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BANDAR LAMPUNG
November 2013

Furosemide: A Review of its Use in

Infants and Children
Marcia L. Buck, Pharm.D., FCCPDisclosures
Pediatr Pharm. 2009;15(8)
Furosemide, the first of the loop diuretics, was introduced in the United
States in 1966. After nearly half a century of use, furosemide has
become one of the most frequently prescribed medications in the
United States.[1,2] In pediatric patients, furosemide is used to reduce
edema in both acute and chronic cardiovascular, pulmonary, and
kidney diseases.[3,4] This issue of Pediatric Pharmacotherapy will
review the basic pharmacology of furosemide and describe recent
studies of its use in infants and children.

Mechanism of Action
Furosemide (4-chloro-N-furfuryl-5-sulfamoylanthranilic acid), like other
loop diuretics, reversibly binds to a chloride binding site on the
Na+2ClK+ cotransporter present on the luminal cell membrane of the
thick ascending limb of the loop of Henle. This cotransporter is
responsible for the movement of sodium out of the urinary space and
into the tubular cell via a concentration gradient. The primary effect of
blocking Na+2ClK+ cotransporter activity is the reduction of sodium
reabsorption by approximately 20 to 30% resulting in natriuresis.
Significant diuresis occurs because water reabsorption is inhibited in
the collecting duct due to reduction in the medullary interstitial
concentrating gradient.[1-4]
To a lesser degree, furosemide also inhibits sodium reabsorption in the
proximal tubule, likely through carbonic anhydrase inhibition and
prostaglandin-mediated changes in renal hemodynamics. A number of
other actions have been proposed as additional mechanisms for the
drug's diuretic effect. The ability of furosemide to accumulate in the
adrenals, lung, spleen, and liver, in addition to the kidneys, has led to
the theory that it may influence fluid status by inhibiting endogenous
corticosteroid production or stimulating metabolism. Other studies
have suggested that furosemide administration results in stimulation of
the renin-angiotensinaldosterone system and prostaglandin production,
as well as increased release of endogenous atrial naturetic factor and
endothelin-1. These effects are tightly interconnected in compensatory
pathways making isolated effects of furosemide difficult to assess in
the intact organism. Very importantly, adaptation in the distal tubule to

the increased sodium concentration produced by prolonged furosemide

administration may result in increased sodium and water reabsorption,
leading to diuretic tolerance.[1-4]

Pharmacokinetics and Pharmacodynamics

Pharmacokinetic studies of furosemide have revealed considerable
interpatient variability. After oral administration, peak serum
furosemide concentrations occur at approximately 1 to 1.5 hours. The
oral bioavailability of furosemide in adults has been estimated at 40 to
60% in most studies. Peak serum concentrations do not differ
significantly between tablets and the oral solution. Estimates of the
volume of distribution in adults range from 4 to 13 L. Furosemide is
highly protein bound (91 to 99%). It is primarily metabolized in the liver
to furosemide glucuronide. The half-life of furosemide in adults is
approximately 1 to 2 hours, but is prolonged in patients with hepatic
disease.[1,2,5]
The pharmacokinetic profile of furosemide has also been evaluated in
infants and children. Mirochnick and colleagues evaluated furosemide
clearance in 10 preterm infants (mean birthweight 0.8290.217 kg,
mean gestational age 26.62.9 weeks).[6] All patients received an
initial dose of 1 mg/kg followed by doses of 1 to 2 mg/kg every 12 or
24 hours, based on clinical response. Serum sampling was conducted
at timed intervals after dose administration. The average volume of
distribution in the sample patients was 0.480.14 L/kg. Bioavailability
of oral furosemide (assessed in three patients) was approximately 84%.
Protein binding was nearly 95%. Clearance was significantly prolonged
in this patient population, with half-life values ranging from 1.8 to 67.3
hours. The half-life of furosemide in infants born at less than 31 weeks
gestation often exceeded 24 hours. In these patients, dosing every 12
hours frequently resulted in furosemide accumulation to potentially
ototoxic levels ( 25 mcg/mL). Renal clearance of furosemide
increased with increasing postconceptional age. By 36 weeks, the
average half-life had declined to 4 hours, similar to that of term
neonates.
The pharmacodynamic response to furosemide is influenced by the
patient's renal function and hydration status. The efficacy of the drug is
dependent on the amount of furosemide excreted into the proximal
tubular lumen. In older children and adults, the typical onset of diuresis
after intravenous (IV) administration is 5 minutes, with a peak effect
within 30 minutes and a duration of 2 to 6 hours.[1-4] A delayed
response is seen in preterm infants or in infants after cardiac surgery,

with an onset within an hour after IV dosing, peak action occurring over
a 3 hour period, and a duration of 6 hours.[7,8]

