QUELQUES CONTROVERSES EN ANESTHESIE-REANIMATION DU GRAND BRULE

CHU de CharleroiService d’Anesthésie

J.PIRSON, MD

Burn Mortality(TBSA associated with LD50)

35n=67

78n=152

82n=420

98n=1083

SBI/UTMB 1989-2005Patients 1722

19n = 63

46n = 127

70n = 450

98n = 1524

SBI/UTMB 1980-892164 Patients

23n = 114

38n = 178

63n = 413

77n = 803

Curreri & Abston 1975-79

1508 Patients

17n = 144

40n = 246

56n = 565

64n = 962

Bull 1967-701917 Patients

10n = 144

27n = 330

46n = 967

49n = 1366

Bull & Fisher (1942-52)2807 Patients

>6545-6415-440-14

Age Groups (years)

Decreased Mortality From Major Thermal InjuryHas Been Due To Advances In:

• Resuscitation

• Support of theHypermetabolicResponse To Trauma

• Early Closure of theBurn Wound

• Control of Infection

Integrins and Tissue Pressure• Integrins: a group of adhesion molecules that attach to• collagen fibers and fibroblast cells-ties putting a restrain on the

gel in the collagen matrix• Unleashing/cutting of ties volume → expansion possible →

tissue pressure negative → fluid sucked into the wound →edema will bring Pif to normal

Reed et al. News Physiol Sci. 1987; 12: 42-8

History of Fluid Resuscitation in Burns

• Before WW II, most burnvictims with more than 20%TBSA were at mortal riskof acute renal failure

• Fluid resuscitation usedbut ill defined until early1950 ’s (Evans et al1952)

• This culminated in thederivation of the Parkland(or Baxter, 1968) formula

Fluid and ElectrolyteBalanceIn BurnsReiss E., Stirman J.A., Artz C.P.,Davis J.H.JAMA 1953; 152: 1309-1313

Fluid Volume andElectrolyte ChangesOf the Early Postburn Period

C.R. BaxterClin Plast Surg 1974; 1: 643-709

Fluid volume really given ?

• We know that more is needed :1. In severe inhalation : about 5,7 ml / kg /%2. If initial fluid resuscitation is late (> 2 HrPB) !3. If the burn is deep (mainly 3rd)

• Fluid administration in 7 Burn units the 1st24 h: 40-80% more than the BaxterformulaKeymalyan et al. Annual Meeting of ABA, 1996

Reanimation EndpointsInvasive Hemodynamic

Monitoring• The majority of studies using

invasive hemodynamicmonitoring (PA, TPID) to guidefluid resuscitation in burn,reported significant higher fluidrequirements than Baxter orother empirical formulae: 4,5-9,5 ml/kg.BSA/24 h

Schiller et al. J Burn Care Res 1973;18: 64-73

Urinary Output• Acceptable urinary output does

not always guarantee or reflectadequate resuscitation afterburn injury

Kaups et al. J Burn Care Rehab 1998; 19:346-8

Jeng et al. J Burn Care Rehab 1997; 18:402-5

Dries et al. Crit Care Med 2001; 22: 161-6Holm et al. Burns 2000; 26: 25-33

AACS• Definition: high intra-abdominal pressure without

trauma/surgery to abdomen• No consensus definition: constellation of clinical

abnormalities including respiratory failure andoliguria with an acute elevation of IAP to morethan 25 mm Hg

• Oliguria at IAP = 15-20 mm Hg• Anuria above 30 mm Hg• Causes: ↓ CO and renal parenchyma

compressionKron et al. Ann Surg 1984; 199: 28-30.Hartman et al. Ann Surg 1982; 196: 594-7.

AION & PION

• AION– Anterior portion of ON– optic disc and scleral canal portion of optic n.– posterior ciliary arteries (< ophthalmic art.)– incompetent anastomotic ring (circle of Zinn & Hallen)

= watershed zone

• PION– Posterior portion of ON– Centripetal pial vessels easily compressible– Branches of ophthalmic art. and central retinal art.

