Evaluation of respiratory alkalosis

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.[1]Arbus GS, Herbert LA, Levesque PR, et al. Characterization and clinical application of the "significance band" for acute respiratory alkalosis. N Engl J Med. 1969 Jan 16;280(3):117-23. http://www.ncbi.nlm.nih.gov/pubmed/5782512?tool=bestpractice.com 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.[2]Foster GT, Varizi ND, Sassoon CS. Respiratory alkalosis. Respir Care. 2001 Apr;46(4):384-91. http://www.ncbi.nlm.nih.gov/pubmed/11262557?tool=bestpractice.com

Respiratory alkalosis can be classified into three categories:

1. as a component of disease processes

2. accidentally induced

3. deliberately induced (therapeutic).[3]Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med. 2002 Jul 4;347(1):43-53. http://www.ncbi.nlm.nih.gov/pubmed/12097540?tool=bestpractice.com

Accidental respiratory alkalosis develops as a consequence of inappropriate settings of mechanical ventilation, or associated with extracorporeal membrane oxygenation.[3]Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med. 2002 Jul 4;347(1):43-53. http://www.ncbi.nlm.nih.gov/pubmed/12097540?tool=bestpractice.com Therapeutic respiratory alkalosis or hypocapnia has been applied to temporarily treat intracranial hypertension or neonatal pulmonary artery hypertension.[4]Allen CH, Ward JD. An evidence-based approach to management of increased intracranial pressure. Crit Care Clin. 1998 Jul;14(3):485-95. http://www.ncbi.nlm.nih.gov/pubmed/9700443?tool=bestpractice.com [5]Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000 Jan;105(1 Pt 1):14-20. http://www.ncbi.nlm.nih.gov/pubmed/10617698?tool=bestpractice.com

Epidemiology

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%.[6]Hodgkin JE, Soeprono FF, Chan DM. Incidence of metabolic alkalemia in hospitalized patients. Crit Care Med. 1980 Dec;8(12):725-8. http://www.ncbi.nlm.nih.gov/pubmed/6778655?tool=bestpractice.com [7]Mazzara JT, Ayres SM, Grace WJ. Extreme hypocapnia in the critically ill patient. Am J Med. 1974 Apr;56(4):450-6. http://www.ncbi.nlm.nih.gov/pubmed/4818411?tool=bestpractice.com 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%.[8]Palange P, Carlone S, Galassetti P, et al. Incidence of acid-base and electrolyte disturbances in a general hospital: a study of 110 consecutive admissions. Recenti Prog Med. 1990 Dec;81(12):788-91. http://www.ncbi.nlm.nih.gov/pubmed/2075281?tool=bestpractice.com

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.[9]Barillo DJ, Dickerson EE, Cioffi WG, et al. Pressure-controlled ventilation for the long-range aeromedical transport of patients with burns. J Burn Care Rehabil. 1997 May-Jun;18(3):200-5. http://www.ncbi.nlm.nih.gov/pubmed/9169941?tool=bestpractice.com [10]Hooper RG, Browning M. Acid-base changes and ventilator mode during maintenance ventilation. Crit Care Med. 1985 Jan;13(1):44-5. http://www.ncbi.nlm.nih.gov/pubmed/3871184?tool=bestpractice.com 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 intensive care unit arrival.[11]Millar SM, Alston RP, Andrews PJ, et al. Cerebral hypoperfusion in immediate postoperative period following coronary artery bypass grafting, heart valve, and abdominal aortic surgery. Br J Anesth. 2001 Aug;87(2):229-36. http://bja.oxfordjournals.org/content/87/2/229.full http://www.ncbi.nlm.nih.gov/pubmed/11493494?tool=bestpractice.com The study did not report the actual frequency of hypocapnia.[11]Millar SM, Alston RP, Andrews PJ, et al. Cerebral hypoperfusion in immediate postoperative period following coronary artery bypass grafting, heart valve, and abdominal aortic surgery. Br J Anesth. 2001 Aug;87(2):229-36. http://bja.oxfordjournals.org/content/87/2/229.full http://www.ncbi.nlm.nih.gov/pubmed/11493494?tool=bestpractice.com

