
Again, the one-time lab reading cannot capture the extent of the endocrine dysfunctions occurring during prolonged critical illness. Indeed, the concentration of tropic hormones at any one time gives little indication of the frequency and amplitude of their release by the pituitary, which is a determining factor of their function.
Pituitary pulsatility suppression ultimately translates into low or relatively low concentrations of “peripheral hormones,” including cortisol, T3, IGF-1 and testosterone. Similar patterns of altered hormone levels have been documented in ME/CFS and fibromyalgia patients.
Lower ratio of T3 to RT3
In addition to pituitary suppression, another endocrine anomaly underlies prolonged critical illness: the ratio of active thyroid hormone (T3) to inactivated thyroid hormone (RT3) is lower than normal. Significantly, this same pattern has recently also been documented in ME/CFS patients. This is largely the result of changes in the activity of the various enzymes that convert thyroid hormones.
The decrease in the T3 to RT3 ratio in prolonged critical illness contributes to a general slowing-down of metabolism. Moreover, tissue specific changes in T3 and RT3 concentrations variably impact the function of the liver, kidney, brain, heart, adipose tissues, gut and other organs, and may increase the laxity of ligaments and tendons. Relatively low plasma concentrations of T3 (and prevalence of RT3) also depress the activity of immune cells, including natural killer cells.
Cytokines and oxidative stress
Research indicates that immune modulators called cytokines play a role in inducing and maintaining the aforementioned endocrine dysfunctions in a number of ways including:
- modifying the expression of the hormone receptors on the hypothalamus and pituitary
- altering the activity of enzymes that convert hormones
- changing the affinity and number of hormone-binding carriers
- varying the rate of break-down of hormones, etc.
Finally, researchers have shown that “vicious cycles” involving oxidative and nitrosative stress (O&NS), cytokines, and low thyroid hormone activity can perpetuate the endocrine dysfunctions, and thus explain why some critically ill patients fail to recover. O&NS, moreover, can cause mitochondrial damage.
The good news is that researchers have successfully reactivated the pulsatile secretion of tropic hormones by the pituitary in chronic ICU patients. Similarly, researchers have also had some positive results in breaking the vicious cycles that can perpetuate critical illness in ICU patients. However, many of the promising treatments for prolonged critical illness are not yet standard practice, and patients continue to hang on for their lives in ICUs.
Interestingly, some of the approaches tested to remedy prolonged critical illness are used by a few ME/CFS and fibromyalgia practitioners, including supplementation with T3.
In sum, the stress of a severe injury or infection induces endocrine changes that are mediated by cytokines and may be perpetuated by mechanisms involving O&NS. The subsequent endocrine dysfunctions result in a slew of ME/CFS-like symptoms, including an inability to deal with stressors, susceptibility to excessive inflammatory responses, loss of muscle and bone mass, muscle weakness, changes in glucose and fat metabolism, pain, and general as well as tissue-specific metabolic down-regulation.
These endocrine dysfunctions elude clinicians and researchers who fail to measure RT3 or rely on one-off blood tests to measure pituitary secretions.
Can these observations from ICUs help us understand ME/CFS and fibromyalgia? Can the results of treatment trials for prolonged critical illness contribute to solve ME/CFS? …
Please read my blog posts to find out more about the relevance of critical illness research for ME/CFS and fibromyalgia:
- Neuroendocrine Dysfunctions in Prolonged Critical Illness: Relevance for Chronic Fatigue Syndrome ME/CFS and Fibromyalgia Pt. I and Pt 2 (Sept 2019)
- The Relevance of Research on Critical Illnesses for Chronic Fatigue Syndrome ME/CFS: A vicious cycle between cytokines, oxidative stress and thyroid hormones (July 2019)
- Pure T3 Thyroid and Stories of Recovery from Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia: An Overview (March 2019)
Key reference document: Here the link to arguably the most eye-opening article I have read on the topic of endocrine dysfunctions in prolonged critical illness:
- Van den Berghe G. On the Neuroendocrinopathy of Critical Illness. Perspectives for Feeding and Novel Treatments. Am J Respir Crit Care Med. 2016 Dec 1;194(11):1337-1348