Clinical Trials in Infants and Children

Furosemide is used in the treatment of many pediatric disease states.
In the acute setting, it is used to treat edema associated with shock or
traumatic brain injury, as well as postoperative volume overload. Longterm furosemide therapy is used in infants with chronic lung disease or
children with nephrotic syndrome or cardiac failure. A wide variety of
pediatric studies have been conducted with furosemide over the past
40 years.[3] Early studies were primarily conducted in preterm infants
with chronic lung disease. More recent papers have focused on the use
of furosemide as a continuous infusion in critically ill infants after
cardiac surgery.[8-12] Continuous infusions of furosemide have been
suggested as a means of optimizing sodium and water excretion while
avoiding wide fluctuations in serum furosemide concentrations and
volume status.
The initial study in this population was published in 1992 by Singh and
colleagues.[8] They conducted a prospective, randomized clinical trial
to compare the effects of intermittent and continuous administration of
furosemide in 20 children (newborn to 4 years of age) after cardiac
surgery. The intermittent group was given 1 mg/kg furosemide IV every
4 hours. This dose was increased by 0.25 mg/kg increments if urine
output was less than 1 mL/kg/hr, up to a maximum of 1.5 mg/kg. The
continuous infusion group received a loading dose of 0.1 mg/kg (up to
1 mg) followed by an infusion starting at 0.1 mg/kg/hr. The infusion was
titrated by doubling the rate at 2 hour intervals for a urine output less
than 1 mL/kg/hr, to a maximum of 0.4 mg/kg/hr. Although the 24-hour
urine output was no different between the two groups (3.361.79
mL/kg/day in the infusion group and 3.534.10 mL/kg/day in the
intermittent group), the infusion group had a lower total daily
furosemide dose compared to the intermittent group (4.901.78
mg/kg/day versus 6.230.62 mg/kg/day, p=0.045). Sodium and
chloride loss was greater in the intermittent group, but by relatively
small amounts. Serum sodium decreased by 0.290.15 mmol/kg/day in
the intermittent group and 0.200.06 mmol/kg/day in the infusion
group (p=0.0007). Chloride decreased by 0.400.20 mmol/kg/day and
0.300.12 mmol/kg/day, respectively (p=0.045). Potassium loss was
similar in both groups.
In 2002, Schoemaker and colleagues utilized quantitative modeling
techniques to assess the relationship between furosemide dosing,
serum concentrations, and urinary excretion.[12] The goal was to

create a dosing regimen that would optimize urine output while

maintaining serum furosemide concentrations < 50 mcg/mL. To
develop the model, the authors collected urine and blood samples from
18 infants (ages 0.5-48.4 weeks) given furosemide at a rate of 0.1
mg/kg/hr after cardiac surgery. Using nonlinear mixed effects modeling
to simulate alternative dosing strategies, the authors found that a
regimen of a 1 to 2 mg/kg bolus dose, followed by an infusion of 0.2
mg/kg/hr, would maximize diuresis. This regimen was evaluated in a
follow-up study with another 18 cardiac patients. The infusion was
adjusted by 0.1 mg/kg/hr increments for a urine output outside of the
desired 2 to 6 mL/kg/hr goal. Twelve infants completed the follow-up
phase. Three patients required titration to 0.3 mg/kg/hr and two
required 0.4 mg/kg/hr. Serum furosemide concentrations remained
below 50 mcg/mL. Based on the follow-up results, the use of higher
initial doses to promote greater furosemide tubular excretion in the
face of reduced urine output, with subsequent downward titration as
function improves, appears warranted.

Contraindications and Precautions

Furosemide is contraindicated in anuric patients or those with a history
of hypersensitivity to it. Patients with allergies to sulfonamides should
be monitored for cross-sensitivity to furosemide. Furosemide should be
used with caution in patients with significant hepatic dysfunction;
doses should be adjusted based on individual response. It should also
be used with caution in patients with systemic lupus erythematosus or
hyperuricemia, where it may precipitate gout.[1,2]

Adverse Effects
When used in recommended doses, furosemide is generally well
tolerated. High-dose therapy may produce excessive diuresis, resulting
in hypotension, dehydration, and placing susceptible patients at
increased risk for vascular clot formation. Careful attention to fluid and
electrolyte status is necessary when high-dose therapy is used. All
patients should be monitored for signs and symptoms of a
hypochloremic metabolic alkalosis, hyponatremia, hypokalemia,
hypomagnesemia, or hypercalciuria.[1-4]
Nephrocalcinosis, a consequence of the high urinary calcium excretion
rate and an alkaline urine pH caused by furosemide, is a well known
risk of long-term therapy, particularly in infants.[3,4,13] Saarela and

