key: cord-0806629-ph6s34by
authors: de Athayde Soares, Rafael; de Arruda Cáceres, Nayara; Barbosa, Anndya Gonçalves; Matielo, Marcelo Fernando; Sacilotto, Roberto
title: The catastrophic impact of Covid-19 infection in patients with Chronic Limb Threatening Ischaemia
date: 2021-10-21
journal: Surgery
DOI: 10.1016/j.surg.2021.10.016
sha: f9684fa98b2ab7a73d1b20063570a23b09d98a15
doc_id: 806629
cord_uid: ph6s34by

OBJECTIVE: To determine the impact of COVID-19 infection in patients with chronic limb threatening ischemia (CLTI), mainly the limb salvage estimates rate and the overall survival rate. METHODS: This was a retrospective, consecutive cohort study of CLTI patients with COVID-19 infection. RESULTS: Overall, 35 patients with CLTI and COVID-19 infection were evaluated. The mean age of the patients was 72,51 years, and most of them were male (60%), with arterial hypertension (85.7%), followed by diabetes mellitus (80%) and tobacco user (71.4%). There was a higher prevalence of WIfI classification 3 with 58.8% and Rutherford grade 5 (74.3%). The factors related to overall mortality rate were: D-dimer > 1000mg/dl (HR = 22.7, p < 0.001, CI = 10.49-26.52), respiratory symptoms (HR = 16.6, p < 0.001, CI = 9.87 – 20.90), CT-Chest compromising higher than 50% of the pulmonary tract (HR = 16,0, p < 0.001, CI = 10.41-20.55), acute kidney failure (AKF) (HR = 21.58, p < 0.001, CI = 16.5-30.5), chronic kidney disease (CKD) (HR = 4.4, p = 0.036, CI = 1.45-10.1), therapeutic anticoagulation (TA) (HR = 8.37, p = 0.004, CI = 1.35-8.35) and WIfI classification (HR = 5.28, p = 0.022, CI = 1.34-10.01). The following were related to limb loss: d-Dimer > 1000mg/ml (HR = 5.47, p = 0.02, CI = 1.94-10.52), respiratory symptoms (HR = 5.42, p = 0.02, CI = 1.87-10.90) and WIfI classification (HR = 4.44, p = 0.035, CI = 1.34-8.01). CONCLUSION: This study concluded that COVID-19 has a catastrophic impact among patients with CLTI. The main factors related to overall mortality were D-dimer > 1000mg/dl, respiratory symptoms, CT-Chest compromising higher than 50% of the pulmonary tract, AKF, CKD, TA and WIfI classification. The factors related to limb loss were WIfI classification, d-Dimer > 1000mg/ml and respiratory symptoms.

Since the outbreak of Covid-19 infection, it is well known that the virus affects disproportionately patients with cardiovascular disease. 1, 2 Furthermore, SARS-CoV-2, the causative agent of Covid-19, has been shown to establish itself in the host by exploiting angiotensin-converting enzyme 2 as its cellular receptor. 3 Moreover, diabetes was present in 42.3% of 26 fatalities due to COVID-19 in Wuhan, China. 4, 5 Notwithstanding the COVID-19 pandemic, chronic limb threatening ischemia (CLTI) continues to be a life-threatening condition, requiring appropriate intervention to avoid mortality and major amputations. 5 The impact of Covid-19 infection on patients with CLTI has not yet been thoroughly studied in the literature. There are case reports in literature showing that patients with CLTI are linked to poorer prognosis when infected with SARS-Cov-2, due to medical comorbidities such as advanced age, hypertension, cardiovascular disease and diabetes. 5 Patients with COVID-19 infection are at risk of developing disseminated intravascular coagulation and thrombotic complications. 6 There are studies reporting higher failure rate of revascularization surgery in patients with acute limb ischemia, CLTI and COVID-19 pneumonia. 7 Frequent early recurrent thrombosis and absence of forefoot microcirculation are also described as factors related to major amputations. 7 Therefore, the main objective of this study was to determine the impact of COVID-19 infection in patients with CLTI, mainly the limb salvage estimates rate and the overall survival rate.

J o u r n a l P r e -p r o o f

The study was approved by the Ethical committee for research. All patients treated in our institution consented to the use of anonymized and aggregate data linked to the data basis for the purposes of research. were systematically submitted to Chest-CT, in order to stratify the pulmonary infection in less or more than 50% of the lungs, or normal. Aspirin at a dose of 100mg/day and statins were prescribed for all patients before the procedures and continued after the endovascular surgery. Moreover, all patients submitted to endovascular therapy received clopidogrel with a loading dose of 300 mg, immediately after the procedure and a maintenance dose of 75 mg/day for 6 months. Therapeutic anticoagulation was administered according to COVID-19 infection and patient`s clinical condition.

Wounds were classified according to the Society for Vascular Surgery WIfI classification system 8 based on two blinded and independent providers consensus at initial presentation. The WIfI classification scores wounds on the basis of their wound, infection, and ischemia characteristics to generate a clinical stage that has been shown to correlate with wound healing.

