J. clin. Path., 23, suppl. (Coll. Path.), 4, 56-64

Protein metabolism following injury

J. W. L. DAVIESFrom the MRC Industrial Injuries and Burns Unit, Accident Hospital, Birmingham 15, England

An increased rate of breakdown of body proteinfollowing injury was described almost 40 yearsago (Cuthbertson, 1930 and 1932). Patients withlimb fractures were shown to have an increasedrate of catabolism of tissue protein as demon-strated by nitrogen-containing products excretedin urine. More recently, further studies (reviewed

ALBUMIN

B.M.R.60

above 40

normal20

0

cool air0

0

) 0 0 03 04

worm air

B.M.R. so* *

above

20

'6 '02 C4mp'eKg pgins per Kg per daiy

-G-GLOBULIN

cool air0

0~~~~~

0 006 012 0418

warm air

. *

0~~~~

0

0'06 0x12 0*'18gms per Kg per day

Fig. 1 Comparisons in two burned patients betweenthe rate of catabolism ofplasma albumin and y Gglobulin (as glkg body weight) and the basal meta-bolic rate (BMR) as percentages above the expectednormal value. The patient treated in the cool en-

vironment had a burned area covering 30% of thebody surface, 10% being full-thickness skin loss;the patient treated in the warm environment had a

burned area covering 50% of the body surface, 25%being full-thickness skin loss. The expected normalrange of catabolism ofalbumin lies between 015and 0-20 g per kg, and that for y G globulin between0.035 and 0.055 g per kg per day.

by Kinney, 1962) have elucidated some of thecomplex mechanisms of this catabolic response.It appears to be dependent on the severity ofinjury (Moore and Ball, 1952; Cuthbertson andTilstone, 1968); on the environmental tempera-ture at which the experimental animals or injuredpatients are treated after injury (Caldwell, 1962;Campbell and Cuthbertson, 1967; Cuthbertson,Smith, and Tilstone, 1968; Davies, Liljedahl, andBirke, 1969); and on the state of protein nutritionbefore injury (Munro and Chalmers, 1945;Abbott and Albertsen, 1963). It is probablyindependent of an intact nervous pathwaybetween the site of injury and the brain (Davies,Liljedahl, and Reizenstein, 1970b).

In most patients with injuries other than burnsthere is a close correspondence between the in-creased rate of nitrogen excretion and the in-crease in the metabolic rate (Cairnie, Campbell,Pullar, and Cuthbertson, 1957; Kinney, 1962). Asimilar close correspondence has been observedin patients with extensive burns (Cope, Nardi,Quijano, Rovit, Stanbury, and Wight, 1953;Rabelo, Clark, and Kinney, 1961) and alsobetween plasma albumin catabolism and nitrogenexcretion in patients with burns and other injuries(Davies, Ricketts, and Bull, 1959). A less satis-factory correspondence (Fig. 1) has been foundbetween plasma albumin and y G globulin cata-bolism and basal metabolic rate in patientswith burns treated in different environmentaltemperatures (Davies et al, 1969).

Studies of the catabolic response to injury havebeen considerably assisted by the development ofmethods for the isolation of single plasmaproteins and their trace labelling with radioactiveiodine (McFarlane, 1964). These methods ofisolation and labelling do not alter the biologicalfunctions or survival of the proteins if they arecarried out with considerable care (Cohen,Freeman, and McFarlane, 1961; McFarlane,

10

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1963a). The usefulness of almost pure labelledplasma proteins in studies of the catabolic processhas been enhanced by the observations mentionedabove, that the rate of catabolism of plasmaalbumin closely corresponds to the rate ofexcretion of nitrogen in the urine from patientswith a variety of injuries. Further examples ofthis correspondence are shown in Fig. 2 frompatients with burns or other forms of injury of

57

minor or major severity. Comparison of thequantities of albumin catabolized and the totalquantity of protein catabolized to give the amountof nitrogen excreted in the urine indicates thatalbumin contributes between 10 and 15% of theurinary nitrogen. As will be discussed in moredetail below the remaining nitrogen is probablyderived from the labile protein pool (Munro,1964).

ins

gms ;

ALBUJMII

40 INJURY

35.0,

30 0

25 * 0 *

0 ~~~015 /

000 0sC00

5 0 0

'o 5 io 1-5 2,0 2'S 3b 3s

gms. N

Fig. 2.

.5

.4 1

gins. .~perKg 20perday OM

BURN

O 5 10 15 20 25 30

gms.N

Fig. 2 The correspondence between the daily rate ofcatabolism ofplasma albumin and the quantity ofnitrogen excreted in the urine each day for twopatients with burns and two patients with other formsof injury. The filled circles denote the patients withsevere injury and extensive burns, the open circles thepatients with the less severe injury and the smallerburned area.

