00468
2013
AOPXXX10.1177/1060028013500468Annals of PharmacotherapyAndrews et al
Research Report-Pediatrics
Acetazolamide in Critically Ill Neonates and Children With Metabolic Alkalosis
Annals of Pharmacotherapy 47(9) 1130–1135 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013500468 aop.sagepub.com
Megan G. Andrews, PharmD1, Peter N. Johnson, PharmD, BCPS1, Erin M. Lammers, PharmD, BCPS2, Donald L. Harrison, FAPhA, PhD1, and Jamie L. Miller, PharmD, BCPS1
Abstract Background: Acetazolamide is an option for hypochloremic metabolic alkalosis, but there are limited reports in children. Objective: To describe the acetazolamide regimen and outcomes in critically ill children with metabolic alkalosis. Methods: This was a descriptive, retrospective study of patients 7.45 and bicarbonate [HCO3] > 26 mEq/L). Patients receiving other treatments for metabolic alkalosis within 24 hours of acetazolamide were excluded. The primary objective was to identify the mean dose and duration of acetazolamide. Secondary objectives were to determine the number of patients with treatment success (ie, serum HCO3 22-26 mEq/L) and occurrence of adverse events. Results: Thirty-four patients were included for analysis, the median age was 0.25 years (range = 0.05-12 years). The acetazolamide regimen included a mean dose of 4.98 ± 1.14 mg/kg for a mean number of 6.1 ± 5.3 (range = 3-24) doses. The majority (70.6%) received acetazolamide every 8 hours. Treatment success was achieved in 10 (29.4%) patients. Statistically significant differences were noted between the preacetazolamide and post-acetazolamide pH and HCO3, 7.51 ± 0.05 versus 7.37 ± 0.05 (P < .001) and 39.4 ± 6.1 mEq/L versus 31.4 ± 7.5 mEq/L (P < .001), respectively. Conclusions: This is the first study to evaluate acetazolamide dosing for metabolic alkalosis in children with and without cardiac disease. Acetazolamide treatment resulted in improved HCO3, but the majority of patients did not achieve our definition of treatment success. Future studies should elucidate the optimal acetazolamide regimen. Keywords acetazolamide, metabolic alkalosis, pediatric, critically ill, neonate
Introduction Metabolic alkalosis is a common acid-base disorder that occurs in critically ill children. This complication has been reported in approximately half of pediatric patients after cardiac surgery.1,2 Without treatment, severe metabolic alkalosis may result in significant adverse consequences, including impaired perfusion, diminished respiratory drive, cardiac arrhythmias, seizures, and death.3-5 Identifying the underlying pathophysiology is essential to the management of this acid-base disorder. Metabolic alkalosis is classified as chloride responsive or chloride resistant.3,6 Etiologies of chloride-responsive metabolic alkalosis are chloridedepleting diuretic therapy (eg, furosemide and chlorothiazide) and gastrointestinal loss (eg, vomiting and nasogastric suctioning). Alternatively, chloride-resistant metabolic alkalosis commonly occurs secondary to excessive mineralocorticoid activity or severe hypokalemia.
Chloride-responsive metabolic alkalosis is treated by correcting the underlying cause and/or replacing chloride with or without extracellular fluid replacement.6 Chloride can be replaced by enteral or intravenous (IV) sodium or potassium chloride supplements. However, the use of these electrolyte supplements may be limited in the presence of hypernatremia and hyperkalemia. Other options for chloride replacement include hydrochloric acid, ammonium chloride, and arginine hydrochloride.7 Children with volume overload may not be able to tolerate the additional 1
University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA University of Missouri Healthcare, Columbia, MO, USA
2
Corresponding Author: Jamie L. Miller, PharmD, BCPS, Department of Pharmacy; Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, PO Box 26901, Oklahoma City, OK 73117, USA. Email: [email protected]
1131
Andrews et al fluid necessary to replace their chloride deficit. In these patients, the initiation of acetazolamide, a carbonic anhydrase inhibitor, may be beneficial. Acetazolamide inhibits the carbonic anhydrase enzymes in the proximal renal tubule, resulting in excretion of bicarbonate and sodium while preserving the serum chloride concentration.6,8 There are several reports of successful use of acetazolamide for the treatment of metabolic alkalosis in adult patients.8-11 However, only 1 published study has evaluated the use of acetazolamide for treatment of hypochloremic metabolic alkalosis in children with cardiac disease.12 Because of differences in pharmacokinetic parameters between adults and children and those with and without cardiac disease, it is difficult to extrapolate the results of this study to all critically ill children. Currently, pediatric medication references contain dosing recommendations for acetazolamide in children for the treatment of glaucoma, edema, and epilepsy; however, there are no standard dosing recommendations for the management of metabolic alkalosis.13 Therefore, the purpose of this study was to evaluate acetazolamide dosing in critically ill neonatal and pediatric patients with and without cardiac disease to provide additional data to support dosing of acetazolamide in this population.
