Chronic psychic stress can cause metabolic syndrome through mild hypercapnia.

The author presents a new psychosomatic stress model. All the elements of the hypothesis are well known but, in this context, are published first. The following are the most critical aspects of the recommended chronic stress model. 1/ Stress contains both sympathetic and parasympathetic elements, but the latter predominate. 2/ The mediator of stress is carbon dioxide, the substance that can turn the psyche into soma. 3/ In humans, chronic stress is mainly social; people cause it to each other. Chronic social stress is created frequently due to deviations in civilisation, education and tolerance. 4/ The freeze response (or freezing behaviour) plays a subordinate role in the animal world; it lasts mainly for a maximum of minutes, while in humans, it dominates and can continue for decades. 5/ The decisive step of freeze is apnea, hypopnea, which occurs due to aversive psychological eff ects. After a more extended existence, mild chronic respiratory acidosis develops and most often appears in the clinical form of obstructive sleep apnea. 6/ Chronic hypercapnia can shape the metabolism into metabolic syndrome. 7/ After that, various cardiovascular and metabolic complications (hypertension, atherosclerosis, type 2 diabetes, depression) may develop - partly due to genetic and lifestyle reasons. (Neuropsychopharmacol Hung 2022; 24(3): 126-133).

[A new hypothesis on vascular calcification: the exhausting buffer syndrome (EBS)].

Here we propose that the Western world lifestyle disrupts phosphate metabolism and homeostasis due to caloric or acidic hyperphagia. Psychic factors such as social defeat due to stressed social coexistence characterized by reduced activity and chronic hypoventilation (hypercapnia) also play a role. At least two mechanisms mediate the harmful vascular effects of phosphates with intracellular acidosis being a feature in both of them. First, insufficient lifestyle and adjacent diet together with the psychosomatic mechanism of social defeat (mainly through chronic hypercapnic acidosis) lead to insulin resistance characterized by the classical Cardiometabolic Syndrome. Secondly, overload with fixed acids caused by renal insufficiency or acidic diet (due to intracellular metabolic acidosis) leads to our here proposed Exhausting Buffer Syndrome (EBS) which tends to elevate serum inorganic phosphate levels. These two mechanisms overlap and are regulated through genetically determined processes that drive the disruption of phosphate metabolism and lead to vascular calcification. To have a lower intake of calories and less acidic foods combined with low-grade hypocapnia, might be one of several solutions. (Neuropsychopharmacol Hung 2021; 23(1): 215-220)

Pathophysiology and clinical consequences of arterial blood gases and pH after cardiac arrest.

Post cardiac arrest syndrome is associated with high morbidity and mortality, which is related not only to a poor neurological outcome but also to respiratory and cardiovascular dysfunctions. The control of gas exchange, and in particular oxygenation and carbon dioxide levels, is fundamental in mechanically ventilated patients after resuscitation, as arterial blood gases derangement might have important effects on the cerebral blood flow and systemic physiology.In particular, the pathophysiological role of carbon dioxide (CO2) levels is strongly underestimated, as its alterations quickly affect also the changes of intracellular pH, and consequently influence metabolic energy and oxygen demand. Hypo/hypercapnia, as well as mechanical ventilation during and after resuscitation, can affect CO2 levels and trigger a dangerous pathophysiological vicious circle related to the relationship between pH, cellular demand, and catecholamine levels. The developing hypocapnia can nullify the beneficial effects of the hypothermia. The aim of this review was to describe the pathophysiology and clinical consequences of arterial blood gases and pH after cardiac arrest.According to our findings, the optimal ventilator strategies in post cardiac arrest patients are not fully understood, and oxygen and carbon dioxide targets should take in consideration a complex pattern of pathophysiological factors. Further studies are warranted to define the optimal settings of mechanical ventilation in patients after cardiac arrest.

Hypocapnia and mental stress can trigger vicious circles in critically ill patients due to energy imbalance: a hypothesis presented through cardiogenic pulmonary oedema.

The pathophysiologic significance of hypocapnia is strongly underestimated both in functional and organic diseases. Alterations of carbon dioxide levels immediately appear in the cytoplasm, causing abrupt pH changes. Compensatory mechanisms develop with latency, so intracellular alkalosis or acidosis can affect metabolism for hours/days. Hyperventilation alkalosis increases metabolic energy/O2 demand, while ATP production is often reduced due to developing hypophosphatemia. A healthy organism serves the increased energy demand conveniently, as a consequence, the excitability of the corticospinal and neuromuscular systems grows. Functional diseases can occur due to increased membrane Ca2+ transients but tissues remain structurally unchanged. By contrast, a critically ill myocardium cannot satisfy the increased energy demand caused by acute hypocapnia. Vicious circles can occur, with cardiac forward and backward failure; pulmonary wedge pressure increases parallel with the lack of energy which can lead to pulmonary oedema and death. Hypocapnia can generate fatal vicious circles in several critical illnesses. Sympathicotonia and hypocapnia enhance arousal and make biological systems energetically unstable, thus vicious circles almost unavoidably occur. Somatic and psychic processes mutually influence each other, resulting in psychosomatic or somatopsychic disorders. The ability to provide energy supplies can be an important dividing line between organic and functional diseases.

