Respiratory alkalosis is a systemic acid-base disorder characterised by a primary reduction in arterial partial pressure of carbon dioxide (PaCO2), which produces an elevation in pH, and consequent decrease in bicarbonate (HCO3-) concentration, as buffering mechanisms. It may occur as a simple primary disorder, a sole respiratory abnormality in which a decrease in PaCO2 results from excess alveolar CO2 excretion relative to CO2 production. Respiratory alkalosis may also occur as compensation for an underlying process, such as metabolic acidosis, or as a separate component of a mixed acid-base disorder, in which case the PaCO2, HCO3-, and pH are determined by the combined effects of the underlying acid-base disorders. Respiratory alkalosis can be classified into three categories: 1) as a component of disease processes, 2) accidentally induced, and 3) deliberately induced (therapeutic). Accidental respiratory alkalosis develops as a consequence of inappropriate settings of mechanical ventilation, or associated with extracorporeal membrane oxygenation. Therapeutic respiratory alkalosis or hypocapnia has been applied to temporarily treat intracranial hypertension or neonatal pulmonary artery hypertension.
Respiratory alkalosis is common. Two large studies of inpatients from the US evaluating arterial blood samples showed a respiratory alkalosis prevalence of 22.5% to 44.7%. Because arterial blood was withdrawn at various times in the patients' hospital course, these figures probably represent instances of respiratory alkalosis from disparate categories. In an Italian study, arterial blood samples obtained from 110 consecutive patients at the time of hospital admission demonstrated respiratory alkalosis in 24%.
The occurrence of accidentally induced respiratory alkalosis may be inferred from a retrospective study of intubated patients with burns (146 people) who received mechanical ventilation for aeromedical transport. The frequency of respiratory alkalosis was 19%, in which 39% of patients received volume-assist control and 17% of patients on intermittent mandatory ventilation experienced hypocapnia. In volume-assist control (or volume control), patients may receive either controlled or assisted breaths. When the patient triggers the ventilator, a breath of identical duration and magnitude is delivered from the machine. In intermittent mandatory ventilation, machine breaths are interposed among the patient's spontaneous breaths. Yet another study reported that the majority of patients undergoing cardiopulmonary bypass (86 people) were hypocapnic during the re-warming phase, and that this disorder persisted in many until the time of ICU arrival. The study did not report the actual frequency of hypocapnia.
Therapeutic respiratory alkalosis or hypocapnia has traditionally been applied to temporarily treat intracranial hypertension. However, the benefit of therapeutic hypocapnia remains unproven and it should be limited to life-threatening elevated intracranial pressure. Its application in either elevated intracranial pressure or neonatal pulmonary hypertension has not been shown to improve survival, and therefore its use should be carefully limited. With the availability of nitric oxide and other vasodilators, therapeutic hypocapnia application in neonatal pulmonary hypertension will be expected to decline.
In respiratory alkalosis, initial suppression of the respiratory centre and reduction in plasma bicarbonate concentration attenuate the rise in pH. Excess CO2 excretion (alveolar hyperventilation) and the resulting hypocapnia, through a negative feedback loop, inhibit the respiratory centre. The systemic effect of the initial reduction in PaCO2 can be described by the modified Henderson-Hasselbalch equation as follows:
The decrease in PaCO2 reduces the PaCO2/HCO3- ratio, hence reducing the H+ concentration, which results in alkalaemia. The decrease in PCO2 also leads to a reduced rate of H+ secretion and increased rate of bicarbonate excretion by the renal tubules as an intracellular buffering mechanism. Within the renal tubular cells, CO2, under the influence of carbonic anhydrase enzyme, combines with H2O to form carbonic acid (H2CO3), which then dissociates into HCO3- and H+. Alkalaemia inhibits carbonic anhydrase activity, resulting in reduced H+ secretion into the renal tubule. HCO3- reabsorption is dependent on combining with H+ to form carbonic acid, which later dissociates into H2O and CO2. Owing to the reduced H+ concentration in the renal tubule, there is inadequate H+ concentration to react with the filtered HCO3-. HCO3- reabsorption decreases, resulting in reduced plasma HCO3- concentration and attenuation of pH.
