Resp h'atot3, Medicine (1992) 86, 349-351
Recurrent hyperventilation tetany due to mild asthma W. N . GARDNER, C. BASS* AND J. MOXHAM
Department of Thoracic Medicine and Department of Psychological Medicine, Kings College School of Medicine and Dentistry, Bessemer Road, London SE5 9PJ, U.K.
Introduction
thus lead to the sequence of misattribution described above. The present case study is important in that it is an example of mild asthma presenting as hyperventilation in the absence of clinical features either of airflow obstruction of anxiety.
There is uncertainty about the boundaries, definition and diagnosis of disorders related to hyperventilation (1,2). The original definition of the hyperventilation syndrome implied an association between anxiety and hyperventilation (3), but more recent reports suggest that severe symptomatic hyperventilation can occur in the absence of reported anxiety and psychiatric morbidity (4-6). The interrelationship of anxiety, panic and hyperventilation is complex and controversial (7). Hyperventilation implies excessive respiratory drive and hypocapnia. Many organic disorders are associated with hypocapnia (2) which can occur in the early stages of most respiratory diseases, left ventricular failure, pulmonary embolus, chronic pain, most major system failures, and drug overdoses (e.g. aspirin). Hypocapnia also occurs with physiological states such as prolonged talking, pyrexia, pregnancy and in the second half of the menstrual cycle. Hyperventilation can cause the sudden onset of alarming symptoms due to both increased chest wall movement, and vasoconstriction and nervous hyperirritability induced by hypocapnic alkalosis. Hypocapnia is only of clinical relevance if it is associated with symptoms, and it has been suggested that hyperventilation only becomes self perpetuating and ultimately chronic if the patient misattributes these symptoms to serious disease, especially if the physician fails to recognise the true nature of the complaints (8). Such misattribution may prove to be the key to the etiology of the hyperventilation syndrome. Mild and moderate asthma can cause profound hypocapnia (9) and clinical experience suggests that asthma is often one of a number of factors contributing to the etiology of recurrent symptomatic hyperventilation (10). However, there is no evidence that an asthmatic, in the absence of other factors, can present with symptoms of hypocapnia sufficiently severe to overshadow the symptoms of airflow obstruction and
FiE, 1
Received5 December 1991and accepted9 December1991. *Presentaddress:BarnesUnit,John RadcliffeHospital,Oxford,U.K.
over 4 days before (O) and after ( 0 ) inhaled salbutamol. Note marked morning dipping which was responsive to salbutamol.
0954-6111/92/040349 + 03 $03.00/0
Case Report A 23-year-old staff nurse was referred to our care with a 2-week history of intermittent episodes of apparently unprovoked severe hyperventilation tetany. An upper respiratory tract infection associated with an unproductive cough lasting 2 days had led to difficulty in breathing and chest tightness. She attended her general practitioner and while in his surgery developed giddiness and peripheral paraesthesiae which were followed by an episode of dramatic tetany involving most muscle groups. Subsequently, a diagnosis of hysterical hyperventilation was made by a chest physician but despite treatment with oral and intramuscular diazepam episodic tetany continued to occur. Following transfer to Kings College Hospital the attacks were
450
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1822 6 1218 22 612 18 2 2 6 1218 2 2 6 I 18 Time o f doy ( h )
Peak expiratory flow recorded at 6-hourly intervals
© 1992BaillirreTindall
350
W. N. Gardner et al.
Time
(s) ......................................................................
.-r
3E 30 I
ff ,~
0 VHV
~
]k 3 min posl-recovery
Fig. 2 Retouched experimental record of PCO2 at the mouth showing end-tidal PCO. (PaCOz) during resting breathing, voluntary over breathing (VHV) and recovery from VHV. Note good end-tidal plateaux throughout and persistence of hypocapnia during the recovery period. (7.5 mm Hg = I kPa)
3-0 4O -r
E
°~°~°~"~
o 2-0
30
>lu_ad
~ 20
I'0 I0 I
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0.25 0-5 I 2 Post-salbutarnol Histamine concentration (rag mL -l]
Fig. 3 End-tidal PCO~ • and FEV, during a histamine challenge.with doubling concentrations ofhistamine and the response to salbutamol at the end ofthe challenge on the x-axis. Note progressive fall of PACO2as the histamine concentration increased with recovery of both FEV~ and PACO2 following salbutamoL (7-5 mmHg = 1 kPa.) noted to occur more frequently in the evening and early morning during sleep. The patient was aware of, but unable to respond to, verbal commands during these episodes, which lasted between 5 and 50 min and could not be terminated voluntarily. The patient described a long history of chest infections dating from the age of four. There was no definite history of childhood asthma, although from the age of 11 she was excused from sports at school because of exertional breathlessness and wheeze. During adolescence, colds and bronchitis occurred three times each winter but little school was missed. After good academic school performance she commenced nursing training at 17. There was no family history of asthma or atopy and she smoked 10-15 cigarettes per day. Psychiatric enquiry revealed a number of recent distressing life events including the death of a close relative and the dissolution o f a close relationship. In addition, she had suffered a severe whiplash injury to her neck a year previously resulting in 6 months away from work. Although a compensation claim was pending, a factitious component was considered unlikely.
