Saptadi Yuliarto

Division of Pediatric Emergency and Intensive Care Hemodynamic Disturbance in Septic Shock
Department of Pediatrics, Faculty of Medicine, Universitas Brawijaya

PRELOAD DISTURBANCE AFTERLOAD DISTURBANCE

• Vascular leakage • Vascular tone disturbance
• Diastolic dysfunction

MICROVASCULAR
DISTURBANCE

Fluid Resuscitation in Pediatric

Septic Shock INOTROPY DISTURBANCE
PICU NICU UPDATE - PICU WEBINAR SERIES • Cardiomyopathy

new england The

The Impact of Pathology to Management journal
Problems medicine
with FluidofTherapy (1): Is it Safe? The n e w e ng l a n d j o u r na l of m e dic i n e
established in 1812 june 30, 2011 vol. 364 no. 26
6 Court et al.

INOTROPY Mortality after Fluid Bolus in African Children with Severe Infection
Frank-Starling Curve in Sepsis PRELOAD
AFTERLOAD A Mortality atKathryn
48 Hours

• 3141 children with septic shock

Figure 3 Maitland, M.B., B.S., Ph.D., Sarah Kiguli, M.B., Ch.B., M.Med., Robert O. Opoka, M.B., Ch.B., M.Med.,
Charles Engoru, 0.14
1.0 M.B., Ch.B., M.Med., Peter Olupot-Olupot, RR:M.B., Ch.B.,
1.45 (95%Samuel O. Akech,
CI, 1.13 M.B., pCh.B.,
to 1.86; = 0.003)
Richard Nyeko, M.B., Ch.B., M.Med., George Mtove, M.D., Hugh Reyburn, M.B., B.S., Trudie Lang, Ph.D.,
Normal • Open randomised 0.9control
Bernadette Brent, trial
M.B., 0.12
B.S., Jennifer A. Evans, M.B., B.S., James K. Tibenderana, M.B., Ch.B., Ph.D.,
• Intervention: NS orand
0.8
5%Diana
albumin 20-40
Jane Crawley, M.B., B.S., M.D., Elizabeth C. Russell, M.Sc.,
0.10
Michael Levin, F.Med.Sci.,Bolus
Ph.D., Abdel G. Babiker, Ph.D.,
M. Gibb, M.B., Ch.B., M.D., for the FEAST Trial Group*
Sepsis mL/kg in 1 hour

Cumulative Probability of Death

0.08
Fluid Fluid Restriction • Control: maintenance
0.7
uid
A BS T R AC T

Septic Shock Resuscitation or De-resuscitation 0.06

•
Background
CONCLUSION:
The 0.6
role of fluid resuscitation in the treatment of children No Bolus
0.04 with shock and life- From Kilifi Clinical TrialsAlbumin bolus
Facility, Kenya

• Fluid boluses0.5increased 48-hour

n fraction (LVEF) plotted
nonsurvivors. Overall, septic
F at the time of initial
d early depression of LVEF
days and returned to normal
d LVEF in the normal range.
ange. Reproduced with
n septic shock is not as
left ventricle [16] and the
onary artery wedge pres-
end-diastolic volume [17]
threatening infections who live in resource-limited settings is not established.
Methods 0.02
Medical Research InstituteSaline
(KEMRI)–Well-
bolus
come Trust Research Programme, Kilifi,
No bolus
Kenya (K.M., S.O.A., T.L., B.B.); Well-
mortality in critically ill children with
We randomly assigned children with severe febrile illness and impaired perfusion to come Trust Centre for Clinical Tropical
HIPOVOLEMIA vs HYPERVOLEMIA impaired perfusion in these resource-
receive boluses of 20 0.4
to 40 ml of 5% albumin solution 0.00
(albumin-bolus
0 6
group)
12
or 0.9%
18
Medicine, Department of Paediatrics,
Faculty
24 of Medicine,
30 36Imperial 42College48
saline solution (saline-bolus group) per kilogram of body weight or no bolus (control (K.M., B.B., M.L.), and the Medical Re-
group)limited settings
at the time of0.3 in Africato a hospital in Uganda, Kenya, or Tanzania (stratum search Council (MRC) Clinical Trials Unit
admission
(J.C., E.C.R., A.G.B., D.M.G.) — both in
A); children with severe hypotension were randomly assigned to one of the bolus groups London; the Department of Paediatrics,
only (stratum B). All 0.2
children received appropriate antimicrobial treatment, intravenous Mulago Hospital, Makerere University,
maintenance fluids, and supportive care, according to guidelines. Children with mal- Kampala (S.K., R.O.O.), Soroti Regional
Referral Hospital, Soroti (C.E.), Mbale Re-
nutrition or gastroenteritis
0.1 were excluded. The primary end point was 48-hour mor- gional Referral Hospital, Mbale (P.O.-O.),
tality; secondary end points included pulmonary edema, increased intracranial and St. Mary’s Hospital, Lacor (R.N.) —
Frank–Starling ventricular performance relationship for each of the Ognibene, et.al, Chest 1988 pressure, and mortality
0.0 or neurologic sequelae at 4 weeks. all inMaitland,
Uganda; the et.al, NEJMPro-2011
Joint Malaria
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 gramme, 32 34 Teule
36 Hospital,
38 40 Muheza,
42 44 Tanza-
three patient groups. Data points plotted represent the mean
prevolume and postvolume infusion values of end-diastolic volume 46 48
Results nia (G.M., H.R.); and the Department of
index (EDVI) and left ventricular stroke work index (LVSWI) for each
patient group. Control patients showed a normal increase of EDVI and Hours since Randomization
The data and safety monitoring committee recommended halting recruitment after Paediatrics, University Hospital of Wales,
LVSWI in response to volume infusion. The absolute increases of EDVI Cardiff, United Kingdom (J.A.E.). Address
and LVSWI in patients with sepsis without shock were less than those
3141 of the projected
Hr 1 3600 children Hr in
2 stratum A were
Hr 3 enrolled. Malaria
Hr 4 status (57%
Hr 5–8 Hr 9–24
reprint requests to Dr. MaitlandHrat24–48
the
of control subjects, but the slope of the curve is similar to control overall) and clinical severity were similar across groups. The 48-hour mortality was KEMRI–Wellcome Trust Programme,
bo s

