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Implication of cytokines in the aggravation of malnutrition and hypercatabolism in elderly patients with severe pressure sores.

Introduction

Pressure sores remain a considerable problem in geriatric medicine [1] owing to their frequency and severity. The pressure-time product is of fundamental importance in initiating ischaemia and tissue necrosis [2-4]. Once present, the pressure sore may be considered as a largely autonomous object, with its own evolution, but nutritional status, and particularly protein malnutrition, is an important cofactor in the process of tissue breakdown [5-8] or healing [7]. Severe pressure sores may be comparable with injury processes known to induce production of acute-phase proteins by the liver [9]. This process may aggravate the underlying malnutrition promoting a vicious circle.

To test this hypothesis we investigated the production of cytokines (IL-1, IL-6 and TNF) responsible for the dramatic increase in synthesis of acute-phase reactants [10-13] and the secretion of cortisol [14] (known to interact with cytokines) in malnourished elderly patients with severe pressure sores living in a long-term care unit.

Methods

Patients: Nineteen consecutive bedridden elderly patients with pressure sores (stage III or IV according to SHEA's classification [15, 16]), living in a long-term care unit, entered the study. Twelve elderly bedridden patients without pressure sores, living in a long-term care unit, but with identical risk for pressure ulcer development according to the Norton Scale [3] were also studied. We also enrolled 12 elderly control patients with good activity and mobility living in the same unit.

No subject had other documented septic or inflammatory foci.

Study protocol: IL-1, IL-6, and TNF circulating levels together with IL-1, IL-6 and TNF production in an ex vivo model were measured. Blood cortisol levels were determined on samples withdrawn at 08 h 00. Nutritional status was evaluated using anthropometric measurements, biochemical analyses, and delayed-hypersensitivity skin testing.

Anthropometric measurements: Anthropometric measures are an important part of nutritional assessment of elderly people. Our results will be compared with reference data available for people aged 75 years and older. Several anthropometric reference data for elderly people living in the United States have been published [17, 18], but few reference data are available from Europe [19].

Anthropometry of elderly people presents particular difficulties [20] owing to mobility problems, abnormal kyphosis, and muscular contractures. For bedridden patients, duplicate measurements were made with the patient supine using a measuring-tape stretched from crown to heel. For patients with contractures, recumbent knee height was used to estimate stature [21]. Weight was calculated with an electronic scale (Support System International[R]). The mid-arm circumference (MAC) and the triceps skin-fold (TSF) were measured at the mid-point between acromion and olecranon processes, according to the method defined by Lohman et al. [22]. The MAC was measured with a flexible tape, and the TSF with Harpenden skin-fold calipers.

Biochemical analyses: Blood samples were collected after overnight fasting. The usefulness of albumin and prealbumin as nutritional markers has already been validated [23]. In addition, acute-phase proteins (APP) which are consequences of sepsis and severe injury [9] are known to be prognostically important [24].

C-reactive protein (CRP), albumin and alpha-1 acid glycoprotein (AAG) were measured by kinetic immunoturbidimetry with a Behring Turbitimer. Prealbumin and retinol binding protein (RBP) were quantified by an immunoturbidimetric assay using the Fara centrifugal analyser (Roche Analytical Instruments) and commercially available antiserum (Behring for RBP and Atlantic Antibodies for prealbumin). For each protein, between-run coefficient of variation was less than 5% within the analytical range. Transferrin was not measured, as it is known to be influenced by iron levels [25].

Immunological status: Delayed hypersensitivity was determined by skin testing with multitest Merieux[R]. Seven antigens were used (Tetanus, Diphtheria, Streptococcus C, Tuberculin, Candida, Trichophyton, Proteus). The induration area was measured 48 h after intracutaneous injection. The sum of mean diameters (A + B)/2 of positive reaction was calculated. The reaction was considered as anergic when induration was below 2 mm. Lymphocyte and monocyte counts were also determined.

