Lack of effect of enteral antibiotics on the post-burn hypermetabolic response

Lack of effect of enteral antibiotics on the post-burn hypermetabolic response

Burns (1987) 13. (5). 365-370 365 Printed in Great Britain Lack of effect of enteral antibiotics on the post-burn hypermetabolic response J. P. Way...

575KB Sizes 0 Downloads 32 Views

Burns (1987) 13. (5). 365-370

365

Printed in Great Britain

Lack of effect of enteral antibiotics on the post-burn hypermetabolic response J. P. Waymack,

0. Trocki, J. Wesley Alexander,

T. J. Heyd and G. D. Warden

Shriners Burns Institute, Cincinnati Unit and Department Cincinnati Medical Center, Ohio, USA

Summary Burn patients who survive the inirinl 23 h tollowing millOr hurn injur!, commonly develop a marhal hypermctaholism. One of rhe possihlc mechanisms oi- this incrcascti mctaholic riitc is gut Iranslocnkm of hnclcri;l and wJotoxin following hum injury. Wc nrtemptcd to ciccrcasc the hvp”“‘c‘tilholism hy adminisrering various anlihiotic and cndotoxin binding qenrs ciitcrnll!, in :I hurncd puinca-pig model. Adult guincn-pigs wrc given polymyxin t3. trimclhoprim and sulph;~~mcthoxazc,Ic. or neomycin and clindnmycin. or Kwpcctatc. sodium dcox~cholalc. nwmycin. clindmn~cin and polymyxin R. A control group rcccivcd no drugs. The drugs wrc ndministcrcd thro@ a gastrosfom~ tube hcginning the day hcforc hurn injury and continuing for II days. ‘l‘h~re was no sipnilicnnt decrcasc in the resting mctaholic rate in any ol' the trc’il1cd +voups compared lo controls. Neither c‘ntcrnl ;mtihiotics nor entlotoxin hindins agents u’crc ;ihlc 10 in&cc in signilicant rcduction in the posl-burn hypermcrnholic rcsponsc in this moclcl.

INTRODUCTION BIIHN patients who survive the initial 11 h following major burn injury characteristically develop ;I marked hyprrmetaholism (Wilmore. lY7Y) with associated protein catabolism and a loss of lean body mass (C’urrcri. lY7Y). Aggrcssivr nutritional support with adequa’e protein and caloric sources to meet these increased demands can br difficult to achieve for a variety of reasons. Previous work from this Iah&atory has shown that LI reduction in hypwmetabolism can be achieved burned

by irnmcdiate pulnca-pig

post-burn

feedings

in 21

model (Mochizuki et al.. lYX3). In that study. the reduction of post-burn hypcrrmetabolihm correlated with preservation of the intestinal mucctal thickness. mass and pro-

of Surgery,

University

of

tein content l‘hc protection of the gut mucosa could influence hypermetabolism by preventing translocation of agents which result in hypermetabolism, such as bacteria and endotoxin. To ebaluate further the potential relationship between the translocation of bacteria and endotoxin and the hypermetabolic response. untibiotics and endotoxin bincling agents were administer4 enterally to guinea-pigs prior to inflicting ii burn injury.

MATERIALS AND METHODS Animal model Forty-three adult female iiartley guinea-pigs weight 305 +- 3 g) underwent placement of a silastic catheter pastrostomy under pencral anaesthcsia. Following the gastrostomy they were housed in individual capes and were fed ;I standard guinea-pig diet for 7 days. Thih allowed the animals to regain the IO per cent body weight loss which occurred immediately following operation. The animals were then given 21g!neral NKIC~thetic, their backs were clipped of hair and a 30 per cent total body surface area full thickness flame hurn was inflicted. The animals were resuscitated with 2Oml of inlraperitoneal htctated Kingcr’s solution. The guinea-pip were placed in individual metabolic cages. given additional lactated Ringer’s solution by continuous gastrostomy infusion by ;I Holter TM Pump (Tampa, FL. USA) for 24 h and then switched to a standardized liquid diet as described previously, (Mochizuki et After ;I 3&v adaptive period, all al.. lY&l). animals received 17s kcaI;kgIday until post-burn day 14. (b&y

Burns (1987) Vol. 13lNo. 5

Treatment groups The animals were randomly

Evaluation of cell-mediated

allocated to four groups. Group I (CON. II = 16) served as the control and did not receive any tklXp\;. Groups II. 111 and IV were given antibiotics cnterally through their gastrostomy tubes beginning the day prior to burning and continuing for 14 days. Group II (POLY. )I = 12) was given polymyxin B sulphate 50 mp/kg/day. trimethoprim 3 m.@kg/ and sulph;ltnethoxazole 20 mg/kg/day. day. tl= 8) received neomycm Group Ill (NEO. IS mg/kg/day. 50 mg/kg/day and clindamycin Group IV (KAO, !I = 7) was given Kaopectate 0.5 ml/kg/day. sodium dcoxycholate 20 mg/kg/ day, neomycin 50 mg/kg/day, clindamycin I5 mg/ kg/day. and polymyxin B sulphate IO mg/kg/day.