Fig. 3 The rates of catabolism of albumin and y Gglobulin (as g per kg body weight) in patients withminor, moderate, and severe injuries for two to threeweeks after the accident. The open circles denote sixpatients with burned areas of different extent of thebody surface. The filled circles denote six patientswith other forms of injury of varying severity. Thehorizontal broken lines indicate the expectednormal range of the catabolic rate of each protein.

ALBUMIN

(-G-GLOBULIN

DAYSFig. 3.

A

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J. W. L. Davies

Numerous studies of the catabolism of plasmaalbumin, gamma G globulin, and fibrinogenlabelled with radioactive iodine have been madein patients with a variety of injuries arising fromaccidents or major surgery. These changes in thecatabolic rate of the various plasma proteinshave been compared with changes in the con-centration of the proteins in plasma. A summaryof the results from many of these studies isincluded in the following sections.

Factors Modifying the Catabolic Response toInjury

SEVERITY OF INJURYStudies with labelled plasma proteins have con-firmed the observations made before the intro-duction of these materials (see review by Mooreand Ball, 1952) that the catabolic response in-creases in proportion to the severity of injury.Examples of the results from studies with labelledplasma proteins in patients with minor, moderate,or severe injuries due either to burning or otherforms of accidental injury are shown in Figure 3.The catabolic rate of both albumin and gamma Gglobulin (as g/kg/day) increases as the severity ofinjury increases.The injury caused by a single simple mastec-

tomy does not cause an increased catabolic rateof albumin (Mouridsen, 1967) and would not beexpected to produce an increased rate of excretionof nitrogen in urine. The operative repair of afractured tibia by compression plating is a moresevere injury and causes a transient twofoldincrease in the rate of albumin catabolism(Davies et al, 1970b). Increased urinary nitrogenexcretion also occurs in patients with injuries ofsimilar severity (Flear and Clarke, 1955) and inpatients with burns of up to one third of the bodysurface (Moore, Langohr, Ingebretsen, and Cope,1950). Moderate injuries, such as an open com-pound fracture of the femur or burns involvingmore than one third of the body surface, andsevere injuries arising from multiple fracturesshow a prolonged and greatly increased rate ofcatabolism of albumin and y G globulin (Birke,Liljedahl, Plantin, and Wetterfors, 1959/60;Davies, Ricketts, and Bull, 1962 and 1963) andnitrogen excretion in urine (Moore et al, 1950;Moore and Ball, 1952). In these moderate andsevere injuries prompt therapy of substantialhaemorrhage by the transfusion of a volume ofblood equal to that lost results in a less severecatabolic response than if the lost blood is onlypartly replaced (Flear and Clarke, 1955).The proportional increase in catabolic response

and severity of injury is reflected in changes ofconcentration of various plasma proteins. Thecharacteristic pattern of these changes, reviewedby Owen (1967), consists of a decreasing albuminconcentration and increasing concentrations of

58

alpha 2 globulin, gamma G globulin, andfibrinogen. The concentrations of alpha 2 globulinand fibrinogen usually increase soon after injurywhile that of gamma G globulin is usuallydelayed until the second or third week afterinjury. The effect of minor, moderate, or severeinjury on the concentrations of albumin, alpha 2globulin, and gamma G globulin are shown inFigure 4. The average concentration of albumindecreased in all patients; with minor and moderateinjuries the concentrations only just became sub-normal whereas in the patients with severeinjuries the albumin concentrations were tran-siently 20% below the expected normal range.The concentrations of alpha 2 globulin did notincrease above the expected normal range ofvalues during the two-week period of study inany of the patients. The concentrations of gammaG globulin changed according to the character-istic pattern, the subnormal values observedduring the first week after injury changing tonormal or supranormal values during the sub-sequent weeks. These changes in injured patientshave also been described by Baar and Topley(1956).The patients with burns showed more marked

depressions of the albumin concentration andmore marked increases in the concentration ofalpha 2 and gamma globulin than observed in thepatients with other forms of injury. These moremarked changes in patients with burns have beendescribed by many authors (including Prender-gast, Fenichel, and Daly, 1952; Birke, Liljedahl,and Troell, 1957; Davies et at, 1962 and 1963;Baar, 1965; Davies, Ricketts, and Bull, 1966;Davies et al, 1969).The reductions in albumin concentration in

some of these patients, particularly those withextensive injuries, may be due partly to haemo-dilution resulting from undertransfusion, as wellas to the increased rate of catabolism of albumin.The accumulation ofalbumin in the tissues aroundthe wound may also account for some of thealbumin lost from the plasma (Birke et al,1960; Liljedahl, Olhagen, Plantin, and Birke,1963; Mouridsen, 1969).