There was no evidence of histrionic behaviour and extensive psychiatric assessment failed to reveal evidence of anxiety or any other psychiatric disorder. There was no past history or family history of psychiatric illness. She was a regular church attender. The chest radiograph was normal. A ventilation] perfusion scan showed patchy unmatched perfusion defects initally suggesting pulmonary embolus, but pulmonary angiography was normal as were T4, EEG, serum biochemistry, autoantibodies, full blood count and ESR. Lung function tests (FEV I, slow VC, gas transfer and flow volume loop) were within normal limits but there was a small increase in FEVt and VC after inhaled salbutamol. Peak flow charts subsequently showed marked morning dipping with heightened responsiveness to nebulized sa[butamol during the dips (Fig. 1). Skin tests were positive to common allergens. Resting end-tidal PCO 2(PACO2) , measured by mass spectrometer, was within the range which we regard as normal (5,6) at 4.1-4-7 kPa (31-35 mm Hg), but 3 min of voluntary hyperventilation induced severe
Recurrent hyperventilation tetany due to mild asthma h y p o c a p n i a (PACO 2 = l ' 2 - 2 k P a or 9-15 mm Hg; Fig. 2) lasting more than 30 min and associated with severe tetany which was relieved only by prolonged CO 2 inhalation. Bronchial challenge testing via a Wright nebulizer with doubling inhaled doses of histamine starting at 0"5 mg ml -j induced severe bronchoconstriction at a dose of 2 mg m l - t indicating bronchial hyperreactivity. The PACO z was normal initially and fell progressively as the histamine dose was increased, returning to near normal after inhaled salbutamol (Fig. 3). Treatment with inhaled salbutamol and beclamethasone, slow release aminophylline and oral prednisolone abolished the attacks of tetany as well as the 'bronchitis' and exercise dyspnoea. After 3 months of treatment, voluntary hyperventilation still induced hypocapnia which was more prolonged than in normal subjects, but was not associated with tetany; PACO 2 gradually and spontaneously returned to normal without the need for CO z inhalation. Over a period of 3 years (until she ceased attending our clinic), the patient reported that every time she developed asthmatic symptoms she also developed tetany which was rapidly relieved by treatment of the asthma.
Discussion This study provides evidence that some patients with mild asthma can present with overwhelming symptoms of hyperventilation in the absence of clinically obvious airflow obstruction. The past history of exertional wheeze and chestiness, morning dips of peak flow, bronchial hyperreactivity to histamine, positive skin tests and response to treatment established the diagnosis of mild asthma. Hyperventilation was repeatedly confirmed by clinical observation and measurement of PCO 2, and an unequivocal causative link between the two established by the history of frequent occurrence of tetany in the early morning, induction of hypocapnia by histamine with relief by salbutamol, cessation of attacks of tetany after commencement of asthma treatment, and recurrence of tetany with each subsequent asthma attack. It is uncertain why this patient should have presented in this way. Her asthma was longstanding and had never been diagnosed. However, a vicious circle in which misattribution of the manifestations of asthma to serious disease leading to increasing anxiety would be unlikely in this case as she continued to complain of tetany associated with asthma attacks long after diagnosis and explanation. Undoubtedly she understood the explanation and there was no evidence of anxiety or depression.
