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NDT Advance Access published online on October 21, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn585
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Exaggerated compensatory response to acute respiratory alkalosis in panic disorder is induced by increased lactic acid production

Yoshiyasu Ueda1, Masayo Aizawa2, Atsushi Takahashi2, Masamitsu Fujii2 and Yoshitaka Isaka1,3

1 Department of Nephrology, Osaka University Graduate School of Medicine, Suita 2 Osaka Kousei-Nenkin Hospital, Osaka 3 Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Japan

Correspondence and offprint requests to: Yoshitaka Isaka, Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. Tel: +81-6-6879-3746; Fax: +81-6-6879-3749; E-mail: isaka{at}att.med.osaka-u.ac.jp



   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. In acute respiratory alkalosis, the severity of alkalaemia is ameliorated by a decrease in plasma [HCO3–] of 0.2 mEq/L for each 1 mmHg decrease in PaCO2. Although hyperventilation in panic disorder patients is frequently encountered in outpatients, the drop in plasma [HCO3–] sometimes surpasses the expectation calculated from the above formula. The quantitative relationship between reduced PaCO2 and plasma [HCO3–] in acute respiratory alkalosis has not been studied in panic disorder patients. Our objective was to provide reference data for the compensatory metabolic changes in acute respiratory alkalosis in panic disorder patients.

Methods. In 34 panic disorder patients with hyperventilation attacks, we measured arterial pH, PaCO2, plasma [HCO3–] and lactate on arrival at the emergency room.

Results. For each decrease of 1 mmHg in PaCO2, plasma [HCO3–] decreased by 0.41 mEq/L. During hypocapnia, panic disorder patients exhibited larger increases in serum lactate levels (mean ± SD; 2.59 ± 1.50 mmol/L, range; 0.78–7.78 mmol/L) than previously reported in non-panic disorder subjects. Plasma lactate accumulation was correlated with PaCO2 (P < 0.001).

Conclusions. These results suggest that the compensatory metabolic response to acute respiratory alkalosis is exaggerated by increased lactic acid production in panic disorder patients. Here, we call attention to the diagnosis of acid–base derangements by means of plasma [HCO3–] and lactate concentration in panic disorder patients.

Keywords: lactic acid; panic disorder; respiratory alkalosis



   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Acid–base derangements are encountered frequently in clinical situations, and many have life-threatening implications. The co-existence of respiratory alkalosis and high anion gap acidosis is commonly observed in critically serious patients, such as those with sepsis, salicylate intoxication and coexistence of renal failure and hepatic failure [1]. Treatment depends on correctly identifying the acid–base disorder and repairing the underlying causal process. The severity of alkalaemia produced by a reduction in arterial carbon dioxide tension (PaCO2) in normal humans is ameliorated by buffer and renal responses that diminish plasma bicarbonate concentrations ([HCO3–]) [2]. In contrast, these adjustments are complicated when hypocapnia develops into metabolic acidosis. To determine whether adaptation is appropriate for a given disorder, it is essential to know the expected renal response. The {Delta}plasma bicarbonate slope ({Delta}[HCO3–]/{Delta}PaCO2) is generally considered to be 0.2 mEq/L/mmHg in acute respiratory alkalosis [3–5].

Respiratory alkalosis is the most common acid–base derangement among seriously ill patients, and can be observed in hypoxemic conditions, sepsis, metabolic disorders, drug intoxication, inappropriate mechanical ventilation, some psychiatric conditions and central nervous system disorders [6]. Although hyperventilation in panic disorder patients is frequently encountered in outpatients and induces marked alkalaemia, the quantitative relationship between reduced PaCO2 and plasma [HCO3–] in acute respiratory alkalosis has not been studied in panic disorder patients. Therefore, we undertook this study to provide reference data for the compensatory metabolic changes in acute respiratory alkalosis in panic disorder patients.