ENVIRONMENTAL TEMPERATUREStudies reported by Caldwell (1962) in burnedrats indicate that a much smaller catabolicresponse is observed when the animals are keptbefore and after burning in an environmentaltemperature of 30°C. More recent studies in ratswith a fractured femur (Campbell and Cuth-bertson, 1967) and in patients with limb fractures(Cuthbertson et al, 1968), maintained at the sameenvironmental temperature, have shown similarreductions in the severity of the catabolic re-sponse with less nitrogen excreted in the urine.More detailed studies have been made in

patients with burns, who were treated either in avery warm, dry environment (air temperature,

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32°C, relative humidity 20-30%) or in a cooler,moister environment (air temperature 22°C,relative humidity 30-70 %) (Barr, Birke, Liljedahl,and Plantin, 1968; Davies et al, 1969). Twogroups of patients with comparable burnedareas were studied, one group of patients beingtreated in the warmer environment and the othergroup in the cooler environment. Some of theresults from two patients, one taken from eachgroup, with comparable burns are shown in

59

Figure 5. The results are representative of thosefound in the two groups of patients and indicatethat the patients treated in the warm, dry en-vironment had lower basal metabolic rates,lower rates of catabolism of albumin and y Gglobulin, and smaller losses of body weight thanin the control group treated in the cooler, moisterenvironment.The plasma concentrations of albumin and

gamma G globulin only reflect to a limited

SEVERE,albumin

MODERATE, albumin

qglobulin

.6 t 1,.

gms000

0

fgIobulin

0 4 8 12 6

yGiobulin

048 22 16

0 4 8 12 6

DAYSFig. 4 Average plasma concentrations ofalbumin,alpha 2 globulin, and y G globulin from groups offour to six patients with minor, moderate, or severeinjuries. The open circles (B) denote the results inpatients with barns of differing extent of the bodysurface; the filled circles (I) denote the concentrationsobserved in the patients with other forms of injuryofdiffering severities. The horizontal interruptedlines indicate the range of the expected normalconcentrations of the three proteins.

gms

gins

MINOR,olburr,in

q,globulinP

.R j# 6.¢QQd %g -~~~~~~~~~~~~~~~~~~~~~~~~~~~~

1

O.Q.4C01% O&Oe

d

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weight

albumin *20 yG-globulin

*1j

f .~05--

5202530So35 0 5 105 20 25 303

AYS DAYS

Fig. 5 Values for the basal metabolic rate (BMR),body weight, and the catabolic rate (g/kg) ofplasmaalbumin and y G globulin in two patients with burnsfor five weeks following the accident. The filledcircles indicate the results in a patient treated in acool environment with a burn of30% of the bodysurface, 10% of which was full-thickness skin loss.The open circles indicate the results from a patienttreated in a warm, dry environment with a burn of20% of the body surface, 15% of which was full-thickness skin loss. The single horizontal brokenline indicates the body weight on admission to hospital(called 100 %) and the other horizontal brokenlines indicate the expected normal range of thecatabolic rates ofalbumin and y G globulin. TheBMR values are expressed as percentages of theexpected normal value. Op. denotes the time ofthe operations for excision of the burned area andthe transplantation ofskin.

Fig. 6 Average values for the changes in theconcentration ofplasma albumin, alpha 2 globulin,and y G globulin in two groups ofpatients with burnsfor three to four weeks after the accident. Thepatients treated in the warm, dry environment are

denoted by the open circles (W) and the patientstreated in the cooler environment by the filled circles(C). The horizontal broken lines indicate theexpected normal range of the concentrations of eachprotein.

60

extent the catabolic rates of these proteins. Withalbumin the catabolic rate is highest in thepatients treated in the cool environment, whoshow the lowest albumin concentrations. In thewarm environment the lower catabolic rate isassociated with slightly higher albumin con-centrations. Different results are found withgamma G globulin, since the highest catabolicrate is associated with high concentrations of theprotein, and the lower catabolic rates found in thepatients treated in the warm environment withlower plasma concentrations of the protein.These differing results with the two plasmaproteins most probably reflect changes in therates of synthesis of the proteins (see below). Theconcentration of the remaining serum globulins(alpha 1, alpha 2, and beta) does not appear tobe modified by the treatment in a warm, dryenvironment (see the results for alpha 2 globulinin Fig. 6).

EFFECTS OF PROTEIN DEPLETION OR STAR-VATIONPart of the body stores of protein are in a formwhich is labile. When the diet contains adequateamounts of protein (about 2 g/kg body weightper day) the amount of labile protein in the bodyreaches a maximum of about 5% of the totalbody content of protein. A change to a lowprotein content or a protein-free diet results in arapid depletion of the body content of labileprotein (Munro, 1964). A chronic deficiency ofdietary protein is associated with a very smalllabile protein pool.

