Acetazolamide Therapy for Metabolic Alkalosis in
Pediatric Intensive Care Patients
Carolina Lpez, MD1; Andrs Jos Alcaraz, MD, PhD2,3; Blanca Toledo, MD4;
Luca Cortejoso, PharmD, PhD5; Maite Augusta Gil-Ruiz, MD4
Objective: Patients in PICUs frequently present hypochloremic
metabolic alkalosis secondary to loop diuretic treatment, espe-
cially those undergoing cardiac surgery. This study evaluates the
effectiveness of acetazolamide therapy for metabolic alkalosis in
PICU patients.
Design: Retrospective, observational study.
Setting: A tertiary care childrens hospital PICU.
Patients: Children receiving at least a 2-day course of enteral
acetazolamide.
Interventions: None.
Measurements and Main Results: Demographic variables,
diuretic treatment and doses of acetazolamide, urine output,
serum electrolytes, urea and creatinine, acid-base excess, pH,
and use of mechanical ventilation during treatment were col-
lected. Patients were studied according to their pathology
(postoperative cardiac surgery, decompensated heart failure, or
respiratory disease). A total of 78 episodes in 58 patients were
identified: 48 were carried out in cardiac postoperative patients,
22 in decompensated heart failure, and eight in respiratory
patients. All patients received loop diuretics. A decrease in pH
and Pco2 in the first 72 hours, a decrease in serum Hco3 (mean,
4.654.83; p < 0.001), and an increase in anion gap values
were observed. Urine output increased in cardiac postoperative
patients (4.52.2 vs 5.12.0; p = 0.020), whereas diuretic
treatment was reduced in cardiac patients. There was no signifi-
cant difference in serum electrolytes, blood urea, creatinine, nor
1
Division of Neonatal Critical Care, Gregorio Maran General University
Hospital, Madrid, Spain.
2
Department of Pediatrics, Getafe University Hospital, Universidad Euro-
pea de Madrid, Research Network on Maternal and Child Health and
Development, Getafe, Madrid, Spain.
3
Red SAMID, Spain.
4
Division of Pediatric Critical Care, Gregorio Maraon General University
Hospital, Madrid, Spain.
5
Hospital Pharmacy Service, Gregorio Maran General University Hos-
pital, Madrid, Spain.
The authors have disclosed that they do not have any potential conflicts
of interest.
For information regarding this article, E-mail: aaromero@um.es
Copyright 2016 by the Society of Critical Care Medicine and the World
Federation of Pediatric Intensive and Critical Care Societies
DOI: 10.1097/PCC.0000000000000971
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Copyright 2016 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.
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chloride after the administration of acetazolamide from baseline.
Acetazolamide treatment was well tolerated in all patients.
Conclusions: Acetazolamide decreases serum Hco3 and Pco2
in PICU cardiac patients with metabolic alkalosis secondary to
diuretic therapy. Cardiac postoperative patients present a signifi-
cant increase in urine output after acetazolamide treatment. (Pedi-
atr Crit Care Med 2016; XX:0000)
Key Words: acetazolamide; heart surgery; loop diuretics; metabolic
alkalosis
M
etabolic alkalosis is the most common acid-base
alteration in patients in intensive care. Furthermore,
this complication is commoner in the pediatric
population than in adults. Metabolic alkalosis is associated
with increased morbidity and mortality, especially in patients
admitted to intensive care (13).
Hypochloremic metabolic alkalosis in pediatric patients
admitted to the PICU is associated with high-dose diuretic
therapy, especially in cardiac postoperative patients on loop
diuretics (27). Elevated digestive losses through nasogastric
tube can also contribute to this effect.
Furthermore, metabolic alkalosis may lead to alveolar
hypoventilation and an increase in arterial Pco2, associated to
a compensatory mechanism on the pH. There is limited and
not conclusive data about the possible effect of acetazolamide
treatment that could hasten extubation and reduce duration
of mechanical ventilation (MV) (4, 715). There is until now
no sufficient evidence to support the idea that acetazolamide
accelerates extubation.
First-line therapy for patients with metabolic alkalosis is
fluid/electrolyte replacement or deescalating diuretic therapy
when possible. As a pharmacologic approach in the treatment
of metabolic alkalosis, acetazolamide inhibits carbonic anhy-
drase, a key enzyme for Hco3 reabsorption in the proximal
tubule of the nephron, inducing natriuresis, kaliuresis, and
bicarbonaturia (6). This increased Hco3 excretion in the urine
leads to a normalization of pH in patients with metabolic alka-
losis. There are several studies in adult patients, especially with
heart failure or chronic lung disease, that evidence the efficacy
 Lpez et al
of acetazolamide for the treatment of metabolic alkalosis and
chronic hypoventilation (8, 1015). However, published data
in critically ill children are sparse (2, 5, 7, 16, 17). A recently
published study questions acetazolamides efficacy in cardiac
patients (2).
The aim of this study was to evaluate the efficacy of acet-
azolamide in children admitted to PICU for treatment of
metabolic alkalosis by decreasing of Hco3 across the entire
cohort and in different subgroups of analysis. As a secondary
objective, the impact of this treatment in urine output and the
diuretic score were analyzed.
