From the perspective of the airways and bronchodilation , the symptoms and signs of bipolar illness make sense.

If the ventilatory system is broken and respiratory rate is very low at rest, then it is important for the brain to make sure that tidal volume is large at rest in order to move enough air in and out of the body in order to maintain adequate minute ventilation and to control pH, 02 and PaC02 of the blood and the tissues. This is true of Paula. Her breathing rate at rest during health is 3 -5 breaths per minute [on average for a period of 20 minutes] and her tidal volume is 750-850ml [on average] and her minute ventilation is adequate. The lung doctor has done tests to prove it! [and it is not a lung problem, it is a neural, motor problem].

Maintaining tidal volume at rest already requires Paula to use active exhaling, which takes strength and physical effort [using abdominal muscles to help exhale]. Respiratory challenges usually would decrease tidal volume at rest. Respiratory challenges are common, for example * allergy- resulting in airway inflammation and mucus buildup, * colds and other viruses obstructing the upper airways, * blood loss, [physical injury, surgery, childbirth, heavy periods] * undernutrition [from loss of appetite from illness], . * conditions of anaemia, iron deficiency, thiamine deficiency, etc.., * conditions of exposure due to poor housing or working conditions-overcrowding, inadequate ventilation, etc..and * muscle weakness, muscle wasting and fatigue from any or all of these conditions.

The average person [with healthy lungs and normal motor function of the respiratory muscles] can easily modulate their breathing rate and tidal volume accordingly; in fact breathing rate usually increases when a person gets sick and their airway is full of mucus, or inflamed and/or obstructed. They may not breathe as deeply so their breathing rate goes up. This is the norm for most.

This does not seem true for Paula. Her respiratory rate stays the same, we think, when she’s sick [this needs more study] and so the brain and body need to try and keep her airway as open as possible; this is no time for a lot of bronchoconstriction.

Paula probably does get somewhat blocked up [upper airways] when sick and her tidal volume must get smaller when she cannot breathe as deeply as usual. BUT if f she cannot increase her respiratory rate at rest , , then how is it she stays alive? [when Paula was very sick, her resting respiratory rate went down to 2.5 breaths per minute].

We do not know, but it probably has something to do with this being a chronic condition. Chronic conditions, even worsening chronic conditions are better tolerated that acute ones.

Paula’s respiratory defect is chronic. We may not have always known of it, but the brain is used to it and can orchestrate strategies to work around it.

The working hypothesis here is that Paula, unable to exhale the correct amount of C02, becomes mildly hypercapnia [or at least more hypercapnic if she was chronically so; chronic hypercapnia may have no signs or symptoms].

How would the brain and body control PaC02 in the face of this quandary?

Well, first of all, there is evidence that carbon dioxide is a major bronchodilator and can move through mucus somehow. So that would be helpful [as long as the hypercapnia is kept in check]. Physiol 1971 May;215(1):33P-34P. The bronchodilator action of carbon dioxide T W AstinG R BarerJ W ShawP Warren American Journal of Respiratory and Critical Care Medicine  2012;185:A2848 B37. NEW INSIGHTS INTO ASTHMA AND COPD …  Investigations Of Mechanisms Of Carbon Dioxide-Induced Bronchial Smooth Muscle Relaxation .

So carbon dioxide, to some extent, will help to open the airways and arteries and such.

Carbon dioxide is also thought to have anti-inflammatory effects, which is also good from the perspective of keeping the airways open as much as possible. No one wants inflammation in the airways limiting tidal volume, if respiratory rate is stuck and cannot rise without major physical effort.

Carbon dioxide has a bad name: too much of it in the atmosphere and it acts as a greenhouse gas, while too much of it inside our bodies can be a harbinger of disease and death. Yet such notoriety is not fully deserved, it seems, as papers published recently highlight CO2’s promise as a new anti-inflammatory agent.

“In the past, CO2 was considered simply a waste product of metabolism, but recent work has highlighted the important role that CO2 plays as a signal molecule affecting multiple processes including inflammation,” says Eoin Cummins, assistant professor of physiology at UCD.

