Click here to download this post

Notes: This is the fourth in a series of 5 blog posts about COVID-19 and Autonomic Dysfunction.  This a pre-publication release that will be featured in a major medical journal.

Coronavirus Induces Oxidative Stress Leading to Autonomic Dysfunction Often With Delayed Symptom Onset

Heather L. Bloom, MD¹ and Joseph Colombo, PhD, DNM, DHS²

1. Electrophysiology, Atlanta Veterans Affairs Medical Center and Emory University Medical School, Atlanta, GA bloom@gmail.com
2. Parasympathetic & Sympathetic Nervous System Consultant, Franklin Cardiovascular Associates, PA & Autonomic Dysfunction and POTS Center, Sewell, NJ, and Senior Medical Director & CTO, Physio PS, Inc., Atlanta, GA, dovetech@erols.com

Correspondence should be addressed to Dr. Colombo, dovetech@erols.com

THERAPY OPTIONS

In general, Oxidative Stress is treated with Antioxidants; more on this below in the Non-Pharmaceutical section.  Non-pharmaceutical therapy is often the primary P&S therapy which may often be accelerated with pharmaceutical therapy.  Often, once P&S balance is re-established, assuming no end-organ dysfunction, the P&S will carry forward independent of pharmaceutical therapy and only non-pharmaceutical, maintenance therapy may be required.  This is typically in the form of Antioxidants to help maintain proper Antioxidant levels in the body.  With chronic disease or disorder, as with aging, antioxidants are depleted in the body and production is slowed; therefore, supplemental therapy is needed.

Pharmaceutical Therapy Options

Pharmaceutical therapy options are recommended based on patient history [[i]].  In general they included the following.  For SW, 2.5 mg Midodrine titrated slowly, as needed, from qd to tid.  For Orthostatic Hypotension, including pre-clinical cases, the first dose is recommended around dinner, four hours before laying down, when BP tended to be lowest.  For POTS patients, morning doses are recommended since symptoms are typically more significant at that time.  Midodrine is contraindicated for patients with supine hypertension and for patients with resting BPs higher than 160/90 mmHg [[ii]].  Some patients do not respond to, or are contra-indicated for, Midodrine.  While Northera is the recommended alternate, it is very expensive and 30 to 60 mg Mestinon, qd, is recommended as the first alternate.  Only if patients are unresponsive to Mestinon is Northera considered, but still must be approved.  Non-pharmaceutical alternates are discussed below.  Low dose Fludrocortisone or Pseudoephedrine may be suitable adjunctives [[iii]].

Note, if patients present with SW and high BP, the high BP is (at least in part) compensatory for the associated Orthostatic Hypotension.  In these cases treating the Hypertension as the primary typically confounds the condition and may even cause BP to increase, as the poor brain perfusion is exacerbated and the body defeats the therapy.  In most cases, relieving SW organically reduces BP [11] and any remaining Hypertension may then be treated as the primary, once the patient’s P&S nervous systems stabilize.

For PE low-dose anti-cholinergic therapy (very low dose antidepressant therapy) is recommended.  For example, no more than 10.0 mg, qd, dinner Nortriptyline (primary) or 20mg, qd, Duloxetine (secondary) is recommended.  Clinical doses of these pharmaceuticals will exacerbate the condition with additional symptoms.  Often patients that present with long standing PE, who have been referred for Psych-eval and have been prescribed much higher doses of these pharmaceuticals, or have been prescribed antidepressants for more than six months with little or no relief, no longer respond or tolerate the recommended low-dose anti-cholinergic therapy, and alternate therapies are needed.  The primary alternate anti-cholinergic therapy recommended is “Low-and-Slow” exercise (see below) and was also recommended to help re-condition the heart muscle for improved cardiac output and thereby improved brain perfusion.  The recommended anti-cholinergic therapy tends to have little effect on BP and helps to pattern sleep.  If a more potent anti-cholinergic is needed and weight-gain is not a problem, 10.0 mg, qd, dinner Amitriptyline is recommended.

If PE presents with SE and with established Hypertension or Cardiovascular Disease, then low-dose or dose equivalent Carvedilol is recommended.  Carvedilol treats all three simultaneously.  It is not only a beta-blocker, but it is also an antioxidant [[iv],[v]].

Note, PE often causes secondary SE.  SE may lead to hypertension.  In these cases, treating the Hypertension as the primary exacerbates the Hypertension, similar to SW.  In most cases, relieving PE organically relieves SE (after a few months) which, in turn, organically reduces BP [2] and any remaining Hypertension may then be treated as the primary, once the patient’s P&S nervous systems stabilize.

For (stand) SE, therapy depends on the differential.  If SE is demonstrated with PE indicating (pre-clinical) Vasovagal Syncope, then PE therapy is followed as the primary and typically the SE is relieved organically.  If SE is demonstrated with a drop in HR from resting to stand indicating (pre-clinical) Neurogenic Syncope, volume building and often Midodrine helps to treat the stand SE.  Any remaining SE indicates (by omission) possible Cardiogenic Syncope and more testing is required to diagnose and treat. [4]

Autonomically mediated arrhythmia, with or without SE may be documented.  Autonomically mediated arrhythmia is associated with inefficient circulation and may be another result of Oxidative Stress.  Autonomically mediated arrhythmia with SE may contribute to Cardiogenic syncope, and treating SE may help to relieve the arrhythmia.  Autonomically mediated arrhythmia with PE may contribute to Vasovagal Syncope, and treating SE may help to relieve the arrhythmia.  Autonomically mediated arrhythmia with normal Sympathovagal Balance (SB = S/P, a resting baseline measurement), the arrhythmia is not autonomic and further testing maybe required to diagnose and treat. [4]

Non-Pharmaceutical Therapy Options

In general, Psychosocial Stress reduction is recommended with history-specific Antioxidant and Nitric Oxide supplement recommendations to reduce Oxidative Stress and improve blood flow [4].  Nitric Oxide also has Antioxidant properties.  Non-Pharmaceutical therapy options are recommended if patients are intolerant or unresponsive to the pharmaceutical options.

