Nephrol Dial Transplant (2009) 24: 825–828
doi: 10.1093/ndt/gfn585
Advance Access publication 21 October 2008
Original Article
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
3
Department of Nephrology, Osaka University Graduate School of Medicine, Suita, 2 Osaka Kousei-Nenkin Hospital, Osaka and
Department of Advanced Technology for Transplantation, Osaka University Graduate School of Medicine, Suita, Japan
Abstract
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
Acid–base derangements are encountered frequently
in clinical situations, and many have life-threatening
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: +81-6-68793746; Fax: +81-6-6879-3749; E-mail: [email protected]
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 plasma bicarbonate slope ([HCO3 − ]/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
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
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Fig. 1. Relationship between plasma [HCO3 − ] and PaCO2 . The
[HCO3 − ]/PaCO2 slope was about twice as steep as previously reported.
Y. Ueda et al.
Fig. 2. Relationship between serum lactate and PaCO2 . Serum lactate was
significantly correlated with PaCO2 (P < 0.001).
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
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 [HCO3 − ]/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 [HCO3 − ]/PaCO2 slope was 0.26 mEq/L/mmHg
(Figure 3).
Discussion
The present study demonstrated that the compensatory
responses to acute respiratory alkalosis were exagger-
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 [HCO3 − ]/PaCO2
slope was 0.26 mEq/L/mmHg.
ated 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 [HCO3 − ]/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 [HCO3 − ]/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
Exaggerated compensatory response to acute respiratory alkalosis
Fig. 4. Relationship between [HCO3 − ] and lactate. Increased plasma
lactate levels were responsible for 39% of the decrease in plasma
[HCO3 − ].
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 nonbicarbonate 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 − ] (lactate =
−0.39 × [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].
The present study demonstrated that the adaptive response to acute respiratory alkalosis is exaggerated in
panic disorder patients. The [HCO3 − ]/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 exag-
827
gerated 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 − ] ([HCO3 − ]/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
[HCO3 − ]/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 [HCO3 − ]/PaCO2 slope of 0.41 mEq/L/mmHg
and a lactate-corrected [HCO3 − ]/PaCO2 slope of
0.26 mEq/L/mmHg.
Conflict of interest statement. None declared.
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Received for publication: 18.7.08
Accepted in revised form: 24.9.08