Evaluation of nutritional

and metabolic state

immunity

Cell-mediated immunity was determined by, the method of Hansbrouph et al. (19X2) as modified by Waymack ct al. (19%). Briefly. on da):, I post-burn the animals had their abdomens chpped of hair and l*Oml of a 0.5 per cent dinitrotluorobenzene (DNFB) solution applied to the skin. The animals’ ear thickness was measured on post-burn day (i using an engineer’s caliper. Each ear then had 0.25 ml of the DNFB solution npplied. Twenty-four hours later ear thickness was again measured and the degree of ear swelling calculated.

Statistical

analysis

All data are expressed as mean I- s.e.m. Statistical significance was determined using NewmanKcules analysis or Fischer’s test.

Each animal

was weighed daily. Rcstins metabolic expenditures wcrc measured by Indirect calorimetry prior to burn and on post-burn days 3. 6. 9 and 12. The occurrence of diarrhoea was noted daily and was defined as the presence of non-formed stool for a minimum of two consccutive days. Following killing, the skin, head, feet and viscera were removed from the animals. ‘l’he net weight of the remaining carcass was determined. The animals’ liver. spleen, adrenal glands, and gastrocnemius muscles were also weighed. The small intestine was excised following killing and the mucosa was removed from a segment of jejunum extending from IOcm to 2Ocm beyond the pylorus by the mcthod of Levine et al. (1974). A IO-cm segment of ileal mucosa was obtained from the middle of the intestinal tract using the same method.

RESULTS All animals in the control group (group I) survived for the duration of the experiment (F&J. I). The survival rate for group II was only 42 per cent (5112) (I’
-

CON

A....A!JOLY &.-.A NE0 o---o

KAO ANOVA N.S.

Post burn day F;,q. 1. Keqing metabolic cxpcnditurc of burned guinea-pigs (expressed iIS perccntape of prc-hum Icv~l). ANOVA. analysis of variance.

367

Waymack et al. The post-burn hypermetabolic response Table 1. Organ weights

of burned

animals

at death (mean

is.e.m.1

Group I (CON)

Group Liver (g) Spleen (9) Gastrocnemius muscle (g) Carcass (g) Adrenals

(g)

Jejunal mucosa (g/10 cm) lleal mucosa (g/lOcm)

16.55 10.70 (n= 16) 0.80 F O-08 in-- 16) 0.91 + 0.03 (n- 16) 120.75 t 3.03 (n= 16) 0.36 + 0.01 (n= 16) 0.48 -I- 0.02 ((n--7) 0.28 + 0.04 h-7)

Ill (NE01 75.92 + 2.07 (n-5) 0.50 .+ 0.06 (n=5) 0.80 rt 0.10 (n=5) 107.89 + 6.55 in=51 0.43 + 0.03 (n=5) n.d. n.d.

Significance

17.65 i 2.76 (n=6) 0.39 f 0.02 (n=6) 0.96 f 0.04 (n=6) 119.65 Sz3.26 (n=6) 0.45 i 0.07 (n=6) 0.47 + 0.02 (n-6) 0.31 + 0.03 (n=7)

16.85+ 1.73 (n=7) 0.42 + 0.05 (n-7) 0.89 + 0.05 (n=7) 113.12+6.00 (n=7) 0.50 f 0.02 (n=7) 0.48 f 0.03 (n=7) 0.31 i 0.03 (n-7)

n.s.

I vs. II,* I vs. ill,* I vs. Iv* n.s. n.s.

I vs. IV” n.s. ns.

” P<@O5 by Newman-Keuls analysis n.d., Not determined. n.s., Difference not significant.

rnucosa weights are listed in 7irhk I. There wet-c no si@ficant differences between the groups except for splenic weights. The spleens of the control group weighed 0%) + OM g, those of group II weighed 0.50 i O%g. ~group 111 were 0.39 _+OX? g and group IV were ()A? L 0~05 g. Each of the three tested groups was statistically signifkant compared to group I control animals (f’
for groups

II.