Alpha-Lipoic Acid (ALA) and Co-Enzyme Q10 (CoQ10) are two of the most potent Antioxidants made in the body.  ALA tends to be more selective for nerves.  CoQ10 tends to be more selective for cardiac tissue.  Both help to recycle other Antioxidants, including Vitamins A, C & E, and Glutathione.  Specifically for SW, 600 mg tid, Alpha-Lipoic Acid, titrated as needed and tolerated [[vi]], is recommended.  Exercise is arguably the most potent Antioxidant available.  For PE (which is an autonomic state that amplifies the stress response of all stressors including healthy stressors such as exercise), six months of “Low-and-Slow” exercise is recommended to retrain the nervous system to accept small, healthy stresses before more significant stresses may be tolerated.  Low-and-Slow exercise is characterized by walking at no more than 2 mph for 40 contiguous minutes per day, for 6 months (suitable alternates include slow motion rowing, or slow motion bicycling or pedaling are options) [4].  Exercise that breaks down muscle or connective tissue or that raises HR and BP too fast should be strictly avoided.  Often “Low-and-Slow” exercise is augmented, especially if the patient reported significant sleep difficulties, by 20 minutes of supine, 15° head-down posture around two hours before bed-time and up to three times per day, as needed, but in any instance, at least 2 hours after low-dose Midodrine dosing.  Patients who are too lightheaded to sit up or too exercise intolerant may perform supine Low-and-Slow exercise by lying on the floor next to the bed with their lower legs on the bed, and only move their lower legs like they were walking at 2 mph, for the prescribed 40 minutes (see insert).

[i] Piña IL, Di Palo KE, Ventura HO.  Psychopharmacology and Cardiovascular Disease.  JACC. 2018; 71(20): 2346-2359.

[ii] Arora RR, Bulgarelli RJ, Ghosh-Dastidar S, Colombo J.  Autonomic mechanisms and therapeutic implications of postural diabetic cardiovascular abnormalities.  J Diabetes Science and Technology.  2008; 2(4): 568-71.

[iii] DePace NL, Vinik AI, Acosta C and Colombo J.  Oral vasoactive medications:  A Review of Midodrine, Droxidopa, and Pseudoephedrine as Applied to Orthostatic Dysfunction.  NEJM.  2020.  Submitted.

[iv] Vinik AI, Bloom HL, Colombo J.  Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity:  A comparison of measures.  Heart International. Heart Int. 2014; 9(1): 7-14; DOI: 10.5301/HEART.2014.12495.

[v] Bloom HL, Vinik AI, Colombo J.  Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity:  A comparison of clinical results.  Heart Int. 2014 ; 9 (1): 15-21; DOI: 10.5301/HEART.2014.12496.

[vi] Murray GL and Colombo J.  (R)Alpha Lipoic Acid is a Safe, Effective Pharmacologic Therapy of Chronic Orthostatic Hypotension Associated with Low Sympathetic Tone.  Int J Angiol. In Print, 2018.

REFERENCES

_________________

[1] Murray GL.  COVID-19 cardiac complications: Is an easy, safe treatment strategy right under our noses?  J Cardiovasc Dis Diag. 2020; 8:5.  doi: 10.37421/jcdd.2020.8.415.

2 DePace NL, Colombo J.  Autonomic and Mitochondrial Dysfunction in Clinical Diseases:  Diagnostic, Prevention, and Therapy.  Springer Science + Business Media, New York, NY, 2019.

3 Acosta C, DePace NL, DePace NL, Kaczmarski K, Pinales JM, and Colombo J.  Antioxidants effect changes in systemic parasympathetic and sympathetic nervous system responses and improve outcomes.  Cardio Open. 2020; 5(1): 26-36.  doi:  10.33140/COA.05.01.04

⁴ Colombo J, Arora RR, DePace NL, Vinik AI.  Clinical Autonomic Dysfunction:  Measurement, Indications, Therapies, and Outcomes.  Springer Science + Business Media, New York, NY, 2014.

5 Vinik A, Ziegler D.  Diabetic cardiovascular autonomic neuropathy.  Circulation. 2007; 115: 387-397.

6 Vinik AI, Maser RE, Nakave AA.  Diabetic cardiovascular autonomic nerve dysfunction.  US Endocrine Disease.  2007; Dec: 2-9.

7 Malik, M.  The Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  Circulation. 1996; 93:1043-1065.

⁸ Malik, M. and the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  European Heart Journal. 1996, 17: 354-381.

⁹ Akselrod S, Oz O, Greenberg M, Keselbrener L.  Autonomic response to change of posture among normal and mild-hypertensive adults: investigation by time-dependent spectral analysis.  J Auton Nerv Syst. 1997 May 12;64(1):33-43.

¹⁰ Piña IL, Di Palo KE, Ventura HO.  Psychopharmacology and Cardiovascular Disease.  JACC. 2018; 71(20): 2346-2359.

1¹ Arora RR, Bulgarelli RJ, Ghosh-Dastidar S, Colombo J.  Autonomic mechanisms and therapeutic implications of postural diabetic cardiovascular abnormalities.  J Diabetes Science and Technology.  2008; 2(4): 568-71.

12 DePace NL, Vinik AI, Acosta C and Colombo J.  Oral vasoactive medications:  A Review of Midodrine, Droxidopa, and Pseudoephedrine as Applied to Orthostatic Dysfunction.  NEJM.  2020.  Submitted.

¹³ Vinik AI, Bloom HL, Colombo J.  Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity:  A comparison of measures.  Heart International. Heart Int. 2014; 9(1): 7-14; DOI: 10.5301/HEART.2014.12495.

¹⁴ Bloom HL, Vinik AI, Colombo J.  Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity:  A comparison of clinical results.  Heart Int. 2014 ; 9 (1): 15-21; DOI: 10.5301/HEART.2014.12496.

¹⁵ Murray GL and Colombo J.  (R)Alpha Lipoic Acid is a Safe, Effective Pharmacologic Therapy of Chronic Orthostatic Hypotension Associated with Low Sympathetic Tone.  Int J Angiol. In Print, 2018.

KEY WORDS

Coronavirus, Parasympathetic, Sympathetic, Oxidative Stress, Antioxidants

ABBREVIATIONS

ALA                            Alpha-Lipoic Acid

ANS                            Autonomic Nervous System

CoQ10                        Co-enzyme Q10

COVID-19                  Coronavirus (SARS-CoV-2)

P&S                             Parasympathetic and Sympathetic

PE                               Parasympathetic Excess

POTS                          Postural Orthostatic Tachycardia Syndrome

SE                               Sympathetic Excess

SW                              Sympathetic Withdrawal

[i] Colombo J, Arora RR, DePace NL, Vinik AI.  Clinical Autonomic Dysfunction:  Measurement, Indications, Therapies, and Outcomes.  Springer Science + Business Media, New York, NY, 2014.

[ii] Vinik A, Ziegler D.  Diabetic cardiovascular autonomic neuropathy.  Circulation. 2007; 115: 387-397.

[iii] Vinik AI, Maser RE, Nakave AA.  Diabetic cardiovascular autonomic nerve dysfunction.  US Endocrine Disease.  2007; Dec: 2-9.

[iv] Malik, M.  The Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  Circulation. 1996; 93:1043-1065.

[v] Malik, M. and the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  European Heart Journal. 1996, 17: 354-381.

[vi] Akselrod S, Oz O, Greenberg M, Keselbrener L.  Autonomic response to change of posture among normal and mild-hypertensive adults: investigation by time-dependent spectral analysis.  J Auton Nerv Syst. 1997 May 12;64(1):33-43.

