Epinephrine-induced hypokalemia: the role of beta adrenoceptors.

Epinephrine was infused intravenously in 9 normal volunteers to plasma concentrations similar to those found after acute myocardial infarction. This study was undertaken on 3 occasions after 5 days of treatment with placebo or the beta-adrenoceptor antagonist, atenolol, which is relatively beta 1 selective, or timolol, which blocks both beta 1 and beta 2 receptors. Epinephrine increased the systolic blood pressure (BP), decreased the diastolic BP and increased the heart rate modestly. These changes were prevented by atenolol. However, after timolol the diastolic BP rose by +19 mm Hg and heart rate fell by -8 beats/min. Epinephrine caused the corrected QT interval to lengthen (0.36 +/- 0.02 to 0.41 +/- 0.06 second). No significant changes were found in the corrected QT interval when subjects were pretreated with atenolol or timolol. The serum potassium decreased from 4.06 to 3.22 mmol/liter after epinephrine. Serum potassium decreased to a lesser extent to 3.67 mmol/liter after atenolol and actually increased to 4.25 mmol/liter after timolol. In a further study with a similar design another nonselective beta blocker propranolol also increased potassium after epinephrine. While atenolol also prevented hypokalemia in this study, it did not block the beta 2-receptor mediated decrease in diastolic BP. Epinephrine-induced hypokalemia results from stimulation of a beta-adrenoceptor linked to membrane sodium/potassium adenosine triphosphatase causing potassium influx. This appears to be predominantly mediated by beta 2 receptors although beta 1 receptors may also play a part.

Peripheral edema in the sleep apnea/hypopnea syndrome.

To clarify the roles of lung function, nocturnal hypoxemia and obesity in the development of peripheral edema in patients with the sleep apnea/hypopnea syndrome (SAHS), 65 consecutive SAHS patients had diagnostic sleep studies and respiratory function testing. Eighteen patients (27%) had peripheral edema without other explanation. Their sleep apnea/hypopnea index was similar to those without edema, but they were more obese (p less than 0.01) and had worse lung function (p less than 0.01) and lower oxygen saturation (SaO2) awake (p less than 0.01). These 18 became more hypoxemic during sleep than predicted from their awake SaO2 (p less than 0.005). Eleven patients with edema had evidence of pulmonary hypertension on cardiac catheterization, chest radiograph, or electrocardiograph and could be weight matched to 11 SAHS patients without edema. Those with right heart failure were more hypoxic (p less than 0.01) when awake, desaturated more frequently during sleep (p less than 0.01), and had lower FEV1% predicted (p less than 0.01). Thus, extent of both daytime and nighttime hypoxemia are important in the development of right heart failure in patients with SAHS.

Role of protriptyline and acetazolamide in the sleep apnea/hypopnea syndrome.

The role of drug therapy in the treatment of the sleep apnea/hypopnea syndrome is unclear. In a randomised, double-blind, placebo-controlled study, we investigated the value of 14-day therapy with protriptyline (20 mg daily) or acetazolamide (250 mg 4 times per day) on symptoms and on the frequency of apneas, hypopneas, arousals, and 4% desaturations in 10 patients with obstructive sleep apnea/hypopnea syndrome. Overall, protriptyline did not have a significant effect either on symptoms or on any of the above polysomnographic criteria. Acetazolamide reduced the apnea/hypopnea frequency [placebo 50 +/- 26 (SD); acetazolamide 26 +/- 20/h of sleep, p less than 0.03] and tended to decrease the frequency of 4% desaturations (placebo 29 +/- 20; acetazolamide 19 +/- 16/h of sleep, p = 0.06). Despite these physiological improvements, acetazolamide did not significantly improve symptoms and paraesthesiae were common. Contrary to earlier studies, we conclude that protriptyline may have a limited role in the treatment of the sleep apnea syndrome. The reason why acetazolamide produced a physiological, but not a symptomatic, response requires further investigation.

Accuracy and significance of scoring hypopneas.