AION & PION• Cause = lack of oxygen carriage of sufficient duration at a critical place for anatomical

reason– visual field loss– loss of visual acuity– painless– visual field loss

• Mean time to diagnosis: 36 days after resusc. Cullinane et al. J Trauma 2000; 44: 381-7

• Association with bleeding and shockMofredj et al. Eur J Gastroenterol Hepatol 2000; 12: 1339-41Johnson et al. Ophtalmology 1987; 94: 1577-84Hayreh. Ophtalmology 1987; 94: 1488-502Shaked et al. J Trauma 1998; 44: 923-5Asensio et al. South Med J 2002; 95: 1053-7

• Association with large resusc.Volume & with ACCS:350 patients with > 20 L resusc. Fluid: 2,6 % AION Cullinane et al. J Trauma 2000; 44: 381-7

Reduction of Resuscitation Fluid Volumewith Ascorbic Acid

Tanaka et al. Arch Surg 2000; 135(3): 326-31

• High-dose Vit C: 66 mg/kg per Hr during first 24-Hr

• 37 patients with more than 30% TBSrandomized

• Conclusions– reduction of fluid requirements (3,0 +1,7 vs 5,5 + 3,1 ml/kg%),

weight gain and edema– reduction of respiratory dysfunction

Fluid Resuscitation in Burn

• Lactate-Ringer or Hartmann (or otherbalanced crystalloid)

• No colloids during the first hoursBaxter. Physiological response in crystalloid resuscitation of severeburn. Ann NY Acad Sc 1968; 150: 874-94.

HES (Voluven®) maintain plasma volume in a porcinemodel of septic shock with capillary leakage

Marx Intensive Care Med 2002; 28: 629-35

• Intravascular persistency of artificialcolloids in the presence of albuminleakage

Albumin & Burns: The Cochrane-group meta-analysisand its 3 studies in burn patients

- Greenhalgh DG. J Trauma; 39: 67-73, 1995 patients >20% TBSA, 1-18 years, 6 weeks follow-up, randomly allocated to: G1 (n=34) albumin substitution to get 2.5-3.5 g/dl G2 (n=36) albumin substitution to get > 1.5 g/dl No differences in terms of survival, morbidity, length of stay or transfusions - Goodwin CW. Ann Surg; 197: 520-9, 1983 patients >50% TBSA, 28 years, 7 days follow-up, randomly allocated to: G1 (n=34) RL after the 1st day post-burn G2 (n=36) RL + albumin 2.5% after the 1st day post-burn Better CI in G2 during day 2, no significant differences later. Trend toward more lung water

in G2 from day 2 to 7.

Jelenko C. Crit Care Med; 7: 157-67, 1979 patients >40-50% TBSA, 96 hours follow-up, randomly allocated to: G1 RL G2 hypertonic saline solution G3 hypertonic saline solution + Albumin 1.25% Faster hemodynamic normalization in G3, similar respiratory outcome

- Cochrane study group conclusions :

relative risk to die = 2.47 (95% CI : .69 - 8.79) No advantage , rather disadvantageous to utilize albumin in burn patients

A quantitative and qualitativeanalysis of protein loss in human

burn woundsM Lehnhardt et al. Burns 31 (2005) 159-67

• Patients with 2nd degree burns (18-68%) studied from admission upto 48h: Burn wound enclosed in vinyl wound chambers covering2.25 cm2. Wound fluid analyzed for total protein content, albuminand immunoglobulin A, E, G, M

• Average loss of 17 g proteins on a wound area of 10% accumulatingin 8 h, with a peak value of 21 g in the first 8 h of the day 2nd.

• For a 20% burn, the total of serum protein is lost to wound surfaceevery 24 h

• Capillary leakage still important for albumin on day 2nd

• Role of loss of IG on susceptibility to infection ?

Burn CareResuscitation1. VolumeFormulae are 50 years old

4 ml/kg/% or 2 ml/kg/%

Pharmacological manipulations ?

Avoid overfilling (< 300 ml/kg/24H)

2. Which fluid

No colloid the first hours?