   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Acid–base disturbances during acute respiratory alkalosis were studied in 34 panic disorder patients (6 males and 28 females) ranging in age from 15 to 63 years (mean; 35.4 years). All subjects were free of metabolic, endocrine, cardiovascular, respiratory and renal diseases, as determined by history, physical examination and laboratory data. All blood samples were drawn from the radial or femoral artery into heparinized syringes on arrival at the emergency room. Arterial lactate, Na, K, Cl, pH, PaCO2, PaO2, anion gap and plasma [HCO3–] were measured using the ABL System 625 (Radiometer Medical, Copenhagen, Denmark). Corrected plasma [HCO3–] was calculated by the following equation; corrected [HCO3–] (mEq/L) = [HCO3–] (mEq/L) + the increase in plasma lactate (mmol/L).



   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
We examined the arterial acid–base composition and lactate levels in panic disorder patients on arrival at the emergency room. As a result of hyperventilation, arterial PaCO2 decreased significantly to a range of 10.6–37.1 mmHg (mean; 23.5 ± 6.7). In association with degree of hypocapnia, arterial pH increased to a range of 7.42–7.70 (mean; 7.57 ± 0.07), and plasma [HCO3–] decreased to a range of 12.7–26.2 mEq/L (mean; 20.9 ± 3.2). Plasma sodium concentration remained virtually within the normal range (135– 145 mEq/L). Plasma potassium concentration decreased significantly (2.6–3.8 mEq/L).

The {Delta}[HCO3–]/{Delta}PaCO2 slope was 0.41 mEq/L/mmHg (Figure 1), which was significantly steeper and virtually twice as large as the previously reported formula [3–5]. The anion gap concentration increased to the range of 11.6–22.9 mEq/L (mean; 17.1 ± 2.7), and serum lactate levels also increased to the range of 0.78–7.78 mmol/L (mean; 2.59 ± 1.50). Serum lactate was significantly correlated with PaCO2 (P < 0.001, Figure 2). Of particular interest is that patients with severe hypocapnia (PaCO2 < 16 mmHg) showed significantly higher plasma lactate concentrations (mean; 4.6 ± 1.6 mmol/L) than those with mild hypocapnia (PaCO2 > 16 mmHg) (mean; 2.0 ± 0.8 mmol/L, P < 0.001). Furthermore, the corrected {Delta}[HCO3–]/{Delta}PaCO2 slope was 0.26 mEq/L/mmHg (Figure 3).


Figure 1
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  		Fig. 1 Relationship between plasma [HCO3–] and PaCO2. The {Delta}[HCO3–]/{Delta}PaCO2 slope was about twice as steep as previously reported.

 

Figure 2
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  		Fig. 2 Relationship between serum lactate and PaCO2. Serum lactate was significantly correlated with PaCO2 (P < 0.001).

 

Figure 3
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  		Fig. 3 Relationship between corrected [HCO3–] and PaCO2. Corrected plasma [HCO3–] was calculated as plasma [HCO3–] (mEq/L) plus the increase in plasma lactate (mmol/L). The corrected {Delta}[HCO3–]/{Delta}PaCO2 slope was 0.26 mEq/L/mmHg.

 


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The present study demonstrated that the compensatory responses to acute respiratory alkalosis were exaggerated in panic disorder patients. In previous studies, the secondary response to acute hypocapnia has been found to be 0.20 mEq/L/mmHg, both in normal humans and in dogs [3–5,7]. When compared with these background data, the {Delta}[HCO3–]/{Delta}PaCO2 slope (0.41 mEq/L/mmHg) was significantly steeper. The unexpected drop in plasma [HCO3–] may be explained by increased serum lactate. Serum lactate levels were significantly correlated with PaCO2, and lactate-corrected {Delta}[HCO3–]/{Delta}PaCO2 slope 0.26 mEq/L/mmHg.

Respiratory alkalosis is caused by a process that leads to a rise in pH due to a decrease in PaCO2, primarily from increased ventilation. Buffering constitutes the first response in respiratory alkalosis [8]. In order to return the pH towards normal, within 10 min after the onset of respiratory alkalosis, H+ ions are released from body buffers and then combine with HCO3–, resulting in an appropriate decrease in plasma [HCO3–]. These H+ ions are primarily derived from the protein, phosphate and haemoglobin buffers in the cells. The second adaptive response in respiratory alkalosis is induced by a renal mechanism, which consists of decreasing the re-absorption of filtered HCO3– and reducing the generation of HCO3–. The process of renal adaptation is probably completed within 24–48 h [4,5]. Thus, the adaptive response observed in chronic respiratory alkalosis is not sufficient in acute respiratory alkalosis.