We previously reported that the best definition of hypopneas in the sleep apnea/hypopnea syndrome (SAHS) is based on reduction in thoracoabdominal movement. However, the repeatability of scoring hypopneas from thoracoabdominal movement has not been assessed, nor has the need to record flow as well as thoracoabdominal movement. Thus, two polysomnographers independently scored both apneas and hypopneas on all-night polysomnograms of patients with SAHS. There was close agreement between the polysomnographers for the number of hypopneas (r = 0.98; mean difference 11%) and for the number of apneas (r = 0.99; mean difference 8%). The agreement was similar for the durations of both hypopneas (r = 0.99; mean difference 13%) and apneas (r = 0.99; mean difference 11%). There was also close agreement between the total number of respiratory events scored with and without reference to the flow signal (r = 0.99; mean difference 1.4%) with a maximum under-recognition of 18 events per night in a subject with 237 apneas per night. Thus, hypopneas can be scored reproducibly. In addition, the value of always recording and scoring flow as well as thoracoabdominal signals is questioned.

Accuracy of respiratory inductive plethysmograph in measuring tidal volume during sleep.

Respiratory inductance plethysmography (RIP) has been widely used to measure ventilation during sleep, but its accuracy in this role has not been adequately tested. We have thus examined the accuracy of the RIP by comparing tidal volume measured with RIP with that measured by a pneumotachograph in eight unrestrained normal subjects during sleep. We have also studied the effect of posture on the accuracy of the RIP. In all sleep stages the correlation between RIP tidal volume measurements and expired volume showed relatively poor correlations (mean r = 0.49-0.60), and the bias of the measurements varied widely. Changes in posture altered the correlations between the two measurements, with no systematic differences between positions. When the subjects resumed a position, the 95% confidence intervals of tidal volume measurement did not overlap the original confidence limits in that posture on 13 of 25 occasions. This study shows that the RIP does not accurately measure tidal volume during sleep in unrestrained subjects and should only be used for semiquantitative assessment of ventilation during sleep.

Dose of nebulized ipratropium bromide in acute severe asthma.

The aim of the study was to determine the maximum effective dose of nebulized ipratropium bromide, 0.5 or 1.0 mg, in the treatment of acute severe attacks of asthma. Thirty-two patients (ten males, 19-53 years) who were admitted with acute severe asthma were, in a double-blind trial, randomized to receive either 0.5 or 1.0 mg of isotonic, preservative-free ipratropium bromide nebulized in saline. Ear oxygen saturation, peak flow and heart rate were measured on admission and regularly following nebulization. Two hours after nebulization of the ipratropium, terbutaline (5 mg) was administered by nebulizer and further measurements taken 30 min later. Twenty-six patients completed the study, 13 in each group. Peak expiratory flow (PEF) increased by 51% [1211 min-1 increasing to 1831 min-1 (mean)] in the 0.5-mg ipratropium group, and by 37% (1551 min-1 to 2071 min-1) in the 1.0-mg group. There were no significant differences in heart rate or ear oxygen saturation changes between the groups. Nebulized terbutaline led to a small further rise in peak flow in both groups (341 min-1 in the 0.5-mg group; 411 min-1 in the 1.0-mg group). No side-effects were noticed in either group. We conclude that 0.5 mg of nebulized ipratropium is as effective as 1.0 mg in the treatment of acute severe asthma.

Home ventilation: the Green Lane Hospital experience.

