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Appendix B: Commissioned Paper
Pages 317-356

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From page 317...
... Rowe, M.D. Professor of Pediatrics; Sunshine Natural Wellbeing Foundation Professor of Chronic Fatigue and Related Disorders; Director, Chronic Fatigue Clinic, Johns Hopkins Children's Center Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA Prepared for the National Academies of Sciences, Engineering, and Medicine's Committee on Selected Heritable Disorders of Connective Tissue and Disability Correspondence: Dr.
From page 318...
... . More recently it has become evident that a relatively large proportion of individuals with orthostatic intolerance lack these abnormal heart rate and blood pressure responses to upright posture, but have substantial reductions in brain blood flow when upright (van Campen et al., 2020a)
From page 319...
... These changes lead to improved vasoconstriction and as much as a 30–40 beatsper-minute (bpm) increase in heart rate, returning sufficient venous blood
From page 320...
... . Figure B-1 illustrates the principal physiological contributors to orthostatic intolerance -- namely, excessive gravitational pooling of blood, often related to a defect in vasoconstriction; low blood volume; and an increased sympathetic nervous system and adrenal catecholamine response to the orthostatic reduction in cerebral blood flow.
From page 321...
... have proposed that the relative balance of epinephrine to norepinephrine can influence the pattern of circulatory response. Individuals with POTS have higher norepinephrine levels, likely related to norepinephrine-mediated vasoconstriction, thereby helping to maintain blood pressure longer, while contributing to the heart rate stimulation that defines POTS.
From page 322...
... In both children and adults, NMH occurs after the 3-minute cutoff for orthostatic hypotension and is characterized by at least a 25 mm Hg reduction in systolic blood pressure. At the time of presyncope or hypotension, affected individuals can develop a relative slowing of the heart rate that can progress to junctional bradycardia or even asystole.
From page 323...
... Low Orthostatic Tolerance This condition is characterized by the presence of frequent orthostatic symptoms without the heart rate and blood pressure changes that characterize OH, NMH, or POTS (IOM, 2015)
From page 324...
... However, OH, POTS, and NMH can be identified before syncope occurs, and the table can be returned to the horizontal position. In most laboratories, heart rate and blood pressure are monitored using beat-to-beat measurements, although in some centers only intermittent blood pressure measurements are made, for example, every 1–2 minutes for 5–10 minutes, then every 5 minutes unless presyncopal symptoms are identified.
From page 325...
... . During the first 5 minutes upright, similar heart rate changes occur during active standing and tilt testing (Hyatt et al., 1975)
From page 326...
... Each minute we will check your blood pressure and heart rate with an automatic measuring device." COMMENTS: If the subject reports any changes in symptoms, list these in the comments column of the Standing Test Data Sheet (see below) , corresponding to the time recorded for the BP and HR.
From page 327...
... Low orthostatic tolerance: the presence of prominent orthostatic symptoms with out the heart rate and blood pressure changes that characterize cOH, dOH, NMH, or POTS. Modified from Freeman et al., 2011 and Bou-Holaigah et al., 1995.
From page 328...
... . While perhaps desirable in clinical settings for patient flow, shorter periods of passive standing or head-up tilt will miss diagnosing a proportion of those who meet POTS criteria after 10 minutes of testing; therefore, a full 10-minute period upright is recommended (Roma et al., 2018a)
From page 329...
... . Differences in cardiovascular responses between ME/CFS patients and healthy controls can be detected
From page 330...
... Applying the same Doppler technology to measure cerebral blood flow during tilt testing in adults with ME/CFS, van Campen and colleagues (2020a) studied 429 adults with ME/CFS and 44 healthy controls.
From page 331...
... NOTE: BP = blood pressure; CBF = cerebral blood flow; dOH = delayed orthostatic hypotension; HC = healthy controls; HR = heart rate; ME/CFS = myalgic encephalomyelitis/chronic fatigue syndrome; POTS = postural tachycardia syndrome. SOURCE: van Campen et al., 2020a.
From page 332...
... , cerebral blood flow was similar to that of the 15 healthy controls when tested in a supine position. However, when tested in a seated position, these patients with ME/CFS developed a 24.5 percent reduction in cerebral blood flow compared with a 0.4 percent reduction in healthy controls (van Campen et al., 2020b)
From page 333...
... Subsequent work by van Campen and colleagues (2021a) has confirmed that adults who have ME/CFS differ in the degree of cerebral blood flow reduction during orthostatic stress depending on their degree of joint hypermobility.
From page 334...
... . Similarly, heart rate and blood pressure abnormalities can be identified in 56–80 percent of joint hypermobility patients; the higher prevalence rates are reported in studies with more prolonged orthostatic testing (Roma et al., 2018b)
From page 335...
