Review for the Expert Committee on the Selection and Use of
Essential Medicines
Are colloid solutions essential
for the treatment of pediatric
trauma or burn patients?
Christina Huwer
Volunteer
Department of Violence and Injury Prevention and Disability
World Health Organization
Geneva, Switzerland
November 2012
Content
Summary………………………………………………………………………………………………………………………..2
Objective………………………………………………………………………………………………………………………..3
Background…………………………………………………………………………………………………………………….3
Search Methods……………………………………………………………………………………………………………..4
Results…………………………………………………………………………………………………………………………….5
Efficacy…………………………………………………………………………………………………………………………...7
Safety……………………………………………………………………………………………………………………………..9
Costs……………………………………………………………………………………………………………………………….9
Conclusion…………………………………………………………………………………………….………………………10
Other Indications………………………………………………………………………………………………………….10
References……………………………………………………………………………………………………………………11
Appendix………………………………………………………………………………………………………………………13
1
Summary
Colloid solutions are widely used for fluid resuscitation including children, although there is an ongoing
controversy concerning their actual use in children. To support the Expert Committee on the Selection
and Use of Essential Medicines in their decision whether to include a colloid solution in the Essential
Medicines List for Children this review of the literature was conducted. No high-level evidence studies
could be identified to answer the question. From the available evidence it appears that colloid solutions
do not have a proven benefit compared to crystalloid solutions. Because colloids are more expensive
and more likely to cause adverse effects an inclusion may not be recommended.
2
Objective
The objective of this review is to examine the available scientific evidence for use of Colloids in children
to enable informed decision whether colloids should be included in the Essential Medicine List for
Children (EMLc) and if yes, which one should be. The review will focus primarily on trauma and burns as
indications for the use of colloids in children.
Currently only Dextran 70 is listed on the adult list.
Background
Injury and violence are major killers of children throughout the world, responsible for over 900 000
deaths in children and young people under the age of 18 years each year (1). In 2004 38,8 per 100.000
children worldwide died from unintentional injuries and nearly 96.000 children globally died from burns
(2). Road traffic injury is the second leading cause of death in children between 1 and 14 years and the
leading cause of death in the age group between 15 and 18 (2). Non-fatal falls are the most common
reason for children to be taken to an emergency room (1).
Approximately 30-40% of trauma mortality can be attributed to hemorrhage (3). Even if most of the
deaths due to hemorrhage occur in the pre-hospital phase, the main reasons for early deaths in hospital
yet are continued hemorrhage, coagulopathy and incomplete resuscitation (3). So it is obvious that fluid
therapy plays an important role in the treatment of trauma patients with substantial blood loss as well
as in patients with burn injuries and remains the cornerstone in resuscitation. But there is an ongoing
controversy concerning the kind of fluid to be used in treatment of hypovolemic patients.
Main available options for fluid resuscitation are either crystalloid or colloid solutions. If more than 40%
of blood volume is lost blood transfusion is recommended additionally because these fluids are helpful
to maintain tissue oxygenation (4).
In contrast to commonly used crystalloid solutions like Normal Saline or Ringer-Lactate, colloid solutions
contain molecules which cannot penetrate the intact cell wall and therefore cause an oncotic gradient
that attracts additional interstitial fluid into the vessels. The type of molecule is different for the
different colloid solutions but is always of biological origin.
3
The most commonly used colloids are albumin, which is the only natural one, others include nonprotein
colloids like hydroxyethyl starches (HES), dextrans and gelatins.
Albumin is a naturally occurring protein in the human organism with a molecular weight of 69 kDa.
There is no limitation to the maximum daily dose for albumin. It may cause hypersensitivity and allergic
reactions and the transfer of infection by administration of albumin is not totally excluded (5).
Hydroxyethyl starches (HES) are high polymeric glucose compounds. They are available in different
concentrations with molecular weights from 70 kDa to 670 kDa. There are other determinants for their
physicochemical characteristics like concentration, degree of substitution and C2/C6 ratio. The
maximum dose that can be administered per day depends on the type of HES (5).