New aspects in the pathomechanism of diseases of civilization, particularly psychosomatic disorders. Part 1. Theoretical background of a hypothesis.

The stress defence-cascade is mostly not biphasic as Cannon thought, the sympathicotonic stress response is preceded by a vagotonic phase called freeze response. Alteration of the carbon dioxide level plays an important role during defence-cascade as its changes interfere with stress hormones, e.g. with catecholamines, thus affecting the degree of arousal. In case of humans, learned behaviour dominates instead of instinctive, so the fight-or-flight often lags; the consequence can be persistent hypocapnia or hypercapnia. The hypoventilation or hyperventilation may continue even after a stressful situation, as tissular and renal compensation stabilizes and makes the pathological breathing patterns chronic. The organism tries to restore the original milieu intérieur (sec. Claude Bernard), but this cannot succeed without restoring pCO2. The regulation operates the preservation of intracellular and extracellular pH as a priority, while neurohumoral compensations change the ionic milieu in the body's cells. Present hypothesis specifies the permanent lack or excess of carbon dioxide which can cause allostatic load by psychosomatic pathomechanism. Carbon dioxide is equivalent to stress hormones; its alterations become a means of somatization, resulting in ion-pattern changes in intracellular and extracellular spaces, consequently causing disintegration of the body's function. (See also: network theory, ripple effect, metabolic remodeling.) Intracellular ion-pattern alterations emerge new genetic phenotypes to the surface. The variety of phenotypes explains the diversity of induced diseases. The theory appreciates the role of ions by considering the instantaneous ion pattern of the cytoplasm (all the ions together) as a decisive second messenger.

New aspects in the pathomechanism of diseases of civilization, particularly psychosomatic disorders. Part 2. Chronic hypocapnia and hypercapnia in the medical practice.

The authors seek to find new connections between recent results of biology and older theories. This paper aims to assemble the jigsaw puzzle. The theoretical background of the hypothesis was described in the previous issue of the journal (Sikter et al. 2017a). Human stress response often coexists with persistent hypocapnia or hypercapnia - developing via psychosomatic pathomechanism - which can lead to mental and psychosomatic illnesses. Chronic hypocapnia mainly generates hyperarousal disorders which may be reversible for an extended time, however, vicious cycles may start when hypoxia and/or severe somatic diseases are simultaneously present (commonly in the elderly), which conditions often end with death without medical help. Chronic hypercapnia devastates the organism initially without symptoms, partly due to neurohumoral contraregulation, consequential dysregulation and metabolic remodeling. Psychosomatic disorders (e.g., diseases of civilization that evolve in people with disadvantaged psychosocial situations) develop over years and decades, causing irreversible changes. Hypercapnia usually occurs in clinical pictures of chronic obstructive pulmonary disease, obesity hypoventilation syndrome, obstructive sleep apnea, and its unobstructed version (sleep-related hypoventilation), generating various organic disorders (hypertension, type 2 diabetes, cardiovascular disorders, immunological diseases, depression, etc.). Because of the above, chronic hypocapnia and hypercapnia cannot be regarded as harmless accompanying phenomena. That is why we have to strive for restoring eucapnia and normalizing the induced ionic changes, which does not appear to be a hopeless task.

The role of carbon dioxide (and intracellular pH) in the pathomechanism of several mental disorders. Are the diseases of civilization caused by learnt behaviour, not the stress itself?

The role of carbon dioxide (CO2) is underestimated in the pathomechanism of neuropsychiatric disorders, though it is an important link between psyche and corpus. The actual spiritual status also influences respiration (we start breathing rarely, frequently, irregularly, etc.) causing pH alteration in the organism; on the other hand the actual cytosolic pH of neurons is one of the main modifiers of Ca2+-conductance, hence breathing directly, quickly, and effectively influences the second messenger system through Ca2+-currents. (Decreasing pCO2 turns pH into alkalic direction, augments psychic arousal, while increasing pCO2 turns pH acidic, diminishes arousal.) One of the most important homeostatic function is to maintain or restore the permanence of H+-concentration, hence the alteration of CO2 level starts cascades of contraregulation. However it can be proved that there is no perfect compensation, therefore compensational mechanisms may generate psychosomatic disorders causing secondary alterations in the "milieu interieur". Authors discuss the special physico-chemical features of CO2, the laws of interweaving alterations of pCO2 and catecholamine levels (their feedback mechanism), the role of acute and chronic hypocapnia in several hyperarousal disorders (delirium, panic disorder, hyperventilation syndrome, generalized anxiety disorder, bipolar disorder), the role of "locus minoris resistentiae" in the pathomechanism of psychosomatic disorders. It is supposed that the diseases of civilization are caused not by the stress itself but the lack of human instinctive reaction to it, and this would cause long-lasting CO2 alteration. Increased brain-pCO2, acidic cytosol pH and/or increased basal cytosolic Ca2+ level diminish inward Ca2+-current into cytosol, decrease arousal--they may cause dysthymia or depression. This state usually co-exists with ATP-deficiency and decreased cytosolic Mg2+ content. This energetical- and ion-constellation is also typical of ageing-associated and chronic organic disorders. It is the most important link between depression and organic disorders (e.g. coronary heart disease). The above-mentioned model is supported by the fact that H+ and/or Ca2+ metabolism is affected by several drugs (catecholemines, serotonin, lithium, triaecetyluridine, thyroxine) and sleep deprivation, they act for the logically right direction.