The mechanisms accounting for the observed reduction in plasma [HCO3–] during acute hypocapnia must have been largely of extrarenal origin, involving increased organic acid production and alkaline titration of non-bicarbonate buffers. We observed significant increases in serum lactate and anion gap in panic disorder patients. The increase in plasma lactate levels was responsible for almost 40% of the decrease in plasma [HCO3–] ({Delta}lactate = –0.39 x {Delta}[HCO3–], Figure 4). While simple acute respiratory alkalosis results in an increase in plasma lactate levels of <1 mEq /L [3,5], the higher plasma lactate observed in panic disorder patients might have resulted from an alkalaemia-induced increase in cellular lactic acid production. Respiratory alkalosis produces a transient left shift in the haemoglobin–oxygen dissociation curve in red blood cells, decreasing delivery of oxygen to the tissues and favouring anaerobic glycolysis. The lactate production increased approximately 15-fold as the pH of the medium was increased from 5.7 to 7.8 [9]. In this phenomenon, the phosphofructokinase (PFK) reaction is critical in the enhancement of glycolysis by a rise in pH [9]. Alkalosis, however, induces glycolysis by directly activating enzymatic proteins, including PFK, in the glycolytic pathway in all tissues. In addition, alkalosis increases the tissue concentrations of all the measurable citric acid cycle intermediates, such as pyruvic acid and lactic acid [9]. Thus, the increase in lactic acid production appears to arise from tissue hypoxia secondary to vasoconstriction and increased haemoglobin affinity for oxygen. However, ten climbers, who reached the summit without supplementary oxygen, showed the same blood lactate level for a given work rate at a high altitude as at sea level [10].


Figure 4
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  		Fig. 4 Relationship between {Delta}[HCO3–] and {Delta}lactate. Increased plasma lactate levels were responsible for 39% of the decrease in plasma [HCO3–].

 
The present study demonstrated that the adaptive response to acute respiratory alkalosis is exaggerated in panic disorder patients. The {Delta}[HCO3–]/{Delta}PaCO2 slope was 0.41 mEq/L/mmHg in acute respiratory alkalosis in panic disorder patients, which is about twice as large as previously reported for hypocapnia in non-panic disorder subjects including mountaineers [3–5,7]. The mechanisms for exaggerated compensatory metabolic response to acute respiratory alkalosis and increased lactic acid production in panic disorder patients remain unknown. It has been reported that panic disorder patients display a significantly greater increase in plasma lactate in response to hyperventilation than non-panic disorder subjects [11–13]. Furthermore, proton magnetic resonance spectroscopy shows greater rises in brain lactate level in panic disorder patients in response to hyperventilation [14]. This exaggerated lactic acid response to respiratory alkalosis may play an important role in the significant decrease in plasma [HCO3–].

It has been reported that some panic disorder patients have a chronic, subtle respiratory alkalosis and acutely increase respiration when stressed [15]. Therefore, acute or chronic respiratory alkalosis may be one of the mechanisms for the exaggerated lactic acid production. Madias et al. [2] demonstrated that dogs with chronic metabolic alkalosis exhibit a large fall in plasma [HCO3–] ({Delta}[HCO3–]/{Delta}PaCO2 slope; 0.43) during acute hypocapnia, and that the plasma lactate concentration increased from 2.4 to 4.4 mEq/L. These results were similar to our observations in panic disorder patients, suggesting that some panic disorder patients are in a steady state of chronic alkalosis at baseline.