351
The mechanism of hyperventilation in asthma is uncertain (I 1). It is unrelated to age, asthma history or duration of attack. Possible mechanisms include stimulation of vagaily mediated airway receptors, hyperinflation stimulating chest wall receptors, cortically mediated load compensation and hypoxic stimulation of carotid bodies. Hypocapnia and hyperinflation also occur when bronchoconstriction is induced by methacholine, but are not induced by breathing through external resistances. In our patient, PACO 2 was inversely related to the dose of inhaled histamine; the sensitivity of this reponse appeared to be excessive. Hyperventilation implies excessive drive to breathe which can be due to a wide range of psychogenic, physiological and organic causes. Initiating and sustaining factors may be different. We believe that in every case of hyperventilation, an attempt should be made to document the cause or causes of excessive respiratory drive. A diagnosis of'hysterical hyperventilation' or 'hyperventilation syndrome' discourages search for such causes, is unhelpful or even dangerous.
Acknowledgements Thanks are due to the Wellcome Trust for financial support.
References I. Gardner WN. Hyperventilation disorders. J R Soc Med 1990; 83: 755-757. 2. Gardner WN, Bass C. Hyperventilation in clinical practice. Br J Hosp Med 1989; 41:73-8 I. 3. Kerr WJ, Gliebe PA, Dalton JW. Physical phenomena associated with anxiety states; the Hyperventilation Syndrome. California Western Med 1938; 48: 12-16. 4. Lum LC. The syndrome of habitual chronic hyperventilation. Rec Adv Psychosom Med 1976; 3: 196-230. 5. Bass C, Gardner WN. Respiratory and psychiatric abnormalities in chronic symptomatic hyperventilation. Br MedJ 1985; 290: 1387-1390. 6. Gardner WN, Meah MS, Bass C. Controlled study of respiratory responses during prolonged measurement in patients with chronic hyperventilation. Lancet 1986; ii: 826-830. 7. Bass C, Kartsounis L, Lelliot P. Hyperventilation and its relationship to anxiety and panic. Integr Psychiatry 1987; 5: 274-291. 8. Salkovskis PM, Clark DM. Affective responses to hyperventilation: a test of the cognitive model of panic. Behav Res Ther 1990; 28: 51-61. 9. McFadden ER Jr, Lyons HA. Arterial blood gas tensions in asthma. N EnglJMed 1968; 278: 1027-1032. 10. Dent R, Yates D, Higgenbottom T. Does the hyperventilation syndrome exist? Thorax 1983; 38: 223. 1I. Lavietes MH. Ventilatory control in asthma. Clin Chest M~d 1984; 5: 607-617.
Recurrent hyperventilation tetany due to mild asthma W. N . GARDNER, C. BASS* AND J. MOXHAM
Department of Thoracic Medicine and Department of Psychological Medicine, Kings College School of Medicine and Dentistry, Bessemer Road, London SE5 9PJ, U.K.
Introduction
thus lead to the sequence of misattribution described above. The present case study is important in that it is an example of mild asthma presenting as hyperventilation in the absence of clinical features either of airflow obstruction of anxiety.
There is uncertainty about the boundaries, definition and diagnosis of disorders related to hyperventilation (1,2). The original definition of the hyperventilation syndrome implied an association between anxiety and hyperventilation (3), but more recent reports suggest that severe symptomatic hyperventilation can occur in the absence of reported anxiety and psychiatric morbidity (4-6). The interrelationship of anxiety, panic and hyperventilation is complex and controversial (7). Hyperventilation implies excessive respiratory drive and hypocapnia. Many organic disorders are associated with hypocapnia (2) which can occur in the early stages of most respiratory diseases, left ventricular failure, pulmonary embolus, chronic pain, most major system failures, and drug overdoses (e.g. aspirin). Hypocapnia also occurs with physiological states such as prolonged talking, pyrexia, pregnancy and in the second half of the menstrual cycle. Hyperventilation can cause the sudden onset of alarming symptoms due to both increased chest wall movement, and vasoconstriction and nervous hyperirritability induced by hypocapnic alkalosis. Hypocapnia is only of clinical relevance if it is associated with symptoms, and it has been suggested that hyperventilation only becomes self perpetuating and ultimately chronic if the patient misattributes these symptoms to serious disease, especially if the physician fails to recognise the true nature of the complaints (8). Such misattribution may prove to be the key to the etiology of the hyperventilation syndrome. Mild and moderate asthma can cause profound hypocapnia (9) and clinical experience suggests that asthma is often one of a number of factors contributing to the etiology of recurrent symptomatic hyperventilation (10). However, there is no evidence that an asthmatic, in the absence of other factors, can present with symptoms of hypocapnia sufficiently severe to overshadow the symptoms of airflow obstruction and
FiE, 1
Received5 December 1991and accepted9 December1991. *Presentaddress:BarnesUnit,John RadcliffeHospital,Oxford,U.K.
over 4 days before (O) and after ( 0 ) inhaled salbutamol. Note marked morning dipping which was responsive to salbutamol.