bo s

bo s

bo s

bo s

bo s

bo s
olic dysfunction in sepsis. patients. Patients with septic shock had a greatly diminished response P.O. Box 230, Kilifi, Kenya, or at kathryn
10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044
lu

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ol s
and showed a marked rightward and downward shift of the
bo

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diography, however, have .maitland@gmail.com.
children) in the albumin-bolus, saline-bolus, and control groups, respectively (rela-
us

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Frank–Starling relationship. Reproduced with permission from [17].
in

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r filling [20] and aberrant
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 new england The

journal
Problems medicine
with FluidofTherapy (1): Is it Safe? Problems (2): Cause of Mortality
The n e w e ng l a n d j o u r na l of m e dic i n e
established in 1812 june 30, 2011 vol. 364 no. 26

Mortality after Fluid Bolus in African Children with Severe Infection

A Mortality atKathryn
48 Hours

• 3141 children with septic shock

Maitland, M.B., B.S., Ph.D., Sarah Kiguli, M.B., Ch.B., M.Med., Robert O. Opoka, M.B., Ch.B., M.Med.,
Charles Engoru, 0.14
1.0 M.B., Ch.B., M.Med., Peter Olupot-Olupot, RR:M.B., Ch.B.,
1.45 (95%Samuel O. Akech,
CI, 1.13 M.B., pCh.B.,
to 1.86; = 0.003)
Richard Nyeko, M.B., Ch.B., M.Med., George Mtove, M.D., Hugh Reyburn, M.B., B.S., Trudie Lang, Ph.D.,
• Open randomised 0.9control
Bernadette Brent, trial
M.B., 0.12
B.S., Jennifer A. Evans, M.B., B.S., James K. Tibenderana, M.B., Ch.B., Ph.D.,
• Intervention: NS orand
0.8
5%Diana
albumin 20-40
Jane Crawley, M.B., B.S., M.D., Elizabeth C. Russell, M.Sc.,
0.10
Michael Levin, F.Med.Sci.,Bolus
Ph.D., Abdel G. Babiker, Ph.D.,
M. Gibb, M.B., Ch.B., M.D., for the FEAST Trial Group*
mL/kg in 1 hour
Cumulative Probability of Death

0.08

•
A BS T R AC T
Control: maintenance
0.7
uid 0.06
• The
Background
CONCLUSION: 0.6
role of fluid resuscitation in the treatment of children
0.04 with shock and life-
No Bolus From Kilifi Clinical TrialsAlbumin bolus
Facility, Kenya
Cardiovascular collapse
• Fluid boluses0.5increased 48-hour
threatening infections who live in resource-limited settings is not established.
Methods 0.02
Medical Research InstituteSaline
(KEMRI)–Well-
come Trust Research Programme, Kilifi,
No bolus
bolus
Kenya (K.M., S.O.A., T.L., B.B.); Well-
mortality in critically ill children with
We randomly assigned children with severe febrile illness and impaired perfusion to come Trust Centre for Clinical Tropical
0.00 Medicine, Department of Paediatrics,
impaired perfusion in these resource-
receive boluses of 200.4
to 40 ml of 5% albumin solution (albumin-bolus
0 6
group) or 0.9% Faculty of Medicine, Imperial College
12 18 24 30 36 42 48
saline solution (saline-bolus group) per kilogram of body weight or no bolus (control (K.M., B.B., M.L.), and the Medical Re-
limited settings in Africa
0.3
group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum search Council (MRC) Clinical Trials Unit
(J.C., E.C.R., A.G.B., D.M.G.) — both in
A); children with severe hypotension were randomly assigned to one of the bolus groups London; the Department of Paediatrics,
only (stratum B). All 0.2
children received appropriate antimicrobial treatment, intravenous Mulago Hospital, Makerere University,
IS FLUID BOLUS THERAPY SAFE?
maintenance fluids, and supportive care, according to guidelines. Children with mal- Kampala (S.K., R.O.O.), Soroti Regional
nutrition or gastroenteritis
0.1
Referral Hospital, Soroti (C.E.), Mbale Re-
were excluded. The primary end point was 48-hour mor- gional Referral Hospital, Mbale (P.O.-O.),
tality; secondary end points included pulmonary edema, increased intracranial and St. Mary’s Hospital, Lacor (R.N.) —
pressure, and mortality
0.0 or neurologic sequelae at 4 weeks. all in Uganda; the Joint Malaria Pro- Maitland, et.al, NEJM 2011 Maitland, BMC Med 2013
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 gramme, 32 34 Teule
36 Hospital,
38 40 Muheza,
42 44 Tanza-46 48
Results nia (G.M., H.R.); and the Department of
Hours since Randomization
The data and safety monitoring committee recommended halting recruitment after Paediatrics, University Hospital of Wales,
Cardiff, United Kingdom (J.A.E.). Address
3141 of the projected
Hr 1 3600 children Hr in
2 stratum A were
Hr 3 enrolled. Malaria
Hr 4 status (57%
Hr 5–8 Hr 9–24
reprint requests to Dr. Maitland Hrat24–48
the
overall) and clinical severity were similar across groups. The 48-hour mortality was KEMRI–Wellcome Trust Programme,
N bo s