Click here to download this post

Notes: This is the third in a series of 5 blog posts about COVID-19 and Autonomic Dysfunction.  This a pre-publication release that will be featured in a major medical journal.

Coronavirus Induces Oxidative Stress Leading to Autonomic Dysfunction Often With Delayed Symptom Onset

Heather L. Bloom, MD¹ and Joseph Colombo, PhD, DNM, DHS²

1. Electrophysiology, Atlanta Veterans Affairs Medical Center and Emory University Medical School, Atlanta, GA bloom@gmail.com
2. Parasympathetic & Sympathetic Nervous System Consultant, Franklin Cardiovascular Associates, PA & Autonomic Dysfunction and POTS Center, Sewell, NJ, and Senior Medical Director & CTO, Physio PS, Inc., Atlanta, GA, dovetech@erols.com

Correspondence should be addressed to Dr. Colombo, dovetech@erols.com

COMMON P&S DYSFUNCTIONS CAUSED BY OXIDATIVE STRESS

The ability to simultaneously and (mathematically) independently measure P&S activity under all conditions enables more information and additional abnormal responses [[i]] that have clinical bearing on Dysautonomia symptoms and their therapy.  For example a normal postural change or stand response is depicted in Figure 1, Graph A.  First the Parasympathetics decrease, potentiating and minimizing the Sympathetic reaction required and then (second) the Sympathetics increase.  Lightheadedness due to Dysautonomia is arguably the most debilitating of Dysautonomia symptoms [[ii],[iii]] and results from abnormal stand responses (the rest of Figure 1, and discussed below).  Note multiple Dysautonomias may occur simultaneously.

• Challenge Parasympathetic Excess (PE) is an abnormal increase in average Parasympathetic activity during a Sympathetic stimulus (g., stress or exercise), including stand (Figure 1, Graph C). Often the PE forces a secondary, excessive Sympathetic response (Sympathetic Excess or SE) to such stimuli (Figure 1, Graph E).  Typically, this is measured as high HR or BP, and treatment responses are often unexpected.  Often the HR or BP increases or becomes difficult to manage.  This is due to the SE being a secondary response, and possibly compensatory for the underlying Sympathetic Withdrawal (SW) masked by the PE [i].  PE affects brain profusion by effecting circulation throughout the cardiovascular system.  Figure 1, Graph D, shows an example of PE with SW (a description of SW is below). [i]
• Head-up postural change (stand) SE (Figure 1, Graph F) is a beta-adrenergic response and is associated with (pre-clinical) Syncope. The Sympathetic response to stand is compared with two other responses:  1) the average resting baseline response and 2) peak (instantaneous) Valsalva response.  For the resting response (1), it is well known that the stand Sympathetic response should be higher than at rest, but not too high.  The normal range is a 10% to 500% increase over the resting response [[iv],[v],[vi]].  The responses depicted in Figure 1 are average responses over the time period of the stimulus.  Sometimes the clinical indications may be averaged out and the instantaneous P&S responses need to be assessed (see Figure 2), such as in comparison with the Valsalva response (2).  SE may be documented as a peak Sympathetic response to standing that is comparable to (Figure 2, Graph C), or greater than the peak Sympathetic response to Valsalva (Figure 2, Graph B).  Of course this makes no sense, physiologically.  The stand Sympathetic response should be significantly lower (< 1/3) than the Sympathetic response to a series of short Valsalva maneuvers (Figure 2, Graph A) which are known to be very significant Sympathetic challenges.  (Note:  Valsalva maneuvers > 20 seconds are well-known, and significant, Parasympathetic challenges.  Valsalva maneuvers < 15 seconds are Sympathetic challenges.)  Stand SE is a symptom of poor brain profusion due to insufficient circulation caused by inappropriate autonomic control of the heart (Vasovagal or Neurogenic Syncope) or due to the heart itself (Cardiogenic Syncope). [i]
• Head-up postural change (stand) Sympathetic Withdrawal (SW, Figure 1, Graph B) is an alpha-adrenergic response and is associated with (pre-clinical) orthostatic dysfunction. Any average decrease in Sympathetic activity with standing, as compared with rest is abnormal and considered SW.  SW may be accompanied by abnormal BP or abnormal HR responses (g., Orthostatic Hypotension or POTS, respectively).  Both PE and stand SE may mask SW.  In these cases a weak or abnormal BP response is often still recorded, or treatment of the PE will unmask SW.  SW may also present with PE (Figure 1, Graph D).  SW affects brain profusion by causing blood volume to shift to the lower extremities, reducing cardiac output and therefore, circulation to the brain.  This may lead to hypertension (high systolic BP) as a compensatory mechanism to prevent brain hypoperfusion.  It may also be associated with poor cardiac perfusion (low diastolic BP) and, if prolonged, may lead to heart failure. [i]
• Autonomically mediated cardiac arrhythmia (see Figure 3 for an example), including Sinus Arrhythmia, is contra-indicated for heart beat interval analyses, and therefore, contra-indicated for most ANS monitors or measurement devices. With the addition of Respiratory Activity signal analyses to the heart beat interval analyses, more information is available to measure the P&S signals in the “noise” of the arrhythmia.  The typical arrhythmia that is associated with P&S dysfunction is Sinus Arrhythmia, which may be described as a normal EKG waveform (a normal heart beat) that occurs with abnormal timing (due to an abnormal P or S input to the heart).  As a result, autonomically mediated cardiac arrhythmia may be perceived as “skipped-beats” or “rapid-beats” or, in general, palpitations.

FIGURES and FIGURE LEGENDS

REFERENCES

_________________

[1] Murray GL.  COVID-19 cardiac complications: Is an easy, safe treatment strategy right under our noses?  J Cardiovasc Dis Diag. 2020; 8:5.  doi: 10.37421/jcdd.2020.8.415.

2 DePace NL, Colombo J.  Autonomic and Mitochondrial Dysfunction in Clinical Diseases:  Diagnostic, Prevention, and Therapy.  Springer Science + Business Media, New York, NY, 2019.

3 Acosta C, DePace NL, DePace NL, Kaczmarski K, Pinales JM, and Colombo J.  Antioxidants effect changes in systemic parasympathetic and sympathetic nervous system responses and improve outcomes.  Cardio Open. 2020; 5(1): 26-36.  doi:  10.33140/COA.05.01.04

⁴ Colombo J, Arora RR, DePace NL, Vinik AI.  Clinical Autonomic Dysfunction:  Measurement, Indications, Therapies, and Outcomes.  Springer Science + Business Media, New York, NY, 2014.

5 Vinik A, Ziegler D.  Diabetic cardiovascular autonomic neuropathy.  Circulation. 2007; 115: 387-397.

6 Vinik AI, Maser RE, Nakave AA.  Diabetic cardiovascular autonomic nerve dysfunction.  US Endocrine Disease.  2007; Dec: 2-9.

