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Demam Berdarah Dengue:

Manifestasi Klinis, Diagnosis, Terapi &


Tatalaksana pada Dengue Syok Sindrom

dr.Bramantono SpPD KPTI FINASIM


Divisi Tropik – Infeksi, Departemen Ilmu Penyakit Dalam
FK UA – RSUD Dr. Soetomo Surabaya
Dengue: Penyakit Arboviral yang Paling Cepat Menyebar

Jumlah insiden DD dan DBD yg


dilaporkan ke WHO (WHO, 2011)

30x incidence increase in


50 yrs
Daerah penyebaran dengue 2008 (WHO, 2009)
Surabaya (2000 - 2009):
↑ insiden: 12.04  48.9
WHO 2009: Perlu upaya yg lebih intensif untuk penelitian
per 100000
tentang patogenesis, perbaikan tata laksana, dan upaya
penemuan obat/vaksin
Belum ada obat/ vaksin
2
• 2003-2005: DENV-2
• 2007-2008: DENV-2
• 2008-2010: DENV-1
• 2012: DENV-1
• 2013: DENV-1
• Further surveillance ???
3
Infeksi virus dengue (DENV)
Merupakan penyakit
demam akut yang
disebabkan oleh virus
dengue dan ditularkan
melalui gigitan nyamuk
Aedes aegypty dan
Aedes albopictus serta
memenuhi kriteria
WHO untuk Demam
Berdarah Dengue (DBD)

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Replication and transmission
of dengue virus (Part 1)
1. Virus transmitted 1
to human in mosquito
saliva
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2. Virus replicates
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in target organs

3. Virus infects white 3


blood cells and
lymphatic tissues

4. Virus released and


circulates in blood
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Replication and transmission
of dengue virus (Part 2)
5. Second mosquito
ingests virus with blood 6

6. Virus replicates
in mosquito midgut
and other organs,
infects salivary
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glands

7. Virus replicates
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in salivary glands

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Pathophysiology

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PATHOPHYSIOLOGY
Dengue Infection

Antibody Formation

Re-infection

Augmentation of virus multiplication

Increased vascular Reduced platelets


permeability
Coagulopathy
Plasma leakage Disseminated intravascular
Hypovolemia Coagulation

Shock Severe bleeding


Death
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Dengue infection causes capillary
leak syndrome Primary target:
monocytes

Serotype cross-
reactive Ab

Virions + non-
neutralizing Ab

Enhanced entry via


FcR

T cells activation

Cytokines +
complements
activation

Capillary Leak
(Rothman, 2004) 9
DHF is not a continuum of DF
Dengue
Self-limited
Viral direct effect Fever

Dengue Virus
infection

Dengue Life-threatening
Secondary infection + Haemorrhagic
Enhanced antibodies DHF is not
Fever
DF plus bleeding

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Manifestation of dengue virus infection
Dengue virus infection

Asymtomatic Symtomatic

Undifferentiated Dengue Fever Dengue haemorrhaegic Expanded dengue


Fever (DF) fever (DHF) syndrome / isolated
(viral syndrome) (with plasma leakage) organopathy
(unusual manifestation)

Without With unusual DHF DHF with shock


haemorrhage haemorrhage Non-shock DSS
Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever, WHO-SEARO 2011 11
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Manifestasi/perubahan patofisiologis utama pada DBD
Infeksi Dengue

Demam Hepatomegali Trombositopeni Derajat


Manifestasi
Anoreksia perdarahan ; paling keparahan
Muntah sering uji torniquet DBD
Peningkatan permeabilitas
(+), petekie vaskular

Hemokonsentrasi
Dehidrasi
Hipoproteinemia Kebocoran Plasma I

Efusi Pleura/Ascites Koagulopati


II
Hipovolemia
Koagulasi
Intravaskular III
Syok Diseminata
(KID)

Perdarahan masif : IV
perdarahan saluran
cerna (tersembunyi),
Kematian perdarahan otak, dll
DBD/SSD
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Demam Dengue
Course of dengue illness

Shock/Bleeding

Dengue: Guidelines for diagnosis, treatment, prevention and control, TDR-WH0 2009
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Febrile phase
Febrile phase
• Facial flushing • (+) TT increases the
• Skin erythema probability of dengue
• Generalized body ache • (+) hemorrhagic
• Myalgia and arthralgia manifestations
• Headache • Enlarged and tender liver
• Sorethroat, injected pharynx, • Abnormality: progressive
and conjunctival injection decrease in total wbc
• Anorexia, nausea and
vomiting