Methods Study Design This was a retrospective, descriptive study of acetazolamide use in patients who were 18 years of age and younger admitted to the institution’s 88-bed, level III-C neonatal intensive care unit (NICU) or 25-bed pediatric intensive care unit (PICU) between August 1, 2010, and July 31, 2011. Patients were included if they received at least 3 doses of acetazolamide for the treatment of metabolic alkalosis. For the purpose of this study, metabolic alkalosis was defined as a pH ≥ 7.45 and bicarbonate (HCO3) > 26 mEq/L. This definition was similar to that of Moffett et al.12 Patients were excluded if they received acetazolamide for any other indication; received ammonium chloride, hydrochloric acid, or arginine hydrochloride within 24 hours prior to the evaluated acetazolamide course; and did not meet the defined criteria for metabolic alkalosis or if no blood gas measurements were obtained within 24 hours of initiation and discontinuation of acetazolamide.
Study Objectives and Data Collection Following institutional review board approval, patients who received acetazolamide during the study period were identified in the electronic medical record. Basic demographic data collected included age, postmenstrual age (if premature), sex, weight, and respiratory status (eg, room air,
ventilator, and continuous positive airway pressure). In addition, it was noted whether the patient had a PICU admission diagnosis for postcardiothoracic surgery (CTS) versus non-CTS. Several characteristics of the acetazolamide regimen were collected including milligrams per kilogram per dose, milligrams per dose, route of administration, dosing interval, and number of doses per treatment course. In the event a patient was treated with more than 1 course of acetazolamide, only the first course received within the study period was included in the primary analysis. Concomitant medications that are known to be associated with the development of metabolic alkalosis (eg, diuretics) were also evaluated. For these medications, daily dose, cumulative dose, and dose prior to initiation of acetazolamide were collected. Blood gas measurements (ie, pH, pCO2, HCO3, and base excess [BE]), serum electrolytes, and laboratory measurements of renal function (ie, blood urea nitrogen [BUN], serum creatinine [SCr]) within 24 hours of initiation and discontinuation of acetazolamide therapy were collected to evaluate therapeutic response and potential adverse effects. If multiple lab values were collected within the 24-hour time frame, the values included for analysis were those closest to the 24-hour mark pretherapy and posttherapy. Urine output (UOP) in milliliters per kilogram per hour was also recorded within the same time frame. Patients were grouped based on response to acetazolamide therapy (ie, success vs failure). The primary objective of this study was to describe the mean dose, frequency, and duration of acetazolamide therapy used to treat metabolic alkalosis in critically ill neonates and children. A secondary objective was to assess the number of patients who achieved treatment success. For the purpose of this study, successful treatment was defined as return of serum HCO3 to between 22 and 26 mEq/L. Failure of treatment was defined as the inability to reach this goal and/or the use of alternative treatment (ie, arginine hydrochloride, ammonium chloride, or hydrochloric acid) or another course of acetazolamide within 24 hours following completion of the evaluated acetazolamide course. An additional secondary objective was to evaluate laboratory abnormalities that could be attributed to acetazolamide.