MATERIALS AND METHODS
Study Design
We carried out a retrospective and observational study from
January 2010 to December 2011 in a tertiary hospital. Patients
receiving acetazolamide were identified using the pharmacy
database.
This study was approved by the Institutional Review Board
of Gregorio Maran Childrens Hospital Medical Center.
Subjects
Patients older than 30 days and younger than 16 years admit-
ted to the PICU receiving at least a 2-day course of oral acet-
azolamide for the treatment of metabolic alkalosis were
included. Patients met criteria for metabolic alkalosis if they
had pH greater than or equal to 7.45, serum Hco3 more than
30 mmol/L, and/or base excess more than 5 mmol/L. Venti-
lated and nonventilated patients were included. Patients who
received acetazolamide for any other indication, those with
primary renal disease or those who underwent any form of
dialysis, were excluded. Patients receiving chronic diuretic use
were not excluded.
Data Collection
Basic demographic variables (age and sex), diagnosis at admis-
sion, morbidity data (hospital stay and need and duration of
MV), and mortality were recorded.
Likewise, diuretic therapy on every patient prior and during
acetazolamide treatment was recorded: furosemide, thiazides,
and spironolactone (dose and route of administration).
Acetazolamide treatment was initiated at the discretion of
the attending physician of PICU, usually at 510mg/kg per
dose every 12 hours. In our institution, acetazolamide was
administered in all patients enterally (nasogastric or transpylo-
ric tube) using hospital pharmacy suspension preparation. We
recorded the doses received each day. Acetazolamide courses
in the same patient were separated at least for 5 days since
the completion of the acetazolamide treatment course to the
beginning of the following one.
Characteristics of the acetazolamide regimen were collected
including milligrams per kilogram per dose, dosing interval,
and number of doses per treatment course. For the purposes
of analysis, the patients with multiple courses of acetazolamide
were considered as separate events.
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Outcome Variables
Baseline and daily (every morning) values of serum sodium,
potassium, chloride, urea, creatinine, and blood gas analysis
(pH, Pco2, calculated Hco3, anion gap [Na + K-Cl-Hco3])
were collected to evaluate the therapeutic response and the
potential complications of acetazolamide administration.
Preacetazolamide and postacetazolamide (after 48hr on acet-
azolamide treatment) values were compared. We searched for
possible adverse effects: metabolic (hyperchloremic acidosis,
hyponatremia, hypokalemia, hypophosphatemia, and poly-
uria), hematologic (agranulocytosis, aplastic anemia, and
thrombocytopenia), immunologic (anaphylaxis), dermato-
logic (rash, Steven-Johnson syndrome, and toxic epidermal
necrolysis), gastrointestinal (vomiting and diarrhea), or neu-
rologic dizziness (confusion).
Similarly, changes in urine output were assessed in catheter-
ized patients by comparing the diuresis (mL/kg/hr) before and
after acetazolamide treatment. We also measured the total daily
diuresis. A diuretic score was calculated before acetazolamide
administration and daily in patients on acetazolamide using
the following formula: furosemide daily dose (mg/kg) plus a
tenth of chlorothiazide daily dose (mg/kg).
We recorded the patients respiratory assistance (ventilated
or nonventilated). Our primary endpoint was to determine the
decrease of Hco3 levels after the initiation of acetazolamide
treatment.
For analysis purposes, patients were stratified into three
groups: postoperative cardiac patients, patients with decom-
pensated heart failure (DCHF), and respiratory patients. We
defined DCHF as the clinical situation with respiratory treat-
ment (invasive or noninvasive positive pressure) and/or IV
vasoactive drug requirements secondary to heart failure in
patients with different cardiac disease including dilated myo-
cardiopathy, acute myocarditis, and congenital cardiac abnor-
malities (not operated, patients having undergone a cardiac
surgery 30 d, and on heart transplant waiting list).
Statistical Analysis
Distributions of continuous variables were tested for normal-
ity with Kolmogorov-Smirnov test. Quantitative variables are
presented as mean and sd or median (interquartile range) and
qualitative variables as frequency and percentage. For normal
distributed variables, a general linear model repeated-measures
procedure with simple contrasts was used, in which the reference
category was the first category (baseline). In addition, differences
to the previous day were analyzed using a paired Student t test. To
compare the measures of different subjects, an unpaired t Student
or one-way analysis of variance test was performed. Multiple/post
hoc group comparisons with Bonferroni test were performed to
determine where the differences between groups were. For non-
normally distributed continuous variables, Wilcoxon signed rank
test or Mann-Whitney Utest were used. To compare qualitative
variables, chi-square and Fisher exact test were used. All tests were
two-sided with the level set at 0.05 for statistical significance.
Data were analyzed using SPSS 20.0 software (IBM SPSS Statistics
for Windows, Version 20.0; IBM Corp, Armonk, NY).
 Online Clinical Investigation