Cytokines production (IL-1-IL-6 and TNF): A whole-blood ex vivo model was used [26]. Blood is drawn into a heparinized tube (Kabi ref. 82 23-12-63/9) tested for absence of endotoxins by the chromogenic kabitest; 675/[[micro]liter] of whole blood are pipetted into a 5 ml propylene sterile tube; 75[[micro]liter] of RPMI 1640 (control, no stimulation) or 75[[micro]liter] of LPS (10 ng/ml of E. coli 055: B5, SIGMA, dissolved in RPMI) are added and vortexed gently. The tubes are incubated for 5 h at 37 [degrees] C in presence of C[O.sub.2] stopped by adding 2250 [[micro]liter] of RPMI and centrifuged for 10 min at 3000 g. Supernatants are frozen in aliquots at -80 [degrees] C for cytokine measurement. Cytokines quantitation has been performed using an ELISA method [TABULAR DATA FOR TABLE I OMITTED] (EASIA Medgenix) on blood samples and on supernatants of stimulated monocytes.

Cortisol: Blood level has been measured using an IMX ABBOTT according to manufacturer's specifications.

Statistics: All data are presented as means [+ or -]SD. Non-parametric statistical methods and 'analysis of variance' were used for between-group comparisons. The Mann-Whitney U test for single comparisons and Kruskall-Wallis test for multiple comparisons were used.

Results

Characteristics of the patients: Forty-three patients were enrolled; 35 were women. Diagnoses of the 19 patients with sores and of the 12 patients bedridden without sores were comparable. Patients with sores were slightly younger than the bedridden without sores (Table I). All bedridden patients with or without sores were assessed for risk of pressure sore development using the Norton scale. The means of the scores did not differ significantly between the groups with or at risk of bedsores. The most common diagnoses were similar to those generally observed in a long-term care unit (Table I).

Anthropometric measurements: Low values of BMI (body mass index) and TSF were seen in patients with sores and correlated with severe malnutrition (BMI = 17.64, SD 4.09, kg/[m.sup.2] and TSF = 9.32, SD 4.99 mm) (Table II). These findings are dramatically lower than mean levels reported for elderly people living in Europe [19]. BMI and TSF were lower in bedridden patients with sores than in the bedridden without sores, although the differences were not significant (Table III). BMI and TSF studied in the three groups (control, bedridden with and without sores) were significantly lower in bedridden patients with sores (Table II).

Biochemical variables: Very low levels of serum transport proteins, compatible with severe protein undernutrition, were observed in patients with sores (albumin = 24.4, SD 4.1, g/l; prealbumin = 136.6, [TABULAR DATA FOR TABLE II OMITTED] SD 38.4 mg/l; Table II). Significant differences were demonstrated between those with and those bedridden without sores (Table III). These results clearly show a dramatic alteration of nutritional status in patients with sores, compatible with an adverse effect of pressure ulcers on nutritional status. The lowest values of albumin (21.8 SD 3 g/l; prealbumin 118 SD 43 mg/l; RBP 29.5 SD 19.3 mg/l) were seen in patients with stage IV sores with a significant difference for albumin (Table IV).

Acute-phase proteins levels were higher in patients with sores (CRP = 54.3, SD 31.3 mg/l; AAG = 1.66, SD 0.31 g/l) (Table II). High levels of acute-phase proteins were encountered only in those patients. The difference was significant only between bedridden with and bedridden without sores (Table III). The highest levels of CRP and AAG were observed in stage IV, pressure sores (Table IV).
Table III. p Values of statistical comparison between groups for
nutritional and inflammatory parameters.


                  Control vs.