The indications for angioplasty instead of bypass surgeries were essentially based on those defined by the TASC-II and the BASIL study (Bypass versus Angioplasty in Severe Ischaemia of the Leg), 8, 9 and based on the clinical condition of the patients.

Patients with severe infection of COVID-19 were submitted to clinical treatment, and, in cases of severe infection of the legs, to primary major amputation. 

All patients were evaluated during hospitalization until discharge, or death. Overall, 35 patients with CLTI and COVID-19 infection were evaluated. The mean age of the patients was 72,51 years, and most of them were male (60%). Regarding the comorbidities, arterial hypertension was the most prevalent (85.7%), followed by diabetes mellitus (80%) and tobacco user (71.4%). There was a higher prevalence of WIfI classification 3 with 58.8% and Rutherford grade 5 (74.3%). All of those data are described in table I.

Regarding the type of treatment performed, 2 (5.7%) patients were submitted to open bypass surgery (one iliacfemoral bypass with Dacron and one iliacfemoral bypass with basilic arm vein), 15 patients (44.1%) were submitted to endovascular treatment, 2 patients to a hybrid procedure (5.9%), 4 patients to debridements (11.4%), 5 patients to J o u r n a l P r e -p r o o f primary major amputations (14.3%) due to WIfI clinical stage 5 (unsalvageable limb at presentation) and seven patients submitted to a clinical treatment, without surgery (20.6%). The lesion location most prevalent were the toes, with 64.5% of cases. The overall mortality rate was 40%, and the major amputation rate was 23.5% (8 patients), transfemoral amputation 4 patients, and transtibial amputation 4 patients. A subanalysis was performed regarding the type of treatment and mortality rate. Among the 5 patients submitted to primary major amputations, the mortality rate was 80% (4 patients died), the patients submitted to clinical treatment had 42.9% mortality rate (3 patients died).

Among the patients submitted to endovascular treatment, the mortality rate was 26.7% Regarding major amputation rates, patients with WIfI 3-4 had higher incidence rates than WIfI 1-2 (27.5% versus 0%, p = 0.01). Furthermore, d-dimer > 1000mg/dl were also related to higher amputation levels than d-dimer < 1000mg/dl (20.6% versus 2.9%, p = 0.018), in a crosstabs analysis. Among the patients submitted to endovascular treatment, there was 13.3% of major amputation rate (2 patients 

The recent coronavirus 2019 (COVID-19) pandemic has significantly increased the pressure on healthcare system around the world, leading to important changes in the treatment of patients without COVID-19, resulting in the most difficult access to care with delays in diagnosis and treatment. 10 Especially patients with CLTI requires rapid revascularization to avoid tissue loss and amputation. Some publications reported that the number of amputations performed in 2020, was significantly greater than the number performed in the same period in 2019, an increase of almost 50%. 10 Similarly, in this present paper we have noticed an increase in amputations rate, higher than 50%, when compared to past papers published in our department in 2016, 2018 and 2019 J o u r n a l P r e -p r o o f (23.5%; 7.7%, 10%, 11%). 11, 12, 13 The possible explanations to this increased amputation rate may be related to an introduction of the lockdown in Brazil, that led to the closure of outpatient activities and prevented early observation of patients with CLTI. Patients arrived with more severe forms of CLTI, such as septic ulcers and gangrene at our vascular surgery department. Furthermore, COVID-19 infection is related to thrombotic complications. Patients infected by this disease are at risk of developing disseminated intravascular coagulation. 14 Increased levels of D-dimer and fibrin degradation products and prolonged prothrombin time have been associated with poor prognosis in patients affected by the novel coronavirus. 15 Similarly in this present study, D-dimer > 1000mg/dl was related to higher major amputation rates than d-dimer < 1000mg/dl (20.6% versus 2.9%, p = 0.018). These patients had more severe clinical conditions, some of them were submitted to primary major amputation, without attempt for revascularization, due to high risk and irreversible conditions of the limbs. Another factor related to major amputation rate in this present study was WIfI 3-4, both in a crosstabs analysis and in a logistic regression. Those data are comparable with overall literature, especially in patients with COVID-19 infection, whose severe clinical conditions make the revascularization procedures and limb salvage even more difficulty. In the overall literature 11, 16, 17 , the WIfI classification was considered more important to limb salvage rates, and ulcer/wound healing rates, than angiosome concept. Moreover, the WIfI classification 1-2 was associated with faster and higher wound/ulcer healing rates than WIfI classification 3-4. The time to heal the ulcer was faster in the WIfI 1-2 groups than WIfI 3-4 groups (164.82 days versus 251,48; P = 0.017). Furthermore, WIfI stage is strongly associated with wound healing, improvement of Rutherford stage, amputation rate, and long-term mortality. 16, 17 In According to this study, the latest literature review suggests that the D-dimer test can be a reliable predictor of thrombosis growth in COVID-19 and its prognosis. Similarly, therapeutic anticoagulation in this present study was associated with a higher mortality.

These findings are similar to those found by Lopes et al 21 J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f 

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