Artificial colloids

Albumin

Decreased Mortality From Major Thermal InjuryHas Been Due To Advances In:

• Resuscitation

• Support of theHypermetabolicResponse

• Early Closure of theBurn Wound

• Control of Infection

The Three Last are Related

Effects of Disease or Trauma on BMR

• Fasting-denutrition -10 à -30%• Surgery +10%• Polytrauma +30%• Sepsis +50%• Burn > 50% TBSA +100% The body aims to deliver the

optimal level of energy andsubstrate to the burn wound atthe expense of other tissuesand to keep a high bodytemperature

Wilmore Surg Clin North Am 1978; 58:1173-87

Metabolic Rates Elevation• Actual metabolic rate depends

on the TBSA– Elevated but near normal

for burns up to 25% TBSA– For burns over 40%, MR

are 1,4-2 times normal• Resting metabolic rates

remains at 180% of RMRduring acute hospitalization,dropping to 150% wheninjuries are fully healed andstay higher than normal up toone year later.Hart Surgery 2000; 128(2): 312-9; Hart Ann Surg2000; 232(4): 455-65

Effect of Ambient Temperatureon Metabolic Rate: We Need Warm Rooms

Herndon. Mediators of metabolism. J. Trauma 21:701-705; 1981.

*

0 1 2 3 4-0.100

-0.075

-0.050

-0.025

0.000

0.025 N=59 N=51 N=41

<130%130-170%

>170%

µmol

/min

/100

cc le

g

Association of Metabolic RateAssociation of Metabolic Rateand Protein Catabolismand Protein Catabolism

% of Predicted Energy ExpenditureHart et al. Determinants of skeletal muscle catabolism after severe burn. Ann. Surg. 233(4):455-465;2000.

Complications of Catabolism

• Consequences associated with erosion ofbody mass1

– 10% Impaired immune function 10%– 20% Decreased wound healing 30%– 30% Pneumonia, pressure sores 50%– 40% Death (pneumonia) 100%

1Chang, DeSanti, Demling. SHOCK. 1998

% Lost Altered Physiology % Mortality

Postabsorptive Net Balance

6 mo 9 mo 12 mo .µmol

PH

E/m

in/1

00 m

l leg

-0.045

-0.030

-0.015

0.000

0.015

Time After BurnNormal

Young Adults

N=25 N=23 N=21 N=21

Data presented as mean±SEM*p<0.05 vs. 6 and 9 months

*

Hart DW, Wolf SE, Mlcak R, Chinkes DL, Ramxy PI, ObengMK, Wolfe RR, Herndon DN. Persistence of muscle catabolism after severe burn. Surgery 2000; 128(2): 312-319.

Change in Lean Mass from Discharge

6 months 9 months 12 months

Gra

ms

-2000

-1500

-1000

-500

0

500

1000

* *

Time After Injury

N=16 N=16

N=16

†

Hart et al. Persistence of Muscle catabolism after severe burn. Surgery 2000; 128(2): 312-319.

Data presented as mean ±SEM *p<0.05 vs Discharge †p<0.01 vs 9 months

Persistence of Muscle Catabolism after Severe Burn

6 Carbon 3 Carbon Flow

Glucose

3-C

LIVER

Glycogen Protein

Heat

WOUND

Anaerobic Metabolism

Lactate

Urea

SKELETALMUSCLE

Heat

Glycogen Protein

3-C

± Insulin++++ Catecholamines

± Insulin++++ Catecholamines++++ Glucagon++++ Glucocorticoids

FAT

Fatty

Acids

Triglycerides

Liver Weight Per Body Weight for Normal vs Burned Patients

(2 mo. to 15 yrs. of age)

Normal(n =14)

Burn(n = 14)

Full-ThicknessBurn (%)

Liverwgt/BW(gm/kg)

WeightIncrease (%)

0

76 ± 5

34.3 ± 1.1

75.6 ± 6.0*

-

120

Burn Size and Liver Weight Ratios Are Means ± SE, BW = Body Weight* Significant Difference at p<.001

DNH-214

Effects of Burn Injury on the Liver

Metabolic ManipulationsMetabolic Manipulations• Warm the patient• Early vs. delayed treatment• Dietary composition• Insulin• Oxandrolone• Propranolol• Growth Hormone• Insulin-like Growth Factor-1• Itraconazole

A New ConceptIn the Early Excision and

Immediate Grafting of Burns

J Trauma 1970; 10: 1103-1108

Herndon et al. A comparison of conservative versus early excision. Ann. Surg. 209(5):547-553;1989.