Therapeutic respiratory alkalosis or hypocapnia has traditionally been applied to temporarily treat intracranial hypertension.[4]Allen CH, Ward JD. An evidence-based approach to management of increased intracranial pressure. Crit Care Clin. 1998 Jul;14(3):485-95. http://www.ncbi.nlm.nih.gov/pubmed/9700443?tool=bestpractice.com However, the benefit of therapeutic hypocapnia remains unproven and it should be limited to life-threatening elevated intracranial pressure.[12]Curley G, Kavanagh BP, Laffey JG. Hypocapnia and the injured brain: more harm than benefit. Crit Care Med. 2010 May;38(5):1348-59. http://www.ncbi.nlm.nih.gov/pubmed/20228681?tool=bestpractice.com [13]Badjatia N, Carney N, Crocco TJ, et al; Brain Trauma Foundation; BTF Center for Guidelines Management. Guidelines for prehospital management of traumatic brain injury 2nd edition. Prehosp Emerg Care. 2008;12(suppl 1):S1-52. http://www.ncbi.nlm.nih.gov/pubmed/18203044?tool=bestpractice.com 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.[3]Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med. 2002 Jul 4;347(1):43-53. http://www.ncbi.nlm.nih.gov/pubmed/12097540?tool=bestpractice.com [5]Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000 Jan;105(1 Pt 1):14-20. http://www.ncbi.nlm.nih.gov/pubmed/10617698?tool=bestpractice.com [14]Rusnak M, Janciak I, Majdan M, et al. Severe traumatic brain injury in Austria VI: effects of guideline-based management. Wien Klin Wochenschr. 2007 Feb;119(1-2):64-71. http://www.ncbi.nlm.nih.gov/pubmed/17318752?tool=bestpractice.com With the availability of nitric oxide and other vasodilators, therapeutic hypocapnia application in neonatal pulmonary hypertension will be expected to decline.[15]Latini G, Del Vecchio A, De Felice C, et al. Persistent pulmonary hypertension of the newborn: therapeutical approach. Mini Rev Med Chem. 2008 Dec;8(14):1507-13. http://www.ncbi.nlm.nih.gov/pubmed/19075808?tool=bestpractice.com [16]Kelly LE, Ohlsson A, Shah PS. Sildenafil for pulmonary hypertension in neonates. Cochrane Database Syst Rev. 2017 Aug 4;(8):CD005494. http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005494.pub4/full http://www.ncbi.nlm.nih.gov/pubmed/28777888?tool=bestpractice.com

Physiology

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:

• (H+)=24(PaCO₂/HCO₃-)

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.[17]Jacobson HR. Effects of CO2 and acetazolamide on bicarbonate and fluid transport in rabbit proximal tubules. Am J Physiol. 1981 Jan;240(1):F54-62. http://www.ncbi.nlm.nih.gov/pubmed/6779638?tool=bestpractice.com 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 toward 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).[18]Seifter JL. Integration of acid-base and electrolyte disorders. N Engl J Med. 2014 Nov 6;371(19):1821-31. http://www.ncbi.nlm.nih.gov/pubmed/25372090?tool=bestpractice.com

