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Orthostatic Intolerance I: The Evidence

electrocardiogram-16948_640This is the first in a four-part series of research articles on orthostatic intolerance.

Standing: a very stressful act 

Standing has little effect on blood flows to the brain in most animals because their brains are roughly on a horizontal level with their hearts. Humans, however, have to deal with the gravitational inevitability of large flows of blood rushing away from the brain every time they stand.

Every time you stand, about 300-800 mls of blood rush from the trunk of your body to your legs causing blood to pool in the legs and producing about a 40% reduction in the output of blood pumped by the heart.

Unless something is quickly done, reduced flows of oxygen to the brain result in dizziness, fatigue, or other symptoms. The body has four primary ways of combating this.

  1. Baroreceptor activation: Reduced levels of heart-blood cause signals from nerve fibers in the heart called baroreceptors to shut down the stream of signals they usually send first to the vagus nerve, then to the hypothalamus, and ultimately to the brainstem. The brainstem reflexively responds to this loss of signal by inducing the sympathetic nerves in blood vessels to release a catecholamine (norepinephrine) that increases the heartbeat and causes the smooth muscles in the peripheral blood arterioles of the lower extremities to (vaso)constrict. (Arterioles are found at the ends of arteries just before the capillaries begin, and are able to regulate the amount of blood flowing into the capillaries by constricting.) By shunting blood from the legs upward, this vasoconstriction counters gravitational flows of blood downward and helps to ensure that bloodflow to the brain and blood pressure are maintained during standing
  2. Muscle pump: Standing activates a series of small muscle contractions in the legs and buttocks (the ‘muscle pump’) that propel blood sequestered in the veins back to the heart. By reducing venous (i.e. returning) blood pressure and thus building a pressure gradient between the veins and arteries, muscle activity increases blood flow through the capillaries and into the veins.  The muscle pump requires some motion to be effective; it is nearly completely defeated when standing completely still. People undergoing tilt-table tests are usually strapped onto the table in order to stop them moving and using their muscle pump.
  3. Local vascular responses are less well delineated but may account for as much as 45% of the orthostatic response. Local smooth muscle responses (myogenic) and metabolic responses to reduced oxygen and increased CO2 levels and venoarteriolar responses originating in the veins may all play important roles in altering blood vessel diameters in the lower extremities during standing (orthostasis).
  4. Hormonal responses occur later but play an important role in maintaining the orthostatic response. Reduced cerebral blood flows can trigger the renin-angiotensin-aldosterone system to increase blood volume.

In short, the body the engages in the following activities in order to maintain blood flow to the heart and brain when one stands: (1) the heart beat increases, (2) the constriction of the arterioles in the legs helps to shunt blood upwards, (3) small contractions in the leg muscles propel blood in the veins upwards, and (4) blood-vessel vasoconstriction triggered by local (non-neuronal) muscle, metabolic and venoarteriolar responses to increased blood flows in the legs reduce blood pooling

A healthy person typically responds to standing with slightly decreased systolic (about -6.5 Hg) and slightly increased diastolic (about +5.6 Hg) blood pressure and a small increase in heart rate. Even so, bloodflow to the brain usually temporarily drops by about 6%. This, however, is unnoticed and in the blink of an eye, for most people the crisis of standing is quietly resolved without incident or notice. For someone with orthostatic dysfunction, however, the inability to maintain proper bloodflow to the brain can have disabling results.

System Failure

Orthostatic dysfunction occurs when people become symptomatic upon standing or while standing. Unsuccessful standing occurs when abnormalities in blood flow, heart activity or blood pressure regulation lower bloodflow to the brain. Because successful standing requires the interplay of physical, neurological, hormonal and vascular factors, it can be difficult to pin down the cause of unsuccessful standing.

The most common form of orthostatic dysfunction – orthostatic intolerance (OI) – primarily affects younger women (aged 15-45). Not all patients have all symptoms (and, importantly, in delayed OI, patients may never feel dizzy or lightheaded before they eventually lie down).

But, generally speaking, OI symptoms upon standing include dizziness, visual changes, head and neck discomfort, poor concentration, fatigue, exercise intolerance, nausea, problems sleeping, palpitations, tremors, anxiety, sensations of feeling hot, and sometimes fainting.

Other symptoms include headache, difficulty swallowing or breathing, pallor, irritable bowel syndrome and tremulousness.  (Sound familiar?) Approximately 500,000 people in the US are believed to have OI. Like CFS, OI is an umbrella term that includes under it a number of different disorders.

