New Perspective in Diabetic Foot Syndrome: From Caregiver to Caregiving – the Role of Clinical Complexity

1. Introduction

Diabetes mellitus is a high prevalence chronic disease with an increasing trend and a high impact on health systems: it is estimated that 61 million people are affected in Europe [1], of which 4 million in Italy [2]. Diabetic subjects have a more than double risk of hospitalization (235 against 99 per 1 000 people) and an average longer hospitalization (11.3 days against 9.9) compared to non-diabetics, with higher costs associated to complications and comorbidities.[3] In the diabetic patient, the presence of multimorbidity worsens the prognosis: in about 80% of the cases there is at least one other chronic disease such as COPD, ischemic cardiomyopathy, heart failure, chronic kidney disease, non-alcoholic fatty liver disease, with a significant increase in mortality for all causes, especially cardiovascular ones (OR 1.22-5.46) [4,5,6].

Diabetic foot syndrome (DFS) is defined by the presence of an ulcer with varying degrees of ischemia, infection, and/or neuropathy in the diabetic individual [7]. It represents a formidable complication of diabetes mellitus, characterized by high mortality, morbidity and commitment of resources. The lifetime risk of a person with diabetes to develop a foot ulcer is 15-25% [8]; every 30 seconds in the world a lower limb is amputated due to diabetes [9] and the probability of an ulcer recurrence is 40% within 12 months [10].

The patient with diabetic foot syndrome can be defined as "complex" and "fragile", with a 4 times higher risk of cardiovascular mortality than diabetics without ulcers; it is known that the patient with a previous amputation has a 5-year mortality risk of 39-68% [11].

Among the main risk factors for amputation in DFS are the presence of PAD (Peripheral Arterial Disease), peripheral neuropathy, a concurrent infection, malnutrition, renal disease, especially in the presence of co-morbidities [12,13,14]. Even the lack of therapeutic education of patients and their caregivers seems to interfere with ulcer healing [15], even if, to date, validated systems to evaluate the adequacy of caregiving in patients with DFS do not exist. The impact of DFS is high in terms of economic resources on Welfare Systems in the World and worsens the patient’s and his caregivers’ quality of life [16]; for these reasons, the patient affected by DFS can be defined as "complex" and "fragile". International guidelines suggest that management by a multidisciplinary team appears to be able to reduce major amputations and alleviate the burden in DFS [16]. Despite this, the rate of re-amputations continues to be high (19% within 12 months and 37% within 5 years) [17]; this could be related to risk factors not yet identified.

Complexity in DFS

In the literature, there are different definitions of "frailty", a condition associated not only with advanced age but above all with bio-psycho-social "complexity" [18,19].

It is defined as “a clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with everyday or acute stressors is compromised” [20] or as “impaired resolution to homoeostasis following a stressor event” [21]. Overall, frailty is associated with a more than doubled risk of mortality in men and women aged 45 years and older, increases the risk of hospitalization (OR 1.82), and results in loss of basic autonomy (OR 2.05) [22]. The risk increases in the presence of multimorbidity [21], outlining a "complex" patient phenotype.

The "complex" phenotype is a peculiar identity that does not result from the mere sum of the individual pathologies that compose it, but from their multidimensional interaction. Furthermore, it includes biological, socioeconomic, cultural, behavioral and environmental characteristics as key determinants of patient health [23] (Table 1).

The fragile and complex patient requires a global and integrated approach (bio-psycho-social approach) [18] and the use of tools capable of assessing multidimensional health that can be adapted to the specific pathology [27,28,29,30]. Currently, there are no validated tools capable of facilitating the multidimensional assessment of the patient with DFS.

The aim of our study is to describe, through specific tools, the degree of multidimensional complexity in a sample of patients with DFS belonging to 3rd level of the Provincial Diabetic Foot ICP (Integrated Care Pathway) of Modena and to evaluate whether it constitutes an additional risk factor for amputation or not. Secondary outcomes: rate of hospitalization and revascularization procedures.

2. Materials and Methods

This retrospective study was conducted on a cohort of patients consecutively referred to the Metabolic Internal Medicine Department of the University Hospital of Modena (Tertiary Center of the Diabetic Foot ICP), both inpatient and outpatient, in the period January-December 2021. The protocol was approved by the relevant ethics committee and according to local regulation (protocol number 855/2019) and written informed consent was obtained from all participants. For the multidimensional evaluation, each patient was given specific forms validated in the literature and/or suggested by the International Guidelines (Table 2).

The general characteristics of the population examined, are described in Table 3.

According to the International Guidelines[7], amputation were classified as "minor" if performed at or distal to the ankle, "major" if performed proximal to the ankle, "absent" if not performed. Revascularization was classified as Percutaneous Transluminal Angioplasty (PTA), “By-pass” of the lower limb, or “no revascularization”.