In injured animals or man having an adequateprotein diet before injury, this labile protein poolis the probable source of the increased amountof nitrogen which is excreted in the urine. Ex-periments in rats (Munro and Chalmers, 1945)maintained on a diet very low in protein and theninjured resulted in very little increase in theamount of nitrogen excreted in the urine, ie, thecatabolic response was substantially reduced,presumably because of the very small labileprotein pool. Similar conclusions have been

albumin

1_- _

W~~~.0---- C

C

C

1202

2. o(,z globulin

1.2

0*4

06 12' 18 24

yGgbbulin C

.0----ow

0. 6 12 lB 240) 26 1' f'S 2'4'

DAYS

EBM.R.

gm5per

perday

5.0

4.0gms 30

/0 20

D)

Fig. 6.

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described by Moore and Ball (1952) and Abbottand Albertsen (1963) in patients undergoingoperations of varying severity, and could beexpected in injured patients suffering fromprotein deficiency diseases such as kwashiorkor.As the survival of labelled albumin in patientssuffering from kwashiorkor has been shown tobe abnormally long, ie, the catabolic rate isreduced (Picou and Waterlow, 1962; Cohen andHansen, 1962), the interpretation of results fromstudies on the effects of injury in these patientswill require considerable care. Neither an in-creased rate of catabolism of albumin nor anincreased rate of urinary excretion of nitrogenmay be observed.

Specific Effects of Injury Shown by ProteinMetabolism Studies

STUDIES OF CATABOLISM WITH LABELLED

FIBRINOGENThe specific function of fibrinogen which resultsin its conversion to fibrin complicates the inter-pretation of metabolic studies with labelledfibrinogen (Davies et al, 1966). Following skeletalinjury the plasma concentration of fibrinogenincreases (Owen, 1967; Davies, Liljedahl, andReizenstein, 1970a). When such patients receiveintravenously fibrinogen tagged with radioiodinethe body content of fibrinogen becomes labelledand then any fibrin that is formed containslabelled protein molecules. Elderly injuredpatients in particular show considerable fibrinformation which accumulates mainly as deepvein thrombi or microthrombi in lung tissue(Sevitt and Gallagher, 1959; Eeles and Sevitt,1967). Patients with burns also show extensiveaccumulations of fibrin, mainly in the tissuesaround the burned area (Sevitt, 1957). The radio-active label excreted in urine arises from bothlabelled fibrinogen and labelled fibrin, so theapparent catabolic rate depends on the pro-portion of the injected labelled protein which isconverted into fibrin. Published data (Davieset al, 1970a) indicate that when the quantity ofextravascular radioactivity is about five timesgreater than the intravascular content the wholebody content of radioactivity decreases at a ratewhich has a biological half life of 6-0 days. Whenthe extravascular:intravascular ratio is about 10,as found in many patients, or less than 1-0, asfound in normal individuals, the biological halflife of the whole body content of radioactivity isshorter, with a value of three to four days.Although anticoagulants have been shown to

reduce the incidence of deep vein thrombusformation following injury (Sevitt and Gallagher,1959), there appear to be no detailed studies ofthe effects of various anticoagulants generallyused for this purpose. The limited evidence fromthree patients given dicoumarol for four to six

61

weeks following myocardial infarction (AdelsonRheingold, Parker, Buenaventura, and Crosby,1961) and from a few dogs (Lewis, Ferguson, andSchoenfeld, 1961) indicates that with the dosagesused the dicoumarol did not alter the catabolicrate of fibrinogen from its normal value.

STUDIES WITH ALBUMIN IN PARALYSEDPATIENTSStudies have been carried out to investigatewhether an intact nervous pathway is essentialfor the production of the increased catabolic rateof tissue and plasma proteins which followsinjury in many patients (Davies et al, 1962).Labelled albumin was injected intravenously intoeight patients with mainly limb injuries, four ofwhom were also paralysed from spinal cordinjury at the level of C7, Th 11 and 12, or L 1(Davies et al, 1970b). Operative repair of the limbinjuries was followed by very similar increasedrates of catabolism of albumin in both the para-lysed and non-paralysed patients (Fig. 7). Notonly was the rate ofcatabolism increased followingthe operation in both groups of patients but alsocertain synthetic mechanisms were stimulated.The alpha 2 globulin levels rose similarly andthere were corresponding rises in the erythrocytesedimentation rates to which increased fibrinogenformation may have also contributed. The con-centration of this latter protein has been observedto increase in other patients with similar injuries(Davies et al, 1970a). These results suggest thatan intact nervous system proximal to the site ofinjury is not required for the initiation of anincreased rate of catabolism of albumin.These results have been compared with those

from studies in injured dogs by Egdahl (1959)and Egdahl, Peck, and Mack (1968). Theseauthors suggest that an intact nervous pathway

