1317 Discussion
patients illustrate the range of disturbance that periodic breathing at night can produce in heart-failure. Patient 3 is similar to the patient described by Harrison et al2 with disturbance caused by dyspnoea during drowsiness and at the start of sleep, but with regular breathing developing after about 1 h. Patient 4 had gross heart-failure and attempts to go to sleep were interrupted by dyspnoea during the phase of hyperventilaThese
tion. The tidal volumes of the breaths that caused arousal were much greater than those during regular breathing and the disturbances seemed to be related to the tidal volume. Patient 1 had very severe periodic breathing with long apnoeic spells and he awoke with paroxysmal nocturnal dyspnoea during the hyperventilatory phase. However, the sleep disturbances did not occur until he had been sleeping for nearly 2 h. He had complained of nocturnal breathlessness for 10 years, but the reason for his investigation was his complaint of tiredness and sleepiness in the day. Patient 2 was recovering from heart-failure with treatment. Her periodic breathing pattern did not include apnoeic periods or paroxysmal dyspnoea but her sleep was disturbed on seven occasions and it is likely that this milder disturbance may have contributed to tiredness or sleepiness in the day. Cheyne-Stokes respiration occurs with many conditions and a study of 2000 subjects without pulmonary or neurological disease found periodic or wavelike respiration in 30 subjects (1.5%) and Cheyne-Stokes respiration in 10 (0-5%). A clinical history was available in 8 of these 10 subjects and it is interesting that 4 had hypersomnia. Cheyne-Stokes breathing is more common during sleep, especially in men over the age of 50.4 The most widely accepted theory for the sensation of dyspnoea is that of length-tension imbalance in which dyspnoea results from an inadequate movement or volume for the force generated. Therefore CheyneStokes breathing with normal lung mechanics should not cause dyspnoea. In left-heart failure the compliance of the lung is decreased and the volume inspired for a given respiratory drive is less than normal. If the respiratory drive is increased, as in exercise or the hyperventilatory phase of Cheyne-Stokes respiration, then dyspnoea is likely to result. At night when these patients lie down venous return to the right heart is increased and this may lead to a further decrease in lung compliance. This increased venous return is the usual explanation for orthopncea and paroxysmal nocturnal dyspnoea. The combination of decreased lung compliance and Cheyne-Stokes respiration produces a situation in which repeated episodes of dyspncea might be expected to occur. Sitting up gives relief by improving lung mechanics and because periodic breathing is exacerbated by the supine posture in heart failure.6 Paroxysmal nocturnal dyspnoea caused by periodic breathing can probably be distinguished from the more severe dyspnoea of cardiac asthma by careful questioning and this may be confirmed by observing the patient closely at night. Aminophylline often eradicates CheyneStokes breathing in man, possibly by reducing the threshold of response to carbon dioxide.7,8 Since aminophylline also increases cardiac output and causes vasodilatation and diuresis it might be an alternative treatment in this situation.
Mild Cheyne-Stokes breathing in heart-failure may contribute to tiredness in the day. When the CheyneStokes breathing is more extreme, the patient may awake with dyspnoea at the start of sleep or later in the night. This picture should be differentiated from more severe situations in which episodes of pulmonary oedema develop during sleep. Severe Cheyne-Stokes breathing may be present all the time, preventing the patient from sleeping for more than a few minutes. Requests for reprints should be addressed
to
P.