Dengue: Guidelines for diagnosis, treatment, prevention and control, TDR-WH0 2009

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Critical phase
Critical phase
• Temp drops to 37.5-38 • if (-) increase in • Shock: critical volume
(days 3-7) capillary permeability of plasma is lost
• (+) increase in capillary  improve • Temperature may be
permeability with • if (+) increase in subnormal
increasing hematocrit
levels capillary permeability • Prolonged shock 
• Significant plasma  pleural effusion and organ hypoperfusion
leakage lasts for 24-48 ascites  organ impairment,
hours • Degree of increase metabolic acidosis,
• Progressive leukopenia above the baseline and DIC  severe
followed by rapid hematocrit reflects the hemorrhage
decrease in platelet severity of plasma • Severe hepatitis,
precedes plasma leakage encephalitis or
leakage myocarditis

Dengue: Guidelines for diagnosis, treatment, prevention and control, TDR-WH0 2009
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Recovery phase
Recovery phase
• Gradual reabsorption of • Hematocrit stabilizes or may be
extravascular compartment fluid (48- lower due to dilutional effect of
72 hours) reabsorbed fluid
• General well-being improves, • Wbc starts to rise
appetite returns, GI symptoms abate, • Recovery of platelet count occurs
hemodynamic status stabilizes and later
diuresis ensues
• (+) rash: “isles of white in the sea of
red”

Dengue: Guidelines for diagnosis, treatment, prevention and control, TDR-WH0 2009

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Pemeriksaan penunjang
• Pemeriksaan darah serta serologi
• DL, LFT, RFT, BG, Coagulation profile, BGA, Electrolyte, lactate, NS1,
Igm/IgG anti-dengue
• EKG
• Pemeriksaan Radiologis
• Foto Thoraks
• USG
• Penunjang lainnya sesuai indikasi

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Diagnosis of dengue
• Antibody detection
• Hemagglutination Inhibition
(HAI)
• IgM & IgG
• Antigen detection
• NS1
• RNA detection
• RT-PCR
• Viral isolation

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Approximate timeline of primary and secondary dengue virus infections and
the diagnostic methods that can be used to detect infection

NS1 detection

Virus isolation
RNA detection

Viraemia

O.D
IgM primary

IgM secondary
HIA

>25
IgG secondary
O.D 60

IgG primary infection 80


0

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16-20 21-40 41-60 61-80 90 >90 Days


Onset of symptoms 20
Differential diagnoses of dengue
• Arboviruses: Chikungunya virus (terutama di Asia
Tenggara)
• Other viral diseases: Measles; rubella; Epstein-Barr
Virus (EBV)
• Enteroviruses; influenza; hepatitis A; Hantavirus
• Bacterial diseases: Meningococcaemia,
leptospirosis, typhoid, melioidosis, rickettsial
diseases, scarlet fever
• Parasitic diseases: Malaria

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WHO Guidelines on dengue
2009

1997 2011
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Criteria for clinical diagnosis of
DHF (2011)
• Clinical manifestations
• Fever: acute onset, high and continuous, lasting two to
seven days in most cases
• Any of the following haemorrhagic manifestations
including a positive tourniquet test (the most common),
petechiae, purpura, ecchymosis, epistaxis, gum
bleeding, and haematemesis and/or melena
• Laboratory findings
• Thrombocytopenia (100 000 cells per mm 3 or less)
• Haemoconcentration; haematocrit increase of ≥20%
from the baseline, plasma leakage : pleura effusion,
ascites, hypoproteinemia / hypoalbuminemia

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Classifications
1997 2009 2011
Dengue Fever Dengue without warning signs Dengue Fever
DHF grade I
DHF grade I
Dengue with warning signs
DHF grade II
DHF grade II

DHF grade III


Severe dengue: DHF grade III
With compensated shock
DHF grade IV With hypotensive shock DHF grade IV

