RESEARCH ARTICLE ISSN 2278 – 2818

THE EFFECT OF BRONCHIAL ASTHMA ATTACK AND ANTI-ASTHMA MEDICATIONS ON THE BLOOD GLUCOSE CONCENTRATION Abdalla Mohamed Albasha1 and Mohamed Faisal Lutfi2† ABSTRACT Background: Theoretically, anti-asthma medications can increase blood glucose concentration, however, several reports failed to demonstrate hyperglycemic effects of these medications. Aims: 1) To evaluate the effects of long-term and short-term anti-asthma medications on the blood glucose concentrations. 2) To assess the effect of acute asthma attack on glycaemic control. Materials and Methods: The study included a study group of 66 asthmatic patients and a control group of 34 apparently healthy subjects. Patients were classified according to the current medications into offtreatment, salbutamol only and combined therapy (salbutamol and steroids) groups. The random blood glucose (RBG) concentrations were measured just before giving (pre-dose) and 20 minutes following (post-dose) salbutamol nebulizer in 33 asthmatic patients. In the remaining asthmatic patients, RBG concentrations were measured just before giving (pre-dose) and 20 minutes following (post-dose) combined therapy i.e. salbutamol nebulizer and intravenous hydrocortisone. Results: The means of RBG concentrations were not significantly different when asthmatic patients on attack (M ± SD = 109.13 ± 23.03 mg/dl) were compared with the control group (M ± SD = 102.59 ± 15.87 mg/dl, P = 0.291). The means of RBG concentrations were not significantly different when off-treatment asthmatic patients (M ± SD = 106.84 ± 17.50 mg/dl) were compared with the control group, those on salbutamol only (M ± SD = 112.55 ± 25.74 mg/dl) and asthmatic patients on both salbutamol and steroid therapy (M ± SD = 99.56 ± 19.60 mg/dl) (P> 0.05 for all). There was significant increase in RBG concentrations following treatment with salbutamol nebulizer (P = 0.000) and combined therapy with both salbutamol nebulizer and hydrocortisone injection (P = 0.009). Conclusion: In contrast long-term anti-asthma medications, acute asthma therapies induce hyperglycemia, probably due to higher bioavailability of these medications in the systemic circulation. KEYWORDS: Anti-asthma medications, bioavailability, hyperglycemia. INTRODUCTION Several evidences suggest intimate relationship between hyperglycemia and bronchial asthma. Physiologically, acute asthma attacks are expected to increase diabetogenic stress hormones like glucocorticoids [1, 2] and catecholamines [3, 4]. Pathologically, recent researches revealed numerous proofs for the co-existence of insulin resistance and bronchial asthma [5-8]. Pharmacologically, beta-2 agonists and steroids are the most popular anti-asthma treatments and, theoretical speaking, both can induce hyperglycemia.

The random blood glucose (RBG) concentrations were measured just before giving (pre-dose) and 20 minutes following (post-dose) salbutamol nebulizer (10 mg/2ml salbutamol solution) in thirty-three asthmatic patients. In the remaining asthmatic patients (thirty-three subjects), RBG concentrations were measured just before giving (predose) and 20 minutes following (post-dose) combined therapy i.e. salbutamol nebulizer (10 mg/2ml salbutamol solution) and intravenous hydrocortisone (100 mg).

However, several recent [9, 10] and old [11] reports failed to demonstrate hyperglycemic effects of these medications. The majority of anti-asthma medications are delivered through inhalation to their main site of action i.e. pulmonary airways. Consequently, only small amounts of these medications are offered to the diseased airways. The general circulation will have only minute concentrations of anti-asthma medications which enhance their clearance by the appropriate excretory systems [12]. Both low concentrations and enhanced clearance of anti-asthma medications are probable explanations for loss of their hyperglycemic effects [11, 13, 14].

Statistical evaluation was performed using the Microsoft Office Excel (Microsoft Office Excel for windows; 2007) and SPSS (SPSS for windows version 19). Normal distribution of studied variables was examined using Shapiro-Wilk test. Unpaired T-test and Mann-Whitney U test were used to assess significant difference in the means of the pre-dose RBG in the different patients groups receiving different long-term therapies for bronchial asthma. The effect of acute asthma attack on glycaemic control was assessed by comparing the blood glucose concentrations of off-treatment asthmatic patients with acute attack with the apparently healthy subjects. Paired Ttest was used to assess the effects of salbutamol nebulizer and combined therapy on RBG. P< 0.05 was considered significant.