colleagues compared the rate of nephrocalcinosis in 36 term infants

(mean age 2.9 months) with cardiac failure receiving furosemide
versus an age-matched control group. Patients were followed for up to
2 years or until resolution of the calcifications was established by
ultrasound. Nephrocalcinosis was observed in 5/36 (14%) of the
furosemide group, but none of the controls (p=0.03). Within the
furosemide group, the patients with nephrocalcinosis had received a
higher average daily dose than those who did not develop calcifications
(1.30.4 mg/kg/day versus 1.00.6 mg/kg/day, p=0.01). As
anticipated, urinary calcium was significantly higher in the furosemide
group, 1.56 mmol/L compared to 0.82 mmol/L in the controls
(p=0.005). Nephrocalcinosis resolved in three of the patients by the
end of the study, but two had persistent calcifications at 2 years of
age. The authors recommend renal ultrasonography to evaluate for
nephrocalcinosis within the first several months of long-term
furosemide therapy in infants and consideration of alternative diuretic
regimens in those with evidence of calcifications.
Ototoxicity is a rare, but serious adverse effect associated with the loop
diuretics. Cases of tinnitus, as well as reversible and irreversible
sensorineural hearing loss have been documented in the literature.
While the mechanism for ototoxicity is not well understood, several
studies have shown alterations in ion transport in the marginal cells of
the cochlear duct with high concentrations of furosemide, resulting in
reduced endocochlear potentials. Hearing loss has most frequently
been associated with elevated serum furosemide concentrations
(typically defined as > 50 mcg/mL). Other factors predisposing patients
to ototoxicity include rapid IV injection (> 4 mg/min), concomitant use
of other ototoxic drugs or drugs that inhibit furosemide clearance, use
in patients with significant renal or hepatic dysfunction, and use in
preterm neonates.[14]
Dermatologic reactions with furosemide include phototoxicity and
conditions ranging from mild pruritic rash to purpura, exfoliative
dermatitis, and erythema multiforme. Other adverse effects reported
with furosemide include paresthesias, dizziness, headache, blurred
vision, rash, pruritus, pancreatitis, jaundice, abdominal cramping or
upset, nausea, vomiting, diarrhea, constipation, muscle spasm,
including urinary bladder spasms, interstitial nephritis, and systemic
vasculitis. There are also case reports of furosemide-induced
thrombocytopenia,
hemolytic
anemia,
aplastic
anemia,
and
agranulocytosis. Anaphylaxis following furosemide administration is
rare, but has been reported several times in the medical literature.[1,2]

Drug Interactions

Concomitant administration of furosemide with other loop diuretics

(bumetanide
or
torsemide),
ethacrynic
acid,
cisplatin,
or
aminoglycosides may increase the risk for ototoxicity. Use of
furosemide with salicylates may produce salicylate toxicity, as a result
of competitive renal excretion. A similar inhibition of renal clearance
may occur when furosemide is given with lithium. Furosemide may
potentiate the effects of other antihypertensive agents, resulting in
significant hypotension. While it antagonizes the effects of
nondepolarizing
neuromuscular
blocking
agents,
furosemide
potentiates the effect of succinylcholine. Potentiation may also occur
when it is given with ganglionic or peripheral adrenergic blocking
drugs.[1,2]
Administration of indomethacin with furosemide may reduce diuresis.
Sucralfate may reduce the absorption of furosemide tablets and reduce
its effectiveness. Doses of furosemide and sucralfate should be
separated by at least 2 hours. Phenytoin, probenecid, and
methotrexate also have the potential to reduce the efficacy of
furosemide. The interaction between furosemide and methotrexate
alters both drugs: furosemide impairs the tubular secretion of
methotrexate, resulting in higher serum methotrexate serum
concentrations and a greater risk for toxicity. Concomitant use of
furosemide and cyclosporine may result in hyperurecemia.[1,2]
In a small number of cases, administration of IV furosemide within 24
hours of a dose of chloral hydrate has resulted in flushing, diaphoresis,
restlessness, nausea, hypertension, and tachycardia. Although not
widely documented in the literature, the manufacturer recommends
that these drugs not be used in combination.[1,2]

Availability and Dosing Recommendations

Furosemide is marketed as the brand name product (Lasix, sanofiaventis U.S., LLC) and as a generic product from a number of
manufacturers. It is available in 20, 40, and 80 mg tablets, 8 mg/mL
(40 mg/5 mL) and 10 mg/mL oral solutions, and a 10 mg/mL injection.
The typical starting dose for furosemide in infants and children is 1
mg/kg IV or PO given every 6 to 24 hours, with the dosing interval
determined by the patient's age, renal function, and clinical status. The
recommended maximum single dose is 6 mg/kg. Continuous
furosemide infusions typically range from 0.05 to 0.5 mg/kg/hr. The
initial dose for furosemide in adults is 20 to 80 mg IV or PO, with
subsequent doses administered at 6 to 8 hour intervals, as needed.