30

.25

gms X2per .1*Kgperr1day v0

*3S1 albuminP.

d

op1rot.onoparotion

:4 -0o -6 -2 0 .2 *6 .10 .14DAYS

Fig. 7 Average catabolic rates ofalbumin in twogroups of injured patients. Four of the patients hadinjuries which included paraplegia (filled circles); theremaining four patients were injured but not paralysed(open circles). Studies were made for two weeks beforethe operative repair of limb injuries as well aspostoperatively in the paralysedpatients and onlypostoperatively in the non-paralysed injured patients.The horizontal broken lines indicate the expectednormal range of the rate of catabolism ofalbumin.

O 1 ' --

- - - .1

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from the site of injury to the brain is required forthe initiation of the adrenocortical responsewhich is associated with accidental or surgicalinjury, and that there is no evidence for theproduction of a 'wound hormone' from damagedtissue since there was no adrenocortical responseto injury by burning or long bone fracture whenthe nerves proximal to the site of injury were

divided before injury.It may be concluded from these studies that

although afferent nerve impulses are requiredfor an adrenocortical response, and an increasein adrenocortical activity is associated with anincreased catabolic rate of plasma and tissueproteins, the role of the adrenal cortical hormonesin this catabolic response is permissive ratherthan causative. Similar conclusions have beendrawn from extensive studies in patients whowere injured but not paralysed (Cuthbertson,1964).

STUDIES OF THE RATE OF PROTEIN SYNTHESISIn studies made more than 20 years ago it wasrarely possible to determine whether the observedincreases in the concentration of various proteinsin the plasma of injured patients were due toincreased rates of synthesis or to reduced rates ofcatabolism of the proteins. An exceptionalsituation concerns proteins such as the C-reactiveproteins and specific immunoglobulins whichappear in the plasma of injured patients thoughabsent in the plasma of normal individuals. Asstudies with radioiodine-labelled albumin, y Gglobulin, and fibrinogen havealmost alwaysshownincreased rates of catabolism of these proteinsfollowing injury, any increase of concentrationsmust be due either to translocation of preformedproteins from the extravascular compartmentinto the plasma or to an increased rate of synthesis.A number of different methods have been

developed to investigate whether the rate ofsynthesis is increased. None of them are entirelysatisfactory however, particularly when thepatient is in an unsteady metabolic state sinceconsiderable assumptions are required for themathematical interpretation of the data.

Albumin synthesis using the 14C carbonate methodThis method (McFarlane, 1963) depends on therelationship between the specific activities of a

single labelled precursor (14C carbonate) andthose of all products derived from the precursor,eg, 14C arginine, 14C urea, and 14C albumin.Measurements of the 14C content of urea andalbumin gives estimates of the rate of synthesisof albumin (Reeve, 1965; Tavill, Craigie, andRosenoer, 1968). Studies in patients in a steadymetabolic state confirmed the assumptions in-volved in the calculation of the rate of synthesisof albumin using 14C carbonate since the cal-culated rate of synthesis was very similar to therate of catabolism deduced from measurements

62

with 1311-labelled albumin (Tavill et al, 1968). Nostudies appear to have been made in patients inthe unsteady metabolic state which followsinjury. As the rate of synthesis of albumin maybe changing in these patients repeated estimatesof the rate of synthesis may be required, but theyare not without some hazard due to the persis-tence of some 14C in the body.

Studies using '.N labelled amino acidsAn increased rate of incorporation of 1"N-labelled glycine into tissue and plasma proteinshas been observed in burned rats compared withthe findings in normal animals (Levenson andWatkin, 1959) even when the amino acid wasgiven at the peak of the catabolic rate of proteina few days after burning. Carcase analysis for15N indicated that the labelled amino acid hadbeen preferentially incorporated at a greater thannormal rate into the essential organs and plasmaproteins rather than into muscle tissue. When thelabelled amino acid was given a few days beforeinjury and had been incorporated into all bodytissues the response to burning was an increasedrate of loss of 15N from the muscle comparedwith little loss from the essential organs (Leven-son, Pulaski, and Guerico, 1966). These studiesstrongly suggest that muscle contains the labileprotein pool (Munro, 1964) which is the mainsource of the excess nitrogen excretion followinginjury.