For further verification of this hypothesis, the present study aimed to assess the effects of long-term and short-term anti-asthma medications on the blood glucose concentrations. Moreover, the effect of acute asthma attack on glycaemic control was also evaluated.

RESULTS

MATERIALS AND METHODS

The means of RBG concentrations were not significantly different when asthmatic patients (M ± SD = 109.13 ± 23.03 mg/dl) were compared with the control group (M ± SD = 102.59 ± 15.87 mg/dl, P = 0.291), and when asthmatic patients on continuous asthma medication (M ± SD = 109.34 ± 25.02 mg/dl) were compared with asthmatic patients on irregular asthma medication (M ± SD = 108.63 ± 17.75 mg/dl, P = 0.686).

The study included a study group of sixty-six asthmatic patients (50% were males, age mean (M) ± standard deviation (SD) = 30 ± 7.8 years) and a control group of thirty-four apparently healthy subjects (50% were males, age M ± SD = 34 ± 9.1 years). The asthmatic patients were recruited from emergency rooms of Khartoum State teaching hospitals – Sudan. All subjects of the study group were known asthmatic patients for more than one year and had acute attacks of asthma at the time of examination. Patients with diabetes mellitus, previous abnormal blood glucose level, glucosuria, chronic illnesses and pregnant ladies were excluded from the study. All examined asthmatic patients had not eaten meals within the last hour and had not taken anti asthmatic medications within the last day before measuring their blood glucose levels. Asthma history was recorded at the time of examination together with the previous asthma medications. Patients were classified according to the current medications into off-treatment, salbutamol only and combined therapy (salbutamol and steroids) groups.

Regarding effects of current daily medications at the time of examination, the means of RBG concentrations were not significantly different when off-treatment asthmatic patients (M ± SD = 106.84 ± 17.50 mg/dl) were compared with the control group (P = 0.464), those on salbutamol only (M ± SD = 112.55 ± 25.74 mg/dl, P = 0.686) and asthmatic patients on both salbutamol and steroid therapy (M ± SD = 99.56 ± 19.60 mg/dl, P = 0.337). As shown in table-1 and figure-1, there was significant increase in RBG concentrations following treatment with salbutamol nebulizer (P = 0.000) and combined therapy with both salbutamol nebulizer and hydrocortisone injection (P = 0.009).

1MSc,

Department of Physiology, Faculty of Medicine and health Sciences, Alneelain University PhD, Department of Physiology, Faculty of Medicine and health Sciences, Alneelain University. †Corresponding author: [email protected] 2MSc,

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Table1. Effect of acute asthma medications on blood glucose concentrations. Asthma medication Salbutamol Nebulizer (10 mg) Salbutamol Nebulizer (10 mg) and Hydrocortisone (IV 100mg)

95% Confidence Interval of the Difference Lower Upper

Pre-dose (M ± SD)

Post-dose (M ± SD)

Mean Difference

P

107.9±17.2

119.3±28.0

-11.4

0.000

-17.8

-5.0

109.2±27.8

117.1±30.1

-7.9

0.009

-13.6

-2.1

Figure 1. Effect of acute asthma medications on blood glucose concentrations.

DISCUSSION The current study revealed three main findings regarding glycaemic control in asthmatic patients: 1) the RBG concentrations were not significantly different in off-treatment asthmatic patients compared with the control group. 2) The RBG concentrations were not significantly different when off-treatment asthmatic patients were compared with those patients receiving different type of anti-asthma medications. 3) There was significant increase in RBG concentrations following treatment of acute asthma attacks with either salbutamol nebulizer alone or combined therapy i.e. salbutamol nebulizer and hydrocortisone injection. Impaired glycaemic control in asthmatic patients is well established in the literature [7, 9, 10, 15]. Hyperglycemia associated with bronchial asthma can be attributed to anti-asthma medications, namely beta-2 agonists and steroid therapy [13-15, 16], or to the higher levels of diabetogenic hormones released as a result of repeated stress induced by asthma attacks [1-4]. Recently, there are growing evidences that suggest coexistence of insulin resistance with bronchial asthma [5-8] especially in obese patients [17].

