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.