Update of the European Society for Vascular Surgery (ESVS) 2020 Clinical Practice Guidelines on the Management of Acute Limb Ischaemia in light of the COVID-19 pandemic, based on a scoping review of the literature


 Objectives
 Perform a scoping review how COVID-19 patients are affected by acute limb ischaemia (ALI). Evaluate the recommendations of the 2020 ESVS ALI Guidelines for these patients.
 
 Methods
 Research questions were defined, followed by a systematic literature search according to the PRISMA guideline. Abstracts and unpublished literature were not included. The definition of ALI accords to ESVS guidelines.
 
 Results
 Most identified papers were case reports or case series; population-based data and data from randomised controlled trials were also identified, 114 unique and relevant papers were retrieved. Data were conflicting concerning whether the incidence of ALI increased, or remained unchanged, during the pandemic. Case reports and series reported ALI in patients who were younger and healthier than usual, and a greater proportion affecting the upper limb. Whether this is coincidental remains uncertain. The proportion of men/women affected seems unchanged. Most reported cases were in hospitalised patients with severe COVID-19. Patients with ALI as their first manifestation of COVID-19 were reported. Patients with ALI have a worse outcome if they have a simultaneous COVID-19 infection. High levels of D-dimer may predict the occurrence of arterial thromboembolic events in patients with COVID-19. Heparin resistance was observed. Anticoagulation should be given to hospitalized COVID-19 patients in prophylactic dosage.
 Most of the treatment recommendations of the ESVS Guidelines remained relevant, but the following were modified regarding COVID-19 patients with ALI: 1) CTA imaging before revascularisation should include the entire aorta and iliac arteries. 2) There should be a high index of suspicion, early testing for COVID-19 infection and protective measures are advised. 3) Preferential use of local or locoregional anaesthesia during revascularisation.
 
 Conclusion
 Although the epidemiology of ALI has changed during the pandemic, the recommendations of the ESVS ALI Guidelines remain valid. The above mentioned minor modifications should be considered in COVID-19 patients with ALI.



What this paper adds: (50 words)
This is the first scoping review of the literature focusing on how the clinical practice 46 guidelines on acute limb ischaemia (ALI) may need to be adapted as a result of the COVID-19 47 pandemic. It is important in order to optimize the care of patients who suffer both COVID-19 48 and ALI.  56 The definition of ALI accords to ESVS guidelines. 57 Results: Most identified papers were case reports or case series; population-based data and 58 data from randomised controlled trials were also identified, 114 unique and relevant papers 59 were retrieved. Data were conflicting concerning whether the incidence of ALI increased, or 60 remained unchanged, during the pandemic. Case reports and series reported ALI in patients 61 who were younger and healthier than usual, and a greater proportion affecting the upper selection based on full text review was performed by two authors (VJ, AS). Apart from the 125 systematic search manual searching by the members of the WC retrieved additional studies. 126 Specific research questions were defined by consensus amongst the WC prior to the 127 systematic search (Table 1) and divided between the authors in groups of 2-3 persons who 128 read the selected manuscripts considering their specific research question. The results were 129 then communicated within the entire group of authors. According to methodology for scoping 130 reviews a descriptive narrative of the data is presented and no data analysis is performed. 6 131 132

