Aetiology

Respiratory alkalosis may present in a variety of clinical settings. Hypocapnia, as a result of tachypnoea, is the usual physiological manifestation. It may occur as a result of improper ventilator settings or by such disparate causes as hypoxia, increased central respiratory drive, and hyperthermia. It may even be applied to treat conditions such as intracranial hypertension or neonatal pulmonary artery hypertension.

Pulmonary

Hypoxaemia is a low arterial PaO₂. Hypoxaemia alone may produce respiratory alkalosis, and the differential diagnosis is broad. Hypoxaemia may be diagnosed by pulse oximetry or arterial blood gas. Arterial blood gases can also identify a concomitant acid-base disorder. Depending on the degree and aetiology of hypoxaemia, its correction involves the administration of supplemental oxygen by nasal cannula or mask, the application of non-invasive positive-pressure ventilation, or intubation and mechanical ventilation with positive-end expiratory pressure. After correction of the hypoxaemia, urgent work-up is indicated to elucidate and treat the underlying disease.

Hypoxaemia and tissue hypoxia affect peripheral chemoreceptors located in the carotid bodies by low PaO₂ and increased H+ concentration, respectively, causing hyperventilation.[49] With hypoxaemia, the intensity of the response depends on the severity of the hypoxaemia. When PaO₂ falls to below 70 mmHg, the firing frequency of the chemoreceptors and minute ventilation increase in an accelerating fashion. Exposure to high altitude can cause hypoxaemia that may lead to respiratory alkalosis by this mechanism.[50][51][52]

Respiratory alkalosis in the setting of hypoxia-induced vasoconstriction; however, can worsen intrapulmonary shunt and systemic oxygenation.[53] Hypocapnia also induces lung injury and potentiates acute lung injury following ischaemic reperfusion.[54] The mechanism may be related to increased capillary permeability.[54] In addition to hypoxaemia, stimulation of vagal afferent receptors in bronchial airways and lungs can produce tachypnoea. In patients with asthma, irritant receptors in the airways are responsible for the tachypnoea.[55] Hypocapnia itself, through an irritant effect and slowly adapting stretch receptors, is an additional stimulus to the bronchoconstriction in the early stage of asthmatic attacks.[56] In interstitial lung disease and fibrosis, there is evidence that increased elastic load and stimulation of both mechanoreceptors of the chest wall and intrapulmonary receptors induce tachypnoea.[57] Other parenchymal lung diseases that may induce hypocapnia are cardiogenic pulmonary oedema and high-altitude pulmonary oedema.[58] Respiratory alkalosis in acute lung injury may be an early sign of adult respiratory distress syndrome that precedes chest radiograph infiltrates.[59][60] It is accepted commonly that primary spontaneous pneumothorax may present with respiratory alkalosis, especially with concurrent pain, anxiety, or hypoxaemia.[61][62] However, the hypocapnia is dependent on the size of the pneumothorax: it only occurs with a large pneumothorax of >50% of lung volume.[63]

Respiratory alkalosis is observed commonly in pulmonary embolism (PE) and pulmonary arterial hypertension.[64][65][66] In fact, patients with exacerbation of chronic obstructive pulmonary disease (a population with higher risk for pulmonary embolus) and a relative respiratory alkalosis may have a concomitant pulmonary embolus.[67]

Therapeutic respiratory alkalosis or hypocapnia has traditionally been applied to temporarily treat neonatal pulmonary artery hypertension.[4][5] With the availability of nitric oxide and other vasodilators, the use of therapeutic hypocapnia in neonatal pulmonary hypertension should decline.[1][15]

Cardiovascular

Hypoxaemia and tissue hypoxia affect peripheral chemoreceptors located in the carotid bodies through low PaO₂ and increased H+ concentration, respectively, causing hyperventilation.[49] With hypoxaemia, the intensity of the response depends on the severity of the hypoxaemia. When PaO₂ falls to below 70 mmHg, the firing frequency of the chemoreceptors and, subsequently, minute ventilation increase in an accelerated fashion. A variety of disorders, such as cyanotic heart disease, can cause hypoxaemia that may lead to respiratory alkalosis by this mechanism. With tissue hypoxia, augmented H+ concentration owing to increased lactate production acts as a stimulus to the carotid bodies, leading to hyperventilation. Such a mechanism by which tissue hypoxia induces hyperventilation may also be seen in cardiogenic shock. It is this mechanism by which tissue hypoxia induces hyperventilation. Pseudorespiratory alkalosis is a type of arterial hypocapnia associated with an atypical form of respiratory acidosis. This condition occurs when there is a critical reduction in pulmonary perfusion but preserved ventilation (e.g., in cardiopulmonary resuscitation). In such cases, the central venous blood bears a high PCO₂ and a low pH, and the systemic arterial blood bears a low PCO₂ and a normal or high pH. Diagnosis rests on comparing arterial and venous blood gases.[68]

Haematological

Severe anaemia and haemoglobinopathies (e.g., thalassaemias and sickle cell anaemia) are associated with tissue hypoxia wherein increased lactate production and augmented H+ concentration acts as a stimulus to the carotid bodies. This causes hyperventilation and respiratory alkalosis.