N bo s

N bo s

N bo s

N bo s

N bo s

N bo s
10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 P.O. Box 230, Kilifi, Kenya, or at kathryn
u

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lu .maitland@gmail.com.
Sa in b

Sa in b

Sa in b

Sa in b

Sa in b

Sa in b

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children) in the albumin-bolus, saline-bolus, and control groups, respectively (rela-
s

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Problems (3): Cause of Mortality
tive risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90;
lin

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Drs. Levin, Babiker, and Gibb contributed
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Al

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No. at RiskP =1050
0.01;1047
relative risk1037
for 1033
albumin
1030bolus
1024vs. saline
1021bolus,
10161.01;
101095%1015CI, 0.781001
to 1.29; equally to this article.
1044 1018 1010 1011 992 980 996 954 945 975
Died P = 0.96;
13 and12relative
14 risk 13 for15
any bolus
9 vs.8control,
7 1.45;
6 95% 6 CI, 91.13 to
4 1.86;
17 P =20
0.003).
14 38 34members
* Additional 20 of16 13 Expan-
the Fluid 9

Clinical Questions of
% The 4-week
1.2 1.1mortality
1.3 1.3 was 1.5
12.2%,
0.912.0%,
0.8 and
0.78.7%
0.6 in the
0.6 three
0.9 groups,
0.4 1.7 respectively
2.0 1.4 3.8as Supportive
sion 3.5 2.0Therapy 1.7 (FEAST)
1.4 study
0.9
(P = 0.004 for the comparison of bolus with control). Neurologic sequelae occurred team are listed at the end of the article.
in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P = 0.92), and This article (10.1056/NEJMoa1101549) was

Fluid Resuscitation
B Mortalitypulmonary
at 4 Weeks edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% published on May 26, 2011, and updated
(P = 0.17), respectively.
1.0 In stratum B, 69% of the children 0.14(9 of 13) in the albumin- on June 2, 2011, at NEJM.org.
bolus group and 56% (9 of 16) in the saline-bolus group died (P = 0.45). The results N Engl J Med 2011;364:2483-95.
were consistent across 0.12
0.9 centers and across subgroups according to the severity of Copyright © 2011 Massachusetts Medical Society.
shock and status with respect to malaria, coma, sepsis, 0.10 acidosis, and severe anemia.
Conclusions 0.8
• What’s the trigger?
Cumulative Probability of Death

Fluid boluses significantly increased 48-hour mortality 0.08 in critically ill children with
impaired perfusion in 0.7these resource-limited settings in Africa. (Funded by the Med-
ical Research Council, United Kingdom; FEAST Current
ISRCTN69856593.) 0.6
0.06
Controlled Trials number,
0.04
Albumin bolus • What kind of fluid?
Saline bolus
• How much?
n engl j med 364;26 nejm.org june 30, 2011 2483
No bolus
0.5 0.02 of Medicine
The New England Journal

• How fast?
Downloaded from nejm.org on May 25, 2013. For personal use only. No other uses without permission.
0.4 0.00 Society. All rights reserved.
Copyright © 2011 Massachusetts Medical
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28