medications which enhance their clearance by the liver and the kidneys [12]. Both low concentrations and enhanced clearance of anti-asthma medications are probably possible causes for decreased endocrinometabolic effects of these drugs [11, 13, 14]. On the other hand, there was significant increase in RBG concentrations following treatment of acute asthma attacks with either salbutamol nebulizer alone or combined therapy i.e. salbutamol nebulizer and hydrocortisone injection. The RBG was measured 20 minutes following administration of intravenous hydrocortisone and/or nebulized salbutamol. Definitely, the bioavailability of both salbutamol nebulizer [19, 20] and intravenous hydrocortisone [21, 22] to the systemic circulation continued for more than 20 minutes following their administration; offering all endocrinometabolic effects of both drugs to the whole body [16, 23-24]. In conclusion, the current data failed to demonstrate hyperglycemic effects of bronchial asthma as well as its long-term medications. In contrast, acute asthma therapies, namely salbutamol nebulizer and intravenous hydrocortisone, induce hyperglycemia putting asthmatic patient at risk of other possible endocrinometabolic effects of these drugs.

However, the current results showed no significant difference when comparing blood glucose levels of asthmatic patients with the control group. Absence of significant difference in the mean of blood glucose levels remained even when comparing of off-treatment asthmatic patients with the control group, disputing previous reports on the hyperglycemic effect of bronchial asthma. This finding preclude from drawing a conclusion that all asthmatic patients are at risk of developing hyperglycemia. Hyperglycemia associated with bronchial asthma appeared to be more frequent in obese asthmatic patients. This hypothesis is supported by the findings of Husemoen et al [8] and others [17, 18] that proved the association of insulin resistance with asthma in obese asthmatic patients. Husemoen et al examined the association of obesity and insulin resistance with asthma and aeroallergen sensitization [8]. Their results revealed that insulin resistance was associated with aeroallergen sensitization and allergic asthma. Moreover, the associations of obesity with aeroallegen sensitization and allergic asthma became nonsignificant after adjustment for insulin resistance, whereas the association of obesity with non-allergic asthma was unaffected. The conclusions of Husemoen et al were further supported by another study with a larger sample size which proved the association of obesity and insulin resistance with the incidence of asthma-like symptoms in adults [18].

ACKNOWLEDGEMENT During this work, the authors have collaborated with many colleagues, for whom they have great regards, and they wish to extend my warmest thanks to Dr. Ramaze F. Elhakeem and Dr. Hamdan Z. Hamdan. REFERENCES 1.

Kapoor U, Tayal G, Mittal SK, Sharma VK, Tekur U. Plasma cortisol levels in acute asthma. Indian J Pediatr. 2003 70:965-8. 2. Nakazawa T, Umegae Y, Matsui S, Yoshie Y, Fueki R, Kobayashi S. Serial changes of plasma cortisol levels during various types of asthmatic responses due to allergen inhalation. Ann Allergy. 1986 56:67-71. 3. Berkin KE, Walker G, Inglis GC, Ball SG, Thomson NC. Circulating adrenaline and noradrenaline concentrations during exercise in patients with exercise induced asthma and normal subjects. Thorax. 1988 43:295-9. 4. Zieliński J, Chodosowska E, Radomyski A, Araszkiewicz Z, Kozlowski S. Plasma catecholamines during exercise-induced bronchoconstriction in bronchial asthma. Thorax. 1980 35:823-7. 5. Gulcan E, Bulut I, Toker A, Gulcan A. Evaluation of glucose tolerance status in patients with asthma bronchiale. J Asthma. 2009 46:207-9. 6. Tutuncuoğlu P, Saraç F, Saygili F, Ozgen AG, Yilmaz C, Tüzün M. Diabetes and impaired glucose tolerance prevalences in Turkish patients with impaired fasting glucose. Acta Diabetol. 2008 45:1516. 7. Agrawal A, Mabalirajan U, Ahmad T, Ghosh B. Emerging interface between metabolic syndrome and asthma. Am J Respir Cell Mol Biol. 2011 44:270-5. 8. Husemoen L, Glümer C, Lau C, Mørch L and Linneberg A. Association of obesity and insulin resistance with asthma and aeroallergen sensitization. Allergy. 2008 63:575-82. 9. Lutfi M F. The Hyperglycemic Effect of Bronchial Asthma. Sudan Med J. 2011 47:69-74. 10. Lutfi M F. Effects of β2-agonist therapy on blood pressure, glycaemic control and electrolytes levels of asthmatic patients. Sud JMS. 2011 6:69-74.