EXPANDED DENGUE
SYNDROME
WHO 2011 Classification of Dengue Infections
and Grading of Severity of DHF
DF/DHF Grade Symptoms Laboratory
DF Fever with two of the following: Leucopenia (wbc ≤5000
Headache, etro-orbital pain, Myalgia, cells/mm 3 ), Thrombocytopenia
Arthtralgia/bone pain, (Platelet count <150 000
Rash,Haemorrhagic manifestations, No cells/mm 3 ), Rising haematocrit
evidence of plasma leakage. (5% – 10% ),
No evidence of plasma loss
DHF I Fever and haemorrhagic manifestation Thrombocytopenia
(positive tourniquet test) and evidence of <100,000, Hct rise >20%
plasma leakage
DHF II As in Grade I plus Thrombocytopenia
Spontaneous bleeding. <100,000, Hct rise >20%
DHF III As in Grade I or II plus Thrombocytopenia
Circulatory Failure (weak pulse, narrow <100,000, Hct rise >20%
pulse pressure(≤20 mmHg),
hypotension,restlessness).
DHF IV As in Grade III plus profound shock Thrombocytopenia
with undetectable BP and pulse <100,000, Hct rise >20%
25 25
Expanded dengue syndrome
NEUROLOGICAL
Febrile seizures in young children. CARDIAC
Encephalopathy. Conduction abnormalities.
Encephalitis/aseptic meningitis. Myocarditis.
Intracranial haemorrhages/thrombosis. Pericarditis.
Subdural effusions.
Mononeuropathies/polyneuropathies/GBS
Transverse myelitis.
RESPIRATORY
GASTROINTESTINAL/HEPATIC Acute respiratory distress
Hepatitis/fulminant hepatic failure. syndrome.
Acalculous cholecystitis. Pulmonary haemorrhage.
Acute pancreatitis.
Hyperplasia of Peyer’s patches.
OTHERS
Acute parotitis.

MUSCULOSKELETAL
RENAL Myositis with raise CPK
Acute renal failure. Rabdomyolysis
Hemolytic uremic syndrome.

Maheshwari A. Atypical manifestations of dengue. Trop Med Int Health. 2007 Sep.; 12(9):1087 – 95 26
Warning signs (2009)
• Abdominal pain or tenderness
• Persistent vomiting
• Clinical fluid accumulation
• Mucosal bleed
• Lethargy, restlessness
• Liver enlargment >2 cm
• Laboratory: increase in HCT concurrent with rapid
decrease in platelet count

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High-risk patients (2011)
The following host factors contribute to more severe disease and
its complications:
•Infants and the elderly
•Obesity
•Pregnant women
•Peptic ulcer disease
•Women who have menstruation or abnormal vaginal bleeding
•Haemolytic diseases
•Thalassemia and other haemoglobinopathies
•Congenital heart disease
•Chronic diseases such as diabetes mellitus, hypertension, asthma,
ischaemic heart disease
•Chronic renal failure, liver cirrhosis
•Patients on steroid or NSAID treatment

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Clinical management
• Complex pathogenesis and manifestations  BUT,
relatively simple and inexpensive treatment
• No spesific treatment  rely on fluid management
• The most effective way to reduce incidence and
morbidity  vector control
• Potential manegement: vaccine and anti-viral
drugs

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DF & DHF in Febrile Phase
• Parcetamole
• Physical methods of controlling fever
• Don’t use Aspirin and NSAID
• Fluid to maintain nutrition and hydration
Recognize the Time of Entry to the Critical Phase
( when blood vessels become leaky)
• Dropping platelet count below 100 000/dl
• Rising HCT & Evidence of plasma leakage

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Choice of fluids
Crystalloid Colloid
Ringer’s lactate Dextran 40 in saline
Ringer’s acetate Hydroxyethyl strach (HES)
0.9% saline Gelatin solutions
5% dextrose 0,9%
5% dextrose 1/2 saline

• Suspected dengue fever


- Isotonic crystalloid : normal saline, Ringer’s lactate, Ringer’s acetate,
Ringer’s dextrose
• Dengue hemorrhagic fever (DHF I and II)
- Isotonic crystalloid : glucose contained solution?
• DSS Crystalloid vs colloid ?
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The general principles of fluid
therapy in DHF
• Isotonic crystalloid solutions should be used
throughout the critical period
• A volume of about maintenance +5% dehydration
• Hyper-oncotic colloid solutions (osmolarity of >300
mOsm/l) such as dextran 40 or starch solutions may
be used in patients with massive plasma leakage,
and those not responding to crystalloid

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Fluid management in DHF gr I & II

Kalayanarooj S. and Nimmannitya S. In: Guidelines for Dengue and Dengue Haemorrhagic Fever Management. Bangkok
Medical Publisher, Bangkok 2003.
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Fluid management in DHF gr III Dengue: Guidelines for diagnosis,
treatment, prevention and control,
(systolic pressure maintained + signs of reduced perfusion) TDR-WH0 2009

