Supplement On-line Table : List of the human studies used to elaborate thepresent recommendations
Chapters / N° / Reference (first author journal, year) / Study Type / N *Burn size / Evidence Level / Principal results, and comments
Nutrition route and timing / 1 / Herndon, JBCR 1987 80 / P, R / 39 (16 vs 23) / III / Study comparing pure EN with a combined EN+PN. The patients on pure EN were less overfed (fatty liver, cholestasis). Increased mortality with combined EN + PN, which was massively overfed.
2 / Chiarelli, Am J Clin Nutr 1990 8 / P, R, / 20 (2 x 10) / II / Very early gastric feeding (5h) achieved an earlier positive nitrogen balance, and reduced urinary catecholamine excretion compared with late EN (58h after injury)
3 / Raff, Burns 1997 81 / Retrospective / 55 ventilated
TBSA 44% / IV / Early gastric feeding (< 18h) improved tolerance to enteral nutrition (EN) and achievement of target. Failure of EN if delayed
4 / Venter, Burns 2007 9 / P, R, open label / 18 children TBSA < 20% / III / Early EN (median time to feeding 11h after admission) improves endocrine profile, reduces weight loss, episodes of diarrhoea and antibiotic requirements compared to delayed EN (median 54h. Intestinal permeabil ity (tested by the dual sugar ratio) is unchanged
5 / Lam, Burns 2008 7 / P, R, open label / 82 (41 vs 41) / II / Early EN increases IgA, IgG and IgM levels, and reduced cortisol by day 7 as well as complications and mortality
Energy requirements / 6 / Allard, J Trauma 1988 82 / P observational / 33
39% TBSA / IV / Study investigating factors modulating the energy expenditure level and aiming at quantifying their respective impact on REE: the results were that basal EE from the Harris-Benedict equation could be used, and modulated by the TBSA, fever, and the previous 24hrs’ caloric intakes
7 / Allard, JPEN 1990 16 / P, cohort study / 10 ventilated / IV / Validation of the Toronto equation: REE = -4343 + (10.5 x %TBSA) + (0.23 x caloric intake) + (0.84 x Estimated Basal EE) + (114 x Temperature °C) - (4.5 x postburn day)
8 / Cunningham, JPEN 1990 12 / P, observational cohort study / 122 ventilated / III / Indirect calorimetry determinations repeated until day 149. The authors observe increased REE during the first 10-15 days with a progressive decline thereafter. Peak increase of REE was correlated with the burn size
9 / Royall et al, CCM 1996 17 / P, observational cohort study / 20 ventilated / IV / Validation study confirming the congruence of the calculated energy requirements with the energy expenditure measured by indirect calorimetry
10 / Suman, Burns 2006 18 / P observational / 91 children / II / Comparison of energy requirement equations and indirect calorimetry measurements: the Schoffield equation resulted in the least differences.
11 / Rimdeika, Burns 2006 14 / P observational / 103
TBSA 10-80% / IV / Caloric value delivered by enteral nutrition was analysed and deliveries < or > 30 kcal/kg/day were compared. Patients receiving > 30 kcal/kg/day resulted in decreased frequency of pneumonia (2.0 times), and of sepsis (1.8 times: p < 0.05), lower mortality (5.3% vs 32.6%: p < 0.01). and shorter duration of the treatment in survivors (12.6 days shorter: p = 0.01)
12 / Berger, Nutr 2006 19 / P observational with paired historical cases / 54 / IV / Study reporting the impact of a computerized nutrition monitoring system on feeding adequacy: it increased the ICU days with energy delivery >30 kcal/kg independently of burn size, resulting in a reduction of weight loss.
Proteins and specific amino acids / 12 / Le Bricon, Am J Clin Nutr 1997 32 / P, pharmaco kinetic study / 42 / III / Bolus ornithine-ketoglutarate (OKG) achieved higher blood concentrations than continuous administration
13 / De Bandt, J Nutr 1998 31 / P, R controlled / 48 / II III / OKG 30g/day improved nitrogen balance. Bolus administration vs continuous delivery reduced length of stay and duration of wound healing
14 / Wolfe, Ann Surg 1983 83 / P, Cross over, interventional stable isotopes / 6
TBSA 60% / III / Using a cross over design with two three-day dietary regimens, Leucine kinetics showed that net protein synthesis did not increase further beyond 1.4 g/kg/day compared with 2,2g/kg/d; the [15N2]-urea urinary balance data were improved with the higher protein regimen
15 / Peng, Burns 2004 25 / P, R, DB, controlled / 48
TBSA 30-75% / II III / Enteral glutamine 0,5g/kg/d for 14 days reduces intestinal permeability, improves wound healing and reduces length of stay
16 / Peng, Burns 2005 26 / P, R, DB, controlled / 48
TBSA 30-75% / II III / Enteral Glutamine 0,5g/kg/d for 14 days increases prealbumin levels and reduces protein catabolism
17 / Peng, Burns 2006 28 / P, R, DB / 48
TBSA 30-75% / II III / Enteral glutamine 0,5g/kg/d for 14 days resulted in higher plasma GLN levels, improved cellular immunity (CD4/CD8 ratio, IL2, etc) and reduced length of stay
18 / Zhou, JPEN 2003 27 / P, R, DB / 40 / II III / Enteral glutamine 0,35g/kg/d for 12 days reduced intestinal permeability, accelerated wound healing, reduced weight loss, length of stay and costs.