• When to stop?
0.3

0.2

0.1 • Goals?
0.0
0 2 4 6 8 10 12 14 16
Levin,18et.al.,20Lancet
22 24
Respir 26
Med 28
2019
Days since Randomization
Day 1 Day 2 Day 3–7 Day 8–14 Day 15–21 Day 21–28
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Trigger to Fluid Resuscitation
Davis, et.al., Crit Care Med 2017
Trigger to Fluid Resuscitation
• Hypotension
• Tachycardia + decrease perfusion: 1
Centre for Geographic Medicine
Research (Coast), Kenya Medical
Research Institute-Wellcome Trust
• Weak peripheral pulse, narrow pulse pressure Programme, PO Box 230, Kilifi,
Kenya
2
Department of Paediatrics and
• CRT > 2 sec Wellcome Trust Centre for Clinical
Tropical Medicine, Faculty of
Medicine, Imperial College,
London W2 1PG
• Cold extremities, pale, mottled Correspondence to: K Maitland,
KEMRIWellcomeTrustProgramme,
PO Box 230, Kilifi, Kenya
• Altered mental status kmaitland@kilifi.kemri-wellcome.
org
Cite this as: BMJ 2010;341:c4416
doi:10.1136/bmj.c4416
Carcillo, et.al., Clin Ped Emerg Med 2007
cacy of treatment of shock included use of secondary one of 191 children who re
resuscitation strategies and incidence of organ failure. xyethyl starch) developed a
urticarial rash in the same
Mortality trial 5/56 (9%) children who
None of the studies were designed or adequately pow- (Gelafundin) and one (1/7
ered to examine mortality as a primary outcome. The developed allergic reaction
Trigger to Fluid Resuscitation
four trials in dengue enrolled 819 children and reported cardiovascular compromise.
five deaths. Because of the expected low mortality in gelatin suffered severe epist
dengue, this was not a stated end point. Therefore no transfusion, and another wh
conclusions can be drawn about the survival benefit oped a haematoma at an inj
between colloids and crystalloids in this disease. in children with sepsis repor
A total of 352 children were enrolled in fluid expansion
trials in children with severe malaria. Two studies Quantitative data synthesis
included 51 children randomised to a “no bolus” (con- Colloids versus crystalloids
trol) strategy.38 39 One study that compared 0.9% saline We selected six trials (three
with human albumin solution showed a significant over- trials, and one sepsis trial)
all reduction in mortality in the albumin group (P=0.013) death to compare colloids an
and in the high risk subgroup, where acidosis and shock mal saline or Ringers lactate).
was complicated by coma (P=0.002). There were, how- participants, 523 randomised
ever, no differences between the fluid intervention arms talloids, and reported 48 dea
colloids). Though the forest p
in cases without coma (P=0.7).38 The survival advantage
heterogeneity (χ2=2.66, P=0.2
was also noted in the trial of human albumin solution
a composite estimate because
compared with Gelofusine (a gelatin polymer), in which
the a priori risk of mortality b
mortality was lower in the albumin group (P=0.06), par-
tions (dengue, severe malaria
ticularly in the subgroup with coma (P=0.04).40
the six studies showed better s
The trial conducted in children with sepsis found no
tated with colloids compared
Decreased Mental Status and Perfusion difference in mortality with fluids used: 9/31 (29%) sal-
ine recipients died compared with 9/29 (31%) in the
wide confidence intervals in t
interpreting this as a true eff
gelatin polymer group summarises the results.
Adverse events
Davis, et.al., Crit Care Med 2017
Albumin crystalloids
There was a non-significant increase in neurological Because of the ongoing deba
sequelae with human albumin solution compared of human albumin solut
with other fluids in children who survived severe survival.5 7 11 46-48 The only t
malaria: 9/136 (7%) with albumin, 2/95 (2%) with sal- in children with severe m
RESEARCH
ine, and 1/37 (3%) with Gelofusine.37-40 One episode of important clinical heteroge
Type of Fluid Resuscitation
allergic reaction was reported in a child receiving one enrolled children with
Gelofusine.40 Pulmonary oedema, unrelated to the fluid resuscitation was g
intervention, was reported in two of 61 (3%) children management, 39 while the tw
who received saline in one trial.38 In children with den- children with severe malar
Choice of fluids for resuscitation in children with severe
gue who received dextran, 15/193 (8%) developed could not calculate combi
infection and shock: systematic review signs of severe reactions, which included fever and The largest of these trials sh
tion in mortality for children
Samuel Akech, clinical
Study or research fellow,
1
Hannah Ledermann,
Events/total paediatric
Adequate Petoclinical trainee,1 KathrynPeto
fixed odds Maitland,
fixed odds albumin solution compared
professor ofsubgroup
tropical paediatricColloids
infectious disease 1,2
Crystalloids sequence ratio (95% CI) ratio (95% CI) showed non-significantly re
generation
Sepsis
the third trial (in those with
ABSTRACT Upadhyaya 200545 9/29 9/31 The
Yes leading cause of circulatory failure in 1.1children is
(0.4 to 3.3)
showed no difference in su
Objective To systemically
Malaria review the evidence from hypovolaemia, usually secondary to severe infection.2 children with severe malar
clinical trials comparing the use
Maitland 200538
of crystalloids and
2/56
colloids for fluid resuscitation in children with severe
11/61
Early and rapid fluid resuscitation with isotonic solu-
Yes 0.23 (0.07 to 0.74)
tions is the cornerstone of management. For children,
albumin solution with Gelo
Maitland 2005 39
4/23 3/20 Yes 1.2 (0.24 nificant reduction in morta
infection. however, there is still no clear consensus over tothe
5.9)
with human albumin solu
Data sources Medline 200337
Maitland(1950-2008), 0/20
PubMed, the 4/32 No
choice 0.18 (0.02
of resuscitation fluid, and colloidal to 1.4)
solutions
Dengue
Cochrane Library, Embase (1980-2008), and reference (such as human albumin solution) might be better human albumin solution arm
lists. Wills 200543 than
Yes the cheaper crystalloids (such3.8as(0.04 normal with 7/44 (16%) in the Gelof
Eligibility criteria Published
Cifra 2003
1/384 0/128
44 studies comparing fluid
1/11 3/16
saline).3-11 Although physiological explanations have
No
to 350)
0.48 (0.06 to 4.0) 0.20, 95% confidence interv
resuscitation with crystalloid or colloidal solutions in been advanced to support potential benefits of colloids
severe infectious illness in children aged >1 month to ≤
12 years. Controlled trials and randomised controlled
over crystalloids, the current evidence does not sup-
port0.01 0.1Earlier1 Cochrane
these.3-5 10 100
meta-analyses con- Sepsis
trials were separately selected by two unblinded Favours Favours
cluded that human albumin solution resulted in In the only trial included, the
investigators who also independently extracted data. colloids
increased mortality,3 5 6 butcrystalloids
these conclusions were dis- risk of mortality between sa
Main outcome measures Efficacy in the treatment of puted and a subsequent meta-analysis showed that use
Fig 2 | Comparison of mortality in children resuscitated with colloids or crystalloids
of human albumin solution or 0.9% saline resulted in
(Peto odds ratio 1.10, 0.37 to
shock, mortality, and reported adverse events.
Results NineBMJ trials fulfilledFIRST
criteria, eight of which similar survival.4 This conclusion was greatly influ-
| ONLINE | bmj.com
compared crystalloids with colloids. All trials were enced by the results of a trial of human albumin Akech,
solu-et.al, BMJ 2010
conducted in settings with poor resources and tion compared with saline in 7000 adults in Australia
predominantly included patients with malaria or dengue and New Zealand (SAFE study), which reported simi-
haemorrhagic shock. None of the trials had mortality as a lar survival in both treatment arms.12 A non-significant
primary outcome. Three out of six studies that reported at trend towards improved survival was noted in the sub-
least one death showed better survival in children group of patients with sepsis treated with human albu-
resuscitated with colloids compared with crystalloids min solution. Successive meta-analyses, however,