Studies with iodine-labelled plasma proteinsAlthough these proteins labelled in vitro havebeen extensively used in catabolism studies,few reports include calculations of the rate ofsynthesis of the proteins. With patients in a steadymetabolic state it has been justifiably assumedthat the rates of synthesis and catabolism areequal. In the unsteady state, however, the rate ofsynthesis can only be deduced from frequentspecific radioactivity measurements (counts permilligram protein) made by isolation of measur-able amounts of the labelled protein followed byassay of the radioactive content and proteinconcentration of each sample. The specificradioactivity values are only altered by thedilution effect of new unlabelled protein enteringthe plasma; they are unaffected by catabolismsince this process equally affects labelled andunlabelled molecules. In the absence of synthesisthe specific radioactivity values remain constant;in patients in a steady metabolic state the specificradioactivity values change at the same rate asthat of the plasma content of radioactivity.

In the unsteady metabolic state followinginjury, rates of synthesis calculated from changesin the specific radioactivity values have beenreported using labelled albumin, y G globulin,and fibrinogen (Davies et al, 1966 and 1969).Examples of the results are shown in Figure 8.In patients with burns treated in a cool environ-ment and given labelled albumin intravenously

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Burns Injuries

T

I25 .-G-GLOBULI N

25 Burns Injuries2

I50 t*ie5

FIBRI NOGENBurns

0 3 6 9 12 15 18 21

DAY'

Injuri es

-1 *-- *- 2-`0 3 6 9 12 15 18 21

Fig. 8 Average values for the maximum and mini-mum rates of synthesis (as mg/kg body weight) ofalbumin, y G globulin, andfibrinogen in groups ofpatients with burns or other forms of injury for thetwo to three weeks after the accident. The horizontalbroken lines indicate the expected normal range

of the rate of synthesis of each protein.

the rate of synthesis ofalbumin was approximatelynormal during the first week after burning andthen subnormal during the following two weeks.When labelled y G globulin was given to the sameburned patients the rate of synthesis of y Gglobulin was always substantially above normal.An even higher rate of synthesis of fibrinogenwas observed in the burned patients studied withlabelled fibrinogen. Patients with burns treatedin a warm environment show similar subnormalrates of albumin synthesis and rates of y Gglobulin synthesis which are considerably less(although still supranormal) than those observedin the patients treated in the cool environment(Davies et al, 1969).These rates of synthesis of the various plasma

proteins are reflected by corresponding changesin the plasma concentrations of the proteins. Asdiscussed in detail above, the albumin concentra-

tion is almost always subnormal followingburning while the concentrations of y G globulinand fibrinogen rapidly become supranormal.

In patients with injuries other than burns asimilar, although less marked, pattern of plasmaprotein synthesis is observed. Albumin synthesisis depressed to below the normal range duringthe second and third weeks after injury, at whichtime the rate of synthesis of y G globulin isapproximately twice normal, and that of fibrino-gen is just above the expected normal range.

Conclusions

A review of protein metabolism following burn-ing and other forms of injury indicates that therate of catabolism of plasma albumin and y Gglobulin increases as the severity of injury in-creases. In patients with burns the catabolic rateof the two plasma proteins is reduced by nursingthe patients in a very warm environment. In thisenvironment less albumin is catabolized and lessy G globulin is synthesized.The plasma concentrations of albumin, alpha 2

globulin, and y G globulin remain nearer theexpected normal values in the patients withskeletal injuries compared with the low albuminconcentrations and the high alpha 2 and y Gglobulin concentrations observed in the burnedpatients. The changes in concentration appear tobe unaffected by the severity of injury or burning.

Studies of the catabolic response to injuryusing labelled fibrinogen are complicated by theformation of insoluble fibrin from the bodycontent of soluble fibrinogen. Fibrinogen andfibrin formation are increased after both burningand other forms of injury.

Studies in patients with paraplegia and otherinjuries indicate that an intact nervous pathwaybetween the site of injury and the brain is notrequired for the initiation of the catabolic re-sponse to injury shown by an increased rate ofcatabolism of plasma albumin.The methods for estimating the rate of syn-

thesis of various plasma proteins in vivo arediscussed. The methods using 14C and 15N aredifficult to perform and require considerableassumptions for the interpretation of the results.The alternative method using iodine-labelledproteins is much simpler and has been used toshow the rate of synthesis of albumin, y Gglobulin, and fibrinogen in patients with burnsand other forms of injury. In these patients therate of synthesis of albumin is usually subnormaland that of y G globulin and fibrinogen usuallysupranormal.

The author acknowledges the help given in someof the studies contained in this review by Dr S.

per'Kgperday

perKgperday

perKgperday

30C

25C

20C

SC

IOc

Sc

I63

Y

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Baar for many of the measurements of proteinconcentration, and to Professor Birke and DrS.-O. Liljedahl for permission to quote resultsfrom studies carried out in the King Gustav VthResearch Institute and the Surgical Departmentof the Karolinska Hospital, Stockholm, Sweden.

