193
Psychiatry Research. 3 I : I93- I99 Elsevier
Specific Sensitivity of Patients Carbon Dioxide Inhalation
With Panic Attacks
Eric Griez, Catrien de Loof, Henk Pals, Jan Zandbergen, Harold Lousberg
to
and
Received March 13. 1989: revised version received July 7. 1989; accepted September
4, 1989.
Abstract. One inhalation of 35% CO, in oxygen was administered to 36 patients with anxiety disorders and 14 healthy controls. Eighteen patients had a diagnosis of panic disorder (PD) and 18 of obsessive-compulsive disorder (OCD). As a placebo control for CO,, compressed air was administered in a double-blind design. Immediately before and after the inhalation, levels of anxiety and DSMIII-R symptoms of panic were assessed. CO, elicited high levels of subjective anxiety in the PD group. Patients with OCD were hardly affected by the inhalation, and did not differ from healthy controls. These results suggest that CO, challenge should be considered as a specific probe for subjects with panicanxiety. It is speculated that CO, may trigger some as yet undefined mechanisms, possibly linked to ventilation control, which demarcate panic from other types of pathological anxiety.
Key Words. Carbon dioxide,
panic attacks,
anxiety disorder.
Acute episodes of fear associated with autonomic disturbance have been described for years in some anxiety-prone individuals. Psychiatrists usually have viewed these attacks as one symptom, among others, in the clinical picture of anxiety neurosis. However, the fact that these symptoms can be precipitated by lactate (Pitts and McClure, 1967) together with the finding that panic attacks may be familial (G-owe et al., 1983), possibly sharing a common diathesis with major depression (Breier et al., 1984) strongly suggested that panic attacks (PA) might characterize a very specific subtype of anxiety. Dizziness, precordial constriction, chest pain, choking, and smothering sensations are all commonly experienced during panic episodes. As a rule, patients indeed show respiratory disturbances during the course of their attacks. This suggested a physiological link between PA and the well-known hyperventilation syndrome. Under controlled experimental conditions, however, forced hyperventilation had a very weak anxiogenic effect in patients with naturally occurring PA, challenging the widely accepted view that hyperventilation precipitates anxiety (Gorman et al., 1984;
Eric Griez. M.D., is Director of the Academic Anxiety Center, Vijverdal Mental Hospital, and Assistant Professor of Clinical Psychiatry, State University of Maastricht, The Netherlands; Catrien de Loof, Ph.D., is clinical and research psychologist at the Academic Anxiety Center and Department of Clinical Psychiatry; Henk Pals, M.D., and Jan Zandbergen, M.D., are Scientific Assistants, and Harold Lousberg, M.D., was formerly Assistant, Department of Clinical Psychiatry, State University of Maastricht, The Netherlands. (Reprint requests to Dr. E. Crier, Department of Clinical Psychiatry, State University of Limburg, P.O. 616, 6200 MD Maastricht, The Netherlands.) Ol65-1781/90/$03.50
@ 1990 Elsevier Scientific
Publishers Ireland
Ltd.
194 Griez et al., 1988). In contrast, it was shown that panic disorder (PD) patients were intolerant to inhalation of hypercapnic air: administering 5% CO, to I2 PD subjects, Gorman et al. (1984) found that 7 of them went into panic within a matter of minutes. It appeared that new findings on a high susceptibility to CO2 in patients with PA might shed light on the physiology of respiratory control in these subjects and might elucidate unexplained links between respiration, anxiety, and the genesis of PA. Some years ago, our group observed that a single inhalation of a 35%) CO,/65% O2 mixture given to 12 patients with PD instantaneously elicited panic-like symptoms and high levels of anxiety (Griez et al., 1987). The present report extends our previous observations in a new sample of patients.