 new englandThe new england

The
journal of medicine journal of medicine
Type of Fluid Resuscitation The n e w e ng l a n d j o u r na l
established in 1812 june 30, 2011
of m e dic i n e
vol. 364 no. 26
Type of Fluid Resuscitation The n e w e ng l a n d j o u r na l
established in 1812 june 30, 2011
of m e dic i n e
vol. 364 no. 26

Mortality after Fluid Bolus in African Children with Severe Infection Mortality after Fluid Bolus in African Children with Severe Infection
A Mortality at 48 Hours A Mortality at 48 Hours
• 3141 children with septic shock • 3141 children with septic shock
Kathryn Maitland, M.B., B.S., Ph.D., Sarah Kiguli, M.B., Ch.B., M.Med., Robert O. Opoka, M.B., Ch.B., M.Med., Kathryn Maitland, M.B., B.S., Ph.D., Sarah Kiguli, M.B., Ch.B., M.Med., Robert O. Opoka, M.B., Ch.B., M.Med.,
Charles 1.0 0.14
Engoru, M.B., Ch.B., M.Med., Peter Olupot-Olupot, M.B.,
RR: Ch.B.,
1.01 (95% Samuel
CI, O. 0.78Akech, M.B., Ch.B.,
to 1.29; p = 0.96) Charles 1.0 0.14
Engoru, M.B., Ch.B., M.Med., Peter Olupot-Olupot, RR:M.B., Ch.B.,
1.01 (95% Samuel
CI, O. 0.78Akech, M.B., Ch.B.,
to 1.29; p = 0.96)
Richard Nyeko, M.B., Ch.B., M.Med., George Mtove, M.D., Hugh Reyburn, M.B., B.S., Trudie Lang, Ph.D., Richard Nyeko, M.B., Ch.B., M.Med., George Mtove, M.D., Hugh Reyburn, M.B., B.S., Trudie Lang, Ph.D.,
•
Open randomised
Bernadette control
0.9 Brent, trial
M.B., 0.12 M.B., B.S., James K. Tibenderana, M.B., Ch.B., Ph.D.,
B.S., Jennifer A. Evans, Albumin •
Open randomised
Bernadette control
0.9 Brent, trial
M.B., 0.12 M.B., B.S., James K. Tibenderana, M.B., Ch.B., Ph.D.,
B.S., Jennifer A. Evans, Albumin
•
Intervention: NS orand 5%Diana
albumin 20-40
Jane Crawley, M.B., B.S., M.D., Elizabeth C. Russell, M.Sc., Michael Levin, F.Med.Sci., Ph.D., Abdel G. Babiker, Ph.D.,
0.8
0.10
M. Gibb, M.B., Ch.B., M.D., for the FEAST Trial Group* •
Intervention: NS orand
0.8
5%Diana
albumin 20-40
Jane Crawley, M.B., B.S., M.D., Elizabeth C. Russell, M.Sc., Michael Levin, F.Med.Sci., Ph.D., Abdel G. Babiker, Ph.D.,
0.10
M. Gibb, M.B., Ch.B., M.D., for the FEAST Trial Group*
mL/kg in 1 hour Saline mL/kg in 1 hour Saline
Cumulative Probability of Death