A shortcoming of the current study is that it did not consider measuring indicators of insulin resistance, such as body mass indices, blood pressures and lipid profiles, to adjust for while comparing asthmatic patients with the control group. Further researches are desirable to explore the possible explanation for the comparable blood glucose levels in asthmatic and apparently healthy subjects. The absence of significant difference of the RBG concentrations between asthmatic patients and the control group also weaken the hypothesis that long term anti-asthma medications persuade hyperglycemia. This fact is further supported by the failure of present study to demonstrate significant different in RBG concentrations when off-treatment asthmatic patients were compared with those receiving different types of antiasthma medications. Actually, absence of hyperglycemic effect of longterm anti-asthma medications was demonstrated by at least two recent reports in Sudanese asthmatic patients [7, 9]. Most anti-asthma medications are given in small doses by inhalation, which lessen their concentrations in the general circulations [13, 14]. Consequently, the systemic circulation will have lower concentrations of anti-asthma

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11. Yernault J, Leclercq R, Schandevyl W, et al. The endocrinometabolic effects of beclomethasonedipropionate in asthmatic patients. Chest 1977 71:698-702. 12. Bendas ER, Tadros MI. Enhanced transdermal delivery of salbutamol sulfate via ethosomes. AAPS Pharm Sci Tech. 2007 8:E07. 13. Smith A, Banks J, Buchanan K, Cheong B and Gunawardena K. Mechanisms of Abnormal Glucose Metabolism during the Treatment of Acute Severe Asthma. QJM .1992 82:71-80. 14. Neville A, Palmer J, Gaddie J May C, Palmer K and Murchison L. Metabolic effects of salbutamol: comparison of aerosol and intravenous administration. Br Med J. 1977 1:413-4. 15. Koh YI, Choi IS. Lactic acidosis associated with the usual theophylline dose in a patient with asthma. Korean J Intern Med. 2002 17:147-9. 16. Dawson K, Penna A, Manglick P. Acute asthma, salbutamol and hyperglycaemia. ActaPaediatr. 1995 84:305-7. 17. Al-Shawwa B, Al-Huniti N, DeMattia L and GershanW. Asthma and insulin resistance in morbidly obese children and adolescents. J Asthma. 2007 44:469-73. 18. Thuesen BH, Husemoen LL, Hersoug LG, Pisinger C, Linneberg A. Insulin resistance as a predictor of incident asthma-like symptoms in adults. ClinExp Allergy. 2009 39:700-7.

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19. Silkstone VL, Corlett SA, Chrystyn H. Determination of the relative bioavailability of salbutamol to the lungs and systemic circulation following nebulization. Br J Clin Pharmacol. 2002 54:115-9. 20. Hindle M, Chrystyn H. Determination of the relative bioavailability of salbutamol to the lung following inhalation. Br J Clin Pharmacol. 1992 34:311-5. 21. Charmandari E, Johnston A, Brook CG, Hindmarsh PC. Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocrinol. 2001 169:65-70. 22. Derendorf H, Möllmann H, Barth J, Möllmann C, Tunn S, Krieg M. Pharmacokinetics and oral bioavailability of hydrocortisone. J ClinPharmacol. 1991 31:473-6. 23. Liou HH, Chiang SS, Wu SC, Huang TP, Campese VM, Smogorzewski M, Yang WC. Hypokalemic effects of intravenous infusion or nebulization of salbutamol in patients with chronic renal failure: comparative study. Am J Kidney Dis. 1994 23:266-71. 24. Weber-Carstens S, Deja M, Bercker S, Dimroth A, Ahlers O, Kaisers U, Keh D. Impact of bolus application of low-dose hydrocortisone on glycemic control in septic shock patients. Intensive Care Med. 2007 33:730-3.

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THE EFFECT OF BRONCHIAL ASTHMA ATTACK AND ANTI-ASTHMA ...

medications are delivered through inhalation to their main site of action .... insulin resistance with the incidence of asthma-like symptoms in adults. [18].

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