Respiratory alkalosis is a systemic acid-base disorder characterized by a primary reduction in arterial partial pressure of carbon dioxide (PaCO₂), which produces an elevation in pH above 7.45, 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:
as a component of disease processes
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 Because arterial blood was withdrawn at various times in the patients' hospital course, these figures probably represent instances of respiratory alkalosis from disparate categories.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 rewarming 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 center and reduction in plasma bicarbonate concentration attenuate the rise in pH. Excess CO₂ excretion (alveolar hyperventilation) and the resulting low arterial PaCO₂ (hypocapnia) inhibits the respiratory centre through a negative feedback loop. 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 alkalemia. 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+. Alkalemia 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 or strong ion difference) approach to acid-base analysis similarly shows that acute hyperventilation and fall in PaCO₂ slowly lead to hyperchloremic renal compensation. The hyperchloremia 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 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- (mEq/L ) = 0.1 x change in PaCO₂ (mmHg)
where the decrease in HCO₃- is from a normal value of 24 mEq/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 mEq/L : that is, a decrease of 2 mEq/L (0.1 x 20) from the normal value of serum HCO₃- of 24 mEq/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- (mEq/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 mEq/L from its normal value of 24 mEq/L, resulting in serum HCO₃- of 16 mEq/L. In patients with isolated chronic respiratory alkalosis, serum HCO₃- rarely decreases below 12 to 14 mEq/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, hyperkalemia occurs owing to hyperventilation-induced augmentation of alpha-adrenergic activity. Afterwards, hypokalemia ensues owing to transcellular shift, decreased renal reabsorption, and bicarbonaturia. Bicarbonaturia increases renal potassium excretion. Hypokalemia is usually mild but 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 hypokalemia leading to flaccid paralysis.
In the acute phase, hypophosphatemia may be related to increased cellular uptake. Conversely, the chronic phase is associated with hyperphosphatemia together with hypocalcemia due to parathyroid hormone resistance.
Bronchoconstriction is a prominent manifestation of physiologic 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 physiologic changes inherent in respiratory alkalosis and is related to increased sympathetic activity and to hypokalemia. Chest pain may occur through coronary vasospasm or decreased myocardial oxygen delivery owing to increased O₂ affinity to hemoglobin. 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 ischemia that ultimately accounts for neurologic symptoms. Peripheral manifestations include tetany and paresthesias. These neurologic manifestations are mediated by hyperventilation-induced increased neural excitability caused by hypocalcemia and, possibly, hypophosphatemia.
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 mEq/L in isolated chronic respiratory alkalosis and values below this suggest an independent component of metabolic acidosis. If hypocapnia occurs with acidemia, 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 edema
- Ischemic stroke
- Hemorrhagic stroke
- Salicylate overdose
- Pseudorespiratory alkalosis
- Asthma in adults
- Asthma in children
- Cardiopulmonary bypass
- Brain tumor
- Traumatic brain injury
- Mechanical ventilation
- High altitude-related illness
- Generalized anxiety disorder
- Idiopathic pulmonary arterial hypertension
- Interstitial pulmonary fibrosis
- Central sleep apnea
- Hypovolemic shock
- Severe anemia
- Lung contusion
- Central neurogenic hyperventilation
- Hyperventilation syndrome
- Hyperthermic hyperpnea
- Cyanotic heart disease
- Extracorporeal membrane oxygenation (ECMO)
- Fulminant hepatic failure
- Hepatopulmonary syndrome
- Portopulmonary hypertension
- Nicotine, xanthines, catecholamines, analeptics, progestational agents
- Situational anxiety
Brian Dang, MD
Fellow in Pulmonary and Critical Care
University of California
BD declares that he has no competing interests.
Catherine S. Sassoon, MD
Professor of Medicine
University of California
CSS is a member of the editorial board of American Journal of Respiratory and Critical Care Medicine. CSS is an author of a reference cited in this topic.
Dr Catherine S. Sassoon and Dr Brian Dang would like to gratefully acknowledge Dr Asad Qasim, Dr Wilson Yan, Dr Jeremy Murdock, and Dr Sterling L. Malish, previous contributors to this topic. AQ, WY, JM, and SLM declare that they have no competing interests.
Feras Hawari, MD
Chief of Pulmonary and Critical Care
King Hussein Cancer Center
FH declares that he has no competing interests.
John G. Laffey, MD
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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