Early Excision and Closure of the Burn Wound

0 1 2 3 4-0.075

-0.050

-0.025

0.000

0.025

<48 hrs 2-7 days >7 days

µmol

/min

/100

cc le

g

N=50 N=56 N=45

Effect of Delay to Excision and Grafting Effect of Delay to Excision and Grafting on Protein Catabolismon Protein Catabolism

Hart et al. Determinants of skeletal muscle catabolism after severe burn. Ann. Surg. 233(4):455-465;2000.

Changes in % Lean Body Massand % Fat Mass

Change in Gross Weight

Caloric Balance0.8 1.0 1.2 1.4 1.6 1.8 2.0

∆ K

g/da

y

-0.2

-0.1

0.0

0.1

r2=0.12

Caloric Balance0.8 1.0 1.2 1.4 1.6 1.8 2.0

∆ %

/ D

ay

-0.3

-0.2

-0.1

0.0

0.1

0.2

0.3

Lean Body Mass

Fat Mass

Hart, et al. Energy expenditure and caloric balance after burn – Increased feeding leads to fat rather than leanmass accretion. Ann. Surg. 235(1): 152-161; 2002.

Diet Study ofFat and Carbohydrates

Plasma Insulin LevelN=14

High Fat Vivonex

µU/m

l

0

20

40

60

80*

Data presented as mean±SEM*p<0.05

Muscle Protein Net Balance with Dietary Manipulation

1st Week 2nd Week

µmol

PH

E/m

in/1

00 m

l leg

-0.15

-0.10

-0.05

0.00

0.05

0.10

High Carb → High Fat, N=7High Fat → High Carb, N=6

Insulin

Sakurai et al.Stimulation of muscle protein synthesis by long-term insulin infusion in severely burnedpatients. Ann. Surg. 222(3): 283-297; 1995.

Insulin - Donor Site Healing Time(Days)

Patients Placebo Insulin123456

Mean ± SD

676857

6.51 ± 0.95

474554

4.71 ± 2.3*

* p<.05 placebo versus insulin period (paired t-test)DNH-328

Pierre et al. Effects of insulin on wound healing. J. Trauma 44(2):342-345; 1998.

Oxandrolone• Anabolic agents ameliorate catabolism• Oxandrolone

– Synthetic testosterone analogue– Oral– Inexpensive– Safe

• Preliminary studies in burn patients• Adults: 10 mg/12 Hr PO• FDA: 23 Oct 1991

Protein Synthetic Efficiency

Baseline Control

Frac

tion

of A

vaila

ble

Am

ino

Aci

ds A

ccre

ted

into

Mus

cle

0.0

0.1

0.2

0.3

0.4

0.5

7 Time ControlSubjects

Data presented as mean ± SEM†p<0.05 vs. Baseline

Baseline OxandroloneFrac

tion

of A

vaila

ble

Am

ino

Aci

ds A

ccre

ted

into

Mus

cle

0.0

0.1

0.2

0.3

0.4

0.5

7 OxandroloneSubjects

†

Fractional Synthetic Rateof Muscle Protein Synthesis

Baseline Oxandrolone%

per

hou

r0.00.10.20.30.40.5

*

Data presented as Mean ± SEM†<0.05 vs. Baseline

*p<0.05 vs. Time Control

Baseline Control

% p

er h

our

0.00.10.20.30.40.5

* †

Hart et al. Anabolic effects of oxandrolone following severe burn. Ann. Surgery. 233:556-564; 2001.

Mea

n %

Cha

nge

from

Adm

issi

on

-30

-20

-10

0

10

20

30 *

Control

Oxandrolone

Lean Body Mass

* p<.05

Weight Change

% W

eigh

t Cha

nge

from

Adm

issi

on

-20

-10

0

10

20

30

40

50

Control Oxandrolone

*

Twenty subjects randomized to receive either 0.1 mg/kg Oxandrolone BID, or placebo diluent

% c

hang

e oxandrolone*

*oxandrolone *oxandrolone *oxandrolonetreatment *

oxandrolone * *oxandrolone *

months after burn

* Significant difference, p<0.05.