Gastrointestinal and hepatic

Gastrointestinal and hepatic symptoms are seen in acute (but not in chronic) respiratory alkalosis. Acute respiratory alkalosis produces nausea, vomiting, and increased gastrointestinal motility. The mechanism for increased colonic tone is dependent on the presence of hypocapnia (and not eucapnic hyperventilation), which seems to have a direct effect on colonic smooth muscle. Another possible mechanism of the changes in colonic tone is through hypocapnia-induced modulation of central autonomic neural control, although the relative influence of parasympathetic and sympathetic neural modulation is unclear.[41][42]

Tachypnoea due to increased respiratory drive is well known in liver disease, such as cirrhosis, with portopulmonary hypertension, hepatopulmonary syndrome, and fulminant hepatic failure.[65][69][70] Chronic respiratory alkalosis is the most prevalent acid-base alteration in cirrhotic patients, deemed 'cirrhotic hyperventilation.' The causes are multifactorial and include stimulating respiratory centres, chronic hypoxemia due to intrapulmonary arteriovenous shunting, and brain stem intracellular acidosis.[71]

Iatrogenic

Hyperventilation may occur with mechanical ventilation, including high-frequency oscillatory ventilation.[72] Respiratory alkalosis is also associated with use of efficient extracorporeal techniques, such as cardiopulmonary bypass and extracorporeal membrane oxygenation.[73][74]

Infectious

Sepsis produces hyperventilation that is mediated by metabolic acidosis and direct lung injury. Endotoxin appears to modulate vagal C-fibre afferents in producing hyperventilation.[75] Hyperventilation secondary to tissue hypoxia may be seen in septic shock. Tachypnoea with hypocapnia is not only common in sepsis but is also a diagnostic criterion for the systemic inflammatory-response syndrome (SIRS).[76]

Hypocapnia is seen in diffuse processes, such as meningitis and encephalitis.[59][77] In patients with meningitis, it is hypothesised that the increased cerebrospinal fluid (CSF) lactate causes decreased CSF pH, leading to stimulation of medullary chemoreceptors and increased minute ventilation.[78]

Metabolic and hormonal

Progestogens cause respiratory alkalosis by stimulating respiratory-centre drive directly, increasing central chemoreceptor sensitivity to carbon dioxide, and increasing carotid-body sensitivity to hypoxia.[79][80] Evidence of progesterone-mediated hyperventilation has been shown in women during the first trimester of pregnancy and in the latter part of the menstrual cycle, and also in those taking progestins as hormone replacement.[81][82][83]

Hyperthermia induces respiratory alkalosis by increasing both respiratory frequency and tidal volume, termed hyperthermic hyperpnoea. The exact mechanism of hyperthermic hyperpnoea is unclear but may include interactions of blood gases and pH with body temperature.[84] The increased ventilatory sensitivity to hyperthermia was not suppressed by the resultant hypocapnia.[85] The hyperventilation results in selective brain cooling, a mechanism for decreasing body-fluid secretions. Hyperthermia and hypocapnia, independently also contribute to decreased cerebral blood flow.[85]

Neurological

Diffuse and focal processes of the central nervous system may produce respiratory alkalosis. Hypocapnia is seen in diffuse processes, such as head injury. In a large study, 40% of non-intubated patients with moderate to severe traumatic brain injury had hypocapnia.[86] The hypocapnia might be a protective mechanism, particularly in the presence of hypoxia. In one study of healthy subjects, hypocapnic hypoxia effectively preserved dynamic cerebral autoregulation.[87] Paradoxically, a further study showed that infants with hypoxic-ischaemic encephalopathy who were exposed to early hypocarbia were at increased risk for death or neurodevelopmental disability.[88] Furthermore, a retrospective study in intubated adults with traumatic brain injury at a trauma center revealed that spontaneous hyperventilation is an independent factor associated with poor functional neurologic outcome.[89]