RESULTS in cardiac patients, at 6.33.6 days after admission in respira-

During the study period, 78 treatment courses in 58 patients met
the inclusion criteria. We excluded 16 courses of acetazolamide:
12 of them had a treatment course shorter than 2 days, and in
another four, the use of acetazolamide was due to another indi-
cation. Patients baseline characteristics, acid-base data, diuretic
scores, urine output, plasma creatinine, and electrolytes are pre-
sented in Table 1. Most acetazolamide courses were adminis-
tered to patients admitted after cardiac surgery (61.5%), and the
rest of the acetazolamide courses were administered to patients
admitted for cardiac disease (28.2%) or for respiratory disease
(10.3%). Cardiac surgeries carried out in the first group of
patients included repair of the mitral or tricuspid valve defects,
Fontan procedure, Glenn procedure, atrioventricular canal
repair, correction of Fallot Tetralogy, interventricular communi-
cation closure, and orthotopic heart transplant in five patients.
No differences in baseline characteristics (creatinine, electro-
lytes, diuretic score, and urine output) were observed between
postoperative cardiac, DCHF, or respiratory patients, except for
age: Postoperative cardiac patients were younger than patients
with DCHF (p = 0.037). Furthermore, respiratory patients had
higher Hco3 values and DCHF patients had longer length of
stay (LOS).
The median PICU LOS was 24 days (1273), and treatment
with acetazolamide was started at 8.16.5 days after admission
tory patients, and at 167.5 days after admission in DCHF.
Most patients were on MV when acetazolamide was adminis-
tered (91%). Mortality was observed in 13.8% of the children
(8/58), most of them were chronic patients with a very long
stay at PICU (median, 113 d [33126 d]), to whom 19.2% of
our courses of treatment were conducted.
All patients were on diuretic therapy at the time of acet-
azolamide initiation. In 75 treatment courses (96.1%), patients
were bladder catheterized. It is noteworthy that the major-
ity of the children received high doses of furosemide (58%
were on furosemide infusion over 0.3mg/kg/hr, 31% were
on furosemide infusion under 0.3mg/kg/hr, and 11% on IV
boluses). Forty-three percentage of the patients were receiving
a thiazide diuretic treatment as well and all of them received
spironolactone.
In the majority acetazolamide courses (62%), the acid-
base data were derived from arterial blood gas, otherwise it
was derived from venous blood gas (none capillary analy-
sis were made). In each patient, we used the same source
of blood for pre- and postacetazolamide therapy blood gas
samples.
No patient received any other treatment for metabolic
alkalosis such as hydrochloric acid, arginine hydrochloride, or
ammonium chloride.