- 1 5

- 5

5

1 5

2 5

3 5

P la c e b o ( n = 2 5 )

O x a n d r o lo n e ( n = 2 4 )

Percent change in the number of patients above the 25th percentile for Weight compared to discharge

oxandrolonetreatment

6 12 18 24months after burn

*%

cha

nge

* **

*oxandrolone ** **

* Significant difference, p<0.05.

oxandrolone

-10

0

10

20

30

40

50

Placebo (n=25)Oxandrolone (n=24)

6 12 18 24

months after burn

Percent change in the number of patients above the 25th percentile for Height compared to discharge

oxandrolonetreatment

**

Propanolol N Engl J Med 2001; 345: 1223-9

– PO 0,33 mg/kg by nasogastric tube every 4 hours– Increase progressively to 1 mg/kg/ 4 hours– Aim at 20% reduction in heart rate

Average Heart Rate

Treatment Days-10 2 4 6 8 10 12 14 28

Hea

rt R

ate

100

120

140

160

180

Control, N=12Propranolol, N=13

* * ** * * * * * * * * * *

* p<0.05

N=10

N=12

Herndon, et al. Reversal of catabolism by beta=blockade after severe burns.

New Engl. J. Med. 345(17):1223-1229; 2001.

∆ Resting Energy Expenditure2 Week Treatment Course

Control Propranolol

% ∆

-60

-40

-20

0

20

40

60

*

*Data presented as mean±SEM

p<0.05

N=12 N=13

Herndon, et al. Reversal of catabolism by beta=blockade after severe burns.

New Engl. J. Med. 345(17):1223-1229; 2001.

Propranolol

∆ in %Fat Free Mass4 Week Treatment Course

Control Propranolol

∆ in

%

-20

-10

0

10

*

*p<0.01Data presented as mean±SEM

% Lean Body Mass at Discharge

Control Propranolol

%

65

70

75

80

85

90

*

Data presented as mean±SEM

*p=0.01

±

Herndon, et al. Reversal of catabolism by beta=blockade after severe burns. New Engl. J. Med. 345(17):1223-1229;2001.

Baseline Controlµmol

PH

E/m

in/1

00m

l leg

-0.10

-0.05

0.00

0.05

0.10

Muscle Protein Net Balance

12 Time ControlSubjects

12 PropranololSubjects

Data presented as mean ± SEM*p<0.01 vs. Time Control

†<0.05 vs. Baseline

*

Baseline Propranololµmol

PH

E/m

in/1

00m

l leg

-0.10

-0.05

0.00

0.05

0.10 †

Herndon, et al. Reversal of catabolism by beta=blockade after severe burns. New Engl. J. Med. 345(17):1223-1229; 2001.

Dual-Image X-Ray Absorptiometry

Bars are Means ± SEM for % change.*Significant difference between Placebo and Propranolol at p<.002, unpaired t-test.

-10

0

10

20

30

40

50

Trunk Fat

% C

hang

e

Placebo (n=14)

Treatment (n=12)

*

Herndon et al. Gene expression patterns in skeletal muscle of burned children after beta-adrenergic blockade: implications in fat metabolism.

One Dimensional Doppler Measurements of Liver

-10

5

20

35

50

% c

hang

e

Placebo

Propranolol

*

Bars are means ± SD for % change.* Significant difference between placebo and propranolol at p < .02, unpaired t-test.

(n=20)

(n=20)

Herndon et al. Gene expression patterns in skeletal muscle of burned children after beta-adrenergic blockade: implications in fat metabolism.