The physicochemical (Stewart's or strong ion difference) approach to acid-base analysis similarly shows that acute hyperventilation and fall in PaCO2 slowly lead to hyperchloraemic renal compensation. The hyperchloraemia is related to excretion of filtered sodium and potassium with bicarbonate as hydrogen secretion decreases in proximal and distal tubules. As the plasma strong ion difference decreases, the plasma bicarbonate concentration decreases, resulting in the return of serum pH towards normal. Both the traditional and the Stewart's approaches illustrate that renal compensation is caused by a change in the ratio of PaCO2 to bicarbonate (see above modified Henderson-Hasselbalch equation).
Respiratory alkalosis can manifest as acute or chronic. Acute respiratory alkalosis occurs from the onset of hypocapnia for up to 6 hours. Chronic respiratory alkalosis with renal compensatory mechanisms begins 6 hours after the onset of hypocapnia and becomes complete within 2 to 5 days. In acute respiratory alkalosis, the relationship between the decrease in serum HCO3- and the decrease in PaCO2 can be expressed as:
change in HCO3- (mmol/L) = 0.1 x change in PaCO2 (mmHg)
where the decrease in HCO3- is from a normal value of 24 mmol/L and the decrease in PaCO2 is from a normal value of 40 mmHg. For instance, an acute decrease in PaCO2 of 20 mmHg will result in serum HCO3- of approximately 22 mmol/L: that is, a decrease of 2 mmol/L (0.1 x 20) from the normal value of serum HCO3- of 24 mmol/L. Notable deviation of serum HCO3- concentration from the predicted value suggests acid-base disorder other than isolated acute respiratory alkalosis.
In chronic respiratory alkalosis, serum HCO3- is further reduced owing to suppression of renal tubular H+ secretion and HCO3- reabsorption. Thus, the magnitude of the decrease in H+ concentration is attenuated to a greater extent than in the acute stage. In chronic respiratory alkalosis, the relation between the decrease in serum HCO3- and the decrease in PaCO2 can be expressed as:
change in HCO3- (mmol/L) = 0.4 x change in PaCO2 (mmHg)
In this instance, a persistent decrease in PaCO2 of 20 mmHg will decrease serum HCO3- by 8 mmol/L from its normal value of 24 mmol/L, resulting in serum HCO3- of 16 mmol/L. In patients with isolated chronic respiratory alkalosis, serum HCO3- rarely decreases below 12 to 14 mmol/L.
Respiratory alkalosis leads to increased serum lactate by mildly increasing lactate production and by decreasing lactate clearance. Interestingly, in one small study, induced respiratory alkalosis in trained athletes by voluntary hyperventilation has been shown to attenuate performance decline as measured by peak and mean power output in repeated sprinting. This is thought to be due to retardation of the acidosis caused by exercise-induced lactic acidosis.
Respiratory alkalosis also alters electrolyte homeostasis, separate from its renal compensatory mechanisms. Initially, hyperkalaemia occurs owing to hyperventilation-induced augmentation of alpha-adrenergic activity. Afterwards, hypokalaemia ensues owing to transcellular shift, decreased renal reabsorption, and bicarbonaturia. Bicarbonaturia increases renal potassium excretion. Hypokalaemia is usually mild, but it can be severe in pregnant women due to high circulating progesterone levels causing hyperventilation and respiratory alkalosis. One case report described a patient with respiratory alkalosis-induced hypokalaemia leading to flaccid paralysis. In the acute phase, hypophosphataemia may be related to increased cellular uptake. Conversely, the chronic phase is associated with hyperphosphataemia together with hypocalcaemia due to parathyroid hormone resistance.