Table 1. Baseline Characteristics of the Patients

Postoperative Decompensated Respiratory
All Treatment Cardiac Heart Failure (Eight
Variables (%) Courses (40 Patients, (10 Patients, Patients,
Median (P25P75) sd (58 Patients) 69.0%) 17.2%) 13.8%) p

Acetazolamide courses, n (%) 78 48 (61.5) 22 (28.2) 8 (10.3)

Age (mo) 5 (317) 6 (345) 5 (213)a 2 (415) 0.022
Weight (kg) 5.5 (4.29.5) 5.6 (4.213.7) 4.6 (48.9) 5.2 (4.37.4) 0.100
Sex (male), n (%) 47 (60.3) 28 (58.3) 10 (45.5) 4 (50) 0.095
Mechanical ventilation, n (%) 71 (91.0) 43 (89.6) 17 (77.3) 6 (75) 0.062
pH 7.450.05 7.450.05 7.440.05 7.450.04 0.089
Hco3 (mmol/L)

36.44.7 35.33.6 37.45.1 40.46.9 b
0.008
Sodium (mmol/L) 136.04.0 136.54.3 135.63.7 133.91.6 0.514
Potassium (mmol/L) 3.530.61 3.520.61 3.530.71 3.560.23 0.987
Chloride (mmol/L) 98.111.7 98.714.3 98.15.4 94.55.2 0.646
Anion gap (mmol/L) 4.6 (1.26.9) 5.1 (2.17.2) 3.4 (1.36.5) 2.7 (1.0 to 5.8) 0.316
Carbon dioxide partial 53.89.6 52.38.6 55.110.3 58.911.9 0.150
pressure (mm Hg)
Diuretic scorec 9.396.8 9.86.7 9.47.7 6.915.1 0.546
Urine output (mL/kg/hr) 4.975.4 4.52.2 5.52.7 6.242.7 0.132
PICU length of stay (d) 24 (1273) 17 (846) 27 (33125) 18 (1430) 0.039
Significant postoperative cardiac patients vs decompensated heart failure, Bonferroni test; p = 0.037.
a

b
Significant postoperative cardiac patients vs respiratory patients, Bonferroni test; p = 0.012.
c
Furosemide daily dose (mg/kg/d) plus a tenth of daily dose/kg of hydrochlorothiazide (mg/kg/d).
% refers to percentages of acetazolamide courses. Mean sd, unpaired t test. Median (interquartile range) and Mann-Whitney U test.

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 Lpez et al

Table 2. Blood Gas and Laboratory Data Before and After Acetazolamide Therapy
Variables Baseline 24 Hr 48 Hr 72 Hr p

pH 7.450.05 7.430.05a 7.410.06a 7.420.05a 0.006

Hco3 (mmol/L)

36.44.7 33.74.7 a
32.04.2 a,b
31.84.5 a
< 0.001
Hco3 (mmol/L) 2.73 4.49a 4.345.35a 4.654.83
Chloride (mmol/L) 98.111.7 99.34.7 98.84.1 98.64.7 0.837
Anion gap (mmol/L) 4.911.0 5.64.1 7.23.6a,b 8.14.0a < 0.001
Sodium (mmol/L) 136.04.0 135.03.7 134.33.1 135.14.4 0.071
Potassium (mmol/L) 3.530.61 3.640.63 3.710.60 3.670.57 0.517
Pco2 (mm Hg) 53.89.6 52.48.9 51.19.0 a,b
49.48.1 a,b
0.009
Serum creatinine (mg/dL) 0.29 (0.210.38) 0.28 (0.200.44) 0.714
Serum urea (mg/dL) 42.130.1 46.331.8 0.220
p < 0.05 respect to baseline.
a

p < 0.05 respect to values in previous day.

b

Mean sd or median (P25P75). Hco3 (mmol/L) refers to reduction from baseline of Hco3.
Empty cells indicate no data available.