Statistical Analysis Descriptive statistics were used to assess the acetazolamide dose and regimen among all patients. Laboratory variables were compared pre-acetazolamide and post-acetazolamide therapy. A dependent measures t test was used to detect significant differences between pretherapy and posttherapy mean lab values. A comparison of acetazolamide regimen characteristics and laboratory alterations was performed between cases categorized as treatment success versus treatment failure using Fischer’s exact tests, χ2 tests of
1132
Annals of Pharmacotherapy 47(9) Table 2. Blood Gas and Laboratory Data Before and After Acetazolamide Therapy.
Table 1. Baseline Characteristics.
Variable Age (years) Weight (kg) Female CTS PICU Respiratory status Ventilator CPAP Room air Concomitant diuretic therapy: Loop diuretic Loop and thiazide diuretics Length of stay (days)
Number (%) or Mean ± SD (Range), n = 34 1.9 ± 3.4 (0.05-12) 10.9 ± 11.8 (1.5-50.2) 18 (52.9) 11 (32.4) 30 (88.2) 28 (82.3) 4 (11.8) 2 (5.9) 27 (79.4) 27 (100) 5 (18.5) 50 ± 68 (4-338)
Variable pH pCO2 (mm Hg) HCO3 (mEq/L) BE Na (mEq/L) K (mEq/L) Cl (mEq/L) BUN (mg/dL) SCr (mg/dL) UOP (mL/kg/h)
Pretreatment (Mean ± SD)
Posttreatment (Mean ± SD)
P Value
7.51 ± 0.05 50.1 ± 10.5 39.4 ± 6.1 16.2 ± 5.5 139 ± 4.9 3.6 ± 0.97 95 ± 13.8 13 ± 11 0.42 ± 0.33 4.77 ± 2.1
7.37 ± 0.05 54.3 ± 14.1 31.4 ± 7.5 6.6 ± 8.3 138 ± 4.6 3.9 ± 1.0 97 ± 16,3 18 ± 17 0.42 ± 0.39 3.80 ± 1.5
2013
AOPXXX10.1177/1060028013500468Annals of PharmacotherapyAndrews et al
Research Report-Pediatrics
Acetazolamide in Critically Ill Neonates and Children With Metabolic Alkalosis
Annals of Pharmacotherapy 47(9) 1130–1135 © The Author(s) 2013 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028013500468 aop.sagepub.com
Megan G. Andrews, PharmD1, Peter N. Johnson, PharmD, BCPS1, Erin M. Lammers, PharmD, BCPS2, Donald L. Harrison, FAPhA, PhD1, and Jamie L. Miller, PharmD, BCPS1
Abstract Background: Acetazolamide is an option for hypochloremic metabolic alkalosis, but there are limited reports in children. Objective: To describe the acetazolamide regimen and outcomes in critically ill children with metabolic alkalosis. Methods: This was a descriptive, retrospective study of patients 7.45 and bicarbonate [HCO3] > 26 mEq/L). Patients receiving other treatments for metabolic alkalosis within 24 hours of acetazolamide were excluded. The primary objective was to identify the mean dose and duration of acetazolamide. Secondary objectives were to determine the number of patients with treatment success (ie, serum HCO3 22-26 mEq/L) and occurrence of adverse events. Results: Thirty-four patients were included for analysis, the median age was 0.25 years (range = 0.05-12 years). The acetazolamide regimen included a mean dose of 4.98 ± 1.14 mg/kg for a mean number of 6.1 ± 5.3 (range = 3-24) doses. The majority (70.6%) received acetazolamide every 8 hours. Treatment success was achieved in 10 (29.4%) patients. Statistically significant differences were noted between the preacetazolamide and post-acetazolamide pH and HCO3, 7.51 ± 0.05 versus 7.37 ± 0.05 (P < .001) and 39.4 ± 6.1 mEq/L versus 31.4 ± 7.5 mEq/L (P < .001), respectively. Conclusions: This is the first study to evaluate acetazolamide dosing for metabolic alkalosis in children with and without cardiac disease. Acetazolamide treatment resulted in improved HCO3, but the majority of patients did not achieve our definition of treatment success. Future studies should elucidate the optimal acetazolamide regimen. Keywords acetazolamide, metabolic alkalosis, pediatric, critically ill, neonate
Introduction Metabolic alkalosis is a common acid-base disorder that occurs in critically ill children. This complication has been reported in approximately half of pediatric patients after cardiac surgery.1,2 Without treatment, severe metabolic alkalosis may result in significant adverse consequences, including impaired perfusion, diminished respiratory drive, cardiac arrhythmias, seizures, and death.3-5 Identifying the underlying pathophysiology is essential to the management of this acid-base disorder. Metabolic alkalosis is classified as chloride responsive or chloride resistant.3,6 Etiologies of chloride-responsive metabolic alkalosis are chloridedepleting diuretic therapy (eg, furosemide and chlorothiazide) and gastrointestinal loss (eg, vomiting and nasogastric suctioning). Alternatively, chloride-resistant metabolic alkalosis commonly occurs secondary to excessive mineralocorticoid activity or severe hypokalemia.