J. R.
REFERENCES
1. Harrison WG, Calhoun JA, Harrison TR. Congestive heart failure. Clinical types of nocturnal dyspnœa. Arch Intern Med 1934; 53: 561-73. 2. Harrison TR, King CE, Calhoun JA, Harrison WG. Congestive heart failure. Cheyne-Stokes respiration as the cause of paroxysmal dyspnœa at the onset of sleep. Arch Intern Med 1934; 53: 891-910. 3. Specht H, Fruhmann G. Incidence of periodic breathing in 2000 subjects without pulmonary disease or neurological disease. Bull Physio-path Resp
1972; 8: 1075-83. 4. Webb P. Periodic breathing during sleep. J Appl Physiol 1974; 37: 899-903. 5. Campbell EJM, Howell JBL. The sensation of breathlessness. Br Med Bull
1963; 19: 36-40. 6. Altschule MD, Iglauer A. The effect of position on periodic breathing in chronic cardiac decompensation. N Engl J Med 1958; 259: 1064-66. 7. Dowell AR, Heyman A, Sieker HO, Tripathy K. Effect of aminophylline on respiratory centre sensitivity in Cheyne-Stokes respiration and in pulmonary emphysema. N Engl J Med 1965; 273: 1447-53. 8. Moyer JH, Miller SI, Tashnek AB, Bowman R. Effect of theophylline with ethylenediamine (aminophylline) on cerebral hæmodynamics in the presence of cardiac failure with and without Cheyne-Stokes respiration. J Clin Invest 1952; 31: 267-72.
COMPARISON OF HORMONAL AND METABOLIC EFFECTS OF SALBUTAMOL INFUSION IN NORMAL SUBJECTS AND INSULIN-REQUIRING DIABETICS A. S. GÜNDOGDU P. M. BROWN S. JUUL L. SACHS P. H. SÖNKSEN
Department of Medicine, St
Thomas’s Hospital Medical
School, London SE1 7EH A comparison of the metabolic effects of salbutamol in diabetic patients and normal subjects showed that salbutamol infused at 5 and 20 µg/min (a) stimulated hepatic glucose production to a greater extent in diabetic patients than in normal subjects despite prior restoration of the diabetic patients’ fasting blood glucose to normal by an overnight infusion of insulin; (b) caused a greater rise in plasma glucose, free fatty acids, glycerol, and ketone-body concentrations in the diabetic patients; and (c) produced a marked fall in plasma-potassium concentrations. The differences between the diabetic and normal groups were accounted for by an immediate (six-fold) stimulation of insulin secretion in the normal subjects.
Summary
Introduction LARGE intravenous doses of theadrenergic agent salbutamol are increasingly being used in the management of premature labour’ and the treatment of status asthmaticus2 and cardiogenic shock. However, ketoacidosis may develop in pregnant diabetic patients given intravenous salbutamol.1-6 In non-diabetic subjects salbutamol infusions slightly raise plasma-glucose and greatly
1318 increase insulin and free-fatty-acid (FFA) concentrations.7-10 The changes in plasma-glucose and FFA concentrations could be accounted for by the known effects of p-adrenergic stimulation in raising glycogenolysis and lipolysis.1’ In diabetic subjects with limited insulin reserves the metabolic consequences of &bgr;2- adrenergic stimtilation may be greater and could result in significant ketonaemia. We have compared the effect of salbutamol infusion on carbohydrate and fat metabolism in normal subjects with that in insulin-treated diabetic patients.