Methods Subjects. The subjects were 36 anxiety patients who had been referred to the local Academic Anxiety Center and 14 healthy normal controls. All patients were diagnosed by experienced clinicians using DSM-III-R criteria (American Psychiatric Association, 1987). Eighteen patients received diagnoses of PD, and the remaining IX patients had obsessive-compulsive disorder (OCD). All diagnoses were independently confirmed by a second psychiatrist. Subjects with two or more concomitant Axis I diagnoses were excluded from the study. In the PD group, there were 8 males and IO females, ranging in age from 21 to 45 years (mean 33. I I. SD 7.21). The OCD group comprised 4 males and 14 females, aged from I7 to 4X years (mean 33.78, SD 9.6X). The healthy controls were 7 males and 7 females, aged from 19 to 47 years (mean 2X.43, SD 7.65). Except for a slight trend for the controls to be younger than the PD patients (t = I .7 17, p < 0. I, Student’s t test), there were no significant differences between the groups in age or gender distribution. At the time of study, all subjects were free of known concomitant physical disease and not under current psychiatric treatment. In particular, they all were medication free for at least 2 weeks, except for incidental use of low dosages of bemodiazepines (< 5 mg dialepam/day). Procedure. The test was conducted by a research nurse, who also provided instructions to the participants. These instructions were identical for all subjects, who were told that they would be administered two mixtures containing different CO? proportions. CO; was said to induce, depending on its concentration and on individual susceptibility, short-loved effects, ranging from hardly noticeable sensations to definite anxiety symptoms. No reference was made to a PA. After a deep exhalation, subjects took a vital capacity breath of either a 35% COzi65% O2 mixture or compressed air, via a self-administration apparatus (EntonoxK, British Oxygen Company, Ltd). The procedure required them to hold their breath for 4 set after inhaling, to enhance alveolar gas exchange. The volume that was delivered at each inhalation was measured by a respirometer (HaloscaleK). For each sub.ject, there was at least a half-hour interval in between the two inhalations. COz mixtures may have a marked taste. Since subjects had been told that they would receive a CO, mixture on both occasions, and were unaware of a possible relationship between taste and psychotropic properties, this was not considered to be a ma.jor problem. Assessments. Before entering the procedure, all subjects completed the Self-Rating Scale for Anxiety (Zung, 1971) and the State Anxiety Inventory (A form; Spielberger et al., 1970). These scales were used to evaluate the general level of anxiety experienced during the week preceding the trial. Just before and within 30 set after each inhalation. subjects expressed their level of anxiety using a IOO-point scale ranging from 0 (“not disturbed at all”) to 100 (“the worst imaginable experience”). This simple system has been widely used in both psychological research and
195
clinical practice (Wolpe, 1973). The method is reliable and correlates fairly well with psychophysiological parameters (Thyer et al., 1984). In addition, before and after each inhalation, the symptoms of panic, as listed in DSM-IIIR, were assessed on a self-rating form, with each symptom being rated on a 5-point intensity scale, ranging from 0 (absent) to 4 (very intense). This yielded a “total symptom score” reflecting the importance of clinical symptomatology.
Data Analysis. For each subject, the data yielded a change under air and a change under CO,. From these scores, an individual net increase in subjective anxiety and in panic symptoms was derived (change under CO, minus change under air). The net scores were the basis for statistical analysis. All data were analyzed using two-tailed t tests. For changes in subjective anxiety, nonparametric (Wilcoxon and Mann-Whitney) tests were also performed whenever a significant result was found with t statistics. This approach was taken because data obtained from the semi-quantitative evaluation of anxiety, as described above, may not meet all requirements for parametric testing.
Results Table 1 presents results of the two anxiety rating scales. As could be expected, all patients had high scores on the anxiety scales, in contrast to normal controls, but the PD and OCD subgroups did not differ significantly in their levels of anxiety. CO, Challenge. To ensure that no systematic intergroup difference existed in the amount of CO, administered, the mean volume (in liters) of inhaled active gas was calculated in each group: PD patients, 3.5 I (SD 0.87); OCD patients, 3.38 (SD 0.91); and normal controls, 4.11 (SD 1.35). No significant differences were found, although there was a trend for controls to have inhaled more CO, than the OCD patients (t = 1.765,p
Psychiatry Research. 3 I : I93- I99 Elsevier
Specific Sensitivity of Patients Carbon Dioxide Inhalation
With Panic Attacks
Eric Griez, Catrien de Loof, Henk Pals, Jan Zandbergen, Harold Lousberg
to
and
Received March 13. 1989: revised version received July 7. 1989; accepted September
4, 1989.