For each patient, 12 variables were identified, 6 of which numerical, relating to the score obtained in BARTHEL INDEX, LAWTON-BRODY SCALE, MMSE (Mini Mental State Examination), CIRS (Cumulative Illness Rating Scale), SINBAD System and based on AGE and 6 categorical variables, based on SEX , on the score obtained in MUST (Malnutrition Universal Screening Tool), ONAS tool (Ordine Nazionale Assistenti Sociali-Italian National Association of Social Workers), whether or not a REVASCOLARIZATION and/or AMPUTATION intervention was performed, presence or absence of a CAREGIVER.

All patients included in the study belong to Tertiary Center of the ICP for the treatment of diabetic foot in the province of Modena, and taken care of by the Multidisciplinary Team made up of internists, vascular surgeons, infectious disease specialists, orthopedists, radiologists, endocrinologists, dermatologists, microbiologists and clinical psychologists in order to standardize care [37].

Statistical analysis

All statistical analyses were performed using R software version 4.1.1.

The p-values obtained from the tests performed were considered significant when <0.05.

Numerical variables were described as mean ± standard deviation or as median and interquartile range, while dichotomous and categorical variables are reported in terms of absolute frequencies and percentages. The association between numerical variables was measured using Pearson's product-moment correlation, while the degree of association between categorical variables was evaluated using Pearson's χ[2] test or Fisher's exact test. The association analysis between categorical and numeric variables was performed using one-way ANOVA. Odds ratios and related confidence intervals were calculated on the basis of coefficients and variances estimated from logistic regression models. A multivariable logistic analysis was performed to correct for the effect of the variables considered. In particular, all the variables associated with the outcome in the univariable analysis were entered into the model, as well as other variables of clinical interest. Observations presenting at least one missing value with respect to the variables of interest were excluded from the analysis.

3. Results

3.1. Characteristics of the sample examined

During the observation period, a total of 115 patients with DFS were identified (84 M, 73%; 31 F, 27%) with a mean age of 70.6±10.6. Of these, 41 (35.7%) were outpatient (mean age 71 years) while 74 (64.3%) were inpatients (mean age 70 years). Both outpatients and inpatients were taken care of by the Multidisciplinary Team (Diabetic-Foot-Care Team) and subjected to standard diagnostic-therapeutic care according to the updated guidelines.

Table 4 describes the characteristics of hospitalized patients (group A) and outpatients (group B). It can be seen, from the descriptive analysis of the sample examined, that inpatients (group A) were characterized, compared to outpatients (group B), by worse ulcer status and greater clinical complexity, with a greater risk of malnutrition and greater recurrence to revascularization and amputation procedures; the autonomy degree was worse in hospitalized patients, both in basic and instrumental activities; the caregiver was found to be more present in hospitalized patients. The cognitive level was comparable between Group A and Group B; the socio-economic complexity was also similar (moderate level), however, due to the large number of missing data it was not possible to evaluate the impact of this last variable on the outcomes, and it was therefore excluded from the statistical analysis.

3.2. The bio-psycho-social "complexity”

By evaluating the sample as a whole, it also emerged that a higher cognitive level is related to greater autonomy in ADL (Activities Daily Living) and IADL (Instrumental Activities Daily Living) and that there is an association between advanced age and a lower MMSE score; advanced age correlates with lower autonomy in ADLs (p 0.002); multimorbid patients (high CIRS score) are less autonomous in both ADL and IADL; there is a direct correlation for the degree of autonomy in ADL and IADL.

In the sample examined, the presence of the caregiver appears to be more frequent in elderly subjects and in no self-sufficient subjects in ADLs. (p-values 0.015 and 0.016, respectively). It seems that many self-sufficient ADL patients have a caregiver: this probably depends on the fact that they are not young patients (mean age of the sample 70 years), that they may have difficulty in IADL and that therefore they still need home assistance.

From our study it is also possible to observe that the male sex is associated with worse autonomy in IADL compared to the female one (p-value = 0.04; mean difference = -.17): this may depend on the fact that for cultural reasons many older males have never performed some of the activities described in the IADL (doing the laundry, housekeeping, food preparation) and this can alter the final score, as already known in the literature [38].

3.3. Outcomes

In our study, 72 patients (62.6% of the total) did not undergo amputation, 43 patients (37.4% of the total) underwent amputation: 38 patients (33% of the total, 2 outpatients, 36 inpatients) underwent surgery with minor amputation, only 5 patients (6.8% of the total) required a major amputation on admission. The prevalence of minor amputation is higher in hospitalized patients (48.6% vs 4.9%) (Table 3).

During the observation period, revascularization was performed in 86% of the subjects undergoing amputation, in line with the guidelines. Only in 6 cases the amputation was not preceded by revascularization during hospitalization: in 5 cases (4 M, 1 F) it had been performed in the previous six months, in 1 case there were good distal flows on Doppler evaluation. 100% of subjects revascularized via bypass subsequently undergo amputation, compared to 69% of patients subjected to revascularization via PTA, probably due to a greater severity of vascular compromise. All patients undergoing “major amputation” had a high score on the SINBAD System classification (between 5 and 6); there are no significant differences between the other variables compared to the total sample.