Dextran is a glucose polymer which is available either as a 6% iso-oncotic solution or as a 10% hyperoncotic solution with a molecular weight of 70 kDa respectively 40 kDa. The maximum recommended
dosage of dextran is 1,5 g/kg/day, it has dose-dependent negative effects on hemostasis and may cause
anaphylactic reactions (5).
Gelatin is made of bovine collagen and has a molecular weight of 30-35 kDa. There is no maximum limit
of dose, anaphylactic reactions may occur following its administration (5).
A recent Cochrane review did not find evidence to prove superiority of any one colloid solution over
others in terms of effectiveness and safety (6).
Search methods
An online database search in the Cochrane library and Pubmed for articles published from 1950 to
present was conducted using the search terms colloids, pediatric and trauma (see appendix 1 for
detailed search strategy). The search was complemented with the use of other resources, such as
trauma care protocols, Google scholar and various national guidelines available on the web.
The identified abstracts were screened and full text versions of possibly relevant articles were obtained.
Reference lists of articles were screened to identify additional sources.
Criteria for final inclusion of an article for this review were:
4
•
English or German language article
•
Human subjects
•
Study referring to children with traumatic or burn injuries
•
The treatment group received a colloid solution of any volume for any duration at any time
Accordingly criteria for exclusion were:
•
Non English or German language article
•
Animal study
•
Study targeting pediatric population with conditions other than traumatic or burn injury
•
Study including pediatric populations, but pediatric specific data not reported separately
•
Individual case report
Results
The search identified 457 articles of which 20 were thought to be relevant after abstract review. After
review of the full text versions the following 14 articles qualified to be included in the review. They
consist of reviews, guidelines and expert opinion based on evidence. No randomized controlled trial to
answer the question was identified.
See tables 1 and 2 for included and excluded studies.
Author
Publication type
Population
Colloid
Cocks A et al.
Retrospective
review
Albumin
Faraklas I et al.
Retrospective
review
Pediatric burn patients
(burned BSA >5%) admitted
to ICU between 01/90 and
12/96
Pediatric patients admitted
to a burn center because of
acute burns >15% BSA and
survived at least 72 h
between 01/04 and 05/09
Level of
Evidence
Very low
Albumin
Very low
5
Hennenberger
A et al.
Expert opinion
Dextran
Albumin
Very low
Guideline
Pediatric burn patients
admitted to a burn care
ward between 04/85 and
05/94
Pediatric burn patients
Schellinger et
al. (German
Society for
Pediatric
Surgery)
Schulman CI et
al.
Pietrini D et al.
Not specified
Low
Expert opinion
Pediatric burn patients
Not specified
Very low
Literature review
HES
Very low
Not specified
Very low
Not specified
Moderate
Not specified
Very low
Not specified
Not specified
Very low
Very low
Guideline
Hypovolemic pediatric
patients
Hemorrhagic pediatric
trauma patients
Pediatric patients with
hypovolemic shock (studies
on adults included
additionally)
Pediatric patients with
hypovolemic shock
Pediatric trauma patients
Critically ill pediatric
patients
Pediatric burn patients
Dehmer JJ
Literature review
Boluyt et al.
(Dutch Pediatric
Society)
Guideline
Kallen RJ
Expert opinion
Turner CLS
Kissoon et al.
Expert opinion
Review
COBIS (Care of
burns in
Scotland)
ATLS
University of
Kentucky
Albumin
Very low
Clinical protocol
Guideline
Pediatric trauma patients
Pediatric trauma patients
None
None
Very low
Very low
Table 1: Included Studies
Author
Spelten O et al. (20)
James MFM (21)
Wade CE et al. (22)
Akech S et al. (23)
Endorf FW et al. (24)
Bailey AG et al. (25)
Reason for exclusion
Does not compare treatment options for children
Does not refer to children
Does not refer to children
Does not refer to trauma or burns
Does not refer to children
Does not refer to trauma or burns
Table 2: Excluded Studies
6
Efficacy
No high-level evidence studies could be identified for the use of colloids in children with traumatic
injuries or burns.