Cumulative Probability of Death

0.08 0.08
• •
A BS T R AC T A BS T R AC T
Control:0.7maintenance uid Control:0.7maintenance uid
Background 0.06 Background 0.06
The role of fluid resuscitation in the treatment of children with shock and life- From Kilifi Clinical Trials Facility, Kenya The role of fluid resuscitation in the treatment of children with shock and life- From Kilifi Clinical Trials Facility, Kenya
0.6 Albumin bolus 0.6 Albumin bolus
threatening infections who live in resource-limited0.04 settings is not established. Medical Research Institute (KEMRI)–Well- threatening infections who live in resource-limited0.04 settings is not established. Medical Research Institute (KEMRI)–Well-
Saline bolus
come Trust Research Programme, Kilifi, Saline bolus
come Trust Research Programme, Kilifi,
Methods 0.5 Kenya (K.M., S.O.A., T.L., B.B.); Well-
No bolus Methods 0.5 Kenya (K.M., S.O.A., T.L., B.B.); Well-
No bolus
0.02 0.02
We randomly assigned children with severe febrile illness and impaired perfusion to come Trust Centre for Clinical Tropical We randomly assigned children with severe febrile illness and impaired perfusion to come Trust Centre for Clinical Tropical
Medicine, Department of Paediatrics, Medicine, Department of Paediatrics,
receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% Faculty of Medicine, Imperial College
0.00 receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% Faculty of Medicine, Imperial College
0.00
0.4 0.4
saline solution (saline-bolus group) per kilogram of body 0weight or 6 no bolus
12 (control
18 (K.M., B.B., M.L.), and the Medical Re-
24 30 36 42 48 saline solution (saline-bolus group) per kilogram of body 0weight or 6 no bolus
12 (control
18 (K.M., B.B., M.L.), and the Medical Re-
24 30 36 42 48
group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum search Council (MRC) Clinical Trials Unit group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum search Council (MRC) Clinical Trials Unit
0.3 (J.C., E.C.R., A.G.B., D.M.G.) — both in
A); children with severe hypotension were randomly assigned to one of the bolus groups London; the Department of Paediatrics, 0.3 (J.C., E.C.R., A.G.B., D.M.G.) — both in
A); children with severe hypotension were randomly assigned to one of the bolus groups London; the Department of Paediatrics,
only (stratum B). All children received appropriate antimicrobial treatment, intravenous Mulago Hospital, Makerere University, only (stratum B). All children received appropriate antimicrobial treatment, intravenous Mulago Hospital, Makerere University,
0.2 and supportive care, according to guidelines. Children with mal- Kampala (S.K., R.O.O.), Soroti Regional
maintenance fluids,
Referral Hospital, Soroti (C.E.), Mbale Re-
No difference off mortality between albumin and saline bolus
0.2 and supportive care, according to guidelines. Children with mal- Kampala (S.K., R.O.O.), Soroti Regional
maintenance fluids,
Referral Hospital, Soroti (C.E.), Mbale Re-
nutrition or gastroenteritis were excluded. The primary end point was 48-hour mor- gional Referral Hospital, Mbale (P.O.-O.), nutrition or gastroenteritis were excluded. The primary end point was 48-hour mor- gional Referral Hospital, Mbale (P.O.-O.),
tality; secondary 0.1 end points included pulmonary edema, increased intracranial and St. Mary’s Hospital, Lacor (R.N.) — tality; secondary 0.1 end points included pulmonary edema, increased intracranial and St. Mary’s Hospital, Lacor (R.N.) —
pressure, and mortality or neurologic sequelae at 4 weeks. all inMaitland,
Uganda; the et.al, NEJMPro-2011
Joint Malaria pressure, and mortality or neurologic sequelae at 4 weeks. all inMaitland,
Uganda; the et.al, NEJMPro-2011
Joint Malaria
gramme, Teule Hospital, Muheza, Tanza- gramme, Teule Hospital, Muheza, Tanza-
Results 0.0 nia (G.M., H.R.); and the Department of Results 0.0 nia (G.M., H.R.); and the Department of
The data and safety 0 monitoring
2 4 6 committee
8 10 12 14 16 18 halting
recommended 20 22 recruitment
24 26 28 after 30 32Paediatrics,
34 36 University
38 40 Hospital
42 44of Wales,
46 48 The data and safety 0 monitoring
2 4 6 committee8 10 12 14 16 18 halting
recommended 20 22 recruitment
24 26 28 after 30 32Paediatrics,
34 36 University
38 40 Hospital
42 44of Wales,
46 48
Cardiff, United Kingdom (J.A.E.). Address Cardiff, United Kingdom (J.A.E.). Address
3141 of the projected 3600 children in stratum A wereHours enrolled. Malaria
since status (57% reprint requests to Dr. Maitland at the
Randomization 3141 of the projected 3600 children in stratum A wereHours enrolled. Malaria
since status (57% reprint requests to Dr. Maitland at the
Randomization
overall) and clinical severity were similar across groups. The 48-hour mortality was KEMRI–Wellcome Trust Programme, overall) and clinical severity were similar across groups. The 48-hour mortality was KEMRI–Wellcome Trust Programme,
Hr 1 Hr 2 Hr 3 Hr 4 Hr 5–8 Hr 9–24 Hr 24–48 Hr 1 Hr 2 Hr 3 Hr 4 Hr 5–8 Hr 9–24 Hr 24–48
10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 P.O. Box 230, Kilifi, Kenya, or at kathryn 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 P.O. Box 230, Kilifi, Kenya, or at kathryn
.maitland@gmail.com. .maitland@gmail.com.
children) in the albumin-bolus, saline-bolus, and control groups, respectively (rela- children) in the albumin-bolus, saline-bolus, and control groups, respectively (rela-
bo s

N bo s

N bo s

N bo s

N bo s

N bo s

N bo s

N bo s

N bo s

N bo s

N bo s

N bo s

N bo s
lu

lu

u
ol

ol

ol

ol

ol

ol

ol

ol

ol

ol

ol

ol
bo s

bo us

bo s

bo s

bo s

bo s

bo s

bo s

bo s

bo s

bo us

bo s

bo s
Pediatric SSC 2020: Type of Fluid Resuscitation Pediatric SSC 2020: Type of Fluid Resuscitation
bo

bo
tive risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; Drs. Levin, Babiker, and Gibb contributed tive risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; Drs. Levin, Babiker, and Gibb contributed
lu

lu

lu

lu

lu

o olu

lu

lu

lu

lu

lu
Sa in b

Sa in b

Sa in b

Sa in b

Sa in b

Sa in b

Sa in b

Sa in b

Sa in b

Sa in b

Sa in b

Sa in b
l

l
s

s
in

in
lu

lu

lu

lu

lu

lu

lu

lu

lu

lu

lu

lu

lu

lu
b
P = 0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; equally to this article. P = 0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; equally to this article.
m

m
bo
e

e
lin

lin

lin

lin

lin

lin

lin

lin

lin

lin

lin

lin

lin

lin
bu

bu

bu

bu

bu

bu

bu

bu

bu

bu

bu

bu

bu

bu
P = 0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P = 0.003). *Additional members of the Fluid Expan- P = 0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P = 0.003). *Additional members of the Fluid Expan-
o