The median acetazolamide dose was 8.7 (5.010.0) mg/kg/d
with a maximum dose of 20mg/kg/d. The treatment of acet-
azolamide was maintained during 4 (36) days. Enteral admin-
istration of acetazolamide was well tolerated. All patients were
on continuous enteral nutrition by nasogastric or transpyloric
tube, and none of them received parenteral nutrition or other
solution containing Hco3, acetate, nor lactate.
Laboratory values, pretreatment and daily postacetazolamide
treatment, in the study group as a whole are presented in Table 2.
We found significant differences in pH, Hco3, anion gap, and
Pco2. No differences in chloride, sodium, potassium, neither
serum creatinine nor serum urea were observed after 72 hours
of acetazolamide (Table2). A significant progressive decrease in
Hco3 values over time was observed with acetazolamide therapy,
Figure 1. Hco3 serum levels (mmol/L) preacetazolamide (pre-ACTZ)
and after 2 d of treatment (48hr ACTZ) in the three groups of patients
(postoperative cardiac surgery [CS], decompensated heart failure [DHF],
and respiratory patients).
as shown in Table2 and Figure 1. This reduction was noticed
already after the first 24 hours of treatment. On the whole, after
72 hours of acetazolamide administration, a significant reduc-
tion from baseline of calculated serum Hco3 (4.654.83; p <
0.001) was noted (Table2). In addition, pH values decreased
significantly from baseline (Table2). However, there was no sig-
nificant difference in chloride levels with acetazolamide therapy.
Additionally, a significant increase of the anion GAP was noted
(mean, 3.56.8; p < 0.001) at the expense of lowering the Hco3,
since no changes in chloride levels were observed (Table2). A
decrease in Pco2 over time in the first 72 hours was observed,
being significant a progressive decrease from the 48 hours of
treatment on (Table2).
Pre- and postacetazolamide subgroup analysis in plasma
Hco3, pH, Pco2, electrolytes, diuretic score, and urine out-
put are shown in Table 3. Unlike postoperative cardiac and
DCHF patients, Hco3 levels did not significantly decrease
in respiratory patients. The pH decreased significantly after
acetazolamide in postoperative cardiac patients and remained
unchanged after acetazolamide therapy in the other sub-
groups. In a similar way, Pco2 values in blood samples dimin-
ished after acetazolamide treatment only in the postoperative
cardiac patients and Pco2 levels were unchanged in the groups
of patients.
Urine output after initiation of acetazolamide was
unchanged in the cohort as a whole, but increased in post-
operative cardiac patients (4.52.2 vs 5.12; p = 0.02), and
remained unchanged in the DCHF and respiratory groups.
Although the diuretic score remained unchanged in the cohort
as a whole, it was reduced in cardiac patients (postoperative
and DCHF) after acetazolamide therapy as shown in Table3.
DCHF group had a decrease in the diuretic score as the use
of diuretics repetition was diminished secondary to a higher
diuresis during the same day resulting in no difference in the
urine output. Meanwhile, in the postoperative patients, the

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 Online Clinical Investigation

Table 3. Pre- and Postacetazolamide Therapy Plasma Levels of Acid-Base Variables, Ions,
Diuretic Score, and Urine Output
All Postoperative Decompensated Respiratory Eight
78 Acetazolamide Cardiac Heart Failure Acetazolamide
Courses 48 Acetazolamide 22 Acetazolamide Courses
Variables (58 Patients) Courses (40 Patients) Courses (10 Patients) (Eight Patients)

pH
Preacetazolamide 7.450.05 7.450.05 7.440.05 7.450.04
Postacetazolamide 7.410.06 7.420.06 7.410.04 7.370.09
p < 0.001 0.008 0.126 0.093
Hco3 (mmol/L)