Bronchoconstriction is a prominent manifestation of physiological changes in the lung. Effects on the pulmonary artery, and pH-related changes in respiratory alkalosis, can induce pulmonary arterial vasodilation, which is used commonly to treat neonatal persistent pulmonary hypertension. Tachycardia is also consistent with physiological changes inherent in respiratory alkalosis and is related to increased sympathetic activity and to hypokalaemia. Chest pain may occur through coronary vasospasm or decreased myocardial oxygen delivery owing to increased O2 affinity to haemoglobin. Data also suggest that respiratory alkalosis significantly decreased in vivo microcirculatory flow as measured by reflectance confocal microscopy during states of sustained hypocapnia (PaCO2 20.9 ± 2.9). This was seen without concomitant decrease in cardiac output. Ventricular and atrial arrhythmias have also been reported in acute and chronic respiratory alkalosis. Gastrointestinal and hepatic symptoms are seen in acute (but not in chronic) respiratory alkalosis. Acute respiratory alkalosis produces nausea, vomiting, and increased GI 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. Peripheral and CNS effects of hypocapnia occur at a threshold of PaCO2 <20 mmHg. Symptoms include vertigo, dizziness, anxiety, euphoria, clumsiness, forgetfulness, hallucinations, and seizure. Unilateral somatic symptoms have also been reported, including partial seizures, migraines, or stroke-like symptoms. CNS symptoms are initiated by changes in pH (rather than changes in PaCO2), which reduce cerebral blood flow, causing cerebral ischaemia that ultimately accounts for neurological symptoms. Peripheral manifestations include tetany and paraesthesias. These neurological manifestations are mediated by hyperventilation-induced increased neural excitability caused by hypocalcaemia and, possibly, hypophosphataemia.
In determining whether a second primary acid-base process coexists with respiratory alkalosis, the pH is a key factor, because compensatory mechanisms do not restore the pH entirely. Significant deviations of HCO3- concentration predicted in acute, or in chronic, respiratory alkalosis indicate a second primary acid-base process. Note that serum HCO3- rarely decreases below 12 to 14 mmol/L in isolated chronic respiratory alkalosis and values below this suggest an independent component of metabolic acidosis. If hypocapnia occurs with acidaemia, a primary respiratory alkalosis is present, if the degree of hypocapnia is greater than would be expected in response to the coexisting metabolic acidosis.
- Pulmonary embolism
- Sepsis and systemic inflammatory-response syndrome (SIRS)
- Acute respiratory distress syndrome (ARDS)
- Cardiogenic shock
- Pulmonary oedema
- Ischaemic stroke
- Haemorrhagic stroke
- Salicylate overdose
- Pseudorespiratory alkalosis
- Asthma in adults
- Asthma in children
- Cardiopulmonary bypass
- Brain tumour
- Traumatic brain injury
- Mechanical ventilation
- High altitude-related illness
- Generalised anxiety disorder
- Idiopathic pulmonary arterial hypertension
- Interstitial pulmonary fibrosis
- Central sleep apnoea
- Hypovolaemic shock
- Severe anaemia
- Lung contusion
- Central neurogenic hyperventilation
- Hyperventilation syndrome
- Hyperthermic hyperpnoea
- Cyanotic heart disease
- Extracorporeal membrane oxygenation (ECMO)
- Fulminant hepatic failure
- Hepatopulmonary syndrome
- Portopulmonary hypertension
- Nicotine, xanthines, catecholamines, analeptics, progestational agents
- Situational anxiety
Professor of Medicine
University of California
CSS is a member of the editorial board of American Journal of Respiratory and Critical Care Medicine and Chest Journal without compensation. CSS received a travel fee from Medtronix for attending a conference. CSS is an author of a reference cited in this topic.
Associate Professor of Medicine
Staff Physician: Pulmonary and Critical Care Medicine
Tibor Rubin VA Medical Center
University of California, Irvine
AQ declares that he has no competing interests.
Dr Catherine S. Sassoon and Dr Asad Qasim would like to gratefully acknowledge Dr Wilson Yan, Dr Jeremy Murdock, and Dr Sterling L. Malish, previous contributors to this topic. WY, JM, and SLM declare that they have no competing interests.
Chief of Pulmonary and Critical Care
King Hussein Cancer Center
FH declares that he has no competing interests.
Professor and Head
Department of Anesthesia
Galway University Hospitals
JGL is an author of a number of references cited in this monograph.
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