Abstract. One inhalation of 35% CO, in oxygen was administered to 36 patients with anxiety disorders and 14 healthy controls. Eighteen patients had a diagnosis of panic disorder (PD) and 18 of obsessive-compulsive disorder (OCD). As a placebo control for CO,, compressed air was administered in a double-blind design. Immediately before and after the inhalation, levels of anxiety and DSMIII-R symptoms of panic were assessed. CO, elicited high levels of subjective anxiety in the PD group. Patients with OCD were hardly affected by the inhalation, and did not differ from healthy controls. These results suggest that CO, challenge should be considered as a specific probe for subjects with panicanxiety. It is speculated that CO, may trigger some as yet undefined mechanisms, possibly linked to ventilation control, which demarcate panic from other types of pathological anxiety.
Key Words. Carbon dioxide,
panic attacks,
anxiety disorder.
Acute episodes of fear associated with autonomic disturbance have been described for years in some anxiety-prone individuals. Psychiatrists usually have viewed these attacks as one symptom, among others, in the clinical picture of anxiety neurosis. However, the fact that these symptoms can be precipitated by lactate (Pitts and McClure, 1967) together with the finding that panic attacks may be familial (G-owe et al., 1983), possibly sharing a common diathesis with major depression (Breier et al., 1984) strongly suggested that panic attacks (PA) might characterize a very specific subtype of anxiety. Dizziness, precordial constriction, chest pain, choking, and smothering sensations are all commonly experienced during panic episodes. As a rule, patients indeed show respiratory disturbances during the course of their attacks. This suggested a physiological link between PA and the well-known hyperventilation syndrome. Under controlled experimental conditions, however, forced hyperventilation had a very weak anxiogenic effect in patients with naturally occurring PA, challenging the widely accepted view that hyperventilation precipitates anxiety (Gorman et al., 1984;
Eric Griez. M.D., is Director of the Academic Anxiety Center, Vijverdal Mental Hospital, and Assistant Professor of Clinical Psychiatry, State University of Maastricht, The Netherlands; Catrien de Loof, Ph.D., is clinical and research psychologist at the Academic Anxiety Center and Department of Clinical Psychiatry; Henk Pals, M.D., and Jan Zandbergen, M.D., are Scientific Assistants, and Harold Lousberg, M.D., was formerly Assistant, Department of Clinical Psychiatry, State University of Maastricht, The Netherlands. (Reprint requests to Dr. E. Crier, Department of Clinical Psychiatry, State University of Limburg, P.O. 616, 6200 MD Maastricht, The Netherlands.) Ol65-1781/90/$03.50
@ 1990 Elsevier Scientific
Publishers Ireland
Ltd.
194 Griez et al., 1988). In contrast, it was shown that panic disorder (PD) patients were intolerant to inhalation of hypercapnic air: administering 5% CO, to I2 PD subjects, Gorman et al. (1984) found that 7 of them went into panic within a matter of minutes. It appeared that new findings on a high susceptibility to CO2 in patients with PA might shed light on the physiology of respiratory control in these subjects and might elucidate unexplained links between respiration, anxiety, and the genesis of PA. Some years ago, our group observed that a single inhalation of a 35%) CO,/65% O2 mixture given to 12 patients with PD instantaneously elicited panic-like symptoms and high levels of anxiety (Griez et al., 1987). The present report extends our previous observations in a new sample of patients.