AIMS: To describe the characteristics and outcomes of patients treated with domiciliary nocturnal support ventilation (NSV). METHODS: Case-note review of all patients treated with home NSV by Green Lane Hospital. RESULTS: 111 patients received home NSV between 1990 and 1999. 59 had respiratory failure due to obesity-hypoventilation syndrome (OHS), most of whom were Maori or Pacific Island people. Their mean BMI was 53 kg/m2. They frequently presented acutely, and often in extremis. After a median duration of 22 months treatment, 37 patients continued treatment. Four have died, but none from respiratory failure. Other causes of respiratory failure included: neuromuscular disease (26), kyphoscoliosis (19) and obstructive sleep apnoea (8). Patients who did not have OHS were mostly of New Zealand European ethnicity, required lower ventilation pressures than patients with OHS, and had better arterial blood gases on treatment. After a median follow-up of 35 months, however, fourteen have died. 33 continued on treatment. Both OHS and non-OHS patients had high deprivation scores according to NZdep96. This was most apparent for patients with OHS. CONCLUSIONS: OHS is an important cause of respiratory failure in New Zealand, particularly affecting Maori and Pacific people. The prognosis of OHS treated with NSV appears to be good despite significant co-morbidity.

Excessive beer consumption and beri-beri.

Alcohol-induced 'wet' or cardiac beri-beri is reported in two middle-aged males who consumed excessive amounts of beer. The high carbohydrate and satiety value of beer together with its low thiamine content places the alcoholic beer drinker at particular risk of thiamine deficiency.

Posture and nocturnal asthma.

To investigate whether the supine posture caused sustained bronchoconstriction and could thus contribute to the development of nocturnal asthma, nine patients with nocturnal asthma were studied on two consecutive days, lying supine for four hours on one day and sitting upright for four hours on the other, the order of the two postures being randomised. Peak expiratory flow (PEF), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) were measured immediately before and after the four hours and over the subsequent hour. There was no significant difference between the erect and supine posture for PEF (248 v 248 l/min), FEV1 (1.31 v 1.22 l), or FVC (2.34 v 2.28 l) at the end of the four hours, nor did any significant change develop subsequently. Thus the supine posture is not associated with prolonged bronchoconstriction. As each patient had previously shown an average overnight fall in PEF of more than 20%, this study strongly suggests that the supine posture is not an important cause of overnight bronchoconstriction.

The effect of diuretic therapy on adrenaline-induced hypokalaemia and hypomagnesaemia.

We have examined the interaction between the administration of bendrofluazide, frusemide, spironolactone, and placebo and increased plasma adrenaline concentrations in a double-blind, placebo-controlled, cross over study. We studied healthy subjects on the fourteenth day of each treatment period and after a two hour infusion of adrenaline (0.06 micrograms.kg-1.min-1 [0.33 nmol.kg-1.min-1]) we measured their heart rates, blood pressures, and plasma potassium and magnesium concentrations. There were no differences in heart rates or blood pressures for all four treatments. Baseline potassium concentrations were not significantly different compared to placebo, and plasma potassium fell during the period of the infusion on all study days. this fall was significantly greater on frusemide (0.5 mmol.l-1) and bendrofluazide (0.4 mmol.l-1) compared with both placebo and spironolactone. Baseline plasma magnesium concentration were not different and similar falls in plasma magnesium were seen on all four treatments during and after the adrenaline infusion. We conclude that chronic diuretic therapy with a thiazide diuretic or frusemide may increase the severity of hypokalaemia during short-term rises in plasma adrenaline. Pretreatment with spironolactone had no effect on adrenaline-induced hypokalaemia. None of the diuretics studied altered adrenaline-induced hypomagnesaemia.

Changes in regional ventilation during histamine bronchial challenge in stable asthma.

Our objective was to examine the changes in regional ventilation during histamine-induced bronchoconstriction in stable asthma. We measured regional ventilation by a new method which measures regional distribution of inhaled 127Xe during tidal breathing by a gated method and, by simultaneously measuring 99mTc counts from labelled macroaggregates, allowed for changes in lung shape during the breathing cycle. We studied 10 asthmatic patients [forced expiratory volume in 1 s (FEV1 2.04-4.37 litres)] and measured, in addition to the regional ventilation, oxygen saturation (SaO2), minute ventilation (VE) and tidal volume (Vt) before and after inhaling enough histamine to lower FEV1 by > 20% and/or SaO2 by > 4%. Histamine inhalation reduced FEV1 by 0.44-1.15 liters and SaO2 by 0-4%. It increased VE and functional residual capacity (FRC) in 8 of the 10 patients. The FEV1 fall did not correlate with the SaO2 fall, VE or FRC changes. Histamine inhalation increased apical ventilation in most patients, but the changes in regional ventilation in the left and right lungs were asymmetrical in 17 out of the 30 lung regions studied (upper, middle and lower paired regions in 10 patients). These results demonstrate that histamine bronchial challenge causes uneven regional ventilation. Any resultant change in ventilation-perfusion balance may be the underlying mechanism of oxygen desaturation seen in this procedure and in spontaneous attacks of asthma.