References

Abbott, W. E., and Albertsen, K. (1963). The effect of starvation,infection and injury on the metabolic processes and bodycomposition. Ann N. Y. Acad. Sci., 110, 941-964.

Adelson, E., Rheingold, J. J., Parker, O., Buenaventura, A., andCrosby, W. H. (1961). Platelet and fibrinogen survival innormal and abnormal states of coagulation. Blood, 17,267-281.

Baar, S., and Topley, E. (1956). Haemoglobin metabolism andserum proteins following trauma. Acta med. scand., 153,3 19-328.

Baar, S. (1965). Serum and plasma proteins in thermally injuredpatients treated with plasma, its admixture with albuminor serum alone. Ann. Surg., 161, 112-126.

Barr, P.-O., Birke, G., Liljedahl, S.-O. and Plantin, L.-O. (1968).Oxygen consumption and water loss during treatment ofburns with warm dry air. Lancet, 1, 164-168.

Birke, G., Liljedahl, S.-O., and Troe'l. L. (1957). Studies onburns. III. The serum protein pattern and nitrogen metab-olism. Acta chir scand., Suppl., 228, 39-56.

Birke, G., Liljedahl, S.-O., Plantin, L.-O., and Wetterfors, J.1960. Albumin catabolism in burns and following surgicalprocedures. Acta chir. scand., 118, 353-366.

Cairnie, A. B., Campbell, R. M., Pullar, J. D., and Cuthbertson,D. P. (1957). The heat production consequent on injury.Brit. J. exp. Path., 38, 504-51 1.

Caldwell, F. T. (1962). Metabolic response to thermal trauma.It. Nutritional studies with rats at two environmentaltemperatures. Ann. Surg., 155, 119-126.

Campbell, R. M., and Cuthbertson, D. P. (1967). Effect of en-vironmental temperature on the metabolic response toinjury. Quart..J. exp. Physiol., 52, 114-129.

Cohen, S., Freeman, T., and McFarlane, A. S. (1961). Metabolismof "31-I-labelled human albumin. Clin. Sci., 20, 161-170.

Cohen, S., and Hansen, J. D. L. (1962). Metabolism of albuminand v-globulin in Kwashiorkor. Clin. Sci., 23, 351-359.

Cope, O., Nardi, G. L., Quijano, M., Rovit, R. L., Stanbury, J. B.,and Wight, A. (1953). Metabolic rate and thyroid function,following acute thermal trauma in man. Ann. Surg., 137,165-174.

Cuthbertson, D. P. (1930). The disturbance of metabolismproduced by bony and non-bony injury, with notes oncertain abnormal conditions of bone. Biochem., J., 24,1244-1263.

Cuthbertson, D. P. (1932). Observations on the disturbance ofmetabolism produced by injury to the limbs. Quart. J.Med., 25, 233-246.

Cuthbertson, D. P. (1964). Physical injury and its effects on proteinmetabolism. Mammalian Protein Metabolism. Edited byH. N. Munro and J. B. Allison, vol. 2, pp. 373-414.Academic Press, New York and London.

Cuthbertson, D. P., and Tilstone, W. J. (1968). Nutrition of theinjured. Amer. J. clin. Nutr., 21, 911-922.

Cuthbertson, D. P., Smith, C. M., and Tilstone, W. J. (1968). Theeffect of transfer to a warm environment (30°C) on themetabolic response to injury. Brit. J. Surg., 55, 513-516.

Davies, J. W. L., Ricketts, C. R., and Bull, J. P. (1959). Serumalbumin catabnlism and nitrogen excretion. Lancet, 1,346.

Davies, J. W. L., Ricketts, C. R., and Bull, J. P. (1962). Studiesof plasma protein metabolism. Part I. Albumin in burnedand injured patients. Clin. Sci., 23, 411-423.

Davies, J. W. L., Ricketts, C. R., and Bull, J. P. (1963). Studiesof plasma protein metabolism. Part 11. Pooled gammaglobulin in burned and injured patients. Clin. Sti., 24,371-382.

Davies, J. W. L., Ricketts, C. R., and Bull, J. P. (1966). Studies ofplasma protein metabolism. Part III. Fibrinogen in burnedpatients. Clin. Sci., 30, 305-314.

Davies, J. W. L., Liljedahl, S.-O., and Birke, G. (1969). Proteinmetabolism in burned patients treated in a warm (32°C)or cool (22°C) environment. Injury, 1, 43-56.

Davies, J. W. L., Liljedahl, S.-O., and Reizenstein, P. (1970a).Fibrinogen metabolism following injury and its surgicaltreatment. Injury, 1, 178-185.

Davies, J. W. L., Liljedahl, S.-O., and Reizenstein, P. (1970b).Metabolic studies with labelled albumin in patients withparaplegia and other injuries. Injury, 1, 271-278.