7 Malik, M.  The Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  Circulation. 1996; 93:1043-1065.

⁸ Malik, M. and the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  European Heart Journal. 1996, 17: 354-381.

⁹ Akselrod S, Oz O, Greenberg M, Keselbrener L.  Autonomic response to change of posture among normal and mild-hypertensive adults: investigation by time-dependent spectral analysis.  J Auton Nerv Syst. 1997 May 12;64(1):33-43.

¹⁰ Piña IL, Di Palo KE, Ventura HO.  Psychopharmacology and Cardiovascular Disease.  JACC. 2018; 71(20): 2346-2359.

1¹ Arora RR, Bulgarelli RJ, Ghosh-Dastidar S, Colombo J.  Autonomic mechanisms and therapeutic implications of postural diabetic cardiovascular abnormalities.  J Diabetes Science and Technology.  2008; 2(4): 568-71.

12 DePace NL, Vinik AI, Acosta C and Colombo J.  Oral vasoactive medications:  A Review of Midodrine, Droxidopa, and Pseudoephedrine as Applied to Orthostatic Dysfunction.  NEJM.  2020.  Submitted.

¹³ Vinik AI, Bloom HL, Colombo J.  Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity:  A comparison of measures.  Heart International. Heart Int. 2014; 9(1): 7-14; DOI: 10.5301/HEART.2014.12495.

¹⁴ Bloom HL, Vinik AI, Colombo J.  Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity:  A comparison of clinical results.  Heart Int. 2014 ; 9 (1): 15-21; DOI: 10.5301/HEART.2014.12496.

¹⁵ Murray GL and Colombo J.  (R)Alpha Lipoic Acid is a Safe, Effective Pharmacologic Therapy of Chronic Orthostatic Hypotension Associated with Low Sympathetic Tone.  Int J Angiol. In Print, 2018.

KEY WORDS

Coronavirus, Parasympathetic, Sympathetic, Oxidative Stress, Antioxidants

ABBREVIATIONS

ALA                            Alpha-Lipoic Acid

ANS                            Autonomic Nervous System

CoQ10                        Co-enzyme Q10

COVID-19                  Coronavirus (SARS-CoV-2)

P&S                             Parasympathetic and Sympathetic

PE                               Parasympathetic Excess

POTS                          Postural Orthostatic Tachycardia Syndrome

SE                               Sympathetic Excess

SW                              Sympathetic Withdrawal

[i] Colombo J, Arora RR, DePace NL, Vinik AI.  Clinical Autonomic Dysfunction:  Measurement, Indications, Therapies, and Outcomes.  Springer Science + Business Media, New York, NY, 2014.

[ii] Vinik A, Ziegler D.  Diabetic cardiovascular autonomic neuropathy.  Circulation. 2007; 115: 387-397.

[iii] Vinik AI, Maser RE, Nakave AA.  Diabetic cardiovascular autonomic nerve dysfunction.  US Endocrine Disease.  2007; Dec: 2-9.

[iv] Malik, M.  The Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  Circulation. 1996; 93:1043-1065.

[v] Malik, M. and the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  European Heart Journal. 1996, 17: 354-381.

[vi] Akselrod S, Oz O, Greenberg M, Keselbrener L.  Autonomic response to change of posture among normal and mild-hypertensive adults: investigation by time-dependent spectral analysis.  J Auton Nerv Syst. 1997 May 12;64(1):33-43.

Click here to download this post

Notes: This is the second in a series of 5 blog posts about COVID-19 and Autonomic Dysfunction.  This a pre-publication release that will be featured in a major medical journal.

Coronavirus Induces Oxidative Stress Leading to Autonomic Dysfunction Often With Delayed Symptom Onset

Heather L. Bloom, MD¹ and Joseph Colombo, PhD, DNM, DHS²

1. Electrophysiology, Atlanta Veterans Affairs Medical Center and Emory University Medical School, Atlanta, GA 
2. Parasympathetic & Sympathetic Nervous System Consultant, Franklin Cardiovascular Associates, PA & Autonomic Dysfunction and POTS Center, Sewell, NJ, and Senior Medical Director & CTO, Physio PS, Inc., Atlanta, GA, dovetech@erols.com

Correspondence should be addressed to Dr. Colombo, dovetech@erols.com

INTRODUCTION

It is generally well known that many chronic and serious pathologies cause an over-production of oxidants, including Reactive Oxygen Species (ROS), Reactive Nitrogen Species (RNS), and many other oxidative molecules. 

What may not be as well-known is the fact that severe acute conditions may also cause an over-production of oxidants.  A recent published review [[i]] highlighted this in COVID-19 patients. 

Many of the other pathogens that cause severe acute diseases are also implicated, including Influenza (like COVID19, a SARS virus) and many other viruses, bacteria like the Borrelia bacterium that causes Lyme Disease, severe physical or physiological stresses or traumas like that which triggers what is known as Fibromyalgia; as well as severe exposures to cold, heat, chemicals, etc., and severe mental or emotional traumas (e.g., PTSD); to name a few.

An over-production of oxidants is known as Oxidative Stress.  While some level of oxidants are necessary for the Immune system as a first-line defense against pathogens, for programmed cell death and other general cellular house-keeping activities, too many oxidants lead to cell and organelle damage, including, damage to Mitochondria. 

The cardiovascular and the nervous systems have the highest numbers of Mitochondria per cell and are therefore more susceptible to Oxidative Stress. 

As the cardiovascular tissue and the Parasympathetic and Sympathetic (P&S) branches of the autonomic nervous systems (ANS) become disordered, P&S dysfunction accelerates cardiovascular disorder and a downward spiral begins; often long before recognized disease symptoms present. 

Further, in addition to collecting oxidants for beneficial use, the Immune system is primarily responsible for balancing the oxidants and antioxidants in the system. With P&S dysfunction this balancing process becomes less effective.

Oxidative Stress-induced P&S Dysfunction may be associated with a huge constellation of symptoms and conditions including  Lightheadedness, fatigue, wild fluctuations in blood pressure, blood glucose, hormone levels, and weight; as well as difficult to describe pain syndromes (including complex regional pain syndromes, or CRPS), excessive symptoms of palpitations without clinical correlation to definitive pathology or seizures, temperature dysregulation (to heat and/or cold and sweat responses), and symptoms of depression and anxiety, ADD/ADHD, exercise intolerance, sex dysfunction, sleep or GI disturbance, cognitive dysfunction or “brain fog”, or frequent headache or migraine.

Given the current high volume of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2, or Coronavirus Disease 2019, or COVID-19 virus, or COVID), it will be the exemplar severe acute pathology used as a model of other severe acute pathologies. 