                                                  With sores vs.
                  No sores        With sores      no sores


Albumin           0.0282(*)       0.0001(***)     0.0002(**)
Prealbumin        0.0072(**)      0.0001(***)     0.0024(**)
RBP               NS              0.0002(**)      0.0059(**)
CRP               NS              0.0001(***)     0.0001(***)
AAG               NS              0.0002(**)      0.0074(**)
IL-6              NS              0.0094(**)      0.0001(***)
ST IL-6(****)     NS              0.0046(**)      0.0102(**)
Cortisol          NS              NS              NS
Monocytes         0.0153(*)       NS              0.0015(*)
Lymphocytes       NS              NS              NS
Multitests        0.0085(**)      0.0003(**)      NS
BMI               0.0056(**)      0.0004(**)      NS
MAC               0.0041(**)      0.0056(**)      NS
TSF               0.0066(**)      0.0019(**)      NS


**** ST IL-6: Interleukin 6 in the supernatant of stimulated
monocytes. Mann-Whitney U test: *** p [less than] 0.001; ** p [less
than] 0.01; * p [less than] 0.05; NS: not significant.


Immunological status: Poor immunological status with a higher frequency of anergy (multitests) was observed in bedridden patients with sores (Table II). Lymphocyte counts were higher (1950/[mm.sup.3], SD 747) in bedridden patients without sores than in the bedridden with sores (1576/[mm.sup.3] SD 819) (Table IV), but this difference was not significant. Monocyte counts were significantly higher in patients with sores (Table II), and higher in stage IV than in stage III although the difference was not significant (Table IV).

Cytokine production: IL-1 and TNF levels in the [TABULAR DATA FOR TABLE IV OMITTED] serum of patients with pressure sores were in the normal range (Table V). In contrast, abnormal IL-6 serum levels were found in patients with pressure sores (Table V) and a significant difference was observed between the patients with sores and the bedridden without sores (Table III); the highest levels of serum IL-6 were observed in the most severe sores (Table IV).
Table V. Cytokine blood levels in bedridden patients with and
without pressure sores: results expressed as mean (SD)


                          Bedridden


                          Without sores       With sores
                          (n = 12)            (n = 19)


IL-6(**)       pg/ml      22.9 (8.7)          93.5 (85.3)
ST IL-6(*)     pg/ml     131 508 (79446)      64 520 (53208)
TNF            pg/ml      18.2 (9.9)          17.9 (7.7)
IL-1 beta      pg/ml     [less than] 15       [less than] 15


Mann-Whitney U test: ** p [less than] 0.01.


* ST IL-6: Interleukin 6 in the supernatant of stimulated monocytes.


IL-1, IL-6 and TNF concentrations were measured in fluids used to clean the sores of the thirteen patients with an exudate. IL-6 was detected in the fluids of 12 patients with sores with levels above 100 pg/ml. Among these, two had levels above 25 000 pg/ml.

IL-1 was only observed in five patients with levels above 100 pg/ml. The highest value was 3400 pg/ml. TNF was found in one patient only (168 pg/ml). Except for one patient who had high levels of the three cytokines (IL-6 = 25 000 pg/ml, IL-1 = 574 pg/ml, TNF = 168 pg/ml), no relation was clearly demonstrated between the local concentrations of the three cytokines. No correlation was noted between the intensity of local production and systemic levels.

IL-6 and IL-1 secretion in the supernatant of stimulated monocytes was significantly lower in the patients with the most severe sores (Table IV). IL-6 production in the ex vivo model was lower in bedridden patients with sores (Table III).

Cortisol: Cortisol levels were higher in patients with sores and significantly higher in patients with stage IV pressure sores (Table IV).

Discussion

This work confirms the significance of hypoalbuminaemia and hypoprealbuminaemia, anergy by skin testing and low anthropometric measures in bedridden patients with sores. The lowest biological and anthropometric indices are seen in patients with the most severe sores [6-8].

Pressure sores may induce a chronic inflammatory process (via the major mediators of inflammation, IL-1, IL-6, TNF, synergized by cortisol) responsible for an aggravation of nutritional status and pressure sore development.