Bronchial compression as a result of lung herniation after pneumonectomy.

A patient developed severe exertional dyspnoea and stridor eight months after a right pneumonectomy for a carcinoid tumour, with a progressive loss of lung function. These events were the result of compression of the left main bronchus against the vertebral column by the mediastinal contents, which had shifted into the right hemithorax with the herniated lung.

The mechanism of salbutamol-induced hypokalaemia.

The following four intravenous treatments were administered in a balanced, randomized Latin square design to eight healthy volunteers: (-)-adrenaline (0.06 microgram kg-1 min-1 for 90 min) + vehicle control (+)-glucose infusion (60 min), salbutamol (120 ng kg-1 min-1 for 30 min) + vehicle control (+)-glucose infusion (90 min), (-)-adrenaline (0.06 microgram kg-1 min-1 for 90 min) + salbutamol (120 ng kg-1 min-1 for 30 min) and two vehicle control infusions of (+)-glucose. All active solutions were preceded by a 1 h control infusion and the control infusion was continued for 1 h following the active solutions. Both the active solutions, (-)-adrenaline and salbutamol were increased stepwise to the above doses. Heart rate and blood pressure were recorded at frequent intervals throughout and venous blood was taken for the estimation of potassium, insulin, glucose, catecholamine and salbutamol levels. Adrenaline levels similar to those seen in acute illness were achieved using this infusion protocol. Salbutamol levels rose throughout the period of the salbutamol infusions and steady-state was not achieved. Potassium levels were unchanged on the control + control study day and fell on all active treatments (0.45 mmol l-1 following (-)-adrenaline + control; 0.48 mmol l-1 following salbutamol + control; 0.93 mmol l-1 following (-)-adrenaline + salbutamol). Insulin levels rose insignificantly after salbutamol alone and fell slightly on all other treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic control of plasma magnesium in man.

Regulation of magnesium balance is poorly understood. However, hypomagnesaemia has been reported in patients in clinical situations where circulating catecholamines are raised including myocardial infarction, cardiac surgery and insulin-induced hypoglycaemia stress tests. The effects of L-adrenaline infusions, sufficient to achieve pathophysiological levels of adrenaline, and of therapeutic intravenous infusions of salbutamol, a beta 2-agonist, on plasma magnesium, plasma potassium, plasma glucose and plasma insulin levels were studied in a placebo-controlled design in eight normal subjects. Plasma magnesium levels fell significantly during the adrenaline infusion and also during the salbutamol infusion, though more slowly. In a 1 h period of observation after cessation of the infusions no recovery of plasma magnesium levels was seen. Significant falls in plasma potassium levels were also observed during both infusions with spontaneous recovery within 30 min after the infusions. No significant changes in plasma insulin levels occurred with either salbutamol or L-adrenaline compared with control. Plasma glucose levels rose significantly during the adrenaline infusion. The study suggests that both L-adrenaline and salbutamol cause shifts in plasma magnesium which are not mediated by insulin. We propose that intracellular shifts of magnesium occur as a result of beta-adrenergic stimulation.

Failure of chronic theophylline therapy to alter circulating catecholamines.

