Discussion
Acro-ischemia and cyanosis have been explained in critically ill patients with COVID-19 due to excessive coagulation status (9). In addition, digital ischemia and necrosis may be observed in other conditions such as diabetes mellitus or drug complications. In this regard, some critically ill patients may need norepinephrine for the treatment of hemodynamic impairment in the ICU. In this condition, high-dose norepinephrine may be needed for circulatory shock, which can lead to more complications and poor outcomes. Accordingly, a previous history of peripheral vascular disease, hemodynamic disturbances, and prolonged hypotension that can be associated with concomitant use of other drugs such as dopamine, may increase the risk of developing norepinephrine-induced digital necrosis (13). Although it is not clear that up to which dose norepinephrine is tolerable, the risk of impaired blood flow and digital necrosis increases when higher doses are administered because of high vasoconstriction effect (13).
Based on our findings and literature review, this is a multifactorial problem and various issues need to be considered the causes of this condition. Both of our patients suffered from type II diabetes mellitus, and diabetes mellitus is a predisposing factor for ischemia and necrosis of extremities and digits. According to a report from China, the mortality rate was 7.3% in patients with COVID-19 who suffers from diabetes compared to the total mortality rate of 2.3% in normal population. It seems that diabetes and other associated comorbidities are aggravating factors for disease severity and complications (14). To the best of our knowledge, one of the most important long-term complications of diabetes is microangiopathy, which causes damage to organs such as the eyes, kidneys, skin, as well as neurons. On the other hand, overexpression of some cytokines e.g., vascular endothelial growth factor (VEGF) and its receptor (VEGF-R) and the pro-sclerotic cytokine of transforming growth factor-β (TGF-β) play critical roles in angiogenesis and angiopathic transformation in these patients (15).
Diabetic vasculopathy may be the reason for an impaired contribution of humoral immunity, and metabolic and hemodynamic conditions (16). Further, complement-mediated thrombotic microangiopathies (TMA) have been reported in patients with COVID-19 that may be a concomitant problem in these patients (17). With this respect, microvascular involvement such as inflammatory accumulation of neutrophils and platelets, as well as intravascular fibrin deposition have been also reported in autopsy studies (18). Consequently, the occurrence of these risk factors may worsen the disease and complications may be aggravated. Therefore, it is vital to take them into consideration.
In our patients, based on the ECG changes and hemodynamics findings, it seems that acrocyanosis and digital necrosis may be accompanied by vascular and thrombotic events in other organs but there was not enough time for systemic vascular evaluation by doppler examination to confirm these hypotheses owing to the critical condition of the patients. We noticed that none of our patients received vasoactive drugs in the course of their disease, and in case of receiving a vasopressor, drug side effects might be an additive factor for digital necrosis. The presence of acrocyanosis in patients with COVID-19 can indicate organ damage due to vascular involvement and is a sign of the severity of the disease. Acrocyanosis can play a prognostic role and demonstrate poor outcomes in these patients. We recommend changing the prophylactic dose to intermediate or therapeutic dose of anticoagulant drugs, possibly plus adequate vasodilator therapy, if the patient presented with acrocyanosis. According to the recent study, catecholamines may play a role in increasing cytokines such as IL-6 (19), which can aggravate the complications of COVID-19.
In conclusion, some important risk factors that increase the chances of microangiopathy and vascular disorders should be considered in critically ill patients with COVID-19. These items include diabetes mellitus, smoking, a history of atherosclerosis, and high plasma levels of CPR, IL-6, D-dimer, and fibrinogen. Moreover, the administration of noradrenaline may be a risk factor for causing acrocyanosis, digital necrosis, and cytokine release via IL-6 production.
Conflict of interest : The authors declare no conflict of interest.
Funding Source: The authors received neither funding/support, nor grant for the publication of this article.
Author Contribution: Both the authors: made substantial contribution to the preparation of this manuscript and approved the final version for submission.GP did the literature search, drafted the initial version of the manuscript and revised the manuscript for critically important intellectual content, ZN repoert the case 1 and acquired images, FS and DM revised the manuscript for critically important intellectual content, HR reported case2, participated in drafting of cases and she has corresponded.