HI and IV

vs. group I).

The resting meMxAic expenditure incrcascd in each group following burn injury (Fig. 2) and was maintained throughout the duration of the c’spcriment l’or all four groups. Thcrc was. however, nostatisticilll!,si~nilicant difference helween any of the groups. Each of the four groups lost approximately IS per cent of total body weight during Ihe first 3 days following burn injury. Thereafter their weight stabilized for the rcmkn-

w

60) 0

CON

A.......A

POLY

&-.-.A

NE0

o-----o

m()

5

10

15

Post burn day !?,q. 2. Body weight of hurncd guinea-pigs (cxprcssed

21spercentage

of prc-hurn

rccciving weight).

different

untihiorics therapies

368

Burns (1987) Vol. 13/No. 5

40

ANOVA N.S. T

0 CON

POLY

NE0

KAO

F;,g. .3. Cell-rncdi;ad immunity mcasurccl hy car swcliing response to ilinitrotluorol~~~i~~~~~.

der of the espcriment and there was no statistically significant difference between the groups. ‘l’he ear swelling of group I animals was 31 I!I 4 per cent. Groups 11. III and IV had statistically insignificant decreases to 31 f6 per cent, 2.5 rt 6 (Fig. 3). per cent and 2X f 6 per cent. respectively

DISCUSSION One of the most significant

physiological altrrations occurring in the post-burn period is the development of ill1 extreme hypcrmet;rboiic response. The hyprrmetabolism can impair wound healing of partial skin thickness burns, donor sites. and skin grafts. Prevention of the hypermetabolic response would therefore bc very desirable in the severely burned patient. The hypermetabolic state begins within the lirst 34 h after thermal injury. increases sharply during the second 2-I h and continues to rise at a slower rate. reaching a maximum level I-1 weeks later (Wilmore. lY7Y). There have been a variety of methods proposed to prevent or reduce the post-burn hypermetaholism. Pharmacological manipulation using high-dose morphine and adrenergic blockade have been shown to bc effective experimentally. however. they are not clinically practical as 21long-term therapy in major burn patients (Wiimore ct al.. 1974). The use of a warm air environment for the burn patient to decrease heat loss by radiation. conduction and evaporation has hecn shown to decrease the metabolic rate. but only to ;I limited extent (Aulick ct al.. 1079). Currently the most widely used method of conibutinp tissue c;rtahoiism in the post-burn period is to provide the patient with rxtrcmcly high caloric awl protein diets (Bartlett et al..

1’977). Achieving these caloric goals can he difficult in the burn patient due both to the stagnant ileus seen immediately following burn injury and during the intermittent septic episodes ii major burn patient experiences. Efforts at achieving adequate nutritional support through the use 07 parenteral nutrition have not been totally successful. due both to the hyperglycaemia seen following the administration of hypertonic plucase solutions and to the colonization with bacteria of the central venous catheter used for the parcnterai nutrition. Reduction or prevention of post-burn h\~permetnbolisln would thus appear to bc the optimum method of preventing tissue catubolism in the severely burned patient. Mochizuki et al. ( 1YX4) have demonstrated in iI burned guinea-pig model that such a reduction can be achieved by cntcraily feeding the burned animals through a gastrostomy tube immediately after burn injury. In this model adult guinea-pigs had _Sastrostomy tubes placed 1 weeks prior to burn nij,ury. Those animals which received tube feedings unmediateIy following burn injury had the post-burn hypermetabolic response blunted. They were also noted to have failed to develop the loss of mucosaI mass normally seen following burn injury. The prevention of the loss of mucosal mass by early feedings has particular signilicance when the recent work of Maejima et al. (1984) is considered. They have demonstrated that followinp a severe burn in,jury trunslocation of bacteria endogenous to the gatrointestinnl tract can take place. These bacteria enter the systemic circulation via the lymphutics draining the intestinal tract. Moejimrt et al. (lYK4) have documentecl a significant increase in the number of bacteria in present in lymph nodes, liver and spleen unburned with animals compnred burned animals. These findings may help to explain the mechanism of prevention of post-burn hyermetabolism previously demonstrated by Mochinuki et al. (lY8-4). If the early feeding of burned ;lnil~lkllS helps to maintain normal mucosal function. this may help to prevent the translocation of endopenous bacteria and endotoxin. Endotoxin has been shown to induce significant alterations in the physiology of nearly ail major orgm systems. One of the effects ot endotoxin is to activate complement components. thereby rclcasing a variety of metabolic products macrophages (Heideman, which can activate IYXl; Ninnemann. lY81). Once activated. matropll:lgcs srcrctc large amounts of interlcukin I which enhance the catabolic response (Cehula et