... Many prefer to study in a horizontal position that reduces gravitational pooling of blood in the legs, and improves brain blood flow. Because large meals and high carbohydrate intake can contribute to a shift of blood volume to the splanchnic circulation, patients often fare better with frequent, smaller meals.
From page 336...
... While this is not comfortable for everyone, and theoretically could reduce brain blood flow in severely impaired patients, in those who tolerate the head-up position, it is thought to help by reducing urine formation and retaining more vascular volume fluid at night (MacLean and Allen, 1940; van Lieshout et al., 2000)
From page 337...
... For example, fludrocortisone might be a good first choice if the patient has a relatively low resting blood pressure for age or an increased desire for salt. Beta blockers would need to be used with caution in those with asthma, but would be a reasonable first choice for those with elevated resting heart rates or headaches.
From page 338...
... IV normal saline is impractical over the longer term but can help restore baseline function after acute infections or as rescue therapy. Fludrocortisone 0.05 mg daily for 1 week, then Suggested as first-line therapy for 0.1 mg daily.
From page 339...
... Hyponatremia can occur. Sympathetic Tone and Heart Rate Modifiers Pyridostigmine Rapid release: 30 mg daily, Effective in POTS and neurally bromide increase by 30 mg every 3–7 mediated hypotension.
From page 340...
... The mechanism by which hormonal contraceptives improve orthostatic symptoms is not entirely clear. Even in nondepressed patients with NMH refractory to other therapies, selective serotonin reuptake inhibitors (SSRIs)
From page 341...
... Selectively blocking these channels can lower heart rate without other important effects on blood pressure and cardiac or autonomic function. Ivabradine has been used in the treatment of idiopathic sinus tachycardia and postural tachycardia syndrome, as has been demonstrated by several groups.
From page 342...
... With improvement in circulation, she could exercise for 40 minutes on the elliptical with a rise in heart rate to a more normal 130 bpm, no longer associated with provoking a migraine. She is not cured, but her symptoms are well-managed with ivabradine.
From page 343...
... They provide objective evidence of changes that correlate with self-reported exacerbations in symptoms, helping to explain why individuals might be able to perform a given activity on one day, only to be impaired for days afterwards. Patients with joint hypermobility and EDS can have other associated comorbid conditions that also contribute to orthostatic intolerance and reduced cerebral blood flow, including pelvic venous insufficiency (pelvic congestion syndrome, ovarian varices, May-Thurner anomaly, and others)
From page 344...
... of the SF-36, the percent peak VO2 (volume oxygen) of a cardiopulmonary stress test, and the number of steps per day using an actometer in 99 female ME/CFS patients in whom the three different measures were completed within 3 months (van Campen et al., 2020d)
From page 345...
... As a corollary to the observation that orthostatic intolerance can be present and correlate with self-reported symptoms, even in the absence of objective heart rate and blood pressure responses to upright tilt, caution is needed in relying exclusively on neuropsychological tests, and self-reported symptoms cannot be ignored. MITIGATING THE IMPACT OF ORTHOSTATIC INTOLERANCE: MODIFICATIONS AND ACCOMMODATIONS AT WORK AND IN SCHOLASTIC SETTINGS Accommodations are unlikely to allow those with severe orthostatic intolerance to be able to work or attend school.
From page 346...
... Similarly, in those satisfying the definition of severe ME/CFS, a 20 degree upright tilt angle lowered cerebral blood flow by 27 percent, almost a four-fold greater reduction than is seen in healthy individuals (van Campen et al., 2020c)
From page 347...
... 2017. Myalgic encephalomyelitis/chronic fatigue syndrome diagnosis and management in young people: A primer.
From page 348...
... 2015. The effect of ivabradine on the heart rate and sympathova gal balance in postural tachycardia syndrome patients.
From page 349...
... 2002–2003. Chronic fatigue syndrome: What role does the autonomic nervous system play in the pathophysiology of this complex illness?
From page 350...
... 2010. Chronic fatigue syndrome: Illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function.
From page 351...
... 2000. The capnography head-up tilt test for evaluation of chronic fatigue syndrome.
From page 352...
... 2012. Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes.
From page 353...
... 2018. Improvement of severe myalgic encephalomyelitis/chronic fatigue syndrome symptoms following surgical treat ment of cervical spinal stenosis.
From page 354...
... 2020b. Reductions in cerebral blood flow can be provoked by sitting in severe myalgic encephalomyelitis/chronic fatigue syndrome patients.
From page 355...
... 2021a. Myalgic encephalomyelitis/chronic fatigue syndrome patients with joint hypermobility show larger cerebral blood flow reductions during orthostatic stress testing than patients without hypermobility: A case control study.
From page 356...
... 2010. Hormonal alterations in adolescent chronic fatigue syndrome.


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