Our results demonstrate significantly higher levels of APP and IL-6 in patients with sores, and especially in patients with the most severe sores. Cortisol levels are also significantly elevated in patients with stage IV sores. Cytokines, together with glucocorticoids, may be important factors for these metabolic changes represented in our study by APP production and hypoalbuminaemia [14]. IL-1, IL-6 and TNF are produced by a great variety of cells. In patients with sores, monocytes/ macrophages, fibroblasts, keratinocytes, and endothelial cells can release these cytokines in response to tissue injury and infection [27-33]. In our study both IL-6 and IL-1 were detected locally by lavage of pressure sores. In two patients with sores, IL-6 concentrations of more than 25 000 pg/ml were found in lavage fluids, IL-1 concentration, when detectable, was generally lower than IL-6; but was present at significant levels in five patients (from 204 pg/ml to 3400 pg/ml). Thus, our data demonstrate important local production of the main cytokines which are known to act in a paracrine way and could be responsible for muscle protein breakdown [34] a factor of major importance in the chronicity of sores. The local production could be also partly the origin of increased plasma levels observed for IL-6, despite lack of correlation between local and serum IL-6 measurements.

In contrast, IL-1 was not detected in the blood of our patients. This could be explained by the paracrine role of IL-1 which is utilized by cells present in the environment of the inflammatory site [35, 36]. A few patients with sores exhibited detectable blood levels of TNF, but without significant difference from the bedridden without sores group. This is consistent with a weak local production of this cytokine [37, 38].

High I L-6 serum levels in patients with pressure sores may result from an amplifying loop. Activated macrophages and monocytes are a potent source of cytokines including IL-1 and TNF [36]. In addition, IL-1, TNF and bacterial lipopolysaccharides [39, 40] can stimulate IL-6 production by the monocytes and macrophage and by a variety of cells in the areas of tissue damage.

In the ex vivo model employed we found a lower production of IL-1, IL-6 in patients with severe pressure sores (Table IV). It is likely that the monocytes and macrophages present in the chronic pressure sores had exhausted their capacity for secreting cytokines. If so, increased IL-6 circulating levels appear to be paradoxical. One explanation may be that IL-6 is produced by many other cells, in addition to activated monocytes and macrophages, and especially by local cells. Furthermore it is clear that chronic tissue necrosis and infection are also responsible for IL-6 production by fibroblasts, keratinocytes and endothelium involved in tissue injury.

The presence of circulating cytokines supports the idea that cellular products are released in patients with sores and that they may have an endocrine-like action [24]. Furthermore the role of cytokines in the hepatic response to sepsis is now well documented [41-45]. It seems however that the combined action of IL-1, IL-6 and TNF is necessary to induce the complete acute-phase response [46] and that this response is augmented by glucocorticoids [24].

The decrease of negative acute-phase proteins (albumin, prealbumin, retinol binding protein), as observed in our study, is probably an effect of both IL-1 and IL-6 [47, 48].

Increased plasma levels of cortisol have been observed in our study in stage IV sores and this fact is of importance. Glucocorticoids are considered the most important catabolic hormones. They play an important role in muscle protein breakdown and protein liver metabolism, even if other mediators are probably involved during sepsis [49]. An important interaction between glucocorticoids and cytokines (ILl, IL-6 and TNF) for regulation of APP [14] and muscle proteolysis has been observed [50, 51]. In our study both cytokines and glucocorticoids may be important cofactors in APP production and hypercatabolism in patients with severe pressures sores.

Pressure sores of stage III and worse may be considered as an autonomous disease constituted by a true vicious circle. Loss of mobility and protein energy malnutrition in bedridden elderly patients affect risks for developing pressure sores. Once sores have occurred, they aggravate nutritional status indirectly by inflammatory stimuli producing anorexia and protein wasting in elderly patients often already frail due to previous poor nutritional status.

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Authors' addresses

M. Bonnefoy, L. Rys Service de Medecine Geriatrique,

L. Coulon, J. Bienvenu, Laboratoire d'Immunologie et de Biologie d'Inflammation,

R. C. Boisson, Laboratoire de Biochimie,

Centre Hospitalier Lyon Sud, Chemin du Grand Revoyet, 69495 Pierre Benite Cedex, France
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Author:Bonnefoy, M.; Coulon, L.; Bienvenu, J.; Boisson, R.C.; Rys, L.
Publication:Age and Ageing
Date:Jan 1, 1995
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