Waymack

et al.:

The post-burn hypermerabolic

369

response

~11.. 1Y7Y: Murphy et al.. IYSO: Baracos et al., IYKi). It would. therefore. appear that early post-burn feedings may decrease the hypermetabolic response by prevailing gut trnnslocation of endotoxin and bacteria. There are several problems with the routine use of immediate post-burn enteral feeding. Iii order to he beneficial in preventin? post-burn hyprrmctaholism. preliminary studies indicate that enteral feeding must bc instituted within the Since many miljor tirst few hours of burn injury. burn injury patients may not be transferred to burn centres until several hours after injury. these patients may not be able to be started on enteral feediqs until it is too late to achieve the beneficial results. An additional problem is the necessity of placing the patient’s feedins tube into the duodenum under fluoroscopic gulclance due to the post-burn aL o*istric ilcu5. Since most hospitals have lluoroscopy readily available only during weekdays. the arrtval of the major burn patient at night or durin_g weekends may result in difficulty in the placement of such ~1feeding tube. Thcrrfore. it woulcl he advantageous to lind an alternate method of preventing the post-burn hypermetabolic respnnse. We attempted to achieve this goal bv the use of entcral antibiotics and endotoxin binding agents. It was hoped that these agents would decrease the intralumenal content of bacteria and of free endotoxin, thereby resulting in smaller amounts being available for gut lranslocation. If the hypermetabolic response was indeed secondary to such translocation. this might have been c‘xpetted to decrease the hypermetabolic response. Our failure to achieve these goals using three different combinations of agents may lla\:c been due to one or more possibilities. First. the possibility that the hypermctabolic response ih not due to translocntion of yut bacteria and rndotoxin. A second possibility is that the antibiotics used did not adequately lower the bacterial content of the intestine and that the binding agents failed to bind a sufticicnt amount of endotoxin. Such f;lilures would obviously have prevented :I successful retardation of the hypermetabolic response. I lowrver. this would appear unlikely since the five antibiotics tested. polymyxin B hulphntc. trimcthoprim. sulph;llnethoxazt~l~. neomvcin and clindamycin, all cover many of the not&l intestinal flora. It would also appear unlikely that the binding agents were totally u~~suc~csst’t~I since Kaopectatr and sodium dcoxycholate have hrcn shown to be excrllcnt binding agents and polymivin 13 sulphntc is well known for its highly effective endotoxin binding capacity (C‘orrip:in

and Bell. possibility

lY7l: tlupheh et al. is that the antibiotics

IYSl). Another resulted in the

liberation of large amounts of endotoxin from the Thih rclrase ma\; have bacteria they destroyed. been of such an extent :IS to exceed the capacity of the bindins agents to neutralize the endotoxin. that antibiotics may injure Finally. it is known the intestinal mucosil directly and thereby may have increased permeability to endotoxin. Further studies which measure serum entlotoxin appear indicated to answer this question. Testing the use of endotoxin binding agents without the use of antibiotics may nlso be indicated.

Acknowledgements This

research

MS supported bv USPHS Grant the Surgical lnfeciion Society-3M Corporation Research Award, and the Shrincrs of North America.

AI-12936.

