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Pathophysiology and therapeutic strategy of respiratory alkalosis 

Pathophysiology and therapeutic strategy of respiratory alkalosis
Pathophysiology and therapeutic strategy of respiratory alkalosis

Thomas Langer

and Pietro Caironi

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date: 16 May 2022

Key points

  • Respiratory alkalosis is an increase in arterial pH due to an imbalance between metabolic CO2 production and CO2 removal, in favour of the latter.

  • Respiratory alkalosis is usually a sign of an underlying pulmonary or central nervous system disease.

  • An excessive CO2 removal during controlled mechanical ventilation or extracorporeal CO2 removal can also cause hypocapnia and, therefore, result in respiratory alkalosis.

  • The metabolic compensation (mainly renal) restores pH values close to normality in 24–48 hours, through the reduction in plasma strong ion difference (increase in plasma chloride concentration).

  • Respiratory alkalosis per se is rarely dangerous, and the clinical approach is directed towards diagnosis and treatment of the underlying disorder.


Respiratory alkalosis is a condition characterized by low partial pressure of carbon dioxide (PCO2) and an associated elevation in arterial pH caused by an imbalance between CO2 production and removal, in favour of the latter. The increase in CO2 removal usually occurs because of increased alveolar ventilation. Respiratory alkalosis is a primary acid–base derangement, i.e. the increased CO2 elimination is the manifestation of a clinical condition and not a compensatory response to metabolic acidosis.

Pathophysiology of the control of breathing

In physiological conditions, alveolar ventilation is finely tuned by the activity of two groups of sensors—central chemoreceptors (located at the ventral surface of the medulla, within the central nervous system) and peripheral chemoreceptors (type 1 glomus cells of carotid and aortic arch bodies) [1]‌. These receptors are mainly stimulated by changes in PCO2 and pH, i.e. an increase in PCO2 and/or a reduction in pH will activate the receptors and thus increase the signal strength (input) to the central controller, causing an increased output signal to the effectors (respiratory muscles), and a consequent increase in alveolar ventilation. This mechanism will eventually reduce PCO2, normalize arterial pH and thereby reduce the input to the central controller. In addition to increases in PCO2/reductions in pH, also very low values of PO2 (less than 50 mmHg) can activate peripheral chemoreceptors and have a similar effect on alveolar ventilation [2]. In the case of hypocapnia and slight alkalosis, however, this hypoxic respiratory response is abolished [3]. Finally, besides central and peripheral chemoreceptors, lung receptors (Table 114.1) might also play a role in the pattern of respiration. These receptors are usually not active in physiological conditions.

Table 114.1 Schematic representation of lung receptors’ types and evoked reflexes

Receptor type



Respiratory reflex/effect

Slowly adapting receptor


Lung inflation

Termination of inspiration (Breuer–Hering reflex), expiratory facilitation, bronchodilation

Rapidly adapting receptor

Mechanosensitive and chemosensitive

Lung inflation and deflation, and chemical irritants

Augmented breath/gasp, irregular inspiration, and shortened expiration

C-fibre receptor, former J-receptors


Irritants, inflammation, congestion, pulmonary oedema, micro-embolism

Rapid, shallow breathing, apnoea (simultaneous chemical stimulation)

Pathophysiology of hypocapnia

Conditions that cause increased alveolar ventilation, without having as input stimulus a reduction in pH, will cause hypocapnia associated with a variable degree of alkalosis. These conditions can be schematically divided into three categories (Table 114.2).

Table 114.2 Causes of respiratory alkalosis



Voluntary hyperventilation


Pain, panic attack, hysteria

Central neurogenic hyperventilation

Brainstem injuries, invasive brain tumours, brain infarcts


Increased progesterone levels in pregnancy and liver cirrhosis


Meningitis, encephalitis

Thermal hyperpnoea

Fever, hyperthermia


Salicylate, topiramate



Hypoxic pulmonary disease, high altitude

Lung receptors

Pulmonary oedema, pneumonia, acute respiratory distress syndrome, asthma, pulmonary embolism, interstitial fibrosis


Mechanical ventilation

Excessive mechanical ventilation (accidental or therapeutic for traumatic brain injury)

Extracorporeal CO2 removal

Excessive extracorporeal CO2 removal

Increased activity of the ‘central controller’

Conditions characterized by an increased activity of the ‘central controller’, dissociated from input arising from peripheral sensors, result in an increased activity of the respiratory muscles, which in turn cause an augmented alveolar ventilation [4,5]. In theory, this might be due to an increased activity of the central controller per se (such as voluntary hyperventilation and central neurogenic hyperventilation) or by an increased activity of central chemoreceptors, as hypothesized in salicylate and topiramate intoxications [6,7].

Increased input from the peripheral chemoreceptors and lung receptors

In case of severe hypoxaemia, the peripheral chemoreceptors (mainly carotid bodies) will increase their signalling activity and cause increased alveolar ventilation [2,3]. Of note, peripheral chemoreceptors respond to PO2, and not to oxygen content or oxygen delivery. Moreover, respiratory alkalosis due to an increased signalling from lung receptors (Table 114.1) is a common finding in several pulmonary diseases, including pneumonia, pulmonary oedema, pulmonary embolism, and fibrosis [8,9]. In fact, in pathological conditions, also vagal afferents, i.e. signals arising from lung receptors, can trigger pulmonary reflexes and might have a role in the control of breathing [10].

Excessive CO2 removal through controlled mechanical ventilation and/or extracorporeal CO2 removal

In case of mechanical ventilation in sedated and paralysed patients, the ‘effectors’, i.e. the respiratory muscles, are no longer regulated by the ‘central controller’. Indeed, it is the attending physician deciding the rate of alveolar ventilation through the settings of the ventilator. The lack of feedback mechanisms can therefore ensue in an excessive CO2 removal, leading to respiratory alkalosis, as often occurring during general anaesthesia in operating rooms. A similar scenario is the result of excessive ventilation of the membrane lung in mechanically-ventilated patients treated with extracorporeal respiratory supports.

Effects of respiratory alkalosis

The major effect of hyperventilation is the increase in pH and the consequent shift of electrolytes that occurs in relation to it. As a general law, anions (chloride) will increase (mainly exiting from erythrocytes), while cations (sodium and potassium) will decrease, as they enter in erythrocytes and other cells. Moreover, the acute reduction in ionized calcium due to the change in extracellular pH may cause neuromuscular symptoms ranging from paraesthesias, up to tetany and seizures. Finally, acute respiratory alkalosis causes a constriction of cerebral arteries that can lead to a reduction of cerebral blood flow [11]. This phenomenon is of particular importance for patients with traumatic brain injury.

Metabolic compensation

The kidneys respond to respiratory alkalosis by uncoupling sodium from chloride excretion. Indeed, sodium is excreted with a weak anion (mainly bicarbonate), while chloride is retained. The effect on urine is an increase in urinary strong ion difference (SID)/urinary anion gap and a consequent increase in urinary pH [12,13]. This, in turn, causes an increase in plasma chloride concentration, and a reduction in plasma SID, which tend to bring back plasma pH towards normal values. The renal compensation restores pH values close to normality within 24–48 hours. Another, quantitatively less important mechanism of compensation, is the electrolyte shift, mainly chloride, from red blood cells to plasma.

Therapeutic strategies

The clinical approach to respiratory alkalosis is usually directed toward the diagnosis and treatment of the underlying clinical disorder. To reduce hypocapnia, especially in pathological activation of the central controller, both physical (increase in dead space) and pharmacological means (opiates and benzodiazepines) have been described [14].


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