Methods Subjects. The subjects were 36 anxiety patients who had been referred to the local Academic Anxiety Center and 14 healthy normal controls. All patients were diagnosed by experienced clinicians using DSM-III-R criteria (American Psychiatric Association, 1987). Eighteen patients received diagnoses of PD, and the remaining IX patients had obsessive-compulsive disorder (OCD). All diagnoses were independently confirmed by a second psychiatrist. Subjects with two or more concomitant Axis I diagnoses were excluded from the study. In the PD group, there were 8 males and IO females, ranging in age from 21 to 45 years (mean 33. I I. SD 7.21). The OCD group comprised 4 males and 14 females, aged from I7 to 4X years (mean 33.78, SD 9.6X). The healthy controls were 7 males and 7 females, aged from 19 to 47 years (mean 2X.43, SD 7.65). Except for a slight trend for the controls to be younger than the PD patients (t = I .7 17, p < 0. I, Student’s t test), there were no significant differences between the groups in age or gender distribution. At the time of study, all subjects were free of known concomitant physical disease and not under current psychiatric treatment. In particular, they all were medication free for at least 2 weeks, except for incidental use of low dosages of bemodiazepines (< 5 mg dialepam/day). Procedure. The test was conducted by a research nurse, who also provided instructions to the participants. These instructions were identical for all subjects, who were told that they would be administered two mixtures containing different CO? proportions. CO; was said to induce, depending on its concentration and on individual susceptibility, short-loved effects, ranging from hardly noticeable sensations to definite anxiety symptoms. No reference was made to a PA. After a deep exhalation, subjects took a vital capacity breath of either a 35% COzi65% O2 mixture or compressed air, via a self-administration apparatus (EntonoxK, British Oxygen Company, Ltd). The procedure required them to hold their breath for 4 set after inhaling, to enhance alveolar gas exchange. The volume that was delivered at each inhalation was measured by a respirometer (HaloscaleK). For each sub.ject, there was at least a half-hour interval in between the two inhalations. COz mixtures may have a marked taste. Since subjects had been told that they would receive a CO, mixture on both occasions, and were unaware of a possible relationship between taste and psychotropic properties, this was not considered to be a ma.jor problem. Assessments. Before entering the procedure, all subjects completed the Self-Rating Scale for Anxiety (Zung, 1971) and the State Anxiety Inventory (A form; Spielberger et al., 1970). These scales were used to evaluate the general level of anxiety experienced during the week preceding the trial. Just before and within 30 set after each inhalation. subjects expressed their level of anxiety using a IOO-point scale ranging from 0 (“not disturbed at all”) to 100 (“the worst imaginable experience”). This simple system has been widely used in both psychological research and
195
clinical practice (Wolpe, 1973). The method is reliable and correlates fairly well with psychophysiological parameters (Thyer et al., 1984). In addition, before and after each inhalation, the symptoms of panic, as listed in DSM-IIIR, were assessed on a self-rating form, with each symptom being rated on a 5-point intensity scale, ranging from 0 (absent) to 4 (very intense). This yielded a “total symptom score” reflecting the importance of clinical symptomatology.
Data Analysis. For each subject, the data yielded a change under air and a change under CO,. From these scores, an individual net increase in subjective anxiety and in panic symptoms was derived (change under CO, minus change under air). The net scores were the basis for statistical analysis. All data were analyzed using two-tailed t tests. For changes in subjective anxiety, nonparametric (Wilcoxon and Mann-Whitney) tests were also performed whenever a significant result was found with t statistics. This approach was taken because data obtained from the semi-quantitative evaluation of anxiety, as described above, may not meet all requirements for parametric testing.
Results Table 1 presents results of the two anxiety rating scales. As could be expected, all patients had high scores on the anxiety scales, in contrast to normal controls, but the PD and OCD subgroups did not differ significantly in their levels of anxiety. CO, Challenge. To ensure that no systematic intergroup difference existed in the amount of CO, administered, the mean volume (in liters) of inhaled active gas was calculated in each group: PD patients, 3.5 I (SD 0.87); OCD patients, 3.38 (SD 0.91); and normal controls, 4.11 (SD 1.35). No significant differences were found, although there was a trend for controls to have inhaled more CO, than the OCD patients (t = 1.765,p