0954-6111/92/040349 + 03 $03.00/0
Case Report A 23-year-old staff nurse was referred to our care with a 2-week history of intermittent episodes of apparently unprovoked severe hyperventilation tetany. An upper respiratory tract infection associated with an unproductive cough lasting 2 days had led to difficulty in breathing and chest tightness. She attended her general practitioner and while in his surgery developed giddiness and peripheral paraesthesiae which were followed by an episode of dramatic tetany involving most muscle groups. Subsequently, a diagnosis of hysterical hyperventilation was made by a chest physician but despite treatment with oral and intramuscular diazepam episodic tetany continued to occur. Following transfer to Kings College Hospital the attacks were
450
E
400
Q.
350 I
226
ii2
p
i
,
,
L
i
i
i
i
I
I
I
I
I
I
/2
I
1822 6 1218 22 612 18 2 2 6 1218 2 2 6 I 18 Time o f doy ( h )
Peak expiratory flow recorded at 6-hourly intervals
© 1992BaillirreTindall
350
W. N. Gardner et al.
Time
(s) ......................................................................
.-r
3E 30 I
ff ,~
0 VHV
~
]k 3 min posl-recovery
Fig. 2 Retouched experimental record of PCO2 at the mouth showing end-tidal PCO. (PaCOz) during resting breathing, voluntary over breathing (VHV) and recovery from VHV. Note good end-tidal plateaux throughout and persistence of hypocapnia during the recovery period. (7.5 mm Hg = I kPa)
3-0 4O -r
E
°~°~°~"~
o 2-0
30
>lu_ad
~ 20
I'0 I0 I
0
|
I
I
I
I
0.25 0-5 I 2 Post-salbutarnol Histamine concentration (rag mL -l]
Fig. 3 End-tidal PCO~ • and FEV, during a histamine challenge.with doubling concentrations ofhistamine and the response to salbutamol at the end ofthe challenge on the x-axis. Note progressive fall of PACO2as the histamine concentration increased with recovery of both FEV~ and PACO2 following salbutamoL (7-5 mmHg = 1 kPa.) noted to occur more frequently in the evening and early morning during sleep. The patient was aware of, but unable to respond to, verbal commands during these episodes, which lasted between 5 and 50 min and could not be terminated voluntarily. The patient described a long history of chest infections dating from the age of four. There was no definite history of childhood asthma, although from the age of 11 she was excused from sports at school because of exertional breathlessness and wheeze. During adolescence, colds and bronchitis occurred three times each winter but little school was missed. After good academic school performance she commenced nursing training at 17. There was no family history of asthma or atopy and she smoked 10-15 cigarettes per day. Psychiatric enquiry revealed a number of recent distressing life events including the death of a close relative and the dissolution o f a close relationship. In addition, she had suffered a severe whiplash injury to her neck a year previously resulting in 6 months away from work. Although a compensation claim was pending, a factitious component was considered unlikely.
There was no evidence of histrionic behaviour and extensive psychiatric assessment failed to reveal evidence of anxiety or any other psychiatric disorder. There was no past history or family history of psychiatric illness. She was a regular church attender. The chest radiograph was normal. A ventilation] perfusion scan showed patchy unmatched perfusion defects initally suggesting pulmonary embolus, but pulmonary angiography was normal as were T4, EEG, serum biochemistry, autoantibodies, full blood count and ESR. Lung function tests (FEV I, slow VC, gas transfer and flow volume loop) were within normal limits but there was a small increase in FEVt and VC after inhaled salbutamol. Peak flow charts subsequently showed marked morning dipping with heightened responsiveness to nebulized sa[butamol during the dips (Fig. 1). Skin tests were positive to common allergens. Resting end-tidal PCO 2(PACO2) , measured by mass spectrometer, was within the range which we regard as normal (5,6) at 4.1-4-7 kPa (31-35 mm Hg), but 3 min of voluntary hyperventilation induced severe
Recurrent hyperventilation tetany due to mild asthma h y p o c a p n i a (PACO 2 = l ' 2 - 2 k P a or 9-15 mm Hg; Fig. 2) lasting more than 30 min and associated with severe tetany which was relieved only by prolonged CO 2 inhalation. Bronchial challenge testing via a Wright nebulizer with doubling inhaled doses of histamine starting at 0"5 mg ml -j induced severe bronchoconstriction at a dose of 2 mg m l - t indicating bronchial hyperreactivity. The PACO z was normal initially and fell progressively as the histamine dose was increased, returning to near normal after inhaled salbutamol (Fig. 3). Treatment with inhaled salbutamol and beclamethasone, slow release aminophylline and oral prednisolone abolished the attacks of tetany as well as the 'bronchitis' and exercise dyspnoea. After 3 months of treatment, voluntary hyperventilation still induced hypocapnia which was more prolonged than in normal subjects, but was not associated with tetany; PACO 2 gradually and spontaneously returned to normal without the need for CO z inhalation. Over a period of 3 years (until she ceased attending our clinic), the patient reported that every time she developed asthmatic symptoms she also developed tetany which was rapidly relieved by treatment of the asthma.