Tests of Orthostatic Intolerance

Chronic fatigue syndrome (ME/CFS) patients have demonstrated great heterogeneity in their responses to the tests that delineate malfunctions in standing.

Tilt Table Testing

Despite its popularity it is surprising to learn that the tilt table test is not particularly accurate. About 25% of adolescents without a history of fainting will faint during a tilt test. Similarly about 25% of people with a history of fainting will not faint on any given tilt test.

The test’s reproducibility rate is not particularly high; someone who tests ‘positive’ on one day may test ‘negative’ on the next. This field of research is plagued as well by different methodologies (angle of tilt, use of pharmacological challenge or not) that makes it difficult to translate results across studies. It is, nevertheless, the most widely used test in diagnosing OI.

The following measures are often taken during tilt table testing.

Blood Pressure

Several measures of blood pressure are taken during tilt table testing. While a healthy person typically registers small increases in systolic BP, some people with OI display large increases, others are unable to maintain blood pressure after a time (neurally mediated hypotension, or NMH) and still others maintain increased blood pressure for too long.

  • CFS Patients: BP results in CFS patients  during tilt testing have been inconsistent. Dramatically reduced (p < .001) systolic BP declines were seen in three studies, significantly reduced diastolic BP declines in two others, and several others have been normal. A rigorously controlled twin study found significant declines and increases in diastolic and systolic BP respectively over time in CFS patients versus their healthy twins but no differences in the rates of neurally mediated hypotension (low blood pressure). The BP changes, while present, were apparently not severe enough to qualify for neurally mediated hypotension.

Baroreflex Sensitivity

Baroreflex (“baro” means “pressure”) sensitivity appears to measure how baroreceptors adapt to changes in BP over time. Overly sensitive baroreceptors would presumably overcompensate for reduced blood volume by overly constricting the blood vessels and dramatically increasing the blood pressure. Baroflex sensitivity is determined by measuring changes in blood pressure during tilt.

  • CFS Patients: One study found increased baroreflex sensitivity while standing in more severely ill CFS patients. This was manifested by systolic BP changes that were normal at first but did not decline as rapidly as did controls. Thus while the body seemed to respond to the ‘crisis’ of standing normally, it remained in ‘crisis’ mode longer than it should have. Problems with baroreflex sensitivity do not, however, appear to be widespread in CFS patients.

Heart Rate

To compensate for the temporarily reduced blood volume occurring during standing the heart rate increases momentarily in order to pump more blood to the organs. A greatly increased heart rate during standing is postural tachycardia syndrome (POTS).

  • CFS Patients: Significantly higher than normal heart rate increases are commonly seen in CFS patients during tilt table testing. Galland found that 25% of adolescents studied met the criteria for POTS (Galland 2008). Galland suggested that the form of POTS found in ME/CFS adolescents (without accompanying hypotension) was unique to ME/CFS.

Cerebral Blood Flow

Certain symptoms (light headedness, poor concentration, head, neck pain and fatigue) experienced by people with chronic orthostatic intolerance (OI) are believed to originate in diminished blood flows to the brain upon standing.

  • CFS Patients: Tests of cerebral bloodflow velocity (CBFV) differed significantly from controls in one study but not in another. (Because the ‘healthy’ control group in the later test had a much higher rate of low blood pressure, the authors suggested that the control group (health workers) may have been skewed; nevertheless,  half of the measures approached significance (p<.06, .07, .08, .09, .10.)) Given the possible confounding factors it is not unlikely that when paired with a more representative control group, CFS patients would have exhibited significantly lower blood flows to the brain.
  • Rowe (2002) reported that a new more sensitive test of oxygenated blood flow indicated that half of CFS patients without OI had reduced flows of oxygenated blood to the brain. Ocon (2012), however, did not find reduced cerebral blood flow velocity during tilt table testing in ME/CFS patients with POTS (but did find reduced cognitive functioning).  Stewart’s (2012) study also did not find significantly reduced CBV in in ME/CFS patients with POTS but the findings suggested that increased vasomotor tone and decreased metabolic control of CBFV were present.

Heart Rate Variability (HRV)

HRV corresponds to the complex changes that the heart is constantly making in response to its environment. These changes are regulated by the two branches of the autonomic nervous system (ANS), the sympathetic and parasympathetic nervous systems (SNS, PNS).