Maintenance therapy is typically given once or twice daily, with

adjustment based on clinical response.[1-4,8-12]
Intravenous injections should be given over at least 1-2 minutes, or at
a rate no more than 0.5 mg/kg/min. Furosemide is compatible with
sodium chloride and dextrose solutions. Its pH of 9, however, makes it
incompatible with many drugs commonly used in the pediatric or
neonatal intensive care setting. Oral furosemide doses may be given
with or without food.[1,2]

Summary
Furosemide remains to be one of the most widely used therapies in
pediatric and neonatal intensive care and is a mainstay in the longterm management of cardiac, pulmonary, and kidney diseases in
children. New research has helped to refine our understanding of its
mechanisms of action and its application in the pediatric population.

REFERENCES
1. Lasix
information.
Sanofi-aventis,
2008.
Available
at
http://www.sanofi-aventis.us/live/us/en/index.jsp (accessed 7/13/09).
2. Furosemide. Drug Facts and Comparisons. Efacts [online]. 2009.
Available from Wolters Kluwer Health, Inc. (accessed 7/13/09).
3. Eades SK, Christensen ML. The clinical pharmacology of loop diuretics
in the pediatric patient. Pediatr Nephrol 1998;12:603-16.
4. Prandota J. Clinical pharmacology of furosemide in children: a
supplement. Am J Ther 2001;8:275-89.
5. Boles
Ponto
LL,
Schoenwald
RD.
Furosemide:
a
pharmacokinetic/pharmacodynamic review (Part I). Clin Pharmacokinet
1990;18:381-408.
6. Mirochnick MH, Miceli JJ, Kramer PA, et al. Furosemide pharmacokinetics
in very low birth weight infants. J Pediatr 1988;112:653-7.
7. Ross BS, Pollak A, Oh W. The pharmacologic effects of furosemide
therapy in the low-birth-weight infant. J Pediatr 1978;92:149-52.
8. Singh NC, Kissoon N, Al Mofada S, et al. Comparison of continuous
versus intermittent furosemide administration in postoperative
pediatric cardiac patients. Crit Care Med 1992;20:17-21.
9. Klinge JM, Scharf J, Hofbeck S, et al. Intermittent administration of
furosemide versus continuous infusion in the postoperative
management of children following open heart surgery. Intensive Care
Med 1997;23:693-7.
10.Luciani GB, Nichani S, Chang AC, et al. Continuous versus intermittent
furosemide infusion in critically ill infants after open heart operations.
Ann Thorac Surg 1997;64:1133-9.

11.van der Vorst MMJ, Ruys-Dudok van Heel I, Kist-van Holthe JE, et al.
Continuous intravenous furosemide in hemodynamically unstable
children after cardiac surgery. Intensive Care Med 2001;2:711-5.
12.Schoemaker RC, van der Vorst MMJ, Ruijs-Dudok van Heel I, et al.
Development of an optimal furosemide infusion strategy in infants with
modeling and simulation. Clin Pharmacol Ther 2002;72:383-90.
13.Saarela T, Lanning P, Koivisto M, et al. Nephrocalcinosis in full-term
infants receiving furosemide treatment for congestive heart failure: a
study of the incidence and 2-year follow-up. Eur J Pediatr
1999;158:668-72.
14.Rybak LP. Pathophysiology of furosemide ototoxicity. J Otolaryngol
1982;11:127-33.

Vol.58, No 4, 2005

Furosemide : Tinjauan Pemakaiannya pada

Neonatus dan Anak
MARCIA L. BUCK, Pharm. D, FCCP
Pediatr Pharm, 2009; 15(8)

Furosemid, loop diuretik pertamayang diperkenalkan di Amerika

Serikat pada tahun 1966. Setelah hampir setengah abad pemakaian,
furosemid telah menjadi salah satu obat yang paling sering diresepkan
di Amerika [1,2]. Pada pasien anak, furosemide digunakan untuk

mengurangi edema pada penyakit akut ataupun kronik yang

mengenai system kardiovaskular, paru, dan ginjal. [3,4]. Makalah
Pediatric Pharmacoterapy ini akan meninjau farmakologi dasar
furosemid dan menjealskan penelitian terbaru dari penggunaanya pada
neonatus dan anak.