Subjects
and Methods
Six male medical students, aged 19-22 (mean 20) years, and five male and one female insulin-treated diabetic patients, aged 26-50 (mean 32) years, have been studied. All subjects were within 10% of their ideal body-weight (Metropolitan Life Insurance table). The study was approved by the ethical committee of St Thomas’ Hospital, and informed consent was obtained from all subjects. The diabetic patients were on twice-daily injections of a variety of short and medium acting insulins, their average daily insulin requirements being 46 units (range 16-88) and their duration of insulin treatment ranging from 6 months to 6 years. ’Actrapid MC’ insulin was substituted for the patient’s normal morning insulin 24 h before the study; that evening the patients were admitted to hospital for an intravenous infusion of insulin after their evening meal. The rate of infusion was
adjusted frequent ’Dextrostix’/’Eyetone’ blood-glucose determinations, so as to maintain the blood-glucose concentrawith
tion between 4 and 5 mmol/1; the rate of insulin infusion required ranged from 0-24 to 0.90 units/h and correlated closely with the patients’ normal daily insulin requirements (r=0-87) The rate of insulin infusion that maintained normoglycsmia was continued overnight and throughout the study. All subjects were given a priming dose of 33 :.:.Ci of 3tritiated glucose (Radio Chemical Centre Amersham), followed by a constant intravenous infusion of 0.33 ;.Ci/min. After a 2 h equilibration period salbutamol was infused intravenously at 5 ::g/min for 1 h and then at 20 ;’.g/min for 1 h. The salbuHORMONAL, METABOLIC, HEART-RATE, AND BLOOD-PRESSURE
tamol infusion was then stopped and the experiment was continued for a further hour. Blood samples were taken from an indwelling intravenous cannula at 10 min intervals for the measurement of plasma glucose, glucose specific activity, insulin, growth hormone, and C-peptide concentrations, at halfhourly intervals for plasma FFA, potassium, glucagon, and cyclic AMP determination, and at hourly intervals for blood glycerol, 3-OH-butyrate, acetoacetate, lactate, and pyruvate. Measurements of systolic and diastolic blood-pressure with ’Arteriosonde 1217’ (Roche Ltd) and heart-rate were recorded at 10 min intervals. Plasma glucose was measured by a glucose-oxidase method with a Beckman glucose analyser. Glucose specific activity was measured after deproteinisation and lyophilisation by liquid scintillation counting, and the rates of appearance (Ra) and disappearance (Rd) of glucose were calculated by the method of Steel et al.12,13 Plasma insulin, growth hormone, C-peptide, glucagon, cortisol, and cyclic AMP were measured by radioimmunoassay by the use of specific antisera. FFA were determined by fluorometry after Dole extraction,14 intermediary carbohydrate metabolites by enzyme fluorometry,"’" and plasma-potassium by flame photometry. Standard statistical methods by the use of paired and un-
paired t tests were applied. Results Cardiovascular Responses Heart-rate in the normal subjects rose significantly from 56+2.5/min (mean+SEM) to (p
patients illustrate the range of disturbance that periodic breathing at night can produce in heart-failure. Patient 3 is similar to the patient described by Harrison et al2 with disturbance caused by dyspnoea during drowsiness and at the start of sleep, but with regular breathing developing after about 1 h. Patient 4 had gross heart-failure and attempts to go to sleep were interrupted by dyspnoea during the phase of hyperventilaThese
tion. The tidal volumes of the breaths that caused arousal were much greater than those during regular breathing and the disturbances seemed to be related to the tidal volume. Patient 1 had very severe periodic breathing with long apnoeic spells and he awoke with paroxysmal nocturnal dyspnoea during the hyperventilatory phase. However, the sleep disturbances did not occur until he had been sleeping for nearly 2 h. He had complained of nocturnal breathlessness for 10 years, but the reason for his investigation was his complaint of tiredness and sleepiness in the day. Patient 2 was recovering from heart-failure with treatment. Her periodic breathing pattern did not include apnoeic periods or paroxysmal dyspnoea but her sleep was disturbed on seven occasions and it is likely that this milder disturbance may have contributed to tiredness or sleepiness in the day. Cheyne-Stokes respiration occurs with many conditions and a study of 2000 subjects without pulmonary or neurological disease found periodic or wavelike respiration in 30 subjects (1.5%) and Cheyne-Stokes respiration in 10 (0-5%). A clinical history was available in 8 of these 10 subjects and it is interesting that 4 had hypersomnia. Cheyne-Stokes breathing is more common during sleep, especially in men over the age of 50.4 The most widely accepted theory for the sensation of dyspnoea is that of length-tension imbalance in which dyspnoea results from an inadequate movement or volume for the force generated. Therefore CheyneStokes breathing with normal lung mechanics should not cause dyspnoea. In left-heart failure the compliance of the lung is decreased and the volume inspired for a given respiratory drive is less than normal. If the respiratory drive is increased, as in exercise or the hyperventilatory phase of Cheyne-Stokes respiration, then dyspnoea is likely to result. At night when these patients lie down venous return to the right heart is increased and this may lead to a further decrease in lung compliance. This increased venous return is the usual explanation for orthopncea and paroxysmal nocturnal dyspnoea. The combination of decreased lung compliance and Cheyne-Stokes respiration produces a situation in which repeated episodes of dyspncea might be expected to occur. Sitting up gives relief by improving lung mechanics and because periodic breathing is exacerbated by the supine posture in heart failure.6 Paroxysmal nocturnal dyspnoea caused by periodic breathing can probably be distinguished from the more severe dyspnoea of cardiac asthma by careful questioning and this may be confirmed by observing the patient closely at night. Aminophylline often eradicates CheyneStokes breathing in man, possibly by reducing the threshold of response to carbon dioxide.7,8 Since aminophylline also increases cardiac output and causes vasodilatation and diuresis it might be an alternative treatment in this situation.