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The search strategy identified 226 studies. Some 53 studies were excluded based on title and 134 abstract. After reading full texts, 114 studies were included in the review ( Figure 1). There 135 were 89 case reports or small series (n<10), 1 randomized controlled trial (RCT), 3 systematic 136 reviews, and 9 cohort studies reporting on 13 to 49 patients with ALI associated with COVID-137 19. Other included studies included cohort studies only on incidence or mortality of ALI 138 associated with COVID-19, or review of organization of care for ALI during the pandemic. A 139 complete reference list of all included studies is presented in Appendix A. No studies could be 140 identified reporting ALI in patients after receiving vaccination to prevent COVID-19.
In patients with pre-existing peripheral arterial disease (PAD) it may be difficult to ascertain 144 whether the cause of ALI was related to a "normal" atherosclerotic process, or if it was 145 influenced or precipitated by the presence of COVID-19. The pathophysiology of COVID-19 146 associated ALI is multifactorial and not yet fully understood. Coagulopathy, 147 hyperinflammation and endothelial injury play a role, leading to micro-and macrovascular 148 thrombosis. 7-9 Endothelial injury and infiltration by inflammatory cells can occur in 149 previously healthy endothelium. In pathology specimens after major amputation following 150 COVID-19 associated ALI in patients without a history of peripheral arterial disease, 151 inflammation of the endothelium with small vessel congestion was found. 10 There are 152 multiple case reports of COVID-19 associated ALI in patients without known peripheral 153 arterial disease, and even in young patients without comorbidities or atherosclerosis. 11-15 154 Coagulopathy is most apparent in hospitalised patients with severe COVID-19 155 infection, but COVID-19 associated ALI is also reported in patients with mild COVID-19 156 symptoms recovering at home. [14][15][16][17] Patients may present with ALI as their first manifestation The first research questions focused on how the epidemiology of ALI may have changed 163 during the pandemic. The data on the number of patients being treated with ALI during the 164 COVID-19 pandemic are heterogeneous and conflicting. This is hardly surprising given that 165 the number of patients with ALI presenting to vascular surgeons is likely to be influenced by 166 the phase of the pandemic, local COVID-19 prevalence rates, public health and specialty 167 guidelines in surgery and vascular surgery, as well as the availability of local resources. 168 Data from the US and Italy suggested that the pandemic had a major impact on the 169 delivery of vascular services in general. [22][23][24] In Italy when resources were particularly The incidence of ALI in patients who are admitted to hospital with mild symptoms 182 from COVID-19 is relatively low: 0.4-0.9%. 19,30-32 In critically ill patients who need intensive 183 care it is higher. In a systematic review of 5 cohort studies the prevalence of ALI was 2.5% 184 (58% of all arterial thromboses) in critically ill COVID-19 patients. 7 Similar incidences of ALI in 185 critically ill patients who were treated with prophylactic or therapeutic anticoagulation were 186 found by (multicentre) studies from France and Italy: 0.6 33 , 2.2 34 and 2.4%. 16 187 Another important question is whether there has been a change in demographics of 188 ALI due to COVID-19, namely age, sex and ethnic background. Most of the patients cerebral arteries, coronary arteries, but that most are located in the lower limb. 7,11,12,17,19 We 200 did not find data on the proportion of embolus versus thrombosis in patients with ALI. 201 Although the focus of this review was arterial thrombosis and embolism leading to To avoid any airway manipulation, regional anaesthesia might be preferable over 302 general anaesthesia. Benefits of regional anaesthesia include preservation of respiratory 303 function, and avoidance of aerosolization and hence less viral transmission to staff 304 members. 46 This may be especially important in COVID-19 patients. There is no scientific 305 evidence to support this theory although one cohort series showed local anaesthesia with 306 sedation or locoregional anaesthesia was feasible for thrombo-embolectomy or bypass in 17 307 patients. 44 Recommendation #15 in the ESVS Guidelines states: "For patients requiring 308 surgical thrombo-embolectomy for acute limb ischaemia, regional or local anaesthesia may 309 be considered, but always with an anaesthetist present (Class IIb, Level C)". 1 The authors of 310 this paper agree that this recommendation needs to be strengthened during the pandemic, One issue that was studied with particular interest was if Recommendation #29 330 against using continuous systemic therapeutic heparinisation during thrombolysis would 331 need to be modified. 1 We identified no data in the literature suggesting this. The specific risk 332 and benefits of systemic therapeutic heparinisation may be different than in non-infected 333 patients, but we were unable to identify data to support modification of the treatment 334 algorithms.

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Outcomes after treatment 337 Emerging patterns suggest that the outcomes of patients with ALI are worse in patients with 338 COVID-19 (Table 3). Imaging studies in a North American cohort found that the mortality and The reasons for worse outcomes may be related to a reluctance of surgeons to 347 operate on ALI in severely ill patients with COVID-19 infection (perceived futility), late presentation with severe ischaemia (there is surprisingly little evidence for this -see above) 349 and worse outcomes following the revascularisation itself. In a series from New York, The results of this scoping review need to be interpreted with caution, since the large 439 majority of data is observational and derived from case-reports or small case series, which 440 are inherently biased. It is, however, the best evidence available to date. We suggest that    The optimal anticoagulation prophylaxis for COVID-19 patients.
The ideal therapeutic anticoagulation strategy and monitoring in patients with COVID-19 and ALI.  In boxes, write all n in italics. Check that spaces have been added around each = symbol (currently there is variation in the presentation). In exclusion boxes, start each new line with capital letter (i.e. capitalize in sentence-style). Check that every arrow starts from a box or a line (not from the "air"). Delete "etc." from the second box from the right (at the quite bottom)