In patients that recover from COVID, the basic model is: 

1) COVID causes Oxidative Stress in most patients who recover;

2) The severity of the resulting Oxidative Stress is debilitating to a sub-population of the patients affected (perhaps 15%, in the case of COVID, [personal clinical observations]);

3) Oxidative Stress damages cell membranes, DNA, and (especially) Mitochondria;

4) as the cells that utilize the most energy (ATP) in the body, nerve and cardiovascular cells are the most susceptible to Oxidative Stress damaged Mitochondrial dysfunction;

5) Mitochondrial dysfunction in the P&S nerve cells themselves and the mitochondrial damaged cardiovascular cells, both cause changes in P&S that manifest three to six months after relief of the initiating pathology (COVID);

6) due to this delay, and the normalcy of the interim, the resulting P&S Dysfunction is not associated with COVID,

7) the resulting P&S Dysfunction causes many symptoms the most complained about is lightheadedness and persistent fatigue that is not treatable by standard therapies.

Both Oxidative Stress and P&S imbalance are treatable [[ii]], depending on individual history, 9) rebalancing oxidation and P&S leads to improved outcomes including quality of life (i.e., fatigue is relieved) and improved productivity [[iii]].

The main clinical dilemma is that the connection between COVID and P&S Dysfunction is not obvious.  The symptoms of P&S Dysfunction, presenting three to six months after the disease is relieved and apparent normal function is returned, are interpreted as a new condition and misinterpreted as not a continuation of the previous condition. 

This causes three problems.  First, since only the symptoms are being treated, the therapy plan is often confounded due to conflicting dysfunctions.  For example, fatigue is often accompanied by lightheadedness or dizziness, anxiety, depression, sleep difficulties, and loss of productivity. 

Treating all of these symptoms individually involves competing agents.  Furthermore, and the second problem, since what is being treated are symptoms and not the underlying cause (Oxidative Stress and P&S imbalance), therapies are usually titrated to higher doses; and yet, the patients still do not respond as expected. 

Moreover, if and when P&S Dysfunction is suspected, the high doses of these medications often leave the patient sensitized to these medications.  This sensitization precludes their use at the very low levels needed for balancing the P&S nervous systems. 

All of these treatment issues can leave the Physician thinking that the patient is non-compliant or psychosomatic, which often leads to a psychology referral.  This can lead to the breakdown of the physician-patient relationship since the patient is sure that the symptoms are real and not in her or his head.

As suggested by the title of the recently published article [i], a simple P&S assessment may be made in the clinic to identify any P&S imbalance.  Relieving the P&S imbalance, which often involves Antioxidants [ii], and thereby restoring P&S and oxidant balance, relieves or prevents the symptoms of P&S imbalance post-COVID; thereby, minimizing any further reductions in quality of life and losses in productivity.

P&S testing is not ANS testing.  Most ANS test only test total autonomic function and force assumption and approximation to theorize P&S activity.  There is only one P&S test that provides simultaneous, independent measures of P&S activity.  What is expected from P&S testing is one or more of four possible P&S Dysfunctions that underlie the Dysautonomia typically associated with Oxidative Stress.

REFERENCES

_________________

[1] Murray GL.  COVID-19 cardiac complications: Is an easy, safe treatment strategy right under our noses?  J Cardiovasc Dis Diag. 2020; 8:5.  doi: 10.37421/jcdd.2020.8.415.

2 DePace NL, Colombo J.  Autonomic and Mitochondrial Dysfunction in Clinical Diseases:  Diagnostic, Prevention, and Therapy.  Springer Science + Business Media, New York, NY, 2019.

3 Acosta C, DePace NL, DePace NL, Kaczmarski K, Pinales JM, and Colombo J.  Antioxidants effect changes in systemic parasympathetic and sympathetic nervous system responses and improve outcomes.  Cardio Open. 2020; 5(1): 26-36.  doi:  10.33140/COA.05.01.04

⁴ Colombo J, Arora RR, DePace NL, Vinik AI.  Clinical Autonomic Dysfunction:  Measurement, Indications, Therapies, and Outcomes.  Springer Science + Business Media, New York, NY, 2014.

5 Vinik A, Ziegler D.  Diabetic cardiovascular autonomic neuropathy.  Circulation. 2007; 115: 387-397.

6 Vinik AI, Maser RE, Nakave AA.  Diabetic cardiovascular autonomic nerve dysfunction.  US Endocrine Disease.  2007; Dec: 2-9.

7 Malik, M.  The Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  Circulation. 1996; 93:1043-1065.

⁸ Malik, M. and the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Heart rate variability, standards of measurement, physiological interpretation, and clinical use.  European Heart Journal. 1996, 17: 354-381.

⁹ Akselrod S, Oz O, Greenberg M, Keselbrener L.  Autonomic response to change of posture among normal and mild-hypertensive adults: investigation by time-dependent spectral analysis.  J Auton Nerv Syst. 1997 May 12;64(1):33-43.

¹⁰ Piña IL, Di Palo KE, Ventura HO.  Psychopharmacology and Cardiovascular Disease.  JACC. 2018; 71(20): 2346-2359.

1¹ Arora RR, Bulgarelli RJ, Ghosh-Dastidar S, Colombo J.  Autonomic mechanisms and therapeutic implications of postural diabetic cardiovascular abnormalities.  J Diabetes Science and Technology.  2008; 2(4): 568-71.

12 DePace NL, Vinik AI, Acosta C and Colombo J.  Oral vasoactive medications:  A Review of Midodrine, Droxidopa, and Pseudoephedrine as Applied to Orthostatic Dysfunction.  NEJM.  2020.  Submitted.

¹³ Vinik AI, Bloom HL, Colombo J.  Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity:  A comparison of measures.  Heart International. Heart Int. 2014; 9(1): 7-14; DOI: 10.5301/HEART.2014.12495.

¹⁴ Bloom HL, Vinik AI, Colombo J.  Differential effects of adrenergic antagonists (carvedilol vs. metoprolol) on parasympathetic and sympathetic activity:  A comparison of clinical results.  Heart Int. 2014 ; 9 (1): 15-21; DOI: 10.5301/HEART.2014.12496.

¹⁵ Murray GL and Colombo J.  (R)Alpha Lipoic Acid is a Safe, Effective Pharmacologic Therapy of Chronic Orthostatic Hypotension Associated with Low Sympathetic Tone.  Int J Angiol. In Print, 2018.

KEY WORDS

Coronavirus, Parasympathetic, Sympathetic, Oxidative Stress, Antioxidants

ABBREVIATIONS

ALA                            Alpha-Lipoic Acid

ANS                            Autonomic Nervous System

CoQ10                        Co-enzyme Q10

COVID-19                  Coronavirus (SARS-CoV-2)

P&S                             Parasympathetic and Sympathetic

PE                               Parasympathetic Excess

POTS                          Postural Orthostatic Tachycardia Syndrome

SE                               Sympathetic Excess

SW                              Sympathetic Withdrawal

[i] Murray GL.  COVID-19 cardiac complications: Is an easy, safe treatment strategy right under our noses?  J Cardiovasc Dis Diag. 2020; 8:5.  doi: 10.37421/jcdd.2020.8.415.