Mild Cheyne-Stokes breathing in heart-failure may contribute to tiredness in the day. When the CheyneStokes breathing is more extreme, the patient may awake with dyspnoea at the start of sleep or later in the night. This picture should be differentiated from more severe situations in which episodes of pulmonary oedema develop during sleep. Severe Cheyne-Stokes breathing may be present all the time, preventing the patient from sleeping for more than a few minutes. Requests for reprints should be addressed
to
P.
J. R.
REFERENCES
1. Harrison WG, Calhoun JA, Harrison TR. Congestive heart failure. Clinical types of nocturnal dyspnœa. Arch Intern Med 1934; 53: 561-73. 2. Harrison TR, King CE, Calhoun JA, Harrison WG. Congestive heart failure. Cheyne-Stokes respiration as the cause of paroxysmal dyspnœa at the onset of sleep. Arch Intern Med 1934; 53: 891-910. 3. Specht H, Fruhmann G. Incidence of periodic breathing in 2000 subjects without pulmonary disease or neurological disease. Bull Physio-path Resp
1972; 8: 1075-83. 4. Webb P. Periodic breathing during sleep. J Appl Physiol 1974; 37: 899-903. 5. Campbell EJM, Howell JBL. The sensation of breathlessness. Br Med Bull
1963; 19: 36-40. 6. Altschule MD, Iglauer A. The effect of position on periodic breathing in chronic cardiac decompensation. N Engl J Med 1958; 259: 1064-66. 7. Dowell AR, Heyman A, Sieker HO, Tripathy K. Effect of aminophylline on respiratory centre sensitivity in Cheyne-Stokes respiration and in pulmonary emphysema. N Engl J Med 1965; 273: 1447-53. 8. Moyer JH, Miller SI, Tashnek AB, Bowman R. Effect of theophylline with ethylenediamine (aminophylline) on cerebral hæmodynamics in the presence of cardiac failure with and without Cheyne-Stokes respiration. J Clin Invest 1952; 31: 267-72.
COMPARISON OF HORMONAL AND METABOLIC EFFECTS OF SALBUTAMOL INFUSION IN NORMAL SUBJECTS AND INSULIN-REQUIRING DIABETICS A. S. GÜNDOGDU P. M. BROWN S. JUUL L. SACHS P. H. SÖNKSEN
Department of Medicine, St
Thomas’s Hospital Medical
School, London SE1 7EH A comparison of the metabolic effects of salbutamol in diabetic patients and normal subjects showed that salbutamol infused at 5 and 20 µg/min (a) stimulated hepatic glucose production to a greater extent in diabetic patients than in normal subjects despite prior restoration of the diabetic patients’ fasting blood glucose to normal by an overnight infusion of insulin; (b) caused a greater rise in plasma glucose, free fatty acids, glycerol, and ketone-body concentrations in the diabetic patients; and (c) produced a marked fall in plasma-potassium concentrations. The differences between the diabetic and normal groups were accounted for by an immediate (six-fold) stimulation of insulin secretion in the normal subjects.