Chloride-responsive metabolic alkalosis is treated by correcting the underlying cause and/or replacing chloride with or without extracellular fluid replacement.6 Chloride can be replaced by enteral or intravenous (IV) sodium or potassium chloride supplements. However, the use of these electrolyte supplements may be limited in the presence of hypernatremia and hyperkalemia. Other options for chloride replacement include hydrochloric acid, ammonium chloride, and arginine hydrochloride.7 Children with volume overload may not be able to tolerate the additional 1
University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA University of Missouri Healthcare, Columbia, MO, USA
2
Corresponding Author: Jamie L. Miller, PharmD, BCPS, Department of Pharmacy; Clinical and Administrative Sciences, University of Oklahoma College of Pharmacy, PO Box 26901, Oklahoma City, OK 73117, USA. Email: [email protected]
1131
Andrews et al fluid necessary to replace their chloride deficit. In these patients, the initiation of acetazolamide, a carbonic anhydrase inhibitor, may be beneficial. Acetazolamide inhibits the carbonic anhydrase enzymes in the proximal renal tubule, resulting in excretion of bicarbonate and sodium while preserving the serum chloride concentration.6,8 There are several reports of successful use of acetazolamide for the treatment of metabolic alkalosis in adult patients.8-11 However, only 1 published study has evaluated the use of acetazolamide for treatment of hypochloremic metabolic alkalosis in children with cardiac disease.12 Because of differences in pharmacokinetic parameters between adults and children and those with and without cardiac disease, it is difficult to extrapolate the results of this study to all critically ill children. Currently, pediatric medication references contain dosing recommendations for acetazolamide in children for the treatment of glaucoma, edema, and epilepsy; however, there are no standard dosing recommendations for the management of metabolic alkalosis.13 Therefore, the purpose of this study was to evaluate acetazolamide dosing in critically ill neonatal and pediatric patients with and without cardiac disease to provide additional data to support dosing of acetazolamide in this population.
Methods Study Design This was a retrospective, descriptive study of acetazolamide use in patients who were 18 years of age and younger admitted to the institution’s 88-bed, level III-C neonatal intensive care unit (NICU) or 25-bed pediatric intensive care unit (PICU) between August 1, 2010, and July 31, 2011. Patients were included if they received at least 3 doses of acetazolamide for the treatment of metabolic alkalosis. For the purpose of this study, metabolic alkalosis was defined as a pH ≥ 7.45 and bicarbonate (HCO3) > 26 mEq/L. This definition was similar to that of Moffett et al.12 Patients were excluded if they received acetazolamide for any other indication; received ammonium chloride, hydrochloric acid, or arginine hydrochloride within 24 hours prior to the evaluated acetazolamide course; and did not meet the defined criteria for metabolic alkalosis or if no blood gas measurements were obtained within 24 hours of initiation and discontinuation of acetazolamide.