Respiratory alkalosis can manifest as acute or chronic. Acute respiratory alkalosis occurs from the onset of hypocapnia for up to 6 hours.[1]Arbus GS, Herbert LA, Levesque PR, et al. Characterization and clinical application of the "significance band" for acute respiratory alkalosis. N Engl J Med. 1969 Jan 16;280(3):117-23. http://www.ncbi.nlm.nih.gov/pubmed/5782512?tool=bestpractice.com Chronic respiratory alkalosis with renal compensatory mechanisms begins 6 hours after the onset of hypocapnia and becomes complete within 2 to 5 days.[1]Arbus GS, Herbert LA, Levesque PR, et al. Characterization and clinical application of the "significance band" for acute respiratory alkalosis. N Engl J Med. 1969 Jan 16;280(3):117-23. http://www.ncbi.nlm.nih.gov/pubmed/5782512?tool=bestpractice.com [19]Santra G, Paul R, Das S, et al. Hyperventilation of pregnancy presenting with flaccid quadriparesis due to hypokalaemia secondary to respiratory alkalosis. J Assoc Physicians India. 2014 Jun;62(6):536-8. https://www.japi.org/r28464a4/hyperventilation-of-pregnancy-presenting-with-flaccid-quadriparesis-due-to-hypokalaemia-secondary-to-respiratory-alkalosis http://www.ncbi.nlm.nih.gov/pubmed/25856925?tool=bestpractice.com [20]Berend K, de Vries AP, Gans RO. Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014 Oct 9;371(15):1434-45. http://www.ncbi.nlm.nih.gov/pubmed/25295502?tool=bestpractice.com 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:[21]Gennari FJ, Goldstein MB, Schwartz WB. The nature of the renal adaptation to chronic hypocapnia. J Clin Invest. 1972 Jul;51(7):1722-30. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC292319 http://www.ncbi.nlm.nih.gov/pubmed/5032522?tool=bestpractice.com [22]Krapf R, Beeler I, Hertner D, et al. Chronic respiratory alkalosis: the effect of sustained hyperventilation on renal regulation of acid-base equilibrium. N Engl J Med. 1991 May 16;324(20):1394-401. http://www.ncbi.nlm.nih.gov/pubmed/1902283?tool=bestpractice.com

• 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.[20]Berend K, de Vries AP, Gans RO. Physiological approach to assessment of acid-base disturbances. N Engl J Med. 2014 Oct 9;371(15):1434-45. http://www.ncbi.nlm.nih.gov/pubmed/25295502?tool=bestpractice.com

Respiratory alkalosis leads to increased serum lactate by mildly increasing lactate production and by decreasing lactate clearance.[23]Eldridge F, Salzer J. Effect of respiratory alkalosis on blood lactate and pyruvate in humans. J Appl Physiol. 1967 Mar;22(3):461-8. http://www.ncbi.nlm.nih.gov/pubmed/6020228?tool=bestpractice.com [24]Druml W, Grimm G, Laggner AN, et al. Lactic acid kinetics in respiratory acidosis. Crit Care Med. 1991 Sep;19(9):1120-4. http://www.ncbi.nlm.nih.gov/pubmed/1884611?tool=bestpractice.com 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.[25]Sakamoto A, Naito H, Chow CM. Hyperventilation as a strategy for improved repeated sprint performance. J Strength Cond Res. 2014 Apr;28(4):1119-26. http://www.ncbi.nlm.nih.gov/pubmed/23838981?tool=bestpractice.com

Respiratory alkalosis also alters electrolyte homeostasis, separate from its renal compensatory mechanisms.

Potassium

• 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.[26]Krapf R, Caduff P, Wagdi P, et al. Plasma potassium response to acute respiratory alkalosis. Kidney Int. 1995 Jan;47(1):217-24. http://www.ncbi.nlm.nih.gov/pubmed/7731149?tool=bestpractice.com [27]Sanchez MG, Finlayson DC. Dynamics of serum potassium change during acute respiratory alkalosis. Can Anaesth Soc J. 1978 Nov;25(6):495-8. http://www.ncbi.nlm.nih.gov/pubmed/31968?tool=bestpractice.com 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.[19]Santra G, Paul R, Das S, et al. Hyperventilation of pregnancy presenting with flaccid quadriparesis due to hypokalaemia secondary to respiratory alkalosis. J Assoc Physicians India. 2014 Jun;62(6):536-8. https://www.japi.org/r28464a4/hyperventilation-of-pregnancy-presenting-with-flaccid-quadriparesis-due-to-hypokalaemia-secondary-to-respiratory-alkalosis http://www.ncbi.nlm.nih.gov/pubmed/25856925?tool=bestpractice.com