An increase in circulating adrenaline and noradrenaline has been reported following acute dosing with theophyllines. This effect on catecholamines has been proposed as a possible mechanism of action of theophyllines. In a double-blind placebo controlled trial we have studied the effects of 5 days oral theophylline therapy on circulating catecholamines and adrenaline clearance. There were no significant changes in circulating catecholamines or adrenaline clearance following theophylline. We also examined the effects of theophylline on the hypokalaemic and haemodynamic actions of adrenaline. Theophylline increased the hypokalaemia, tachycardia and rise in systolic blood pressure which occurs in response to intravenous infusion of doses of L-adrenaline (0.02-0.06 microgram kg-1 min-1). Our results suggest that chronic theophylline therapy does not significantly increase circulating catecholamines. Increased circulating catecholamine concentrations are thus not an explanation for the chronic actions of theophylline. We have demonstrated significant, potentially hazardous metabolic and haemodynamic interactions between theophylline and adrenaline.

Salbutamol induced hypokalaemia: the effect of theophylline alone and in combination with adrenaline.

1. We have previously shown that salbutamol induced hypokalaemia, like adrenaline induced hypokalaemia, is the result of stimulation of a membrane bound beta 2-adrenoreceptor linked to Na+/K+ ATPase. We have also demonstrated that adrenaline induced hypokalaemia is potentiated by therapeutic concentrations of theophylline. 2. In a single-blind study of 14 normal volunteers, we infused salbutamol in doses used in clinical practice and examined the effects of the addition of theophylline alone or combined with (-)-adrenaline on plasma potassium levels, heart rate and blood pressure. The combinations studied were (i) salbutamol + vehicle control adrenaline infusion + placebo theophylline; (ii) salbutamol + vehicle control adrenaline infusion + theophylline; (iii) salbutamol + adrenaline + theophylline. 3. In a randomised, balanced placebo controlled design oral slow release theophylline or placebo was given for 9 days. Subjects were studied twice on the active limb (days 7 and 9) and once on the placebo limb (day 9) and the procedure was identical on each of the 3 study days except for the solutions administered. 4. Theophylline increased salbutamol induced hypokalaemia and in some individuals profound hypokalaemia (less than 2.5 mmol l-1) was observed with these relatively low doses of salbutamol and theophylline. Adrenaline did not further increase the magnitude of the fall in potassium observed. Combining theophylline with salbutamol increased the tachycardia resulting from the salbutamol infusion. Salbutamol infusion caused a fall in diastolic and rise in systolic blood pressure on all 3 study days and this was not altered by either theophylline or adrenaline alone or together.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary hemodynamics, gas exchange, and the severity of emphysema as assessed by quantitative CT scan in chronic bronchitis and emphysema.

We have used the CT transthoracic scan to measure regional lung density in vivo, as our previous studies have shown that this correlates with the increase in size of distal air spaces, which is a defining characteristic of emphysema. We have studied 32 patients with chronic airflow limitation (FEV1, 15 to 68% predicted) caused by chronic bronchitis and emphysema (synonym, COPD), with a wide range of arterial PO2 (38 to 90 mm Hg) and PCO2 (32 to 63 mm Hg) while breathing air at rest. We could find no significant relationships between the extent of emphysema (as assessed in vivo by the EMI number defining the lowest fifth percentile of the CT density histogram of the lung fields) and either arterial blood gas tensions, mean pulmonary arterial pressure, cardiac output, or calculated total pulmonary vascular resistance while at rest (n = 32) or during supine leg exercise (n = 29). We conclude that the extent of emphysema does not correlate with the clinical or pathologic features of the "pink and puffing" (i.e., mild hypoxemia, no CO2 retention, no pulmonary hypertension, etc.) or "blue and bloated" (i.e., hypoxemia, CO2 retention, pulmonary hypertension) pattern of patients with COPD nor to the spectrum of hemodynamic and gas exchange abnormalities that commonly occur in patients between these two extreme examples. Thus, "pink puffers" should not be equated with "the emphysematous" pattern of this disease. Although these clinicophysiologic patterns remain valid as descriptions, they do not relate to the extent of underlying emphysema in COPD.