Study Objectives and Data Collection Following institutional review board approval, patients who received acetazolamide during the study period were identified in the electronic medical record. Basic demographic data collected included age, postmenstrual age (if premature), sex, weight, and respiratory status (eg, room air,
ventilator, and continuous positive airway pressure). In addition, it was noted whether the patient had a PICU admission diagnosis for postcardiothoracic surgery (CTS) versus non-CTS. Several characteristics of the acetazolamide regimen were collected including milligrams per kilogram per dose, milligrams per dose, route of administration, dosing interval, and number of doses per treatment course. In the event a patient was treated with more than 1 course of acetazolamide, only the first course received within the study period was included in the primary analysis. Concomitant medications that are known to be associated with the development of metabolic alkalosis (eg, diuretics) were also evaluated. For these medications, daily dose, cumulative dose, and dose prior to initiation of acetazolamide were collected. Blood gas measurements (ie, pH, pCO2, HCO3, and base excess [BE]), serum electrolytes, and laboratory measurements of renal function (ie, blood urea nitrogen [BUN], serum creatinine [SCr]) within 24 hours of initiation and discontinuation of acetazolamide therapy were collected to evaluate therapeutic response and potential adverse effects. If multiple lab values were collected within the 24-hour time frame, the values included for analysis were those closest to the 24-hour mark pretherapy and posttherapy. Urine output (UOP) in milliliters per kilogram per hour was also recorded within the same time frame. Patients were grouped based on response to acetazolamide therapy (ie, success vs failure). The primary objective of this study was to describe the mean dose, frequency, and duration of acetazolamide therapy used to treat metabolic alkalosis in critically ill neonates and children. A secondary objective was to assess the number of patients who achieved treatment success. For the purpose of this study, successful treatment was defined as return of serum HCO3 to between 22 and 26 mEq/L. Failure of treatment was defined as the inability to reach this goal and/or the use of alternative treatment (ie, arginine hydrochloride, ammonium chloride, or hydrochloric acid) or another course of acetazolamide within 24 hours following completion of the evaluated acetazolamide course. An additional secondary objective was to evaluate laboratory abnormalities that could be attributed to acetazolamide.
Statistical Analysis Descriptive statistics were used to assess the acetazolamide dose and regimen among all patients. Laboratory variables were compared pre-acetazolamide and post-acetazolamide therapy. A dependent measures t test was used to detect significant differences between pretherapy and posttherapy mean lab values. A comparison of acetazolamide regimen characteristics and laboratory alterations was performed between cases categorized as treatment success versus treatment failure using Fischer’s exact tests, χ2 tests of
1132
Annals of Pharmacotherapy 47(9) Table 2. Blood Gas and Laboratory Data Before and After Acetazolamide Therapy.
Table 1. Baseline Characteristics.
Variable Age (years) Weight (kg) Female CTS PICU Respiratory status Ventilator CPAP Room air Concomitant diuretic therapy: Loop diuretic Loop and thiazide diuretics Length of stay (days)
Number (%) or Mean ± SD (Range), n = 34 1.9 ± 3.4 (0.05-12) 10.9 ± 11.8 (1.5-50.2) 18 (52.9) 11 (32.4) 30 (88.2) 28 (82.3) 4 (11.8) 2 (5.9) 27 (79.4) 27 (100) 5 (18.5) 50 ± 68 (4-338)
Variable pH pCO2 (mm Hg) HCO3 (mEq/L) BE Na (mEq/L) K (mEq/L) Cl (mEq/L) BUN (mg/dL) SCr (mg/dL) UOP (mL/kg/h)
Pretreatment (Mean ± SD)
Posttreatment (Mean ± SD)
P Value
7.51 ± 0.05 50.1 ± 10.5 39.4 ± 6.1 16.2 ± 5.5 139 ± 4.9 3.6 ± 0.97 95 ± 13.8 13 ± 11 0.42 ± 0.33 4.77 ± 2.1
7.37 ± 0.05 54.3 ± 14.1 31.4 ± 7.5 6.6 ± 8.3 138 ± 4.6 3.9 ± 1.0 97 ± 16,3 18 ± 17 0.42 ± 0.39 3.80 ± 1.5
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