ArticlesDouble-blind placebo-controlled study of the hyperventilation provocation test and the validity of the hyperventilation syndrome
Introduction
Hyperventilation is respiration that exceeds metabolic demands, resulting in a decrease in arterial partial pressure of carbon dioxide (pCO2) and an increase in pH of the body fluids (respiratory alkalosis). If hyperventilation is sustained for some time, secondary physiological changes take place and can lead to symptoms such as dizziness, paraesthesias, stiff muscles, cold hands or feet, and trembling.
In 1937, Kerr and colleagues1 introduced the term hyperventilation syndrome (HVS), because of the idea that hyperventilation may be the underlying mechanism in certain symptom patterns (in the absence of organic disease). Important evidence to suggest that HVS is a discrete clinical entity came from the demonstration that, in many patients, the usual symptoms could be reproduced by a brief period of voluntary hyperventilation.1, 2, 3 There has lately been an upsurge in the interest in HVS. Several studies have indicated high frequencies of HVS, 35–83% among patients with anxiety disorder4, 5, 6, 7 and 5–11% among various other medical populations.8, 9, 10
HVS is generally diagnosed on the basis of hyperventilation provocation test (HVPT), which requires voluntary hyperventilation for several minutes. The test is considered positive if the symptoms induced are recognised by the patient as similar to those occurring in daily life.3 Although this test is the most widely used criterion for diagnosis of HVS, the importance of additional psychological criteria has been emphasized, especially lowered arterial or end-tidal resting pCO2 values,11 and a delayed recovery of pCO2 after voluntary hyperventilation.12
Some studies have questioned the validity of symptom recognition during the HVPT. The main criticism is that the HVPT does not distinguish between symptoms produced by hypocapnia and those produced by other factors, such as the mechanical discomfort of rapid deep breathing, or the stressfulness of the procedure. Exposure of patients to other types of challenges can reproduce similar symptom patterns.13, 14, 15, 16 We and others15, 16 have shown that most patients positive on the HVPT also had symptoms during a stressful mental load task that did not involve or induce hypocapnia. This finding implies that the frequency of HVS may have been grossly overestimated. Despite these doubts, no placebo-controlled study has directly addressed the specificity and validity of the HVPT.
The strength of our study lies in the combination of a double-blind placebo-controlled study on the HVPT and a follow-up study with ambulatory monitoring of pCO2. The latter technique has the potential to be a gold standard, since it allows measurement of pCO2 during spontaneous symptom episodes.17, 18 Our hypothesis was that if hyperventilation is an important symptom-producing factor in some patients, these patients must experience symptom recognition during the HVPT but not during the placebo test. We predicted that these true-positive patients would have more typical hyperventilation symptoms than the other groups, that a larger proportion would meet physiological HVS criteria, and most importantly, that they would show decreases in pCO2 during spontaneously developing symptom attacks.
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Patients and methods
The study was approved by the medical ethics committee of Slotervaart Hospital. The sample consisted of 115 consecutive outpatients (62 male, 53 female; mean age 38·8 years [SD 15.0], range 16–72), referred by medical specialists and general practitioners because of medically unexplained somatic symptoms that suggested HVS. Inclusion criteria were adequate command of the Dutch language, no anxiolytic medication above the regular dose (ie, no special medication taken out of fear for the test),
Results
End-tidal pCO2 and respiratory rate were averaged over the last 30 s of each period (baseline, overbreathing, and recovery). During the HVPT, end-tidal pCO2 fell by more than 50% (table 1). During the placebo test, brief changes in end-tidal pCO2 could not be prevented, but overall the baseline value was successfully maintained. There were no differences between the HVPT and the placebo test in respiration rate or depth of overbreathing (data not shown; available from authors).
The HVPT induced
Discussion
Our results clearly demonstrate the low validity of the HVPT when used for diagnosis of HVS. Two-thirds of the patients who were positive on the HVPT were also positive on the placebo test. The hypothesis that the placebo test would be useful in distinguishing true-positive from false-positive patients was not confirmed: the groups did not differ on any of the symptom variables, physiological variables, or pCO2 during spontaneous symptom episodes. A high percentage of false-positive results
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