Start isotonic crystaloid


5-10 ml/kg/hr for 1 hour
Yes
No
IMPROVEMENT
Check ABCS
HCT HCT
IV crystaloid, reduce or High Check
gradually HCT
5-7 ml/kg/hr for 1-2 hours No
Yes
3-5 ml/kg/hr for 1-2 hours Severe
2-3 ml/kg/hr for 1-2 hours Crystaloid (2nd bolus) or overt
colloid bleed
As clinical improvement is 10-20 ml/kg/hr for 1 hour
noted, reduced fluids
accordingly Urgent Colooid 10-20
blood ml/kg/hr
IMPROVEMENT transfusion Evaluate to
Further boluses may be No
Yes
Consider
needed for the next 24-48 Blood
hours Transfusion if
Reduce IV crystaloids 7-10 No clinical
Stop IV fluids at 48 hours ml/kg/hr for 1-2 hours improvement
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Pemeriksaan laboratorium syok berat atau tidak
ada perbaikan dengan resusitasi cairan
Singkatan Pemeriksaan Kepentingan
Laboratorium
A-Asidosis Analisa gas Menandakan syok yang sedang berlangsung. Keterlibatan
darah (kapiler organ juga harus dievaluasi ; fungsi hati, BUN dan kreatinin
dan vena)
B-Bleeding Hematokrit Jika terjadi penurunan nilai HCT dibandingkan dengan nilai
sebelumnya atau jika tidak berubah, lakukan cross-match
untuk transfusi darah secepatnya
C-Calsium Elektrolit, Ca++ Hipokalsemia terjadi pada kebanyakan DBD namun tanpa
gejala. Pemberian suplementasi kalsium pada kondisi yang
lebih berat/kompleks dapat diindikasikan. Dosis yang
dianjurkan 1 ml/kg maksimal 10cc kalsium glukonas, dilarutkan
dengan perbandingan 1:2, diberikan secara IV perlahan (dapat
diulang tiap 6 jam jika diperlukan)
S-Blood Kadar gula Kebanyakan kasus DBD disertai penurunan selera makan dan
Sugar darah muntah. Hipoglikemia dapat terjadi pada pasien dengan
(fingerstick) gangguan fungsi hati, namun pada kondisi lain dapat terjadi
hiperglikemia
Comprehensive Guidelines for Prevention and Control of Dengue and Dengue Haemorrhagic Fever, WHO-SEARO 2011
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Dengue shock sydrome
Kriteria DHF dengan tanda tanda syok
•Takikardia, ekstremitas dingin, waktu pengisian kapiler
memanjang, nadi lemah, lesu atau gelisah, yang mungkin
merupakan tanda dari penurunan perfusi otak

•Tekanan nadi ≤20 mmHg dengan peningkatan tekanan


diastolik , misalnya 100/80 mmHg

•Hipotensi yang disesuaikan dengan usia, yakni tekanan


sistolik < 80 mmHg untuk mereka yang berusia < 5 tahun atau
80 - 90 mmHg untuk anak-anak dan orang dewasa

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Fluid management in DSS
Fluid bolus 10- 20 ml/kg crystalloid/ 15 mt
NO IMPROVEMENT IMPROVEMENT DHF gr III

A Check HCT before fluid bolus or after fluid bolus


B
C If HCT is dropping Rising HCT
S < 40 for Children and female
< 45 for adult male 2nd bolus - Colloids
10 – 20 ml/kg/1 hr

Blood transfusion 3rd bolus - Colloids


whole blood 10 -20 ml/kg 10 – 20 ml/kg/1 hr
Packed RBC 5-10 ml/kg
Dengue: Guidelines for diagnosis, treatment, prevention and control, TDR-WH0 2009 37
Algorithm for fluid management in hypotensive shock/DSS

Hypotensive shock
Fluid resuscitation with 20ml/kg isotonic crystaloid or colloid
over 15 minutes
Try to obtain a HCT level before fluid resuscitation

IMPROVEMENT
No
Yes
Review 1st HCT
Crystaloid/colloid 10 ml/kg/hr for 1 HCT or High HCT
hour, then continue with :
In cristaloid 5-7 ml/kg/hr for 1-2 hours Administer 2nd bolus fluid (colloid) Consider significant occult/overt bleed
Reduce to 3-5 ml/kg/hr for 2-4 hours 10-20 ml/kg over 1/2 hour Initiate transfusion with fresh whole
Reduce to 2-3 ml/kg/hr for 2-4 hours blood