[ii] DePace NL, Colombo J.  Autonomic and Mitochondrial Dysfunction in Clinical Diseases:  Diagnostic, Prevention, and Therapy.  Springer Science + Business Media, New York, NY, 2019.

[iii] Acosta C, DePace NL, DePace NL, Kaczmarski K, Pinales JM, and Colombo J.  Antioxidants effect changes in systemic parasympathetic and sympathetic nervous system responses and improve outcomes.  Cardio Open. 2020; 5(1): 26-36.  doi:  10.33140/COA.05.01.04

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COVID, like all other viruses, attacks primarily the Mitochondria and DNA of cells see figure [adapted from [i]].  It attacks the DNA to help them replicate.  In this way, the virus is able to produce the proteins that it needs to live.  It cannot do this on its own.  This is one reason why viruses are very species-specific[1].  As parasites, they attack the mitochondria to obtain the energy they need to live by siphoning off a significant portion of the energy molecules (called ATP – adenosine tri-phosphate) that we also need to be active or even live.  The virus, by infecting us, leaves less energy for us the host.

Nerve cells and heart muscle cells contain, by far, the most mitochondria in the human body.  This attack on the mitochondria results in what is known as oxidative stress.  Oxidative stress[2] causes fatigue, exercise intolerance, and many of the other mental, cognitive, and physical (including pain) symptoms reported with PACS.  In most cases, it is like having a full fuel tank in your car with a clogged fuel filter.  You seem fine at rest (while idling), but as soon as you step on the gas to go (and be active), nothing happens because the necessary, additional gas (energy molecules) does (do) not reach the engine (the brain and nervous system and the heart).  In this case, the extra energy molecules are actually not available because they have been stolen by the virus.  All parasites (viruses, bacteria, molds, mildews, etc.) affect the mitochondria and energy supply this way.  This is why you are fatigued and have no energy when you are sickened by these agents.  Add to this the fact that COVID also compromises the lungs, reducing the host’s oxygen intake, causing less fuel to generate energy molecules, and you have the SARS effect.

One cause of Oxidative Stress is indeed cytokine dysregulation.  The “Cytokine Storm,” referenced as a “Viral Tornado” in the 20/20 interview of Mount Sinai Hospital in November 2020, is due to oxidants, including reactive oxygen species (ROS).[3]  Cytokine storm and oxidative stress are the main players of Acute Respiratory Distress Syndrome development during respiratory virus infections.[4]  Mechanisms of cytokine production (cytokine storm) and epithelial barrier disruption by respiratory virus infection leads to the enhanced ROS production.  

Cytokine Storm and Oxidative Stress in COVID-19 patients result in a vicious cycle[5], causing Hypercytokinemia, known as cytokine storm[6].  Given this, simple therapies to prevent oxidation and excessive cytokine release (Hypercytokinemia) are prevalent and readily available.  In fact, some are already being used, including Vitamins C & D and Zinc, tacitly confirming the Oxidative Stress hypothesis.

If the politically motivated powers that be would simply admit this commonly and well-known fact, Oxidative Stress is readily treated with antioxidants.  Again, that is, in large part, the reason why Vitamin C & D and Zinc are a significant part of COVID therapy.  The problem for the politicals is that these therapeutic agents do not make anyone any money.  They have to fear the public into believing that special medications and vaccines are required.  This is why commonly used and effective medicines that have worked here in the US and elsewhere around the world were pulled from doctors, because, again, they did not make any of the political powers any money.

The effect on nerve cells, especially Parasympathetic and Sympathetic (P&S) nerve cells, is what eventually leads to post-COVID syndrome[7].  These authors wrote an Op/Ed back in March of 2020 stating that a post-COVID syndrome will present.  We still cannot get that manuscript published (over 10 journals have refused to print it – that is why we have had to create our own journal and print it here in our own journal).

Oxidative Stress and its effect on the P&S nervous systems explain the first issue of PACS, a potential delay in the symptoms.  Initially, this was a problem of doctors, and may still be a problem based on a recent Op/Ed[8], writing about “echoes of chronic fatigue in the effort to blame the coronavirus for a host of questionable symptoms.”  This delay seems to separate COVID from PACS.  Add to this the general lack of knowledge about the P&S nervous systems, and this sort of ignorance gains credibility.  Especially when the patients seem normal at rest, for when most tests are administered, the patient is either sitting or lying down.  However, the P&S nervous systems are rarely resting.  In fact, when you are resting is, arguably, when the P&S nervous systems are most active.

The P&S nervous systems control or coordinate all organs and organ systems within the body (including themselves).  The job of the P&S nervous systems, collectively, is to maintain normal organ function, even though they themselves may not be functioning normally.  Until the P&S system fails, the organs remain functioning normally, unless they are attacked directly.  Once the organs fail, then symptoms present.  It is the unhealthy or improperly controlled organs that generate symptoms.  The delay in symptoms presenting is based on how long it takes the P&S systems to fatigue or become significantly un-balanced (fail), permitting the organs to then function abnormally. resulting in symptoms.

It is like the heating and cooling systems of your house.  Assume you have no knowledge of, nor are able to see, hear, or access the cooling and heating systems of your house, and that they are individual systems working together to keep you comfortable.  Assume all you have to assess the function of those systems is the thermostat in the house.  Say you set the temperature on the thermostat to 70°F (like 70 beats per minute for heart rate).  Assume it is a hot, humid summer day in the south somewhere.  Assume that the cooling system is well.  Now assume that a $5.00 heater switch fails and the heater turns on to full capacity.  What happens to the temperature of the house as measured by the thermostat?  …  NOTHING!  …  The cooling system amps up to compensate not only for the ambient heat but also for the heat from the heating system.  Now both systems are operating at full capacity or more, and the thermostat temperature still reads 70°F, and everyone is still happy.

How long will this situation last until there is a catastrophic failure in one or both of the air conditioning systems?  Only after a catastrophic failure does the temperature change.  Then it is too late, and the repair is $5,000.00 or more.  The change in temperature, indicating a failure, is too late!  The $5.00 repair is simpler, and easier, but you have to be measuring both the cooling and heating systems, not just the net result of their combined activities.

The autonomic nervous system in the human body is very similar in this regard.  We are still surprised by heart attacks and strokes and other organ failures because we only measure the autonomic nervous system (the net result of the P&S nervous systems) and not the individual P&S nervous systems themselves.  This is made more poignant by the fact that it is the purpose of the P&S nervous systems to work together to maintain normal organ function, even when they themselves are dysfunctional.  Current, common-place healthcare measurements are made more effective and efficient with the additional information of P&S Monitoring.