The SNS plays an excitatory role – it kicks in when blood pressure or volume are too low to ensure adequate flows of oxygen and nutrients to the organs. The PNS, on the other hand, plays an inhibitory role. The SNS regulates heart activity when we are active; the PNS regulates heart activity when we’re at rest.

The heart is an amazingly complex organ. Different heart signals, for instance, oscillate at different frequencies and amplitudes. Researchers have been able to detect ultra-low frequency (ULF), very low frequency (VLF), low frequency (LF) and high frequency (HF) patterns of heart activity.

The low and high frequency oscillations are believed to reflect, respectively, sympathetic and parasympathetic nervous system activity. Others may reflect the 24-hour circadian rhythm cycle, and so on. Many variables can be formed out of these measures.

Although it seems paradoxical, ‘a healthy heartbeat is slightly irregular and to some extent chaotic’ (Sztajzel 1999). A healthy heart is able to respond to the variety of signals constantly given to it by the brain; an unhealthy heart does not. (Impaired HRV does not necessarily mean a heart is unhealthy – it can indicate problems with autonomic nervous system functioning.)

Certain cardiac conditions as well as aging are, however, associated with reduced HRV. Low HRV has been shown to significantly increase the risk of death and/or arrythmias in heart attack patients. In short, healthy heart activity has a slightly irregular pattern of heartbeats; unhealthy heart activity has a very regular pattern of heartbeats.

Some researchers believe that increased sympathetic activity enhances automaticity while increased parasympathetic activity inhibits it.  Increased sympathetic activity in cardiac patients is believed to be a protective response designed to reduce the possibility of life-threatening arrythmias.

In the face of a potentially chaotic environment the SNS essentially clamps down on nervous system activity: the patient survives but at a cost of reduced responsiveness to the overall environment.

Despite several years of study, however, the significance of HRV is still unclear. The only time healthy individuals exhibit low HRV is during sleep. Because the input of the higher brain centers to the medullary cardiovascular areas is low at this time, some believe this suggests that reductions in HRV are probably caused by injuries to this part of the brain.

  • CFS Patients consistently display low levels of HRV during tilt table testing (Naschitz et. al. 2003, Tanaka et. al. 2002, Yamamoto et. al. 2002, Wyller 2007, Galland 2008). That the low frequency (LF) part of the spectrum is typically increased in CFS patients suggests increased sympathetic nervous system and decreased parasympathetic nervous system activity. Intriguingly (along with many other CFS-like symptoms such as fatigue, poor concentration, palpitations, etc.) over-trained athletes have similar HRV findings.

The reduced HRV in combination with the increased LF activity seen in CFS patients suggests either that the sympathetic nervous system has ‘clamped down’ on the hearts responsiveness in order to maintain consistency or that there is  a higher brain dysfunction.

Pulse Timing

A small 2012 photoplethysmography study found significant abnormalities in pulse timing, both at rest and in response to standing in ME/CFS patients which suggested that reduced blood volume was present. The prevalence of waveform abnormalities in the ear suggested impaired regulation of brain bloodflow was present – a finding that often occurs in POTS patients. A correlation between fatigue severity and reduced pulse timing suggested the finding may be central to the fatigue levels present.

Valsalva Maneuver

The tilt table is not employed during the Valsalva maneuver. By blowing against a closed tube, increased pressure in the throat reduces venous flows of blood to the heart. (Basically you hold your breath, pinch your nose and blow – like divers do before they descend.) The Valsalva maneuver assesses how the heart responds to these reduced heart and increased peripheral bloodflow and to the increased flows once the maneuver is stopped. It tests how the parasympathetic nervous system responds (via the vagus nerve) to a simulation of the reduced heart bloodflow occurring during standing.

  • CFS Patients usually display a normal response to the Valsalva maneuver. As we shall see, abnormalities of the parasympathetic nervous system (PNS) rarely occur in CFS but abnormalities of the opposing system – the sympathetic nervous system (SNS) – appear to occur regularly.


Chronic fatigue syndrome (ME/CFS) patients commonly experience increased heartrates (tachycardia) during tilt tests. Reduced heartrate variability and indications of increased SNS activity and reduced PNS activity appear to suggest inhibited cardiac responsiveness that could be indicative of a higher brain dysfunction. CFS patients also sometimes exhibit reduced BP and reduced bloodflow to the brain. They usually pass tests of vagal nerve functioning.