Summary
Introduction LARGE intravenous doses of theadrenergic agent salbutamol are increasingly being used in the management of premature labour’ and the treatment of status asthmaticus2 and cardiogenic shock. However, ketoacidosis may develop in pregnant diabetic patients given intravenous salbutamol.1-6 In non-diabetic subjects salbutamol infusions slightly raise plasma-glucose and greatly
1318 increase insulin and free-fatty-acid (FFA) concentrations.7-10 The changes in plasma-glucose and FFA concentrations could be accounted for by the known effects of p-adrenergic stimulation in raising glycogenolysis and lipolysis.1’ In diabetic subjects with limited insulin reserves the metabolic consequences of &bgr;2- adrenergic stimtilation may be greater and could result in significant ketonaemia. We have compared the effect of salbutamol infusion on carbohydrate and fat metabolism in normal subjects with that in insulin-treated diabetic patients.
Subjects
and Methods
Six male medical students, aged 19-22 (mean 20) years, and five male and one female insulin-treated diabetic patients, aged 26-50 (mean 32) years, have been studied. All subjects were within 10% of their ideal body-weight (Metropolitan Life Insurance table). The study was approved by the ethical committee of St Thomas’ Hospital, and informed consent was obtained from all subjects. The diabetic patients were on twice-daily injections of a variety of short and medium acting insulins, their average daily insulin requirements being 46 units (range 16-88) and their duration of insulin treatment ranging from 6 months to 6 years. ’Actrapid MC’ insulin was substituted for the patient’s normal morning insulin 24 h before the study; that evening the patients were admitted to hospital for an intravenous infusion of insulin after their evening meal. The rate of infusion was
adjusted frequent ’Dextrostix’/’Eyetone’ blood-glucose determinations, so as to maintain the blood-glucose concentrawith
tion between 4 and 5 mmol/1; the rate of insulin infusion required ranged from 0-24 to 0.90 units/h and correlated closely with the patients’ normal daily insulin requirements (r=0-87) The rate of insulin infusion that maintained normoglycsmia was continued overnight and throughout the study. All subjects were given a priming dose of 33 :.:.Ci of 3tritiated glucose (Radio Chemical Centre Amersham), followed by a constant intravenous infusion of 0.33 ;.Ci/min. After a 2 h equilibration period salbutamol was infused intravenously at 5 ::g/min for 1 h and then at 20 ;’.g/min for 1 h. The salbuHORMONAL, METABOLIC, HEART-RATE, AND BLOOD-PRESSURE
tamol infusion was then stopped and the experiment was continued for a further hour. Blood samples were taken from an indwelling intravenous cannula at 10 min intervals for the measurement of plasma glucose, glucose specific activity, insulin, growth hormone, and C-peptide concentrations, at halfhourly intervals for plasma FFA, potassium, glucagon, and cyclic AMP determination, and at hourly intervals for blood glycerol, 3-OH-butyrate, acetoacetate, lactate, and pyruvate. Measurements of systolic and diastolic blood-pressure with ’Arteriosonde 1217’ (Roche Ltd) and heart-rate were recorded at 10 min intervals. Plasma glucose was measured by a glucose-oxidase method with a Beckman glucose analyser. Glucose specific activity was measured after deproteinisation and lyophilisation by liquid scintillation counting, and the rates of appearance (Ra) and disappearance (Rd) of glucose were calculated by the method of Steel et al.12,13 Plasma insulin, growth hormone, C-peptide, glucagon, cortisol, and cyclic AMP were measured by radioimmunoassay by the use of specific antisera. FFA were determined by fluorometry after Dole extraction,14 intermediary carbohydrate metabolites by enzyme fluorometry,"’" and plasma-potassium by flame photometry. Standard statistical methods by the use of paired and un-
paired t tests were applied. Results Cardiovascular Responses Heart-rate in the normal subjects rose significantly from 56+2.5/min (mean+SEM) to (p