Respiratory alkalosis may play a role in febrile seizures in children. One prospective study demonstrated that children presenting with febrile seizures had hypocapnia measured from venous blood (mean PCO₂ 23 mmHg, pH 7.43) prior to the seizures with higher PCO₂ (mean 29 mmHg, pH 7.41) obtained 2 hours after the seizures. The investigators suggested that fever-induced hypocapnia is one of the precipitating factors inducing seizures.[90]

Focal processes, such as brain mass or stroke, may also cause respiratory alkalosis. A review of 21 case reports demonstrated respiratory alkalosis in patients with astrocytoma, lymphoma, laryngeal carcinoma metastasis, medulloblastoma, and pontine glioma, all involving the brainstem.[91]

In one small study of patients with ischaemic stroke involving the brainstem, tachypnoea or Cheyne-Stokes respiration were found in a majority of patients and were usually associated with respiratory alkalosis.[92] In another study of 27 patients with strokes (24 ischaemic and 3 haemorrhagic) not involving the brainstem, 40% had respiratory alkalosis.[93] The 3 patients in the study with haemorrhagic stroke did not have respiratory alkalosis, although central neurogenic hyperventilation was reported.[94] Acute respiratory alkalosis has also been reported as a complication of endoscopic third ventriculostomy in a patient with obstructive hydrocephalus.[95]

Respiratory alkalosis may also be seen in non-hypercapnic central sleep apnoea (CSA), the most common form of CSA.[96] In this disorder, oscillations in respiratory drive are associated with hyperventilation and hypocapnia, and are characterised by enhanced ventilatory response to hypercapnia.[97][98] The association of daytime hypocapnia with non-hypercapnic CSA suggests that chronic hypocapnia may have a role in the mechanism of this disorder.[98][99] Nocturnal hypocapnia, therefore, may be a result of CSA, whereas daytime hypocapnia suggests that a patient is at risk for CSA. Additionally, a study showed that hypocapnic-induced central hypopnoea (a reduction in flow of 30% or more from control without inspiratory effort) produces pharyngeal narrowing in the expiratory phase that may be responsible for the pathogenesis of upper airway obstruction during sleep.[99]

Therapeutic respiratory alkalosis or hypocapnia has traditionally been applied to temporarily treat intracranial hypertension.[4] In patients with intracranial hypertension, therapeutic hypocapnia decreases length of ICU stay.[14] However, excessive hypocapnia induces cerebral vasoconstriction and can exacerbate cerebral ischaemia. Indeed, current guidelines for the management of traumatic brain injury do not recommend prolonged prophylactic hyperventilation with partial pressure of carbon dioxide in arterial blood (PaCO₂) of 25 mmHg or less.[100] The benefit of therapeutic hypocapnia remains unproven and it should be limited to life-threatening elevated intracranial pressure.[12][13]

Pharmacological

Medications known to induce respiratory alkalosis through hyperventilation include salicylates (in overdose), nicotine, xanthine derivatives (e.g., theophylline), catecholamines (e.g., beta-2 agonists, such as terbutaline or salmeterol, norepinephrine [noradrenaline]), analeptics (e.g., nikethamide, doxapram), and progestational hormones (e.g., medroxyprogesterone).[101][102] Levofloxacin has been reported to cause acute encephalopathy accompanied by severe respiratory alkalosis.[103]

Psychiatric

Hyperventilation syndrome is a clinical entity reported predominantly in women in the third to fourth decades of life, consisting of hyperventilation associated with psychiatric disorder, especially anxiety and panic.[104] Patients experience episodic dyspnea with inappropriately high alveolar ventilation.[105] Generalized anxiety disorder may mimic many of the symptoms of respiratory alkalosis (e.g., dizziness, forgetfulness, somatic illness). These symptoms are triggered by PaCO₂ <20 mmHg.[43] The anxiety component may be absent and it may be difficult to distinguish whether anxiety is the trigger or the result of hyperventilation. The aetiology of hyperventilation syndrome remains unclear, and it is a diagnosis of exclusion.

The diagnosis may be made by the hyperventilation provocation test. A test is positive if, during voluntary hyperventilation, the patient experiences symptoms similar to those during attacks. However, this test has been noted to have a high false-positive rate, and its validity has been questioned.[104]

Cardiopulmonary exercise testing has been proposed as a diagnostic tool with one study noting patients with hyperventilation syndrome had a relatively unchanged end tidal CO₂ (PETCO₂) and VE/VCO₂ ratio (minute ventilation per unit carbon dioxide production) at peak exercise compared to rest, whereas control subjects exhibited an increase in PETCO₂ and a decrease in VE/VCO₂.[105] This lack of change in PETCO₂ and VE/VCO₂ at peak exercise was demonstrated to have a specificity of 93% and 83%, respectively.

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