Diabetic foot ulcers are responsible for considerable morbidity and mortality of diabetic patients. Both hospitalized and patients attending ambulatory care settings who have DFUs are shown in worldwide studies to have higher mortality rates than patients without.19, 20 Identification of factors that contribute to this high mortality – the focus of this article - may go a long way in improving survival in patients with DFU.
Intra-hospital mortality of 21.4% was recorded in this observational study. This finding is higher than what was reported previously, both within and outside Nigeria. For instance, Edo et al21 reported a mortality rate of 14% in Benin (Southern Nigeria). Similarly, Rigato et al in a meta-analysis of studies conducted in many parts of Africa reported a mortality of 14%9, an Indonesian study observed mortality rate of 10.7%,22 while much lower mortality rates of 4% and 2% were respectively reported in Manchester, England23 and the United States(US).24 On the other hand, Ekpebegh et al7 in 2009 reported a much higher in-hospital mortality of 40.5% in a single-center study conducted in Lagos, South-western Nigeria. These observations suggest that although there are wide geographical variations in DFU-related mortalities, they appear to be worrisomely higher in Nigeria than in most parts of the world. Several reasons may account for the disproportionately high mortality observed in this study. First, the majority of the patients (72%) enrolled in this study did not access routine diabetes care at the study centres but were referred from primary and secondary health facilities which are usually lacking in requisite expertise and facilities. Secondly, delay in hospital presentation is another plausible explanation for this observed mortality. For instance, we observed that subjects with ulcer duration longer than one month had more than twice the odds of dying than those with a shorter duration of ulcer. It is a fact that the longer an ulcer lasts, the higher the likelihood of wound infection that may progress to sepsis. This notion is supported by the fact that sepsis, as evidenced by positive blood culture, remained as an independent predictor of mortality after adjusting for other confounding variables in the study by Nanna Panday et al.25 The much lower mortality in the fore mentioned studies from Manchester and the US may reflect the impact of an advanced healthcare system available in these countries on disease outcomes.
In this study, we found that age was significantly associated with mortality, with the highest mortality recorded among individuals 65 years and above. Foryoung et al in Cameroon, Boyco et al in the US, Katz et al in Israel and Lynar et al in Australia reported similar findings.5, 11, 26, 27 This finding may be explained by the fact that the prevalence of medical comorbidities that may lead to organ dysfunctions and death tend to increase with advancing age. Furthermore, micro and macrovascular diabetes complications are usually more life-threatening when they present in older than younger persons. It has been previously observed that diabetes in older adults is linked to higher mortality, reduced functional status, and increased risk of institutionalization.28 On the contrary, some researchers did not observe any association between age and DFU-related mortality.23 The observed relationship between age and mortality however disappeared on multivariate analysis, suggesting that the effect of advancing age on DFU-related mortality is indirect, probably through other diabetes complications. This view is supported by the fact that the presence of some co-morbid complications such as shock, cardiac failure, and renal impairment was significantly associated with increased mortality in our study. It is also noteworthy that the mean age of those hospitalised for DFU in this study (57.2 11.9yrs.) belongs to the working-age population, in contrast to what obtains in developed nations where the elderly (70 years and above) predominate.4 The public health implication is that this may contribute to the depletion of the Nigerian labour force with the resultant negative effect on national output and national income.