Eeles, G. H., and Sevitt. S. (1967). Microthrombosis in injured andburned patients. J. Path. Bact., 93, 275-293.

Egdahl. R. H. (1959). Pituitary adrenal response followingtrauma to the isolated leg. Surgery, 46,9-21.

Egdahl, R. H., Peck, L., and Mack, E. (1968). Pituitary adrenalactivation following different types of trauma. In Symp-osium on Combined Injuries and Shock (IntermedesProceedings, 1967), pp. 91-98. Forsvarets Forskningsan-stalt, Stockholm.

Flear, C. T. G., and Clarke, R. (1955). The influence of blood lossand blood transfusion upon changes in the metabolism ofwater, electrolytes and nitrogen following civilian trauma.Clin. Sci., 14, 575-599.

Kinney, J. M. (1962). The effect of injury upon human proteinmetabolism. In Protein Metabolism, Ciba InternationalSymposium, p. 275-296, edited by F. Gross. Springer,Berlin.

Levenson, S. M., and Watkin, D. M. (1959). Protein requirementsin injury and certain acute and chronic diseases. Fed. Proc.,1S, 1155-1190.

Levenson, S. M., Pulaski, E. J., and Del Guerico, L. R. M. (1966).Physiologic Principles of Surgery, p. 1. Saunders, Phila-delphia.

Lewis, J. H., Ferguson, E. E., and Schoenfeld, C. (1961). Studiesconcerning the turnover of fibrinogen-I131 in the dog.J. Lab. clin. Med., 58, 247-258.

Lil3edahl, S.-O., Olhagen, B., Plantin, L.-O., and Birke, G. (1963).Studies on Burns. VII. Theproblem of infection with specialreference to gamma globulin. Acta chir. scand., Suppl.,309.

McFarlane, A. S. (1963a). In vivo behaviour of 1131-fibrinogen.J. clin. Invest., 42, 346-359.

McFarlane, A. S. (1963b). Measurement of synthesis rates of liverproduced plasma proteins. Biochem. J., 89, 277-290.

McFarlane, A. S. (1964). Metabolism of plasma proteins. Mant-malian Protein Metabolism, edited by H. N. Munro andJ. B. Allison, vol. 1, pp. 299-341. Academic Press, New Yorkand London.

Moore, F. D., Langohr, J. L., Ingebretsen, M., and Cope, 0.(1950). The role of exudate losses in the protein andelectrolyte imbalance of burned patients. Ann. Surg.,132, 1-19.

Moore, F. D., and Ball, M. R. (1952). The Metabolic Responseto Surgery, chapters 2 and 3. Thomas, Springfield, Illinois.

Mouridsen, H. T. (1967). Turnover of human serum albuminbefore and after operations. Clin. Sci., 33, 345-354.

Mouridsen, H. T. (1969). The extravascular retention of albuminin wound tissue and its contribution to the postoperativehypoalbuminaemia in rabbits. Clin. Sci., 37, 431-441.

Munro, H. N. (1964). General aspects of the regulation ofprotein metabolism by diet and by hormones. MammalianProtein Metabolism, edited by H. N. Munro and J. B.Allison, vol. 1, pp. 381-481. Academic Press, New Yorkand London.

Munro, H. N., and Chalmers, M. 1. (1945). Fracture metabolismat different levels of protein intake. Brit. J. exp. Path.,26, 396-404.

Owen, J. A. (1967). Effect of injury on plasma proteins. Advan.clin. Chem., 9, 1-41.

Picou, D., and Waterlow, J. C. (1962). The effect of malnutritionon the metabolism of plasma albumin. Clin. Sci., 22, 459-468.

Prendergast, J. J., Fenichel, R. L., and Daly, B. M. (1952).Albumin and globulin changes in burns as demonstratedby electrophoresis. Arch. Surg., 64, 733-740.

Rabelo, A., Clark, R. G., and Kinney, J. M. (1961). Energyexpenditure in two severely burned patients. Surg. Forum,12, 462-464.

Reeve, E. B. (1965). The measurement of the synthesis rate ofliver synthesized proteins in animals. Technical ReportSeries 45, Radio-isotope Techniques in the Study of ProteinMetabolism. p. 57. International Atomic Energy Agency,Vienna.

Sevitt, S. (1957). Burns-Pathology and Therapeutic Applications,chapter 2. Butterworth, London.

Sevitt, S., and Gallagher, N. G. (1959). Prevention of venousthrombosis and pulmonary embolism in injured patients.Lancet, 2, 981-989.

Tavill, A. S., Craigie, A., and Rosenoer, V. M. (1968). Themeasurement of the synthetic rate of albumin in man.Clin. Sci., 34,1-28.

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