Discussion This study provides evidence that some patients with mild asthma can present with overwhelming symptoms of hyperventilation in the absence of clinically obvious airflow obstruction. The past history of exertional wheeze and chestiness, morning dips of peak flow, bronchial hyperreactivity to histamine, positive skin tests and response to treatment established the diagnosis of mild asthma. Hyperventilation was repeatedly confirmed by clinical observation and measurement of PCO 2, and an unequivocal causative link between the two established by the history of frequent occurrence of tetany in the early morning, induction of hypocapnia by histamine with relief by salbutamol, cessation of attacks of tetany after commencement of asthma treatment, and recurrence of tetany with each subsequent asthma attack. It is uncertain why this patient should have presented in this way. Her asthma was longstanding and had never been diagnosed. However, a vicious circle in which misattribution of the manifestations of asthma to serious disease leading to increasing anxiety would be unlikely in this case as she continued to complain of tetany associated with asthma attacks long after diagnosis and explanation. Undoubtedly she understood the explanation and there was no evidence of anxiety or depression.
351
The mechanism of hyperventilation in asthma is uncertain (I 1). It is unrelated to age, asthma history or duration of attack. Possible mechanisms include stimulation of vagaily mediated airway receptors, hyperinflation stimulating chest wall receptors, cortically mediated load compensation and hypoxic stimulation of carotid bodies. Hypocapnia and hyperinflation also occur when bronchoconstriction is induced by methacholine, but are not induced by breathing through external resistances. In our patient, PACO 2 was inversely related to the dose of inhaled histamine; the sensitivity of this reponse appeared to be excessive. Hyperventilation implies excessive drive to breathe which can be due to a wide range of psychogenic, physiological and organic causes. Initiating and sustaining factors may be different. We believe that in every case of hyperventilation, an attempt should be made to document the cause or causes of excessive respiratory drive. A diagnosis of'hysterical hyperventilation' or 'hyperventilation syndrome' discourages search for such causes, is unhelpful or even dangerous.
Acknowledgements Thanks are due to the Wellcome Trust for financial support.
References I. Gardner WN. Hyperventilation disorders. J R Soc Med 1990; 83: 755-757. 2. Gardner WN, Bass C. Hyperventilation in clinical practice. Br J Hosp Med 1989; 41:73-8 I. 3. Kerr WJ, Gliebe PA, Dalton JW. Physical phenomena associated with anxiety states; the Hyperventilation Syndrome. California Western Med 1938; 48: 12-16. 4. Lum LC. The syndrome of habitual chronic hyperventilation. Rec Adv Psychosom Med 1976; 3: 196-230. 5. Bass C, Gardner WN. Respiratory and psychiatric abnormalities in chronic symptomatic hyperventilation. Br MedJ 1985; 290: 1387-1390. 6. Gardner WN, Meah MS, Bass C. Controlled study of respiratory responses during prolonged measurement in patients with chronic hyperventilation. Lancet 1986; ii: 826-830. 7. Bass C, Kartsounis L, Lelliot P. Hyperventilation and its relationship to anxiety and panic. Integr Psychiatry 1987; 5: 274-291. 8. Salkovskis PM, Clark DM. Affective responses to hyperventilation: a test of the cognitive model of panic. Behav Res Ther 1990; 28: 51-61. 9. McFadden ER Jr, Lyons HA. Arterial blood gas tensions in asthma. N EnglJMed 1968; 278: 1027-1032. 10. Dent R, Yates D, Higgenbottom T. Does the hyperventilation syndrome exist? Thorax 1983; 38: 223. 1I. Lavietes MH. Ventilatory control in asthma. Clin Chest M~d 1984; 5: 607-617.