Phosphate

• In the acute phase, hypophosphatemia may be related to increased cellular uptake.[28]Brautbar N, Leibovici H, Massry SG. On the mechanism of hypophosphatemia during acute hyperventilation: evidence for increased muscle glycolysis. Miner Electrolyte Metab. 1983 Jan-Feb;9(1):45-50. http://www.ncbi.nlm.nih.gov/pubmed/6843518?tool=bestpractice.com [29]Hoppe A, Metler M, Berndt TJ. Effect of respiratory alkalosis on renal phosphate excretion. Am J Physiol. 1982 Nov;243(5):F471-5. http://www.ncbi.nlm.nih.gov/pubmed/6291407?tool=bestpractice.com Conversely, the chronic phase is associated with hyperphosphatemia together with hypocalcemia due to parathyroid hormone resistance.[30]Krapf R, Jaeger P, Hulter HN. Chronic respiratory alkalosis induces renal PTH-resistance, hyperphosphatemia, and hypocalcemia in humans. Kidney Int. 1992 Sep;42(3):727-34. http://www.ncbi.nlm.nih.gov/pubmed/1405350?tool=bestpractice.com

Bronchoconstriction is a prominent manifestation of physiologic changes in the lung.[31]Jamison JP, Glover PJ, Wallace WF. Comparison of the effects of inhaled ipratropium bromide and salbutamol on the bronchoconstrictor response to hypocapnic hyperventilation in normal subjects. Thorax. 1987 Oct;42(10):809-14. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC460957 http://www.ncbi.nlm.nih.gov/pubmed/2962333?tool=bestpractice.com [32]Rodriguez-Roisin R. Gas exchange abnormalities in asthma. Lung. 1990;168(Suppl):599-605. http://www.ncbi.nlm.nih.gov/pubmed/2117169?tool=bestpractice.com [33]Bayindir O, Akpinar B, Ozbek U, et al. The hazardous effects of alveolar hypocapnia on lung mechanics during weaning from cardiopulmonary bypass. Perfusion. 2000 Jan;15(1):27-31. http://www.ncbi.nlm.nih.gov/pubmed/10676865?tool=bestpractice.com 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.[5]Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics. 2000 Jan;105(1 Pt 1):14-20. http://www.ncbi.nlm.nih.gov/pubmed/10617698?tool=bestpractice.com [34]Fike CD, Hansen TN. The effect of alkalosis on hypoxia-induced vasoconstriction in lungs of newborn rabbits. Pediatr Res. 1989 Apr;25(4):383-8. http://www.ncbi.nlm.nih.gov/pubmed/2726313?tool=bestpractice.com Tachycardia is also consistent with physiologic changes inherent in respiratory alkalosis and is related to increased sympathetic activity and to hypokalemia.[26]Krapf R, Caduff P, Wagdi P, et al. Plasma potassium response to acute respiratory alkalosis. Kidney Int. 1995 Jan;47(1):217-24. http://www.ncbi.nlm.nih.gov/pubmed/7731149?tool=bestpractice.com [35]Samuelsson RG, Nagy G. Effects of respiratory alkalosis and acidosis on myocardial excitation. Acta Physiol Scand. 1976 Jun;97(2):158-65. http://www.ncbi.nlm.nih.gov/pubmed/949001?tool=bestpractice.com Chest pain may occur through coronary vasospasm or decreased myocardial oxygen delivery owing to increased O₂ affinity to hemoglobin.[36]Neill WA, Hattenhauer M. Impairment of myocardial O2 supply due to hyperventilation. Circulation. 1975 Nov;52(5):854-8. http://circ.ahajournals.org/content/52/5/854.full.pdf+html http://www.ncbi.nlm.nih.gov/pubmed/1175266?tool=bestpractice.com 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.[37]Morel J, Gergelé L, Dominé A, et al. The venous-arterial difference in CO2 should be interpreted with caution in case of respiratory alkalosis in healthy volunteers. J Clin Monit Comput. 2017 Aug;31(4):701-7. http://www.ncbi.nlm.nih.gov/pubmed/27287759?tool=bestpractice.com Ventricular and atrial arrhythmias have also been reported in acute and chronic respiratory alkalosis.[38]Wildenthal K, Fuller DS, Shapiro W. Paroxysmal atrial arrhythmias induced by hyperventilation. Am J Cardiol. 1968 Mar;21(3):436-41. http://www.ncbi.nlm.nih.gov/pubmed/5637848?tool=bestpractice.com [39]Hisano K, Matsuguchi T, Ootsubo H, et al. Hyperventilation-induced variant angina with ventricular tachycardia. Am Heart J. 1984 Aug;108(2):423-5. http://www.ncbi.nlm.nih.gov/pubmed/6464982?tool=bestpractice.com [40]Brown EB Jr, Miller F. Ventricular fibrillation following a rapid fall in alveolar carbon dioxide concentration. Am J Physiol.1952 Apr;169(1):56-60. http://www.ncbi.nlm.nih.gov/pubmed/14923862?tool=bestpractice.com