We demonstrated that patients with severe hypocapnia show significantly higher plasma lactate concentrations than those with mild hypocapnia, and that the corrected {Delta}[HCO3–]/{Delta}PaCO2 slope was 0.26 mEq/L/mmHg, which fits the previously proposed formula in acute respiratory alkalosis. As the coexistence of respiratory alkalosis and high anion gap acidosis is commonly observed in critically serious patients, the exaggerated compensatory metabolic response to acute respiratory alkalosis in panic disorder patients may mislead the diagnosis and treatment in clinical setting. Therefore, we would like to propose a new formula to exclude the life-threatening diseases. Further studies are necessary to evaluate whether the lactate increase is a directly compensatory action against an exaggerated brain pH response in panic disorder patients or a byproduct of another process affected by acid–base perturbation. In conclusion, the increase in plasma lactate levels accounted for the striking decrease in plasma [HCO3–] observed in panic disorder patients. Examination of the plasma lactate levels in panic disorder patients appears to be useful in identifying acid–base derangements. In addition, we would like to propose a new formula for acute respiratory alkalosis in panic disorder patients: a {Delta}[HCO3–]/{Delta}PaCO2 slope of 0.41 mEq/L/mmHg and a lactate-corrected {Delta}[HCO3–]/{Delta}PaCO2 slope of 0.26 mEq/L/mmHg.



   Notes
 
Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Cohen JJ, Kassirer JP. Acid-base metabolism. In: Clinical Disorders of Fluid and Electrolyte Metabolism—Maxwell MH, Kleeman CR, eds. (1980) New York: McGraw-Hill. 181–232.
  2. Madias NE, Cohen JJ, Adrogue HJ. Influence of acute and chronic respiratory alkalosis on preexisting chronic metabolic alkalosis. Am J Physiol (1990) 258:F479–F485.[Web of Science][Medline]
  3. 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) 280:117–23.[Web of Science][Medline]
  4. DuBose TDJ. Disorders of acid-base balance. In: The Kidney—Brenner BM, ed. (2008) Philadelphia: Saunders. 505–546.
  5. Gennari FJ, Kassirer JP. Respiratory alkalosis. In: Acid/Base—Cohen JJ, Kassirer JP, eds. (1982) Boston, MA: Little Brown. 349–376.
  6. Mazzara JT, Ayres SM, Grace WJ. Extreme hypocapnia in the critically ill patient. Am J Med (1974) 56:450–456.[CrossRef][Web of Science][Medline]
  7. Madias NE, Schwartz WB, Cohen JJ. The maladaptive renal response to secondary hypocapnia during chronic HCl acidosis in the dog. J Clin Invest (1977) 60:1393–1401.[Web of Science][Medline]
  8. Giebisch G, Berger L, Pitts RF. The extrarenal response to acute acid-base disturbances of respiratory origin. J Clin Invest (1955) 34:231–245.[Web of Science][Medline]
  9. Relman AS. Metabolic consequences of acid-base disorders. Kidney Int (1972) 1:347–359.[Web of Science][Medline]
  10. West JB. Lactate during exercise at extreme altitude. Fed Proc (1986) 45:2953–2957.[Web of Science][Medline]
  11. Maddock RJ. The lactic acid response to alkalosis in panic disorder: an integrative review. J Neuropsychiatry Clin Neurosci (2001) 13:22–34.[Abstract/Free Full Text]
  12. Maddock RJ, Carter CS, Gietzen DW. Elevated serum lactate associated with panic attacks induced by hyperventilation. Psychiatry Res (1991) 38:301–11.[CrossRef][Web of Science][Medline]
  13. Papp LA, Klein DF, Gorman JM. Carbon dioxide hypersensitivity, hyperventilation, and panic disorders. Am J Psychiatry (1993) 150:1149–1457.[Abstract/Free Full Text]
  14. Friedman SD, Mathis CM, Hayes C, et al. Brain pH response to hyperventilation in panic disorder: preliminary evidence for altered acid-base regulation. Am J Psychiatry (2006) 163:710–715.[Abstract/Free Full Text]
  15. Papp LA, Martinez JM, Klein DF, et al. Arterial blood gas changes in panic disorder and lactate-induced panic. Psychiatry Res (1989) 28:171–180.[CrossRef][Web of Science][Medline]
Received for publication: 18. 7.08
Accepted in revised form: 24. 9.08


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