All articles reviewed indicated that there is very little evidence available currently for or against the use
of colloids in children. Especially randomized controlled trails are not available to support any evidence
for use of colloids in children. Some authors therefore additionally referred to the available evidence for
adults stating that this is scarce too.
Overall only three of the fourteen included articles recommended the use of a colloid solution.
Faraklas et al. showed that through administration of albumin in pediatric burn patients the Input/
Output ratio could be normalized quickly which they thought may have the potential of overcoming the
problem of “fluid creep”. In their study they analyzed 53 patients resuscitated either with crystalloids
alone or with additional use of albumin. Certainly they qualify that results should be looked upon
critically because the patients who received albumin were in general more severely injured and the
decision to use colloids additionally was not made purely objectively (7).
Walker GM on behalf of the Care of Burns in Scotland network (COBIS) recommended in their guideline
for treatment of children with burn injuries to use crystalloid solutions for the first 8 hours and albumin
for the following 16 hours. To formulate their recommendations a group of experts representing the
Scottish centers that are involved in treatment of children with burn injuries assessed existing guidelines
and reviewed the available evidence. Despite they stated that the evidence in general is scarce they
agreed on the inclusion of a colloid in their treatment recommendations (8).
Hennenberger et al. described a formula they had developed which combines Ringer-Lactate and
Dextran for the resuscitation of children with burns and allows the additional use of albumin. Evidence
for the usefulness of their formula was not presented (9).
Several other authors stated that colloids should not be used as general baseline therapy but could be
considered for some special indications.
Schellinger et al. representing the German Society for Pediatric Surgery as leading editor on behalf of
several professional German medical societies issued a consensus-based guideline on the treatment of
7
children with burn injuries. In these guidelines the use of crystalloid solutions was recommended for the
first 24 hours, colloids should be used in prolonged shock and under strict indications only (10).
Because of the small number of pediatric publications the evidence-based guideline of the Dutch
Pediatric Society by Boluyt et al. considered adult studies as well and concluded that the first choice
fluid for initial resuscitation should be isotonic saline. They added that it is possible to use a synthetic
colloid when large amounts of fluids are needed (11).
Schulman et al. stated that no clear evidence for the use of colloids is available and that in their opinion
it should be an expert clinical judgment if colloids are needed in individual cases. The article did not
present any clear evidence (12).
In a recent review of the literature Pietrini et al. had a closer look on pharmacodynamics of colloids,
especially Hydroxyethyl starch (HES) solutions, and due to limited data they concluded that HES may
indeed be considered for plasma volume restoration in children but further clinical trials were needed to
assess if it is actually beneficial in the treatment of hypovolemic children (13).
Likewise there were recommendations by some authors which did not include the use of colloids.
Turner et al. recommended the administration of a bolus of 20 ml/kg normal saline which may be
repeated once. In case of persistent signs of shock administration of 10 ml/kg packed red blood cells was
recommended (14). This recommendation was in line with the recommendations of the Advanced
Trauma Life Support (ATLS) protocol of the American College of Surgeons (4) and the Pediatric Trauma
Care Guidelines of the University of Kentucky (15) however no evidence was named in all of these
publications.
Dehmer et al. proposed principles for a pediatric massive transfusion protocol. In their review of the
literature no specific data supporting the use of colloids were identified, they stressed that mechanisms
causing adverse effects have to be considered (16).
Finally there are authors who were not making a recommendation at all.
Cocks et al. tested their colloid-based fluid formula for resuscitation in children with burns by analyzing
85 pediatric patients (with >5% BSA burned) who were admitted to their ICU. Patients were divided into
two groups. Group one was resuscitated according to the colloid-based formula used in their hospital
whereas the second group included patients who were initially resuscitated in other hospitals with
8
mixed crystalloids and colloids formulas before they were transferred to their hospital. They found that
patients resuscitated with their formula were consistently underestimated concerning fluid
requirements and no significant difference in adverse effects could be seen between the two groups.