21 / Wischmeyer, CCM 2001 23 / P, R, DB / 26 / II III / Glutamine IV 0,57g/kg/d reduced the number of bacteremia (gram negative), reduced the inflammatory response, but had no impact on length of stay, antibiotic requirements or mortality.
22 / Sheridan, Surgery 2004 29 / P, R, stable isotopes / 9 children / III / Investigation of two 48 hour periods with a cross over design: enteral Glutamine delivered for 48hrs did not produce any benefit on protein metabolism assessed with leucine
23 / Coudray-Lucas, CCM 2000 30 / P, R, DB / 47 / II / The delivery of 10 g OKG 2 times/d for 3 weeks reduced wound healing time and increased prealbumin levels
24 / Yan, Burns 2007 33 / P, R, single blind, controlled / 47
TBSA >50% / II => III / 3 groups of patients receiving 0,200 or 400 mg/kg/d diluted in G5% by the enteral route. Enteral Arginine had no effect on blood pressure: ARG was associated with improved oxygenation, reduction of blood lactate levels and of NO production in the mucosa.
Carbohydrates and glycemic control / 25 / Burke, Ann Surg 1979 15 / P, cross over, interventional,
Stable isotopes / 18 + 7 healthy / III / Study investigating the impact of 2 rates of glucose administration (1,4 - 4,5 versus 4,7- 9,3 mg/kg/min): there was no impact on protein synthesis. Two side effects of excessive glucose administration were observed: increased CO2 production and liver steatosis
26 / Sheridan, JPEN 1998 34 / P, observational, cross-over, stable isotopes / 10 children / IV / Study investigating glucose oxidation at different rates: oxidation was maximal at glucose intake = 5 mg/kg/min. Resting energy expenditure was measured by indirect calorimetry
27 / Gibson, Surgery 2009 40 / P, non R / 37 (22 ICU vs 15 burn) / III IV / Intensive insulin therapy (IIT) was associated with better survival.
NB: the groups with tight and liberal glycemic targets were characterized by an important difference of the TBSA (10% and 45% TBSA respectively).In addition the number of burn patients was small compared to ICU patients
28 / Gore, J Trauma 2001 39 / Retrospective cohort study / 58 (33 vs 25)
children / IV / Hyperglycaemia was associated with a higher incidence of bacteriemia / fungemia, and a lower graft take, and higher mortality
29 / Gore, J Trauma 2003 45 / P, R, DB, controlled, stable isotopes / 10
TBSA > 60% / II / Metformine significantly reduced endogenous glucose production and oxidation, increased glucose clearance, and uptake during the induced hyperinsulinemia (euglycemic clamp).
30 / Gore, J Trauma 2005 44 / P, P, DB metabolic, stable isotopes / 6
TBSA >40% / IV / Study comparing the impact of insulin and metformin showing that the latter had no significant effect on either peripheral glucose clearance or the rate of glucose oxidation. Both metformin and insulin separately increased the rate of muscle protein synthesis
31 / Pham, J Trauma 2005 41 / P, Observational before and after design / 64 (33 vs 31) children / IV / IIT improved survival and reduces the incidence of infectious complications.
32 / Hemmila, Surgery 2008 84 / Observational before and after design / 152 (71 vs 81) / IV / IIT reduces infectious risk but does not influence length of stay or mortality.
NB: the patients included in the trial were of low severity with TBSA <20% burns
33 / Pidcoke, J Trauma 2009 42 / Retrospective cohort study / 49 (23 vs 26) / IV V / Glucose variability was associated with increased mortality.
NB: nutritional data were insufficient to really assess the variability
34 / Jeschke, AJRCCM 2010 43 / P, R, mono-centric / (60 vs 179) children / II III / ITT (target 80-110 mg/dl Glucose) was associated with a reduction of infections (p<0,05) compared to control (140-140 mg/dl), with attenuation of the inflammatory response and of protein catabolism.