If patient is not stable, act according to IMPROVEMENT


HCT levels No
If HCT increase, consider bolus fluid
administration or increase fluid Yes
administration; Repeat 2sd HCT
If HCT decreases, consider transfusion
with fresh whole transfusion HCT or High HCT
Administer 3rd bolus fluid
Stop at 48 hours (colloid) 10-20 ml/kg over 1 hour

IMPROVEMENT
No
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Yes Repeat 3sd HCT
Fluid management in DSS IV Adjust on shock grade III, IV
Name…………………..BW……………….kg. M=………….CC/days………..cc/hr M+5%=……….….CC/days………..cc/hr

10 6 hrs…….cc
9 10-5 ml/kg/hr
(200-120 ml/hr)
8
7 8 hrs…….cc
IV Transfusion
(ml/kg/hr)

6 5-3 ml/kg/hr
5 (120-80 ml/hr) 18 hrs…….cc
4 3-1.5 ml/kg/hr
3 (80-40 ml/hr) 24 hrs…….cc

2 1.5 ml/kg/hr-KVO
(40 ml/hr-KVO)
1
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
shock Rate of KV fluid for children (Rate for adults) hour
Hour 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
1
Time
Type IV
Intake
Urine (mL)
Hct (%)
Kalayanarooj S. and Nimmannitya S. In: Guidelines for Dengue and Dengue Haemorrhagic Fever Management. 39
Bangkok Medical Publisher, Bangkok 2003.79
Tatalaksana perdarahan masif
• Sumber pedarahan diidentifikasi, mis : epitaxis
dikontrol dgn nasal packing
• Perdarahan saluran cerna diberikan H-2 antagonis
atau PPI, monitor HCT
• Tranfusi darah segera diberikan, 10 ml/kg WB atau
PRC
• Trombosit konsentrat / fresh frozen plasma (FFP)
meningkatkan resiko kelebihan cairan

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Fase pemulihan
• Perbaikan parameter klinis serta hemodinamik
• HCT kembali ke base line atau lebih rendah
• Cairan intravena dihentikan cegah overload
• Pada pasien dengan efusi masif dan ascites,
hypervolemia dapat terjadi dan terapi diuretik
dapat dipertimbang untuk mencegah edema paru

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Criteria for transfer IGD Soetomo
• Early presentation with shock (on days 2 or 3 of
illness)
• Severe plasma leakage and/or shock
• Undetectable pulse and blood pressure
• Severe bleeding
• Fluid overload
• Organ impairment (such as hepatic damage,
cardiomyopathy, encephalopathy, encephalitis and
other unusual complications) Expanded dengue
syndrome

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Kriteria KRS
• Tidak ada demam dalam 24 jam terakhir, tanpa
antipiretik
• Kembalinya nafsu makan
• Perbaikan klinis yang nyata
• Produksi urin yang baik
• Setidaknya 2-3 hari setelah sembuh dari syok
• Tidak ada distres nafas
• Tidak ada asites
• Trombosit lebih dari 50000 sel/mm3

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Key message

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TERIMA KASIH
Jalur triase untuk infeksi dengue
Demam dengan dugaan manifestasi perdarahan akibat dengue, sakit kepala,
nyeri retro orbital, mialgia, atralgia/nyeri tulang, ruam kulit

Uji torniquet

Demam < 3 hari Demam > 3 hari

Dengan Tanpa warning Darah lengkap

warning sign sign


Leukopenia dan atau Tanpa Leukopenia
trombositopenia atau trombositopenia
• Darah lengkap • Darah lengkap
• Gula darah sebagai baseline
• Pertimbangkan • Edukasi keluarga Warning Warning Warning Warning
resusitasi cairan (kotak 12) sign (-) sign (+) sign (+) sign (-)
IV/atasi dehidrasi • Pulang berobat jalan
• DD kondisi lain • Follow up tiap hari
• Observasi jangka jika memungkinkan
pendek/panjang Observasi/rawat
tergantung dx Beresiko
Perimbangan cairan IV
tinggi
Monitoring denge
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Requirement of fluid based on
body weight
Ideal body Maintenance M +5% Ideal body Maintenance M +5%
weight (ml) deficit (ml) weight (ml) deficit
(Kgs) (kgs) (ml)
5 500 750 35 1800 3550
10 1000 1500 40 1900 3900
15 1250 2000 45 2000 4250
20 1500 2500 50 2100 4600
25 1600 2850 55 2200 4950
30 1700 3200 60 2300 5300

Source: Holiday M.A., Segar W.E.. Maintenance need for water in parenteral fluid therapy. Pediatrics 1957;19: 823.78

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