Mekanisme Kerja
Furosemid
(4-chloro-N-furfuryl-5-sulfamoylanthranilic
acid),
seperti loop diuretik lain, berikatan reversibel direseptor cotransporter Na + 2Cl - K + yang ada pada membran sel yang
pada lapisan tebal di lengkung Henle. Kotransporter ini
bertanggung jawab untuk pergerakan natrium keluar dari saluran
kemih dan ke dalam sel tubular melalui gradien konsentrasi. Efek
utama pada penghambatan aktifitas kotransporter Na+2Cl-K+
adalah penurunan reabsorpsi natrium sekitar 20-30% yang
menyebbakan natriuresis. Diuresis yang signifikan terjadi karena
reabsorpsi air terhambat di duktus colectivus karena penurunan
gradient konsentrasi di medula interstisial.[1-4]
Untuk tingkat yang lebih rendah, furosemid juga menghambat
reabsorbsi natrium di tubulus proksimal, kemungkinan melalui
jalur inhibisi anhidrase karbonat dan prostaglandin dalam hal
perubahan hemodinamik ginjal. Sejumlah cara lainnya telah
diusulkan sebagai mekanisme tambahan untuk efek diuretik
obat. Kemampuan furosemid untuk berakumulasi pada kelanjar
adrenal, paru, limpa, dan hati, terutama di ginjal, telah
mendukung teori bahwa hal itu dapat mempengaruhi keadaan
cairan dengan menghambat produksi kortikosteroid endogen
atau
meningkatkan
metabolisme.
Penelitian
lain
telah
menemukan bahwa furosemid dapat menstimulasi sistem reninangiotensionaldosteron
dan
produksi
prostaglandin,
dan
meningkatkan pelepasan faktor endogen berupa naturetic atrium
dan endotelin-1. Efek ini berhubungan erat dengan rantai
kompensasi yang membuat efek isolasi furosemid sulit dicapai
suatu organisme.Yang sangat penting, adaptasi pada tubulus
distal dalam peningkatan konsentrasi natrium yang dihasilkan

oleh pemakaian kortikosteroid dalam jangka waktu panjangdapat

menyebabkan peningkatan reabsorpsi air dan natrium,
menyebabkan toleransi diuretik.[1-4]

Farmakokinetik dan Farmakodinamik

Penelitian
farmakokinetik
furosemid
telah
mengungkapkanvariabiltas yang cukup pada pasien. Setelah
pemakaian oral, konsentrasi furosemid tertinggi dicapai setelah
1 sampai 1,5 jam. Biovabilitas furosemid oral pada dewasa telah
telah diperkirakan 40 sampai 60% pada kebanyakan studi.
Konsentrasi serum puncak tidak berbeda secara signifikan antara
tablet dan larutan oral.Perkiraan volume distribusi pada orang
dewasa berkisar 4-13 L. Furosemide berikatan kuat dengan
protein (91 99%). Dimetabolisme utama di hati untuk
furosemide glucuronide. Waktu paruh furosemid pada orang
dewasa berkisar 1-2 jam, tetapi lebih lama padapasien dengan
penyakit hati.
Farmakokinetik furosemid juga telah di teliti padaneonatus dan
anak. Mirochnik dkk mengevaluasi bersihan furosemid pada 10
neonatus preterm (berat lahir rata-rata 0.8290.217 kg, umur
kehamilan rata-rata 26.62.9 minggu)[6] semua pasien
menerima dosis awal 1mg/kg yang diikuti dengan dosis 1-2mg/kg
setiap 12-24 jam, berdasarkan respon klinis. Sampel serum
dikumpulkan pada interval waktunya setelah pemberian dosis.
Distribusi volume rata-ratapada pasien 0.480.14 L/kg.
Bioavaibilitas furosemid oral (diberikan pada 3 pasien) rata-rata
84%. Ikatan protein hampir 95%. Bersihan kreatinin menjadi
lebih lama pada populasi pasien ini, dengan waktu paruh
bervariasi dari 1.8-67.3 jam. Waktu paruh furosemid pada
neonatus lahir minimal umur kehamilan 31 minggu sering
meningkat 24 jam. Padapasien ini, dosis setiap 12 jam
menyebabkan akumulasi furosemid sampai pada level ototoksik
(25 mcg/mL). Bersihan ginjal dari furosemid meningkat seiring
meningkatnya umur kehamilan. Pada neonatus 36 minggu, waktu
paruh rata-ratamenurun 4 jam, sama dengan neonatus cukup
bulan.
Reaksi farmakokinetik pada furosemid dipengaruhi fungsi ginjal
pasien dan status hidrasi, efikasi obat tergantung dari jumlah

furosemid yang di ekskresikan di lumen tubulus proksimal. Pada

anak yang lebih tua dan orang dewasa, onset umum dari diuresis
setelah pemakaian intravena (IV) terjadi dalam 5 menit, dengan
efek puncak 30 menit dan durasi 2-6 jam . [1-4]. Respon yang
lambat terlihat pada neonatus preterm atau neonatus dengan
operasi jantung, dengan onset satu jam setelah dosis IV,
puncaknya lebih dari 3 jam, dan durasi 6 jam [7,8].