Preacetazolamide 36.44.7 35.13.4 37.75.1 38.1 5.0

Postacetazolamide 32.04.2 30.54.0 33.13.3 36.4 3.8
p < 0.001 < 0.001 0.002 0.631
Sodium (mmol/L)
Preacetazolamide 136.04.0 136.54.3 135.63.7 133.91.6
Postacetazolamide 134.33.1 134.83.5 133.42.3 134.32.3
p < 0.001 0.012 0.006 0.465
Potassium (mmol/L)
Preacetazolamide 3.530.61 3.520.61 3.530.71 3.560.23
Postacetazolamide 3.710.60 3.760.53 3.650.51 3.360.64
p 0.145 0.191 0.331 0.632
Chloride (mmol/L)
Preacetazolamide 98.111.7 98.714 98.15.4 94.55.2
Postacetazolamide 98.84.1 99.64.3 97.93.8 97.23.3
p 0.673 0.544 0.680 0.529
Pco2 (mm Hg)
Preacetazolamide 53.89.6 52.38.6 55.110.3 58.911.9
Postacetazolamide 51.19.0 48.47.4 53.58.1 59.314.3
p 0.039 0.007 0.322 0.515
Diuretic scorea
Preacetazolamide 9.396.8 9.86.7 9.47.7 6.915.1
Postacetazolamide 7.56.5 84.9 7.15.4 5.44.6
p < 0.001 0.012 0.012 0.469
Urine output (mL/kg/hr)
Preacetazolamide 4.975.4 4.52.2 5.52.7 6.242.7
Postacetazolamide 5.32.1 5.12 5.62.1 5.82.6
p 0.153 0.020 0.933 0.617
Furosemide daily dose (mg/kg/d) plus a tenth of daily dose/kg of hydrochlorothiazide (mg/kg/d).
a

diuretic score was also lowered but presented an increase in Figure 1 graphically represents Hco3 pre- versus 48 hours
urine output; in the respiratory group, both diuretic score and postacetazolamide repetition levels in the different subgroups,
diuresis remained unchanged. which was predefined as primary endpoint.