Overall they were not able to recommend a definite approach to the fluid resuscitation in pediatric burn
patients (17).
Kallen et al. merely stated that it is imperative to substitute lost volume however recommendations as
to which solution should be used were not made (18).
In their review Kissoon et al. were not able to identify a clear benefit of one fluid over the other. The
review referred to critically ill patients with all kinds of etiology and the studied patient population
included patients other than children. It was concluded that the choice of fluid depended upon personal
preference, purported physiologic benefits and practical considerations (19).
Safety
For crystalloids like Ringer-lactate and Normal saline 0,9% no side effects are described when used in
accordance with regulations.
Possible side effects of all colloids are hypersensitivity and anaphylactic reactions up to anaphylactic
shock and affection of coagulation. This applies especially to HES and dextran. HES may also cause
pruritus which is often refractory to treatment (5,26,27).
Costs
Colloid solutions are much more expensive than crystalloid fluids. The prices of common colloid and
crystalloid solutions according to WHO International Drug Price Indicator Guide, 2010 Edition can be
found in table 3.
9
Drug
Albumin
Dextran 70
Polygeline 3,5%
Normal saline 0,9%
Ringer’s lactate
Median price/ml buyer in USD
0,5980
Not stated
0,0272
0,0009
0,0009
Median price/ml supplier in USD
0,7500
0.0105
0,0098
0,0009
0,0009
Table 3: Prices of solutions according to WHO
Conclusion
There is very little evidence to support the use of colloids in children with traumatic injury or burns.
Much of the available evidence is not specifically for children and not derived from randomized,
placebo-controlled trials.
From the evidence identified, however, it appears that colloids do not have a proven benefit compared
to crystalloids. This view is also supported by a recent Cochrane review addressing the question, for all
indications and all types of colloids in adults (28). Colloids are more expensive and are more likely to
cause adverse effects. Therefore they may not be considered essential for the treatment of children
with traumatic injury or burns.
There may be other legitimate indications that may justify inclusion of colloids on the essential medicine
list for children but considering the indications of trauma and burns we conclude that there is not
sufficient evidence to recommend the inclusion of any colloid in the Essential Medicines List for Children.
Other Indications
Other possible indications for colloids that were not further considered in this review may be Sepsis/
septic shock, Malaria and Dengue, Dialysis, Chronic liver disease and Heart surgery.
10
References
(1) World Health Organization “World report on child injury prevention” 2008, Geneva, Switzerland
(2) World Health Organization “Global Burden of disease: 2004 update” 2008, Geneva, Switzerland
(3) Kauvar DS et al. “Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical
presentations, and therapeutic considerations” J Trauma. 2006 Jun;60(6 Suppl):S3-11
(4) American College of Surgeons Committee on Trauma “Advanced Trauma Life Support for Doctors” 8th
Edition 2008
(5) Niemi TT wt al. “Colloid solutions: a clinical update” J Anesth 2010 24:913-925
(6) Bunn F et al. “Colloid solutions for fluid resuscitation” Cochrane Database of Systematic Reviews
2012, Issue 7
(7) Faraklas I et al. “Colloid normalizes resuscitation ratio in pediatric burns” J Burn Care Res. 2011 JanFeb;32(1):91-7
(8)Walker GM “Fluid resuscitation of childhood burns-paediatric” Care of Burns in Scotland Managed
Clinical Network (COBIS) 2011
http://www.cobis.scot.nhs.uk/pdf/Paediatric%202011/CoBIS%20Fluid%20Guideleines.pdf