In our study, minor amputation appears to be more frequent in males (although this trend is not statistically significant, OR=2.079, p-value 0.134), consistently with data from the literature in which the male sex is considered to be a risk factor for amputation [12].

As far as the assessment of clinical complexity is concerned, in the sample examined, patients with greater clinical complexity (higher CIRS severity index) and a more severe level of ulcer status (higher score on the SINBAD System) have a greater risk of minor amputation: this confirms the predictive value of tools such as CIRS and SINBAD in amputation risk stratification, especially in “fragile” and “complex” patients. This association is significant both in the univariable analysis (respectively OR 3.5, p 0.006 and OR 1.64, p 0.001) (Graph 1) and in the multivariable analysis (respectively OR 3.13, p 0.035 and OR 1.53, p 0.015) (Graph 2).\

Particularly suggestive is that, unlike what is described in the literature[39,40], in our sample the presence of a caregiver does not appear to be a protective factor (Graph 2). It is probable that the assessment of the mere presence/absence of a caregiver is not sufficient and that a careful assessment of its adequacy is mandatory, in order to be able to take any therapeutic education measures. Further studies will be needed to investigate the role of caregiving in the prevention of major amputation in patients with diabetic foot syndrome.

4. Discussion

Our study analyses the characteristics of a sample of 115 diabetic patients belonging to Tertiary Center of the ICP for diabetic foot care in the province of Modena (74 inpatients vs 41 outpatients). In the sample examined, inpatients (group A) appear to present greater clinical complexity (mean CIRS 2.23) than outpatients (group B, mean CIRS 1.86), confirming the appropriateness of hospitalization and the advantage of a multidisciplinary approach: only 5 patients underwent major amputation. Our study confirms some risk factors for amputation already known in the literature [41,42] and definable as "classics", such as the high score obtained on the SINBAD System and male sex. Our study demonstrates that the approach to DFS through a multidisciplinary team that identifies and manages not only the acute complication of the ulcer, but also the multimorbidity measured through specific assessment forms, is able to reduce major amputations. In particular, the score obtained with the CIRS tool, in addition to correlating with mortality, hospitalization risk, disability and impact of drug therapy [43,44], appears to be independently associated with the risk of major amputation since it identifies the degree of complexity of the patient with DFS.

Currently, there are no specific indications for the management of multimorbidity since most guidelines focus on single diseases and are heterogeneous and not very comparable [21,45,46]. A 2018 review by Chiang et al. emphasizes the need for clinical guidelines to support a 'holistic' approach to the complex care needs of patients affected by type 2 diabetes with multimorbidity, where care of the whole person should be the primary concern[5].

The diabetic foot is to be considered to all intents and purposes just one side of a very complex systemic syndrome, which not only hurts the body in its entirety, and occur as one of the organ damages caused by the chronic hyperglycemia (such as cardiovascular, renal, cerebral, hepatic damage) but also affects the patient's autonomy and ability to fend for himself. In our study, the presence of a caregiver does not seem to be significantly related to the other variables, in particular with the Amputation outcome; this is probably motivated by the fact that the mere presence/absence of a caregiver is not sufficient to be associated (directly or inversely) with the "amputation" outcome as it would be necessary to verify its adequacy.

It is therefore important to underline the importance of correctly investigating the state of the ulcer, the presence of co-pathologies capable of significantly affecting the patient's functional autonomy and the need to evaluate the adequacy, not only the presence, of a caregiver through validated and appropriate tools. To reduce major amputations it is essential to take care of all the pathologies and train the caregiver in the co-management of the diabetic foot ulcer through sessions of therapeutic education and monitoring progress by intervening before the unfavorable evolution.

5. Conclusions

Albeit with some limitations, mainly constituted by the small size of the sample, this analysis on 115 patients with complicated diabetic foot ulcer admitted to the Tertiary Center of Modena showed that, in subjects with diabetic foot syndrome undergoing amputation, risk factors are represented by male gender, ulcer classification, clinical complexity and impairment of functional autonomies in the presence of multimorbidity. In our series, the presence of multimorbidity appears to be an independent risk factor for amputation.

In conclusion, the patient with DFS can be considered "fragile" and "complex" and requires a multidimensional approach: in such patients, the use of specific multidimensional evaluation tools can identify "unconventional" risk factors which, if modified, could delay and/or reduce the risk of amputation.

In our experience, a correct management of the patient with DFS, together with an adequate management of the diabetic ulcer, a choice of the correct medical-surgical therapy, specific training involving health professionals, patients and their caregivers and through the improvement of multidisciplinary pathways, the correction of "conventional" and "unconventional" modifiable risk factors can improve outcomes and must be considered in the Integrated Care Pathway (ICP) aimed at defining a "personalized and holistic" approach.