Uji Klinis pada Neonatus dan Anak

Furosemid banyak digunakan oleh dokter anak sebagai terapi.
Pada proses akut, digunakan untuk mengatasi edema dengan
shock atau trauma otak, seperti juga pada peningkatan volume
setelah operasi. Terapi furosemid jangka panjang digunakan pada
neonatus dengan penyakit paru kronik dan anak dengan sindrom
nefrotik atau gagal jantung. Beragam penelitian pediatrik
furosemid telah dilakukan sejak lebih dari 40 tahun. [3] Penelitian
awal dilakukan pada neonatus preterm dengan penyakit paru
kronik. Penelitian terbaru lebih fokus pada penggunaan
furosemid sebagai infus kontinu pada bayi sakit kritis setelah
operasi jantung. [8-12]infus kontinyu furosemide telah diusulkan
sebagai cara mengoptimalkan natrium dan ekskresi air sambil
menghindari fluktuasi luas dalam serum furosemidedan status
volume.
Penelitian awal pada populasi telah dipublikasikan tahun 1992
oleh Singh dkk[8] mereka menjalankan sebuah penelitian
prospektif, randomized clinical trial untuk membandingkan efek
intermitten dan berkelanjutan dalam pemberian rutin furosemid
pada 20 anak (neonatus baru lahir sampai umur 4 tahun) setelah
operasi jantung. Kelompok intermiten diberikan 1mg/kg
furosemid IV setiap 4 jam. Dosis ini dinaikkan bertahap 0.25
mg/kg jika urin output kurang dari 1mL/kg/hr sampai maksimum
1.5 mg/kg. Kelompok pemberian rutin menerima loading dose 0.1
mg/kg (sampai 1mg) diikuti dengan dosis awal 0.1 mg/kg/hari.
Infus dititrasi dengan menggandakan tingkatannya pada waktu
2 jam untuk urin output kurang dari 1mL/kg/hari, sampai
maksimum 0.4 mg/kg/hari. Walaupun urin output 24 jam tidak
berbeda pada kedua kelompok, (3.361.79 mL/kg/hari pada
kelompok rutin dan 3.534.10 mL/kg/hari pada kelompok
intermitten), kelompok rutin memiliki dosis total furosemid yang

lebih rendah dibandingkan kelompok intermitten, tetapi dengan

jumlah yang relatif kecil. Serum natrium berkurang menjadi
2.90.15 mmol/kg/hari pada kelompok intermitten dan
0.200.06 mmol/kg/hari pada kelompok rutin (p=0.0007). klorida
berkurang 0.400.20 mmol/kg/hari dan 0.300.12 mmol/kg/hari,
masing-masing (p=0.045). hilangnya kalium sebanding pada
kedua kelompok.
Pada tahun 2002, Scoemaker dkk memanfaatkan teknik
kuantitatif untuk menemukan hubungan dosisfurosemid,
konsetrasi serum, dan eksresi urin[12] tujuannya untuk
menciptakan sediaan dosis yang dapat memaksimalkan urin
output ketika konsentrasi serum furosemid <50mcg/mL. Untuk
mengembangkan model, peneliti mengumpulkan sampel urin
dan darah dari 18 neonatus (umur 0.5-48.4 minggu) yang
diberikan furosemid 0.1mg/kg/hari setelah operasi jantung.
Menggunakan efek campuran nonlinier untuk menstimulasi
strategi dosis alternatif, peneliti menemukan bahwa dosis
pemberian 1-2mg/kg bolus dilanjutkan dengan infus 0.2
mg/kg/jam dapat memaksimalkan diuresis. Dosis pemberian ini
dievaluasi pada penelitian lanjutan dengan 18 pasien jantung
lain. Infus ditingkatkan menjadi 0.1 mg/kg/hari untuk urin output
diluar tujuan awal 2-6mL/kg/hari. 12 neonatus berhasil mengikuti
fase follow up. 3 pasien mebutuhkan titrasi 0.3mg/kg/hari dan 2
pasien
membutuhkan
0.4mg/kg/hari.
Konsentrasi
serum
furosemid masih dibawah 50mcg/mL. Berdasarkan hasil follow
up, penggunaan dosislebih tinggi untuk eksresi tubular furosemid
yang lebih tinggi dalam halnya mengurangi urin output, dengan
titrasi berikutnya meningkatkan fungsi, terlihat menjanjikan.

Kontraindikasi dan Perhatian

Furosemid dikontraindikasikan pada pasien anuri atau pasien
dengan hipersensitivitas. Pasien dengan alergi sulfonamid harus
di kontrol untuk cross-sensitivitas dari furosemid. Furosemid
harus digunakan denganhati-hati pada pasien dengan disfungsi
hati; dosis harus ditentukan berdasar respon individu. Hal iIni
juga harus digunakan hati-hati pada pasien dengan SLE atau
hiperuricemia, yang mungkin dapat menyebabkan gout. [1,2]

Efek samping
Ketika digunakan dalam dosis rekomendasi, furosemid ditoleransi
dengan baik. Dosis tinggi terapi mungkin menyebabkan diuresis
berlebihan, yang menyebabkan hipotensi, dehidrasi, dan
peningkatan resiko pembentukan trombus vaskular. Perhatian
pada status cairan dan elektrolit penting ketika terapi dosis tinggi
digunakan. Seluruh pasien harus di kontrol untuk gejala dan
tanda alkalosis metabolik hipkloremik, hiponatremi, hipokalemi,
hipomagnesemia, atau hipercalciuria.[1-4]