o
Sa

Sa
Al

Al

Al

Al

Al

Al

Al

Al

Al

Al

Al

Al

Al

Al
N

N
No. at Risk 1050 The 4-week
1047 1044mortality
1037 1033 was1030
12.2%, 12.0%,
1024 1018and10218.7% in the
1016 1010 three
1015groups, respectively
1010 1001 1011 992 980
sion as 996 Therapy
Supportive 954 (FEAST)
945 975 study No. at Risk 1050 The 4-week
1047 1044mortality
1037 1033 was1030
12.2%, 12.0%,
1024 1018and
10218.7%
1016in the
1010 three
1015groups, respectively
1010 1001 1011 992 980
sion as 996 Therapy
Supportive 954 (FEAST)
945 975 study
Died 13(P = 0.004
12 14 for the13comparison
15 9 of bolus
8 with 7 control).
6 6Neurologic
9 4 sequelae
17 20 occurred
14 38 34listed20at the end
team are 16 of the
13 article.
9 Died 13(P = 0.004
12 14 for the13comparison
15 9 of bolus
8 with7 control).
6 6Neurologic
9 4 sequelae
17 20 occurred
14 38 34listed20at the end
team are 16 of the
13 article.
9
% 1.2 1.1 1.3
in 2.2%, 1.9%, 1.3 1.5 0.9
and 2.0% of the0.8 0.7 in
children 0.6the respective
0.6 0.9 groups0.4 1.7 2.0 1.4
(P = 0.92), and 3.8 3.5 2.0 1.7 1.4 0.9
This article (10.1056/NEJMoa1101549) was
pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% published on May 26, 2011, and updated
% • SUGGEST:
1.2 1.1 1.3
in 2.2%, 1.9%, 1.3 1.5 0.9
and 2.0% of the0.8 0.7 in
children 0.6the respective
0.6 0.9 groups0.4 1.7 2.0 1.4
(P = 0.92), and 3.8
This
3.5 (10.1056/NEJMoa1101549)
article
2.0 1.7 1.4 0.9
pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% published on May 26, 2011, and updated
was

• SUGGEST:
(P = 0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin- on June 2, 2011, at NEJM.org.
B Mortality at 4 bolus
Weeks
(P = 0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin- on June 2, 2011, at NEJM.org.
B Mortality at 4 •bolus
Weeks
group and 56% (9 of 16) in the saline-bolus group died (P = 0.45). The results N Engl J Med 2011;364:2483-95. Against
group and 56% using gelatin.
(9 of 16) in the saline-bolus group died (P = 0.45). The results N Engl J Med 2011;364:2483-95.
were consistent 1.0across centers and across subgroups 0.14according to the severity of Copyright © 2011 Massachusetts Medical Society. were consistent 1.0across centers and across subgroups 0.14according to the severity of Copyright © 2011 Massachusetts Medical Society.
•shock
Using crystalloids,
and status rather
with respect to malaria, than
coma, sepsis, albumin.
acidosis, and severe anemia. shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia.
0.12 • 1 RCT of gelatin vs. 0.9% saline 0.12 in 60 pediatric septic shock showed no
Conclusions 0.9 Conclusions 0.9
• boluses
No difference
significantly of mortality
48-hourbetween difference in mortality, days of using vasoactive, or AKI. (Upadhyay, Indian
Fluid increased 0.10in albumin
mortality and saline
critically ill children with bolus [RR: 1.01; 95% CI, Fluid boluses significantly increased 48-hour mortality 0.10in critically ill children with
impaired0.78 to0.81.29;
perfusion p =resource-limited
in these 0.96]. (Maitland, settings inNEJM 2011) by the Med-
Africa. (Funded impairedPediatr
perfusion2005)
0.8 in these resource-limited settings in Africa. (Funded by the Med-
ical Research Council, United Kingdom; FEAST Current 0.08 Controlled Trials number, ical Research Council, United Kingdom; FEAST Current 0.08 Controlled Trials number,
Cumulative Probability of Death

Cumulative Probability of Death

ISRCTN69856593.) 0.7
• This recommendation takes
n engl j med 364;26 into
0.06consideration
nejm.org june 30, 2011 cost and other barriers of2483 • RECOMMEND:
ISRCTN69856593.) 0.7
0.06 june 30, 2011
n engl j med 364;26 nejm.org 2483
administering
0.6 albumin The New England Journal of Medicine Albumin bolus 0.6 The New England Journal of Medicine Albumin bolus
0.04
Downloaded from nejm.org on May 25, 2013. For personal use only. No other uses without permission. Saline bolus • Against using
Downloaded fromstarches.⭐⭐ 0.04
nejm.org on May 25, 2013. For personal use only. No other uses without permission. Saline bolus
• Using balanced/buffered
0.5 crystalloids, rather
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
0.02 than 0.9% saline.
No bolus
0.5
Copyright © 2011 Massachusetts Medical Society. All rights reserved.
0.02
No bolus
• 2 large adult RCTs showed increased risk of mortality, coagulopathy, and AKI
• Balanced/buffered
0.4 crystalloids 0.00
was0associated with lower mortality [OR: 0.79; 0.00
in HES0.4group. (Perner, NEJM 2012; Myburgh, NEJM 2012). A meta-analysis
2 4 6 8 10 12 14 16 18 20 22 24 26 28 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
95% CI,
0.3
0.65–0.95] but not AKI [OR, 0.98; 95% CI, 0.94–1.02]. (Weiss, J Pediatr confirmed
0.3
the risk of harm with HES. (Zarychanski, JAMA 2013)
2017; Emrath, Crit Care Med 2017)
0.2 • FDA and
0.2 EMA, has restricted and suspended, respectively, the use of HES.