Gastrointestinal and hepatic symptoms are seen in acute (but not in chronic) respiratory alkalosis. Acute respiratory alkalosis produces nausea, vomiting, and increased gastrointestinal motility.[41]Bharucha AE, Camilleri M, Ford MJ, et al. Hyperventilation alters colonic motor and sensory function: effects and mechanisms in humans. Gastroenterology. 1996 Aug;111(2):368-77. http://www.ncbi.nlm.nih.gov/pubmed/8690201?tool=bestpractice.com 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.[42]Ford MJ, Camelleri MJ, Hanson RB, et al. Hyperventilation, central autonomic control, and colonic tone in humans. Gut. 1995 Oct;37(4):499-504. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1382900 http://www.ncbi.nlm.nih.gov/pubmed/7489935?tool=bestpractice.com Peripheral and central nervous system (CNS) effects of hypocapnia occur at a threshold of PaCO₂ <20 mmHg.[43]Rafferty GF, Saisch GN, Gardner WN. Relation of hypocapnic symptoms to rate of fall of end-tidal PCO2 in normal subjects. Respir Med. 1992 Jul;86(4):335-40. http://www.ncbi.nlm.nih.gov/pubmed/1448588?tool=bestpractice.com Symptoms include vertigo, dizziness, anxiety, euphoria, clumsiness, forgetfulness, hallucinations, and seizure.[44]Perkin GD, Joseph R. Neurological manifestations of the hyperventilation syndrome. J R Soc Med. 1986 Aug;79(8):448-50. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1290412 http://www.ncbi.nlm.nih.gov/pubmed/3761286?tool=bestpractice.com 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.[45]Gardner WN. The pathophysiology of hyperventilation disorders. Chest. 1996 Feb;109(2):516-34. http://www.ncbi.nlm.nih.gov/pubmed/8620731?tool=bestpractice.com Peripheral manifestations include tetany and paresthesias. These neurologic manifestations are mediated by hyperventilation-induced increased neural excitability caused by hypocalcemia and, possibly, hypophosphatemia.[45]Gardner WN. The pathophysiology of hyperventilation disorders. Chest. 1996 Feb;109(2):516-34. http://www.ncbi.nlm.nih.gov/pubmed/8620731?tool=bestpractice.com [46]Macefield G, Burke D. Paraesthesiae and tetany induced by voluntary hyperventilation: increased excitability of human cutaneous and motor axons. Brain. 1991 Feb;114 ( Pt 1B):527-40. http://www.ncbi.nlm.nih.gov/pubmed/2004255?tool=bestpractice.com [47]Edmondson JW, Brashear RE, Li TK. Tetany: quantitative interrelationships between calcium and alkalosis. Am J Physiol. 1975 Apr;228(4):1082-6. http://www.ncbi.nlm.nih.gov/pubmed/236662?tool=bestpractice.com

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.[48]Kaehny WD. Respiratory acid-base disorders. Med Clin North Am. 1983 Jul;67(4):915-28. http://www.ncbi.nlm.nih.gov/pubmed/6410136?tool=bestpractice.com 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.