The role of hyperventilation: hypocapnia in the pathomechanism of panic disorder

OBJECTIVE: The authors present a profile of panic disorder based on and generalized from the effects of acute and chronic hyperventilation that are characteristic of the respiratory panic disorder subtype. The review presented attempts to integrate three premises: hyperventilation is a physiological response to hypercapnia; hyperventilation can induce panic attacks; chronic hyperventilation is a protective mechanism against panic attacks. METHOD: A selective review of the literature was made using the Medline database. Reports of the interrelationships among panic disorder, hyperventilation, acidosis, and alkalosis, as well as catecholamine release and sensitivity, were selected. The findings were structured into an integrated model. DISCUSSION: The panic attacks experienced by individuals with panic disorder develop on the basis of metabolic acidosis, which is a compensatory response to chronic hyperventilation. The attacks are triggered by a sudden increase in (pCO2) when the latent (metabolic) acidosis manifests as hypercapnic acidosis. The acidotic condition induces catecholamine release. Sympathicotonia cannot arise during the hypercapnic phase, since low pH decreases catecholamine sensitivity. Catecholamines can provoke panic when hyperventilation causes the hypercapnia to switch to hypocapnic alkalosis (overcompensation) and catecholamine sensitivity begins to increase. CONCLUSION: Therapeutic approaches should address long-term regulation of the respiratory pattern and elimination of metabolic acidosis.

OBJETIVO: Os autores apresentam um modelo de transtorno do pânico que se baseia nos efeitos da hiperventilação aguda e crônica, característicos do subtipo respiratório de transtorno do pânico. O modelo é generalizado a partir desses efeitos. Ele integra três características da hiperventilação: a hiperventilação é uma resposta fisiológica à hipercapnia; a hiperventilação pode induzir ataques de pânico; a hiperventilação crônica representa um mecanismo protetor contra os ataques de pânico. MÉTODO: Revisão seletiva da literatura a partir da base de dados Medline. Foram selecionados relatos referentes à inter-relação entre transtorno do pânico, hiperventilação, acidose, alcalose, liberação de catecolaminas e sensibilidade a catecolaminas, sendo os achados estruturados de modo a formar um modelo integrado. DISCUSSÃO: Os ataques de pânico do transtorno do pânico desenvolvem-se com base numa acidose metabólica, que é uma resposta compensatória à hiperventilação crônica. Os ataques são desencadeados por um súbito aumento da pressão parcial de dióxido de carbono (pCO2), quando a acidose (metabólica) latente se manifesta pela acidose hipercápnica. A condição acidótica induz liberação de catecolaminas. A simpaticotonia não pode manifestar-se durante a fase de hipercapnia, pois o baixo pH diminui a sensibilidade às catecolaminas. As catecolaminas podem provocar pânico quando a hipercapnia comuta para uma alcalose hipocápnica devido à supercompensação pela hiperventilação, situação na qual a sensibilidade às catecolaminas liberadas começa a aumentar. CONCLUSÃO: As abordagens terapêuticas deveriam voltar-se para a regulação em longo prazo do padrão respiratório e a eliminação da acidose metabólica.

The role of hyperventilation: hypocapnia in the pathomechanism of panic disorder.

OBJECTIVE: The authors present a profile of panic disorder based on and generalized from the effects of acute and chronic hyperventilation that are characteristic of the respiratory panic disorder subtype. The review presented attempts to integrate three premises: hyperventilation is a physiological response to hypercapnia; hyperventilation can induce panic attacks; chronic hyperventilation is a protective mechanism against panic attacks. METHOD: A selective review of the literature was made using the Medline database. Reports of the interrelationships among panic disorder, hyperventilation, acidosis, and alkalosis, as well as catecholamine release and sensitivity, were selected. The findings were structured into an integrated model. DISCUSSION: The panic attacks experienced by individuals with panic disorder develop on the basis of metabolic acidosis, which is a compensatory response to chronic hyperventilation. The attacks are triggered by a sudden increase in (pCO2) when the latent (metabolic) acidosis manifests as hypercapnic acidosis. The acidotic condition induces catecholamine release. Sympathicotonia cannot arise during the hypercapnic phase, since low pH decreases catecholamine sensitivity. Catecholamines can provoke panic when hyperventilation causes the hypercapnia to switch to hypocapnic alkalosis (overcompensation) and catecholamine sensitivity begins to increase. CONCLUSION: Therapeutic approaches should address long-term regulation of the respiratory pattern and elimination of metabolic acidosis.