NB: Groups differed regarding age and burn size
35 / Mecott, CritCare 2010 46 / Open label R controlled / 24 children (6 and 18) / II III / The 6 children randomized to exenatide received significantly lower amounts of exogenous insulin to control plasma glucose levels without side effects: 22 ±14 IU/d vs 76 ± 11 IU/d (p = 0,01) (glucose target 80-140 mg/l)
Lipids / 36 / Garrel, JPEN 1995 48 / P R, open label controlled / 43 / II / 3 groups were studied according to the type and proportion of lipid intakes: 35% of energy as fat, 15% fat, or 15% as fish oil): the low fat groups showed a significant reduction of pneumonia with 15% lipids (p = 0,02) and shorter donor site healing time. No difference with fish oil.
NB: overfeeding was in all groups as energy target was set by the Curreri equation
37 / Bernier, CCM 1998 47 / P, R, open label controlled / 37
TBSA >20% / II / Same 3 groups as Garrel et al (35% 15% and 15% including 50% fish oil as energy source): IL-6 was not altered by the fat proportion
NB: overfeeding as energy target was set by the Curreri equation.
38 / Al Jawad, ABFD 2008 50 / P, R, controlled / 180 / III -> IV / 6 groups of 30 patients received various regimens of vitamins and trace elements (group A = control standard care). Reduction of REE in patients receiving vitamin E+C et zinc. Improved wound healing. NB: the elevated number of groups did not enable a good statistical outwork and the methods were insufficiently described.
Micronutrients / 39 / Falder, Burns 2010 51 / P, open label / 20 (6 vs 14) / III / Thiamine 100-200 mg/day produces and increase in plasma B1 levels compared with patient not receiving B1, with a reduction of plasma pyruvate and lactate levels
40 / Barbosa, JBCR 2009 52 / P, R, DB / 32 (15 vs 17) children / III / Supplements of Vit C, Vit E et Zn delivered for 7 days (dose corresponding to 1,5-2 x RDA): reduce malondialdehyde (MDA) levels, increase plasma Vit E and reduced wound healing time
41 / Klein, J Bone Miner Metab 2009 53 / P observational, historical controls / 15 (8 vs 7 controls) children / IV / Vitamin D2, delivered at 400 IU/d for 6 month after discharge does not correct vitamin deficiency and has no impact on bone metabolism (bone density, etc.)
42 / Tanaka, Arch Surg 2000 54 / P, R / 37 ventilated
TBSA 63% / III / Vitamin C 66mg/kg/h for the first 24 hours after injury reduced resuscitation fluid requirements, weight gain, length of mechanical ventilation, and improved oxygenation ratio
43 / Berger, Burns 1992 55 & Clin Nutri 1992 85 / P observational / 10
TBSA 33% / IV / Balance study including the measurement of exudative cutaneous losses and their Cu, Zn and Se content, showing important losses p to 10-20% of the trace elements’ body content and explaining the deficiency syndromes observed in burns
44 / Berger, Am J Clin Nutr 2007 a 57 & b 86 / P, R, DB, controlled / 21 (11 vs 10)
TBSA 40 % / II / Substitution with Cu, Se and Zn for 8 days: in the patients on trace elements improved antioxidant defences were observed with reduction of surgical grafting requirements, of infections and of local cutaneous protein catabolism
45 / Berger, CritCare 2006 56 / P, R, DB, controlled / 41 (20 vs 21)
TBSA 41 % / II / Pooling of 2 randomized trials with analysis of nosocomial infections (i.e. those occurring after day 3). The substitution with Cu-Se-Zn pendant 8 days was associated with a significant reduction of nosocomial pneumonia, with no influence on cutaneous infections
46 / Stucki, CritCare 2010 58 / P, observational / 4 children / V / Substitution doses of Cu,Se,Zn adapted to the children’s body surface resulted in normalization of trace element blood levels, without any observable toxicity.
Non nutritional strategies (anti- catabolic, anabolic) / 47 / Breitenstein, Burns 1990 63 / P, R, controlled, open label, stable isotopes / 10
TBSA 28% / II / Propranolol 40 mg/d (oral or IV)cause a reduction of energy expenditures and of lipid oxidation, with no impact of glucose and protein oxidation.