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 Lpez et al
No adverse events attributable to acetazolamide were seen,
and no known drug interactions were identified.
DISCUSSION
In our study, we found that the use of acetazolamide signifi-
cantly decreases serum Hco3 in children admitted to inten-
sive care with metabolic alkalosis. This reduction takes already
place in the first 24 hours after initiation despite the main-
tenance of diuretic loop therapy (although it was reduced in
cardiac patients). Most of our acetazolamide courses were
administered to patients (90%) undergoing cardiac surgery or
having severe cardiac insufficiency, which is a common set-
ting for the need of intense diuretic therapy leading often to
metabolic alkalosis (5).
Previous reports have assessed the effect of acetazolamide in
critically ill adult patients in the treatment of hypochloremic
metabolic alkalosis. Most of these studies have unfortunately a
limited population (8, 10, 11). Our results confirm the findings
of three retrospective studies of pediatric patients with cardiac
disease who received treatment with acetazolamide mostly
parenterally (IV) (5, 7, 17).A decline in Hco3 values occurred
progressively in the first 48 hours of acetazolamide treatment,
although it could be already objectified in the first 24 hours.
However, in those patients with a treatment lasting over 48
hours, no significant drop in Hco3 values was observed. Like
other authors have suggested, the duration of acetazolamide
treatment for metabolic alkalosis could be limited for periods
under 2448 hours (2). We did not find changes in chlorine
levels, unlike other previous studies (5, 11, 17), probably due to
the continuation of treatment with loop diuretics in combina-
tion with acetazolamide in all our patients.
In this study, we have observed different responses in the
Hco3 decrease, in the diuretics' score, and in the urine out-
put between our different groups of analysis, the cardiac and
the respiratory patients. The milder response to acetazol-
amide in respiratory patients could be due to an additional
effect of retention of carbonic by their respiratory pathology
that would be added to diuretics use. On the contrary, post-
operative cardiac and DCHF patients did present a decrease
in Hco3 levels, which constitutes a significant finding as
hypochloremic metabolic alkalosis is quite a common com-
plication of high-dose diuretic therapies, especially in cardiac
postoperative patients (27).
Our study is the first one to demonstrate an increase
in diuresis in relation to acetazolamide administration in
critically ill children that occurred in postoperative car-
diac patients (and in the DCHF indirectly by decreasing
the diuretic score), and was independent of the decrease in
serum Hco3 levels. Increasing ions and thus the fluid sup-
ply in the luminal tubule may enhance furosemides effect
on the ascending limb of loop of Henle inhibiting the reup-
take, thereby raising the diuretic effect throughout the neph-
ron segments (5, 6, 18). Studies regarding the diuretic effect
of acetazolamide to date are not conclusive (2, 5, 6, 18), an
effect that has been poorly studied. Thus, Caramelo et al (6)
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mention two cases exhibiting a diuresis increase related to
acetazolamide that could be associated to a raise of the fluid
in the tubular loop of Henle acting as enhancer of the effect
of furosemide. A study with animal models by Zahedi et al
(19) shows that a combination of both acetazolamide and
thiazides is a powerful diuretic treatment. However, in the
studies by Bar et al (2) and Moff et al (5) in pediatric criti-
cally ill patients, no changes in urine output related to acet-
azolamide administration were detected.
In our study, the finding of increased urine output in car-
diac patients (postoperative and DCHF) may be influenced
by the fact that the patients continued to be on diuretics and
probably they had high total body water, unlike respiratory
patients. All of them were on furosemide and spironolac-
tone and on thiazides in some cases. The effect of a proximal
tubule diuretic, such as acetazolamide, disappears at more
distal segments where sodium and water are reabsorbed.
However, if diuretics acting in the successive segments
are associated (furosemide and thiazides), the effect holds
proximally achieving thereby greater diuresis (6, 18, 19).
Accordingly, the association of acetazolamide in patients on
diuretic treatment with furosemide, thiazides, and/or spi-
ronolactone can help improve the diuretic effect and decrease
diuretics resistance.
The diuretic resistance in heart failure is secondary to the
interaction of sodium retention and the renal response during
acute or chronic diuretic therapy by several effects such as the
braking phenomenon, postdiuretic effect, rebound sodium
retention, and the renal adaptation (1921). Acetazolamide as
a combination diuretic therapy could help overcome resistance
to loop diuretics, as it inhibits the proximal convoluted tubule
sodium Hco3 reabsorption.
Nevertheless, due to the retrospective nature of the study,
we cannot verify whether a part of the diuretic effect of acet-
azolamide could be secondary to a clinical improvement and
spontaneous diuresis related to a high total body water of our
cardiac postoperative patients. The differences in the improve-
ment in urine output between postoperative cardiac and respi-
ratory patients could be explained this way. We have to take
into account that the cardiac patients group were started on
acetazolamide on day 8 postoperatively.
In addition to the rapid decrease of Hco3 found in children
treated with acetazolamide, we also observed a decrease in Pco2
(except in our respiratory patients). Because of the retrospec-
tive nature of the study, the respiratory minute volume data of
our patients could unfortunately not be collected. The decrease
in Pco2 could potentially be accompanied by an increase in the
minute volume diminishing compensatory hypoventilation
associated with metabolic alkalosis. The decrease in Hco3 and
pH in these critically ill children, many of them previously
hypoxic and hypercapnic, could be accompanied by a decrease
in Pco2 due to increased ventilation. Acetazolamides second-
ary metabolic acidosis would stimulate the peripheral chemo-
receptors of the carotid artery and the central chemoreceptors
(by cerebrospinal fluid acidification), which could induce an
increase in minute ventilation (increasing both respiratory rate