The second issue is that the parasitic effect of COVID is on all mitochondria within all organs.  This compounds the effect of an unbalanced P&S nervous system and the inefficient control from them, which also affects all organs. 

Again, unfortunately, relatively little is known about the P&S nervous systems because, until rather recently, an efficient and simple method of measuring it was not widely accepted, and the more widely known measures of the Autonomic nervous system as a whole were not able to specify the underlying dysfunctions sufficiently so as to develop effective treatments or to demonstrate that treatment was even possible. 

This leaves doctors with the current plan of simply “characterizing the disease.”  In other words, simply listing all of the symptoms and simply treating all of the symptoms individually.  This of course leads to many prescription medications, whose multiple interactions are unknown, perhaps causing more symptoms than they (collectively) are supposed to relieve. 

In fact, this compounding effect of unbalanced P&S control of weakened or dysfunctional organs multiplies the number of symptoms and adds more disorders, some of which appear to be mental illnesses as well.  Note, most of these mental illnesses are also explained by unbalanced P&S control causing reduced blood flow to the heart and brain, resulting in brain fog, cognitive and memory difficulties, depression, anxiety, headache and migraine, muscle and joint pain, and sleep difficulties, as well as the fatigue, lightheadedness, and malaise commonly associated with PACS.

The lack of understanding of the P&S nervous systems leads to a third general problem or issue.  Without the additional information from P&S testing, medicine has no other choice but to simply treat symptoms (which plays into the hands of the pharmaceutical and marijuana industries, enabling them to sell more product).  Yes, understanding the P&S nervous systems does explain all symptoms of COVID and PACS,   including Diarrhea.[9]^,[10] 

Only the P&S nervous systems connect all symptoms and organ systems involved in the COVID and PACS conditions.  In the example of Diarrhea, yes, the virus is in the stool, but then all viruses end up in the stool, so what is special about COVID? COVID strongly affects the immune system, which causes Parasympathetic Excess, which overdrives the motility of the GI system and leads to Diarrhea.  Let’s not trample the issue out of ignorance.  Let’s get to the underlying cause, do our best to minimize mortality risk and target the cause to minimize morbidity risk.  Then, treat the end-organs that were themselves damaged and remain dysfunctional.

Depression (and Anxiety) are also more likely to be a result of dysautonomia.  If the brain receives low levels of blood flow due to at least three types of dysautonomia, some of which may present simultaneously, the brain will be “asleep” while the patient is upright, sitting or standing, all day.  A brain “asleep” is too often misdiagnosed as a brain “depressed.” 

Then, if the blood flow drops any lower (due to a large meal or emotional event, etc.), the brain will issue an “Adrenaline Storm,” which is its way to call for more blood.  The Adrenaline Storm may then cycle Anxiety.  Treating this Depression/Anxiety condition with high dose antidepressants, such as Fluvoxamine (an OCD drug)[11]m ay, in some people, help to increase blood flow to the brain through other P&S interactions, but this is a very inefficient therapy and may be a self-fulfilling prophecy, forcing the patient to think that they have a mental health issue.  Besides, the data are scant, and the conditions are not well controlled to rule out isolation, masks, and social distancing, which are contributing enough to Depression.  We do not need any other causes.

Unfortunately, in many cases, simply increasing the numbers of medications and their dosages, in the hopes of relieving the symptoms faster, actually leads to more complications.  Western pharmaceutical theory is based on the understanding of what one chemical (as a medication) in isolation will do to the human body.  The interactions between more than two or three chemicals (medications) are not well known.  This is the main reason why the very ill or elderly who are on 15 to 17 medications a week are chemically relegated to very poor qualities of life, sitting as lumps in their wheelchairs with no energy of motivation to be productive.

It is like the old nursery rhyme of the old lady that swallowed a fly, then a spider to get the fly, then a cat to get the spider, then a dog, etc.  By the time you get to swallowing the elephant and the doctor is considering prescribing you a blue whale, it may be prudent to consider getting the fly.

The “fly” in the case of COVID is Oxidative Stress, which may be “gotten” with the super antioxidants, r-Alpha-Lipoic Acid (rALA) and Co-Enzyme Q10 (CoQ10).  rALA is selective for nerves and heals the mitochondria, DNA, and other cellular processes that are affected by the virus, and CoQ10 is selective for heart muscle cells effecting the same repairs in those cells.  Furthermore, rALA & CoQ10 are the most powerful antioxidants the body produces (second only to the most powerful antioxidant of all, which is exercise), and they make themselves even more powerful by recycling other antioxidants, such as Vitamin C & D, and Zinc.

So, why are we grasping at straws?  Again, in the hysteria, we are overlooking the simple solutions.  Unless of course it is because the simple solutions do not make the instigators of all of this enough money.  Now there is a KF-94 mask that is 94% effective, as opposed to the KF-95 mask that is 95% efficient in filtering out airborne particulates.  The article[12] states that the bottom line is this: “It’s not always just about filtration efficiency.”  The article continues to state that these (surgical-grade) masks, such as the KF-94, are for use in a hospital because they’re designed for medical settings.  In the real world, it may be they are hard to wear through the course of the whole day.  The best mask is the one you can wear all the time.

So, is it about filtration or comfort?  Viruses are very, very small!  Are we trying to prevent the spread of the virus or not?  Anything but a surgical-grade mask is useless in preventing the spread of the virus because the virus goes through the mask as if it were not there, and even with a surgical-grade mask, by the time a man has “5 o’clock shadow,” his hair has pushed the mask off his face far enough for the virus to escape un-impeded; not to mention men with beards.  Similarly for some women with make-up, the microscopic peaks and valleys may be large enough for the virus to fit through and escape.

Another article[13] is entitled “International team of scientists identifies new treatment for COVID-19 that appears to be far more effective than drugs in use now.”  However, it has only been tested on cells in the lab.  The article concludes that “Even though ‘a drug is effective in cells in the laboratory, we don’t know what effect it will have on cells in the human body.’”  So, how is this a new treatment yet, let alone better than current drugs?  Again, science needs to be left alone to do their work and not give false hopes.  Similarly, another article states that a “new Israeli drug cured 29 of 30 moderate/serious COVID cases in days in hospital.”[14]  Great, 29/30!  But how were the patients picked?  What were their histories?  There are still a million questions to be answered.  There is a reason why it takes years and 10,000 patients to approve a new drug.  What happened to the one that it did not cure and why?  Did that patient die?  A death rate of 1/30, or 3.33% is an awfully high death rate for a new drug.  Killing the patient is not an acceptable side effect.