Nefrokalsinosis, konsekuensi dari ekresi kalsium urin yang tinggi

dan pH alkali urin yang disebabkan oleh furosemid, diketahui
sebagai efek samping terapi jangka panjang, terutama pada
neonatus.[3-4-13]
Saarela
dkk
membandingkan
tingkat
nefrokalsinosis pada 36 neonatus cukup bulan (umur rata-rata
2.9 bulan) dengan kegagalan jantung yang menerima furosemid
degan kelompok kontrol sesuai umur. Pasien diikuti selama 2
tahun atau sampai kalsifikasi ditemukan dengan ultrasound.
Nefrokalsinos ditemukan pada 5/36 (14%) pada kelompok
furosemid, namun tidak pada kelompok kontrol (p=0.03). dalam
kelompok
furosemid,
pasien
dengan
nefrokalsinosis
mendapatkan dosis harian yang lebih tinggi dibandingkan
mereka yang tidak terbentuk kalsifikasi (1.30.4 mg/kg/hari
lawan 1.00.6 mg.kg.hari, p=0.01). Sepertiyang diduga, kalsium
urin lebih tinggi pada kelompk furosemid, 1.56 mmol/L
dibandingkan
0.82
mmol/L
pada
kontrol
(p=0.005).
Nefrokalsinosis sembuh pada 3 pasien di akhir penelitian, tetapi
2 pasien tetap mengalami kalsifikasi pada 2 tahun kehidupan.
Peneliti menganjurkan ultrasonografi ginjal untuk mengevalusi
nefrokalsinosis dalam jangka waktu beberapa bulan dalam terapi
jangka panjang furosemid pada neonatus dan menentukan dosis
pemberian alternatif bagi merekayang mengalami kalsifikasi.
Ototoksik jarang terjadi, tetapi efek samping serius berhubungan
dengan diuretik loop. Padakasus tinitus, tuli sensorineural
reversibel dan nonreversibel telah didokumentasikan pada
literatur. Sedangkan mekanisme ototoksik tidak dimengerti
sepenuhnya, beberapapenelitian dapat menunjukkan hubungan
transpor ion sel marginal
pada duktus koklearis dengan
konsentrasi tinggi furosemid, menyebabakan penurunan potensi

endokoklear. Kehilangan pendengaran

sering dihubungkan
dengan peningkatan konsetrasi serum furosemid (biasanya
didefiniskan >50mcg/mL)/ . Faktor pendukung lain pada pasien
ototksik termasuk injeksi cepatIV (4mg/min), seiring penggunaan
dengan obat ototoksik lain yang menghambat bersihan kreatinin,
digunakan pada pasien dengan disfungsi nyata ginjal, paru,
hepar, dan pada neonatus preterm.
Reaksi dermatologi dengan furosemid mencakup fototoksik dan
kondisi yang bervariasi dar pruruitus ringan sampai purpura,
dermatitis eksfoliasi, dan eritem multiformis. Efek samping lain
yang dilaporkan yaitu parasthesi, pusing, sakit kepala,
pandangan kabur, spasme otot, termausk spasme kandung
kemih, nefritis interstitial, dan vaskulitis sistemik. Juga terdapat
laporan kasus furosemid menyebabkan trombositopeni, anemia
hemolitik, anemia aplastik, dan agranulositosis. Penggunaan
anafilaksis dalam terapi furosemid jarang, tetapi telah dilaporkan
pada beberapa literatur kedokteran.

Interaksi Obat
Pemberian furosemid dengan obat diuretik lain (bumetanide atau
torsemid), ethacrynin acid, cisplatin, atau aminoglikosida dapat
meningkatkan resiko ototoksik. Penggunaan furosemid dengan
salisilat menyebabkan toksisitas salisilat, sebagai hasil dari
ekresi renal kompetitif. Hambatan bersihan kreatinin juga dapat
terjadi
ketika
diberikan
bersama
lithium.
Furosemid
mempengaruhi efek obat antihipertensi, menyebabkan hipotensi.
Sedangkan antagonis efek dari nondepolarizing neuromuscular
blocking agent , furosemid meningkatkan efek susinilkolin.
Potensi juga dapat terjadi ketika diberikan dengan obat
ganglionik atau blocking adrenergik[1,2]
Penggunaan indometasin dengan furosemin menurunkan
diuresis. Sukralfat menurunkan absorpsi tablet furosemid dan
aktifitasnya. Dosisfurosemid dan sukralfat harus dipisah minimal
2 jam. Phenitoin, probenecid, dan metotrexat
jugamemiliki
potensi untuk mengurangi efikasi furosemid. Interaksi diantara
furosemid dan metotrexate melingkupi kedua obat: furosemid
menahan eksresi metotrexate, menyebabkan konsentasi serum
metrotexate yang lebih tinggi dan resiko besar toksiksitas.