and tidal volume) (4), facilitating extubation and shortening
the periods of MV.
We did not collect sufficient data to analyze the potential
effect of acetazolamide on respiratory support, and it should
be noted that our study was not designed to assess this aspect.
We did not collect data of the MV settings and extubation
rates of our subgroup of patients and, since many of them
were receiving MV, blood gas variables could have been
modified by changes in ventilator settings. Further prospec-
tive studies that analyze Pco2 and minute volume would be
required, to assess the real impact that this drug may have on
ventilation.
Contrary to Bar et al (2), a recent retrospective study in
critically ill children, acetazolamide reduces Hco3 concen-
tration in our cardiac patients. Our study population is dif-
ferent from that of Bar et al (2). The main differences to that
of Bar et al (2) were the inclusion criteria: 1) We did not
include neonates, excluding patients with neonatal cardiac
surgeries; 2) We included only patients receiving at least a
2-day course of acetazolamide, different to that of Bar et al
(2) that included any duration of treatment courses; 3) The
route of administration in our study was enterally in all our
patients and IV in the study by Bar et al (2) and we admin-
istered lower dosing of acetazolamide; and 4) Our patients
could be on chronic diuretic therapy, contrary to that of Bar
et al (2), in which these patients were excluded.
Furthermore, we collected a greater proportion of patients
with cardiac surgery, possibly with more complex congenital
heart surgeries, whose physiology and operative management
might be different. They were not able to explain the differ-
ence in Hco3 response to acetazolamide between the cardiac
and noncardiac subgroups. Their cardiac patients received
more diuretics and more inotropic drugs than the noncardiac
patients at the time of initiation of acetazolamide therapy.
They proposed that possible differences in physiology and
fluid- or acid-baserelated therapies could explain the differ-
ent response to acetazolamide treatment. In our study, we do
find a positive response in metabolic alkalosis in our cardiac
patients. We have not compared the inotropic requirement in
our subgroup of patients, but there were no differences in the
diuretic score between them at the time of acetazolamide ini-
tiation (Table1). All these differences altogether could possibly
explain the different conclusions between our study and the
study by Bar et al (2).
We have shown that the administration of this drug by
enteral route is well tolerated for children in critical condition,
no adverse effects or drug interactions were attributable to its
administration. The few previous studies carried out in chil-
dren administrated mostly acetazolamide IV (5, 7, 17), while
the enteral route has been generally used in adults reports (8,
10).
We acknowledge some important limitations in our study.
It is a retrospective single center study with a small group of
patients with concomitant diuretic therapy. Furthermore, we
did not take into account electrolyte additives or electrolyte
supplementation by IV or enteral route.
Pediatric Critical Care Medicine www.pccmjournal.org 7
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Online Clinical Investigation
On the other hand, our study has several strengths.
Acetazolamide administration was performed by enteral route
in all patients, and though there was variability in the admin-
istered dose, the dosing interval was always twice daily. We
included patients who received at least two full day course of
treatment, and thus metabolic effects could be better observed
over time than the effect after an isolated drug dose. Finally, all
children included in this study receive all over the study period
the same diuretic treatment, avoiding therefore the confusion
of acetazolamides effect with other diuretic drug, and none of
them received any other treatment for metabolic alkalosis.
However, it is the first study in children to show a poten-
tial diuretic effect associated with the treatment with acetazol-
amide. Further prospective, multicenter, and controlled studies
are needed that analyze the effect of acetazolamide in pediat-
ric patients and the possible limitation of treatment duration
for periods under 48 hours for the treatment of patients with
metabolic alkalosis.
CONCLUSIONS
The use of acetazolamide significantly decreases metabolic
alkalosis and serum Hco3 in cardiac infants and children
admitted to intensive care with metabolic alkalosis, but it did
not do so in respiratory patients in our cohort. Furthermore,
an increase in urine output in postoperative cardiac patients
was observed. The enteral administration of this drug is well
tolerated for children in critical condition. Further repeti-
tion randomized controlled trials should be done to study
acetazolamide possible respiratory effects and potential
effect on the discontinuation on ventilation.
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