However, just relieving Oxidative Stress does not always repair the damage done to the P&S nervous systems.  Further therapy may be required to rebalance the P&S systems to return health and wellness.  P&S imbalance must be measured and monitored, because everyone is different, and the individual’s P&S systems at that time must be known in order to plan therapy.  Some consider the P&S nervous systems as your physiologic fingerprint.  They include and remember your entire medical and life history.

There are at least four P&S dysfunctions (dysautonomias) that may precipitate the symptoms of post-COVID syndrome, and more than one is quite possible, and their specific interactions are based on the individual patient’s own clinical and personal histories.  All four dysautonomias, inappropriate P- or S-actions, individually explain the majority of PACS symptoms.  Combinations of the four, which are more likely, in our experience, explain the range in severity of PACS.  For more information, visit www.physiops.com.

Treating the P&S nervous systems, however, is rarely a fast process, nor does more medication hasten the process; in fact, quite the opposite.  Much like a pendulum, hitting it hard knocks the pendulum off its hinge and you have many more problems.  Treatment requires small, gentle, easy nudges over time to correct “the pendulum.”  So, it is with the P&S nervous systems.  Further, it is not like the cold where you get ten days of therapy and are healthy again.  It may take up to three months to effect a change in the P&S nervous systems.  It is more like breaking a bad habit and establishing a new, hopefully good habit.  Even still, there are few if any changes in symptoms because the organs have yet to change.  Changing the organs may take another three months depending on the severity of the insult.  These time frames are also lengthened by age and severity of the insult, in this case, COVID.  Patients must be diligent and patient during these six months or the condition will worsen, and it may take years to recover.

The average patient, by the time they visit a P&S clinic, have seen dozens of doctors over decades of time.  The problem is that the other doctors only assess them when they are at rest, sitting or lying down.  Rarely do they assess them while active.  As the typical test results show, they are normal at rest – which is why many are not believed.  They had better be normal at rest – they have had numerous doctors working really hard to make them normal … at rest; as attested to by P&S monitoring results.  Again, a problem is that this portion of the nervous system never rests.  Therefore, the P&S must be tested while active as well.  This is the basis of P&S testing and always shows the reason(s) for a patient’s symptoms, as well as morbidity and mortality risks (respectively, they are the risks of additional symptoms, which is morbidity risk, and the risk of a major adverse event, including heart attack, stroke, and death, which is mortality risk).

The fourth issue, again based on the lack of understand and data on the P&S nervous systems, is that physicians have been left with few therapy options that are specific for the P&S nervous system.  Unfortunately, there are, in fact, only two medications approved for P&S dysfunction, and both are approved for the same, singular dysfunction.  Fortunately, it is a common P&S dysfunction that is common to post-Oxidative Stress conditions:  Orthostatic Dysfunction, typically Postural Orthostatic Tachycardia Syndrome (POTS) or Orthostatic Hypotension.  All other therapies are applied off-label.  This causes other problems, including the fact that in western medicine, titrating patients to high levels of medication is common.  This desensitizes patients to the low dosages needed to treat the P&S systems and not cause more symptoms.  This often forces physicians to use supplements and lifestyle modifications, which are often less reliable or effective; especially if Oxidative Stress is not considered.

Given all of this, you begin to see why medicine is more focused on simply treating the symptoms of post-COVID syndrome or PACS, and then trying to convince you that this is your new normal and you must embrace it.  Even before COVID, we have been railing against that philosophy, because as tens to hundreds of thousands of P&S (not autonomic, but P&S) patients across the country will attest, it does not have to be so – you may have a decent quality of life and productivity restored.

[1] As an example, all human HIV studies were performed on simian (monkey) HIV viruses so enable safety in the lab and not infect the humans doing the research.

[2] PubMed, a very large collection of highly reputable medical journals, alone lists 273 references associating coronavirus, specifically, with oxidative stress.  This does not include the thousands of references associating other viruses with oxidative stress.

[3] Ye S, Lowther S, Stambas J. Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via upregulation of SOCS1 and SOCS3. J Virol. 2015;89(5):2672-2683. doi:10.1128/JVI.03529-14

[4] Meftahi GH, Bahari Z, Jangravi Z, Iman M.  A vicious circle between oxidative stress and cytokine storm in acute respiratory distress syndrome pathogenesis at COVID-19 infection .  Ukr.Biochem.J. 2021; Volume 93, Issue 1, Jan-Feb, pp. 18-29.  doi:https://doi.org/10.15407/ubj93.01.018

[5] Khomich OA, Kochetkov SN, Bartosch B, Ivanov AV. Redox Biology of Respiratory Viral Infections. Viruses. 2018; 10(8):392. https://doi.org/10.3390/v10080392

[6] Suzuki K. Cytokine Response to Exercise and Its Modulation. Antioxidants. 2018; 7(1):17. https://doi.org/10.3390/antiox7010017

[7] PubMed alone lists over 1200 references associating oxidative stress with P&S dysfunction or imbalance.

[8] The Dubious Origins of Long Covid, by Jeremy Devine  March 22, 2021 6:36 pm ET, Wall Street Journal

[9] Coronavirus symptoms: This is the likely order in which COVID-19 symptoms appear after you get infected, by Anushree Gupta  Updated Feb 01, 2021 | 16:14 IST, https://www.timesnownews.com/health/article/coronavirus-symptoms-this-is-the-likely-order-in-which-covid-19-symptoms-appear-after-you-get-infected/714563

[10] COVID-19 and Diarrhea, https://www.news-medical.net/health/COVID-19-and-diarrhea.aspx

[11] What Is Fluvoxamine? OCD Drug Could Be Used to Treat COVID, by Jason Murdock On 3/8/21 AT 9:49 am EST

[12] “Coronavirus FAQ: Why Am I Suddenly Hearing So Much About KF94 Masks?” by Pranav Baskar  January 22, 20216:12 pm ET, https://www.npr.org/sections/goatsandsoda/2021/01/22/959683338/coronavirus-faq-why-am-i-suddenly-hearing-so-much-about-kf94-masks

[13] International team of scientists identifies new treatment for COVID-19 that appears to be far more effective than drugs in use now, by Mark Johnson  Milwaukee Journal Sentinel https://www.jsonline.com/story/news/2021/01/25/international-team-finds-new-more-effective-drug-treat-covid-19/6673529002/

[14] New Israeli drug cured 29 of 30 moderate/serious COVID cases in days — hospital, by Toi Staff 5 February 2021, 3:29 pm, https://www.timesofisrael.com/new-israeli-drug-cured-moderate-to-serious-covid-cases-within-days-hospital/

[i] Rasa S, Nora-Krukle Z, Henning N, Eliassen E, Shikova E, Harrer T, Scheibenbogen C, Murovska M, Prusty BK; European Network on ME/CFS (EUROMENE). Chronic viral infections in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). J Transl Med. 2018 Oct 1;16(1):268. doi: 10.1186/s12967-018-1644-y. PMID: 30285773; PMCID: PMC6167797.