(9) Hennenberger A et al. “Therapy of the severely burned child from the pediatric intensive care
viewpoint” Unfallchirurg 1995 Apr;98(4):193-7
(10) Schellinger et al. “Thermische Verletzungen im Kindesalter (Verbrennung, Verbrühung)” Guideline
of the German Society for Pediatric Surgery 2009 http://www.awmf.org/uploads/tx_szleitlinien/006128_S2k_Thermische_Verletzungen_im_Kindesalter__Verbrennung__Verbruehung__abgelaufen.pdf
(11) Boluyt N et al. “Fluid resuscitation in neonatal and pediatric hypovolemic shock: a Dutch Pediatric
Society evidence-based clinical practice guideline” Intensive Care Med. 2006 Jul;32(7):995-1003
(12) Schulman CI et al. “Pediatric fluid resuscitation after thermal injury” J Craniofac Surg. 2008
Jul;19(4):910-2
(13) Pietrini D et al. “Plasma substitutes therapy in pediatrics” Curr Drug Targets. 2012 Jun;13(7):893-9
(14) Turner CLS et al. “Fluid therapy in paediatric trauma” Trauma 2002; 4: 169-175
(15) Section of Pediatric Surgery, University of Kentucky “Pediatric Trauma Care Guidelines 2011”
http://www.mc.uky.edu/traumaservices/PediatricTraumaCareGuidelines2011.pdf
(16) Dehmer JJ et al. “Massive transfusion and blood product use in the pediatric trauma patient” Semin
Pediatr Surg. 2010 Nov;19(4):286-91
11
(17) Cocks AJ et al. “Crystalloids, colloids and kids: a review of paediatric burns in intensive care” Burns
24 (1998) 717-724
(18) Kallen RJ et al. “Fluid resuscitation of acute hypovolemic hypoperfusion states in pediatrics” Pediatr
Clin North Am. 1990 Apr;37(2):287-94
(19) Kissoon N et al. “Choosing a volume expander in critical care medicine” Indian J Pediatr. 2003
Dec;70(12):969-73
(20) Spelten O et al. “Estimation of substitution volume after burn trauma. Systematic review of
published formulae” Anaesthesist 2011 Apr;60(4):303-11
(21) James MFM “Place of the colloid in fluid resuscitation of the traumatized patient” Curr opin
Anesthesiol 2012, 25:248-252
(22) Wade CE et al. “Efficacy of hypertonic 7,5% saline and 6% dextran-70 in treating trauma: A metaanalysis of controlled clinical studies” Surgery 1997 Sep; 122(3):609-616
(23) Akech S et al. “Choice of fluids for resuscitation in children with severe
infection and shock: systematic review” BMJ 2010;341:c4416
(24)Endorf FW et al. “Burn management” Curr Opin Crit Care. 2011 Dec;17(6):601-5
(25) Bailey AG et al. “Perioperative Crystalloid and Colloid Fluid Management
in Children: Where Are We and How Did We Get Here?” Anesth Analg 2010;110:375–90
(26) Blanloeil Y et al. “Effects of plasma substitutes on hemostasis” Ann Fr Anesth Reanim 2002
Oct;21(8):648-67
(27) Wiedermann CJ “Hydroxyethyl starch- can the safety problems be ignored?” Wien Klin Wochenschr
2004 Sep;116(17-18):583-94
(28) Perel P et al. “Colloids versus crystalloids for fluid resuscitation in critically ill patients” Cochrane
Database of Systematic Reviews 2012, Issue 6
12
Appendix 1 (search terms)
Cochrane
Colloid* AND pediatr*
Colloid* AND children
“Dextran 70” AND pediatr*
“Dextran 70” AND children
Albumin AND children
Albumin AND pediatr*
HES AND children
HES AND pediatr*
Medline
Colloid* AND pediatr* AND trauma; limits: human, Language English or German
Colloid* AND children AND trauma; limits: human, Language English or German
Colloid* AND pediatr* AND resuscitation; limits: human, Language English or German
Colloid* AND children AND resuscitation; limits: human, Language English or German
“Dextran 70” AND pediatr* AND trauma; limits: human, Language English or German
“Dextran 70” AND children AND trauma; limits: human, Language English or German
Albumin AND pediatr* AND trauma; limits: human, Language English or German
Albumin AND children AND trauma; limits: human, Language English or German
HES AND pediatr* AND trauma; limits: human, Language English or German
HES AND children AND trauma; limits: human, Language English or German
13