Pemberian
furosemid
[1,2]
hiperurekemia.

and

siklosporin

menyabbkan

Pada beberapakasus, penggunaan furosemid IV selama 24 jam

dengan dosis chloral hydrate menyebabkan flushing, diaphoresis,
restlessness, nausea, hipertensi, takikardi. Walupun tidak
secaraluas dilaporkan dalam literatur, pabrik menyarankan obat
ini tidak dikombinasikan.[1,2].

Availabiliitas dan Dosis yang Dianjurkan

Furosemid dipasarkan dengan nama produk (lasix, saofi=-aventis
U.S., LLC) dan sebagai produk generik pada banyak pabrik obat.
Tersedia dalam 20,40, dan 80 mg tablet, 8mg/ml (40mg/5ml) dan
10 mg/ml larutan oral, dan 10mg/ml injeksi. Dosis awal yang
umum dari furosemid pada neonatus dan anak adalah 1mg/kg IV
atau PO diberikan 6-24 jam, dengan dosis interval ditentukan
dari umur pasien, fungsi ginjal, dan status klinis. Dosis
maksimum yang dianjurkan adalah 6mg/kg. Infus furosemid
diberikan 0.05-0.5mg/kg/hari. Dosis awal furosemid pada dewasa
adalah 20-80 mg IV atau PO, dengan dosis terusan diberikan
dengan interval 6-8 jam, sesuai yang dibutuhkan. Terapi
maintenance umumnya diberikan sekali atau dua kali sehari,
dengan penambahan sesuai respon klinis.[1-4,8-12]
Injeksi intravena harus diberikan minimal 1-2 menit, atau tidak
lebih dari 0.5mg/kg/menit. Furosemid dapat dicampur dengan
natrium klorida dan cairan dextrose. pH nya yang 9,
bagaimanapun, membuat obat ini tidak dapat diberikan bersama
banyak obat lain yang digunakan pada neonatus dan anak.
Furosemid oral diberikan tanpa makanan.

Kesimpulan
Furosemid masih menjadi salah satu terapi yang paling sering
digunakan pada instansi perawatan neonatus dan anak dan
merupakan andalan pada terapi jangka panjang penyakit
jantung, paru, ginjal pada anak. penelitian baru membantu kita
untuk mengerti mekanisme kerja dan aplikasi nya pada
masyarakat.

DAFTAR PUSTAKA

1. Lasix
information.
Sanofi-aventis,
2008.
Available
at
http://www.sanofi-aventis.us/live/us/en/index.jsp
(accessed
7/13/09).
2. Furosemide. Drug Facts and Comparisons. Efacts [online]. 2009.
Available from Wolters Kluwer Health, Inc. (accessed 7/13/09).
3. Eades SK, Christensen ML. The clinical pharmacology of loop
diuretics in the pediatric patient. Pediatr Nephrol 1998;12:60316.
4. Prandota J. Clinical pharmacology of furosemide in children: a
supplement. Am J Ther 2001;8:275-89.
5. Boles
Ponto
LL,
Schoenwald
RD.
Furosemide:
a
pharmacokinetic/pharmacodynamic
review
(Part
I).
Clin
Pharmacokinet 1990;18:381-408.
6. Mirochnick MH, Miceli JJ, Kramer PA, et al. Furosemide
pharmacokinetics in very low birth weight infants. J Pediatr
1988;112:653-7.
7. Ross BS, Pollak A, Oh W. The pharmacologic effects of furosemide
therapy in the low-birth-weight infant. J Pediatr 1978;92:149-52.
8. Singh NC, Kissoon N, Al Mofada S, et al. Comparison of
continuous versus intermittent furosemide administration in
postoperative pediatric cardiac patients. Crit Care Med
1992;20:17-21.
9. Klinge JM, Scharf J, Hofbeck S, et al. Intermittent administration of
furosemide versus continuous infusion in the postoperative
management of children following open heart surgery. Intensive
Care Med 1997;23:693-7.
10.
Luciani GB, Nichani S, Chang AC, et al. Continuous versus
intermittent furosemide infusion in critically ill infants after open
heart operations. Ann Thorac Surg 1997;64:1133-9.
11.
van der Vorst MMJ, Ruys-Dudok van Heel I, Kist-van Holthe
JE,
et
al.
Continuous
intravenous
furosemide
in
hemodynamically unstable children after cardiac surgery.
Intensive Care Med 2001;2:711-5.
12.
Schoemaker RC, van der Vorst MMJ, Ruijs-Dudok van Heel I,
et al. Development of an optimal furosemide infusion strategy in

infants with modeling and simulation. Clin Pharmacol Ther

2002;72:383-90.
13.
Saarela T, Lanning P, Koivisto M, et al. Nephrocalcinosis in
full-term infants receiving furosemide treatment for congestive
heart failure: a study of the incidence and 2-year follow-up. Eur J
Pediatr 1999;158:668-72.
14. Rybak LP. Pathophysiology of furosemide ototoxicity. J
Otolaryngol 1982;11:127-33.