0.1 0.1
Weiss, et.al., Pediatr Crit Care Med 2020 Weiss, et.al., Pediatr Crit Care Med 2020
0.0 0.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Days since Randomization Days since Randomization
Day 1 Day 2 Day 3–7 Day 8–14 Day 15–21 Day 21–28 Day 1 Day 2 Day 3–7 Day 8–14 Day 15–21 Day 21–28
s

fl
fl

 Volume of Fluid Resuscitation: High Volume?
• Rapid fluid resuscitation >40 mL/kg in 1st hour was associated with
improved survival, decreased persistent hypovolemia, and no increase
cardiogenic pulmonary edema or ARDS. (Carcillo, JAMA 1991)
• Observational study on 34 children with septic shock
• Mortality rate higher in fluid <40 mL/kg and delay treatment >30 min.
(Oliveira, Pediatr Emerg Care 2008)
• Retrospective study on 90 children with severe sepsis and septic shock
• Mortality rate <20 vs. 20-40 vs. >40 mL/kg = 73 vs. 52 vs. 33% (p=0.03)
Volume of Fluid Resuscitation: Low Volume?
Septic Shock Management Guided by Ultrasound:
A Randomized Control Trial (SEPTICUS TRIAL)
• 38 children with septic shock
• Open randomised control trial: pilot study
• Intervention: Doppler US guided
• Control: ACCM protocols of septic shock
• CONCLUSION:
In intervention group:
• Lower 72 hours mortality
• Higher prevalence of meeting therapeutic
goals
• Lower lung US score
• Less liver enlargement in intervention group.
Yuliarto, Pramita, Kadafi, 2020
Volume of Fluid Resuscitation: Low Volume?
• Less volume in intervention than control group (14.5 vs 25.7 mL/kg,
p<0.001). No difference of mortality, PICU LOS, hospital LOS, and LOS
free days. (Inwald, Arch Dis Child 2019)
• FISh Trial: Multicenter RCT pilot study on 75 children with septic shock
• Less volume in intervention than control group (47.1 vs 61.1 mL/kg,
p=0.01). No difference of mortality, ICU LOS, hospital LOS, incidence of
organ failure, and serious adverse effect in 30 days. (Corl, Crit Care Med
2019)
• RIFTS: Multicenter RCT pilot study on 109 adult with septic shock
Pediatric SSC 2020: Volume of Fluid Therapy
• SUGGEST:
USSM • PICU available: fluid bolus up to 40–60 mL/kg (10–20 mL/kg per
bolus) over the 1st hour,
• PICU unavailable, with hypotension: fluid bolus up to 40 mL/kg (10–
20 mL/kg per bolus) over the 1st hour,
ACCM
• titrated to clinical markers of cardiac output and discontinued if signs
of fluid overload develop
• RECOMMEND: PICU unavailable, no hypotension: against bolus fluid
administration while starting maintenance fluids.⭐⭐
Weiss, et.al., Pediatr Crit Care Med 2020

Rate of Fluid Resuscitation: Faster vs. Slower? Terminate the Fluid Resuscitation
• No difference of mortality, rapidity of shock resolution, and
complications. However, hepatomegaly at 20 minutes was higher in • Achieving therapeutic goals
intervention (faster) group. (Santhanam, Pediatr Emerg Care 2008) • Meeting fluid refractory condition:
• Single centre RCT on 147 children with septic shock
• Clinical sign: hepatomegaly, rales. (Davis, Crit Care Med 2017)
• Intervention: 40 mL/kg in 15 minutes followed by dopamine vs. Control: 20 mL/
kg in 20 minutes up to 60 mL/kg over 1 hour, followed by dopamine • Measuring fluid-responsiveness

• Reduce risk of MV and increase OI in intervention (slower) group at 6 and
24 hours. But, no difference in mortality, LOS, and resolution of shock.
(Shankar, Pediatr Crit Care Care 2017)
• Single centre RCT on 96 children with septic shock
• Intervention: FBT 15-20 minutes vs. Control: FBT 5-10 minutes
• PLR: Measurements in CI changes after PLR can be helpful in predicting fluid
responsiveness. (Lukito, Pediatr Crit Care Med 2012)
• Dynamic measurement: Respiratory variation in aortic blood flow peak
velocity shown to predict fluid responsiveness in children. (Gan, Anesth Analg
2013)

Therapeutic Goals Therapeutic Goals

• Threshold HRs

• Normal pulses with same quality of the peripheral and central pulses,
CRT <2 seconds, warm extremities

• Normal mental status

• Urine output >1 mL/kg/hr,

• CI: 3.3 - 6.0 L/min/m2

• Normal perfusion pressure (MAP-CVP, or MAP-IAP) for age

• ScVO2 >70%.

Davis, et.al., Crit Care Med 2017 Davis, et.al., Crit Care Med 2017

 Summary (1) Summary (2)

• Time: slower bolus rather than fast (especially if PICU unavailable)
• Trigger: decrease perfusion
• Termination: good perfusion or fluid-refractory shock
• Type: Crystalloid (balanced solution) rather than albumin (or colloids)
• Target: good perfusion, normal HR and MAP
• Total:

• PICU available: 10-20 mL/kg per bolus up to 40-60 mL/kg

• PICU unavailable, with hypotension: 10-20 mL/kg per bolus up to 40

mL/kg

• PICU unavailable, no hypotension: maintenance fluid⭐⭐

Thank You