48 / Herndon, NEJM 2001 62 / P, R, controlled, stable isotopes / 25 children (13 propranolol) / II / Children receiving propranolol have a significant reduction of REE (better stress control), and increased protein synthesis measured by the incorporation of labelled phenylalanine. Improved nitrogen balance by 8% compared to control
49 / Herndon, Ann Surg 1990 76 / P, R, DB, controlled / 24 children
TBSA >40% / II / rhGH 0.2 mg/kg/d from admission through hospitalisation was associated with significant acceleration of donor site healing and of normalized length of hospital stay
50 / Hart, Ann Surg 2002 64 / P, R, controlled / 56 children TBSA > 40% / II / 4 groups (control, GH, Propranolol, GH+propranolol). No effect of GH alone, no additive effect of GH. Propranolol reduced hypermetabolism. Net protein synthesis balance was improved by propranolol and by the combination with GH.
51 / Arbabi, J Trauma 2004 65 / Retrospective, cohort / 46 propranolol vs 86 controls / V / Patients receiving propranolol had a reduced wound healing time and mortality
52 / Mohammadi, JBCR 2009 / P, R, controlled, DB / 79 (37 propranolol, 42 controls) / II / Propranolol 1-1,8mg/kg/d en 6x : reduction donor site wound healing time, of grafting requirements, of length of stay with no impact on infectious complications
53 / Demling, JCC 2000 70 / P, R, DB / 20 / II / Oxandrolone (20mg/d – starting between day 2 and 4) : reduction of nitrogen losses, of weight loss and of wound healing time without complications
54 / Wolf, JBCR 2006 68 / P, R, DB, controlled, multicentric / 81 / II / Oxandrolone (10mg twice daily – starting on day 5) associated with reduction of length of stay. No impact on the number of surgical sessions. Liver test alterations were observed.
NB: study stopped at interim analysis due to the important differences between groups (-12 days of stay)
55 / Demling, J Trauma 1997 71 / P, R, controlled / 13 (7 vs 6) + 10 controls / II / Oxandrolone (20mg/d the rehabilitation phase) : weight gain and significant physical therapy index improvement
56 / Demling, Burns 1999 69 / P, R, controlled / 36 + 24 controls / II / 3 groups (oxandrolone, rhGH or none): Oxandrolone (20mg/d) et rgGH (0,1mg/kg/d IM) : reduction of nitrogen losses, of weight loss and of healing time of donor sites. Less side effects with oxandrolone than with rhGH (hyperglycemia).
57 / Herndon, Ann Surg 1995 77 / P, R, DB, controlled / 20 children
TBSA >40% / II / The impact of rhGH (0,2mg/kg/d) or placebo on wound healing were investigated using skin biopsies: accelerates wound healing of donor sites was associated with increased coverage of basal lamina, with increased structural proteins
58 / Demling, Burns 2001 72 / P, R, controlled / 40
TBSA 30-55% / II / Study investigating the impact of oxandrolone (20mg/d during rehabilitation) in 4 adult age groups: restoration of lean mass and of weight was observed with oxandrolone independently of age.
59 / Demling, Burns 2003 87 / P, R, controlled / 45 / II / Oxandrolone 20mg/d during rehabilitation was associated 2-3 times faster restoration of lean mass and of weight gain, which persisted for 6 months after discharge and stopping the drug.
60 / Losada, World J Surg 2002 75 / P, R, DB / 24
TBSA > 40% / II / rhGHdid not reduced wound healing time of donor sites, nor length of stay. More episodes of hyperglycemia were observed in the rhGH group
61 / Mc Cullough, JBCR 2007 88 / Retrospective cohort of paired cases / 14 (+ 61 controls) / IV / Comparison of patients on oxandrolone vs none. No significant difference in incidence of liver test alteration was observed
62 / Przkora, Ann Surg 2005 73 / P, R, controlled / 61 children
TBSA 40% / II / Oxandrolone for 12 months vs placebo increases muscle and bone mass, increases muscle strength with effect persisting 12 months after treatment interruption. Significant increases in height were observed.
63 / Pham, JBCR 2008 67 / Observational multicentric / 117
TBSA 44% / V / Oxandrolone administered within 7 days of injury independently reduced mortality
64 / Przkora, Ann Surg 2006 89 / P, R, open label controlled / 44 teenagers
TBSA >40% / III / rhGH (0.05 mg/kg) for one year after injury versus placebo resulted in significant improvement of height, weight, lean body mass, bone mineral content, cardiac function, and muscle strength compared with placebo (P < 0.05)
65 / Branski, Ann Surg 2009 90 / P, R, DB, controlled / 205 children
TBSA >40% / I II / Study comparing long term rhGH (0,2mg/kg/d) and placebo showing that rhGH enhances recovery and has a multimodal action including the reconstruction of the dermo-epidermic junction
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