REFERENCES Aulick 0.. Ilander E. M. and Wiltnow 1). W. (lY7Y) ‘I’hc relative significnnce of thermal and metabolic demands in burn hyprrmctaholisln. .1. Trcrrtnrrr 19. 5.50. Baracos V.. Rodcmann I-1. P.. Dinarcllo C. A. et al. (I 983) Stimulation of muscle protein &gradation and prostaglandin E2 release hy leukocytic pyropcn (intcrleukin-I): a mechanism for the increnscd dcgredalion of muscle proteins during fever. N. EngI. J. Med. 3(w. 553. Bartlett R. 1-l.. Allyn P. A., Medley T. et al. (1977) Nutritional therapy bawd on positive caloric halancc in burn patients. rlrdi. S/q. 112. 074. Cchula T. A.. tlansw D. F.. Moore D. M. et al. (IY7Y) Sythesi!, of four crtdogznous pyrogens by rabbit macrophages. .I. 15th. Cli77. Med. 94. Y5. EndotoxinC‘orrigan J. 1. and Bell B. M. (1071) induced intrwasculw wqulation: prevention with polymyxin B sulfate. J. Lab. C’lin. Med. 77. 802. Curreri P. W. ( 1970) Nutritional rcpkcmcnt modnlities. J. T~1747ncc 19. YOh. ~f:mshrough J. F.. Pctcrson V. and Kontz I?. (IYX2) Posthurn immunowpprcssion in an animal model: nwnocylc dysfunction induced by burned tissue. .S/U~~C~~93, 11 .=I Heidcm;;n M ( IWl) Complement ;lctiv;rtion by thermal injury and its possihlc consequences for immune dcfcnsc. In: Ninnemann J. I_. (cd.). The /777r7774,7e ~‘~~~r.sc~c~rret~~ev (!f Thennd Injq. Baltimore: Williimis and Wilkins. pp. 127-133. Hughe> B., Mdm B. R. and Parratt J. R. (IYXI) Polymyxin B sulphate protects c:lts against the hacmodymunic and metabolic effects of E. coli endotoxin. Hr. .I. Phcwmud. 71. 701. L.winc G. M., Dcrcn J. J.. Stcigcr E. et 111.(lY7-1) Role of owl intake in m~iintcn;mcc of gut mass and disacch;tridc ;Ui\Cly. (;trv/,-r~c~rr/~,rr,/f~~~~ 67. Y7.F.

370

Burns

Maejinw K.. Deitch E. and Berg R. ( I Wl) Promotion ty burn strews of rhc translocation of bacteria from ihc gastrointestinal tracts of mice. Arch. Scrg. 119, Ihh. Mochizuki H.. ‘I’rocki 0.. Dominioni L. c‘t al. (lY83) Mechanism of prevention ofpostlx~rn hypcrmctaholkm and cat;tholism hy wrly cntcral l&ding. AUU. Surg. 200. 2Y7. Murphy P. A.. Simon P. L. and Willoughby W. F. ( IYXO) Endogcnous pyrogcns made by rabbit pcrit<>neul exudate czlls are identical with lymphocytcactivnting factors made by rabbit alveolar m3croph;tges. 1. /r~mrrrnoL 121. 21YX. Ninncmann J. L. (IX?) Immunologic defenses against infection: alptions followinp thermal injuries. J. Hllrrr Cm- Nehtrhl. 3. .35.5.

(1987)

Vol.

13/No.

5

Waymack J. P.. Mctz J.. Garnett D. et al. t IltiS) Effect function in of imnluno~~ic~tlulalors on nlitCr0pllitpc hurncd ilnimals. .Slrrg. I-i,wnr Wilmorc D. W. (lY7Y) In: Artz

36. I IO. C. P.. Moncrief

J. A.

Wilmorc D. W.. Long J. M. ani klason A. D. (1’371) C~ttschotnmin~s: mediators of the hypcrmctabolic response to thermal injury. A~I. Swg. 180, 6.53.

Pqxr

;~cccplcd

4

March

lYX7.

G. WHITAKER INTERNATIONAL BURNS PRIZE PALERMO (ITALY) UNDER THE PATRONAGE OF THE AUTHORITIES OF THE SICILIAN REGION FOR 1988 By law No. 57 of 14 June 1983 the Sicilian Regional Assembly authorized the President of the Region to grant the ‘Giuseppe Whitaker Foundation’, a non-profit-making organization under the patronage of the Accademia dei Lincei, with headquarters in Palermo, an annual contribution for the establishment of a ‘G. Whitaker international Bums Prize’ aimed at recognizing the activity of the most qualified experts from all countries in the field of burns and pathology and treatment. The amount of the prize is fixed at twenty million Italian lire. The prize will be awarded every year by the month of June at the Palermo headquarters of the G. Whitaker Foundation. The adjudicating committee is composed of the President of the Foundation, the President of the Sicilian Region, the representative of the Accademia dei Lincei within the G. Whitaker Foundation, the Dean of the Faculty of Medicine and Surgery of Palermo University, the President of the Italian Society of Plastic Surgery, a legal expert, the previous year’s prize-winner, and not fewer than three experts in the burns field nominated in agreement with the President of the Region as a guarantee of the respect for the scientific purposes which the legislators intended to achieve when establishing the prize. Anyone who considers himself to be qualified to compete for the award may send by 31 January 1988 his detailed curriculum vitae to Dr Michele Masellis M.D., Secretary-Member of the Scientific Committee, G. Whitaker Foundation, via Dante 167, 90141-Palemo, Italy.