Burn CareMetabolism and NutritionPast Present FutureStarvation with Hypermetabolism Hormonal loss of body reduced; manipulation mass preservation of

body mass

Superior Early physical Improved pain mesenteric therapy control artery syndrome

Prolonged Hepatic steatosis Organ specific diets convalescence

Fluid overload

Decreased Mortality From Major Thermal InjuryHas Been Due To Advances In:

• Resuscitation

• Support of theHypermetabolicResponse

• Early Closure of theBurn Wound

• Control of Infection

The Three Last are Related

Deaths from Sepsis

0

5

10

15

20

25

30

35

66-70 71-75 76-80 81-85 86-90 91-95 97-02

Years

Dea

ths

Invasive Burn Wound Infections1991-2004

Admissions: 3,876

Patients with Invasive Wound InfectionsBacterial:

Gram negative bacilli: 20Gram positive cocci: 5

Fungal:Aspergillus sp.: 47Mucor sp.: 16Candida sp.: 2

Incidence 2.3%Mortality 55/90

(61%)

Mortality associated with Fungal Infection in Burns

• 30% of Burn Patients Become ColonizedWith Candida Sp. At Some Time During TheirAcute Hospital Stay.

5

19

0

5

10

15

20

Infected

Control

*p = 0.004

Results (2)

• Characteristics of P. Aeruginosa colonized patients• Most of them were colonized in the unit, so the main factor was the

length of stay (LOS)• Out of 441 patients, 70 patients (16% ) colonized,• 12 (17%) at admission, 58 (83%) later (nosocomially)• Colonization versus hospitalization length, age and TBSA

0.0

10.0

20.0

30.0

40.0

0-6 6-18 18-30 30-40 40-50 50-65 >65

Age (years)

Per

cent

age

colo

nize

d

0.0

20.0

40.0

60.0

80.0

100.0

0-30 30-60 60-90 >90

Hospitalization length (days)

Per

cent

age

colo

nize

d

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

0-15 15-30 30-50 >50

Total Burn Surface Area (%)

Per

cent

age

colo

nize

d

366 Ps. Aeruginosaisolates (incl. 45environmental): 48genotypes

48 AFLP patterns anddendrogram of the Ps.Aeruginosa genotypes

DNA genotyping: Results (1)

• 48 different AFLPgenotypes - N patient = 70(100%)

• 21 exclusively fromenvironment

• 15 from only one patient• 12 from several patients

(N = 57), of which 2 in env.

Conclusion:• No ongoing Ps.

Aeruginosa reservoir inenvironment

• But, 57 events of cross-acquisition

• Concentrating on thegenotypes found in npatients

• 27% of the patientscolonized by 2 to 4 strains

• And, 2 genotypes werefound in 60% of thepatients

– AFLP 35: 131 isolates,29 patients

– AFLP 8: 76 isolates,19 patients

Time course of AFLP 35 and AFLP 8 colonization

Poster-Abstract / BSM / 24-11-2006:Bacteriophages: “To Claim”, “Not to Claim”, “What to Claim”?

At the Burn Centre of the Military Hospital Brussels, as all over the world, we are confronted with antibiotic-resistant bacteria who are infecting patients. We feel the need for alternatives to antibiotic treatments ingeneral. The Burn Unit in Brussels cares for 1350 patients per year (10.000 consultations/year). We are

convinced that Phage-Therapy has to be (re-) introduced in “Western” Europe. For decades, the therapeuticuse of Phages has been documented in e.g. “Eastern” Europe and Russia. Safety has been proven.

Bacteriohages are viruses that only attack bacteria. Genetic material of Bacteriophages was never foundback in Eukaryotic cells. Phage therapy never penetrated to the (Western) European or the U.S. marketpartially because the Pharma Industry preferred to realise the marketing of easily patentable and easilymarketable antibiotics. Antibiotics could be produced for broad-spectrum use. That was not the case for

Phages. Phages act against specific bacteria. Diagnostic tools for exact identification of the infecting bacteriadid not exist. Now phage-cocktails can be prepared an rapid identification of bacteria is possible.

The Phage-cocktails that will be used are now produced in collaboration with the University Hospital of Ghent(Dept. Microbiology), the Tbilisi institute of microbiology and the Moscow Institute of microbiology. Part of

these phages were isolated at the Brussels Burn Unit. Containing Phages present in (e.g.) the wound beds ofthe hospitalized patients. They were up-scaled ‘in vitro’ and will be given back to the patients.