We observed a proportional increase in mortality with increasing ulcer grade in this study. For instance, subjects with advanced Wagner grade ulcers (≥ grade 3) were almost eight times more likely to die compared to those with lower grade ulcers. This is not surprising since higher Wagner foot ulcer grade indicates more advanced disease and increased probability of sepsis which could predispose the patient to multi-organ dysfunction. An earlier Nigerian study also observed increased mortality in patients who presented with Wagner grade 4 and 5 ulcers.7 In contrast, Jeraman et al19 did not find an association between Wagner grade and mortality probably because a higher percentage of the study subjects presented with Wagner grade 1 and 2 ulcers. It is also noteworthy, that the observed association between Wagner grade and mortality in our study was not independent of other variables as ulcer grade failed to emerge as a significant predictor of mortality when controlled for other potential predictors in multivariate analysis. The low frequency of Wagner grade 1 ulcer and corresponding higher mortality of this subset than Wagner grade 2 recorded in this study may be a result of the drawback of the Wagner grading system’s inability to address ischemia and infection which were contributors to mortality in this study. 29
Gender was not observed to significantly influence mortality, neither was cigarette smoking status. However, a longer duration of DM was a significant predictor of mortality. A similar finding was also reported by Martins Mendez et al.30 Long duration of DM is associated with the development of micro and macrovascular complications and death.31
We observed that the presence of peripheral arterial disease, as well as foot gangrene, were significant predictors of death. Subjects with gangrene had eight times higher probability of death than those without. There was also a significant association between the severity of PAD as detected on vascular imaging and mortality, such that subjects with moderate or severe stenosis had significantly higher odds of death compared to those with mild or no stenosis. Peripheral arterial disease in DFUs has been reported to be associated with severe adverse outcomes, which include the lower probability of healing, prolonged healing times, increased incidence of ulcer recurrence, amputations, and higher mortality.32, 33 Presence of PAD may also be a pointer to atherosclerosis in other vessels including coronary vessels, which place such patients at higher risk of myocardial infarction and sudden cardiac deaths.
Laboratory indices that were predictive of mortality in the cohort of patients in this study include proteinuria, positive blood cultures, and low HDL cholesterol. In a meta-analysis of randomized clinical trials of type 2 DM, selection for renal disease which was defined by either decline in renal function or presence of proteinuria signalled important mortality risk.34 Furthermore, Aragon-Sanchez et al reported albuminuria, anaemia, and leukocytosis as predictors of in-hospital mortality in patients admitted for DFU.35
Positive blood culture is indicative of sepsis and the attendant systemic inflammatory response which carries a high risk of thromboses and organ dysfunction which have been associated with higher mortality in sufferers both generally and specifically in those with DFUs.36, 37
Although diabetic patients with DFU have been observed to have a higher prevalence of cardiovascular risk factors such as hypercholesterolemia, hypertriglyceridemia, hyperuricemia, and proteinuria, 38 our observation of an association between mortality in hospitalized patients with DFU and low HDL cholesterol appears to be novel. Diabetes mellitus is associated with low HDL which is an established risk factor for cardiovascular disease in diabetic patients.39 Furthermore, cardiovascular disease is reported to be the most prevalent cause of death in diabetic patients.40, 41
Co-morbid conditions that predicted mortality in this study were cardiac failure, shock, and renal impairment. Diabetic patients have a greater than a two-fold risk of developing cardiac failure and the prognosis is worse in diabetic patients42, which may explain the association between cardiac failure and mortality in this study. The impact of shock on mortality is well documented. It inhibits the perfusion of vital organs. Sang WookYi43 in a Korean study reported an association between low systolic blood pressure and vascular mortality. Similarly, Tringali described an association between reduction in diastolic blood pressure below 70 millimetres of mercury and all-cause mortality. 44 Renal impairment persisted as an independent predictor of mortality on multivariate analysis. The association between mortality and renal impairment may be multifactorial, namely worsening nephrotoxicity from antibiotherapy as well as the underlying cause which in the setting of hospitalization for DFU may be sepsis. Furthermore, renal impairment may contribute directly to mortality in the diabetic patient by promoting cardiovascular risk factors such as hypertension, insulin resistance, oxidative stress, endothelial dysfunction, and inflammation.
A recent study from Saudi Arabia reported similar findings of nephropathy being an independent risk factor for all-cause mortality among patients with diabetic foot complications.45Given the high mortality of hospitalized DFU patients in our setting, identification of the above-stated prognosticators is crucial to guide strategies for improved outcomes.