Inflammation is a term given to how the immune system responds to the presence of an irritant or disease-causing agent in the body. Typically, specialised cells of our immune system, the neutrophils, arrive first at the site of an infection. They work to neutralise the invader, causing pain, swelling, warmth and redness in the process.…………

…………There’s significant evidence, looking at cell and some animal models, that CO2 has the ability to suppress inflammatory pathways and inflammatory cytokines; things that are known to fuel cytokine storms,” says Cummins. There is evidence too, he says, that higher CO2 levels in the blood protects damaged organs. For example, he says, when the lungs of patients in ICU are hyper-ventilated this raises their blood CO2 levels and protects them from lung damage.

It is tantalising for scientists that an entirely new pathway for the development of anti-inflammatory drugs and therapies – one based on a greater understanding of CO2 physiology –could open up. One of the hurdles scientists face is the reluctance of clinicians to conduct clinical trials to test the potential benefits of hypercapnia (build-up of CO2 in the blood) on critically ill people in ICU who might benefit. A potentially good side of carbon dioxide Scientists focus on gas’s promise as an anti-inflammatory agent Tue, Mar 16, 2021, 06:01

In Paula’s case, the last thing she needs is to have inflammation in her upper airway. This would result in narrowing her airway and leaving less room for air to for in and out of the airway – not a good thing if you cannot compensate by breathing faster.

Of course carbon dioxide in increasing amounts is also an asphyxiant so it really needs to be monitored carefully , even if mild or even moderate increases are tolerated.

Too much PaC02 in the blood will eventually cause mental confusion and if it increases a lot, it will kill you. [see Wikipedia page on hypercapnia.]

There is even more to consider. We are now aware of a metabolic reflex response to physical trauma, in this case the physical trauma of slow asphyxiation by a known metabolic product of cell metabolism. It is fascinating!


Stress response caused by events such as surgical trauma includes endocrine, metabolic and immunological changes. Stress hormones and cytokines play a role in these reactions. More reactions are induced by greater stress, ultimately leading to greater catabolic effects. Cuthbertson reported the characteristic response that occurs in trauma patients: protein and fat consumption and protection of body fluids and electrolytes because of hypermetabolism in the early period. The oxygen and energy requirement increases in proportion to the severity of trauma. The awareness of alterations in amino acid, lipid, and carbohydrate metabolism changes in surgical patients is important in determining metabolic and nutritional support. The main metabolic change in response to injury that leads to a series of reactions is the reduction of the normal anabolic effect of insulin, i.e. the development of insulin resistance. Free fatty acids are primary sources of energy after trauma. Triglycerides meet 50 to 80 % of the consumed energy after trauma and in critical illness. Surgical stress and trauma result in a reduction in protein synthesis and moderate protein degradation. Severe trauma, burns and sepsis result in increased protein degradation. The aim of glucose administration to surgical patients during fasting is to reduce proteolysis and to prevent loss of muscle mass. In major stress such as sepsis and trauma, it is important both to reduce the catabolic response that is the key to faster healing after surgery and to obtain a balanced metabolism in the shortest possible time with minimum loss. For these reasons, the details of metabolic response to trauma should be known in managing these situations and patients should be treated accordingly.Keywords: Posttraumatic metabolism, stress response, trauma response Ulus Cerrahi Derg. 2014; 30(3): 153–159. Published online 2014 Sep 1. doi: 10.5152/UCD.2014.2653 Response to trauma and metabolic changes: posttraumatic metabolism Turgay Şimşek,1Hayal Uzelli Şimşek,2 and  Nuh Zafer Cantürk3

Since respiratory rate is relatively fixed at rest, even during inflammation, the reflex reaction must be appropriate to the physical constraints of the system. Since respiratory rate cannot increase easily, then hormonal and behavioural responses must be engaged to keep the patient alive, even at the cost of sanity, at least until ventilation and metabolism can be rescued.

And it worked! Paula was partly out of her mind for over a year and recovered slowly over the period of 10 years, and is now helping me to explain her experience to others.

Biology is truly amazing, if slow to give up its secrets.


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