Vascular complications in 305 severely ill patients with COVID-19: a cohort study

ABSTRACT BACKGROUND: Although an association has been made between coronavirus disease 2019 (COVID-19) and microvascular disease, data on vascular complications (other than venous thromboembolism) are sparse. OBJECTIVE: To investigate the vascular complications in severely ill patients hospitalized with COVID-19 and their association with all-cause mortality. DESIGN AND SETTING: This cohort study was conducted at the Universidade Federal de São Paulo, Brazil. METHODS: All 305 consecutive patients diagnosed with COVID-19 and hospitalized in the intensive care unit (ICU) of a tertiary university hospital from April 2 to July 17, 2021, were included and followed up for 30 days. RESULTS: Of these, 193 (63.3%) were male, and the mean age was 59.9 years (standard deviation = 14.34). The mortality rate was 56.3% (172 patients), and 72 (23.6%) patients developed at least one vascular complication during the follow-up period. Vascular complications were more prevalent in the non-survivors (28.5%) than in the survivors (17.3%) group and included disseminated intravascular coagulation (DIC, 10.8%), deep vein thrombosis (8.2%), acrocyanosis (7.5%), and necrosis of the extremities (2%). DIC (adjusted odds ratio (aOR) 2.30, 95% confidence interval (CI) 1.01–5.24, P = 0.046) and acrocyanosis (aOR 5.21, 95% CI 1.48–18.27, P = 0.009) were significantly more prevalent in the non-survivors than in the survivors group. CONCLUSION: Vascular complications in critically ill COVID-19 patients are common (23.6%) and can be closely related to the mortality rate (56.3%) until 30 days after ICU admission. Macrovascular complications have direct implications for mortality, which is the main outcome of the management of COVID-19. REGISTRATION: RBR-4qjzh7 (https://ensaiosclinicos.gov.br/rg/RBR-4qjzh7).


OBJECTIVE
The aim of this study was to evaluate vascular complications in critically ill patients hospitalized with COVID-19 and investigate their association with all-cause mortality. Second, the association between baseline conditions and vascular complications, invasive mechanical ventilation, vasopressors, and mortality was studied.

Ethical approval and registration
The local research ethics commission approved this study (3.

Patients and study design
The researchers enrolled consecutive patients with confirmed COVID-19 who were admitted to the intensive care unit (ICU) of a tertiary hospital between April 2 and July 17, 2021. The clinical outcomes were monitored until August 30, 2021. All patients were included retrospectively and were diagnosed with COVID-19 by RNA detection, following the WHO interim guidance. 15 Although the researchers planned to exclude patients younger than 18 years old and those who died within 24 hours of admission to the ICU, all 305 enrolled patients were included, and none fulfilled the criteria for exclusion. All patients underwent a clinical examination, laboratory tests, and blood gas analysis. Symptoms were evaluated before ICU admission, that is, at hospital admission. All other outcomes are reported at the longest possible time point. At least one additional objective test, such as chest radiography, computed tomography, or duplex ultrasound, was used to confirm the diagnosis. All patients were treated in the ICU, with electrocardiography, non-invasive pressure, and peripheral oxygen saturation continuous motorization, and received prophylactic anticoagulants if there were no contraindications. Thromboprophylaxis was done according to the American Society of Hematology. 16 The use of low molecular weight heparin was preferred for all patients except those with severe renal impairment and, due to the lack of evidence, no patient received the treatment dose for prophylactic purposes. 8,9,11,16

Outcomes of interest
As primary outcomes, the researchers analyzed the following vascular complications: disseminated intravascular coagulation (DIC), deep vein thrombosis (DVT), acrocyanosis, acute arterial occlusion, rhabdomyolysis, and distal extremity necrosis until 30 days after admission, discharge from the ICU, or death. All diagnoses were made after a specialized physical examination and at least one additional objective laboratory or imaging test. Second, the association between baseline conditions and vascular complications, invasive mechanical ventilation (IMV) requirement, vasopressors, and mortality was studied. All outcomes were monitored until August 30, 2021. The researchers evaluated core outcomes as predefined by the Core Outcome Measures in Effectiveness Trials Initiative for people with COVID-19. 17

Data collection
Epidemiological, demographic, clinical presentation, laboratory, imaging, and clinical data were extracted from electronic medical records. Two physicians independently checked all imputed data to avoid bias during the data collection and analysis processes. Details of the treatment measures (respiratory support, kidney replacement, and anticoagulant therapy) were also analyzed. Laboratory tests were collected at ICU admission, after 7, 10, 14, and 30 days, and at death, following the ICU routine.
The date of disease onset was defined as the day on which the first symptom or sign was observed. DIC was defined according to the International Society on Thrombosis and Hemostasis (ISTH) in 2001. 18 The duration from disease onset to hospital admission, acute respiratory distress syndrome, and ICU admission were recorded.

Laboratory procedures
The method used for laboratory confirmation of SARS-CoV-2 infection was throat swab real-time reverse transcriptase polymerase chain reaction. Blood cell count, alanine transaminase, aspartate transaminase, renal function, coagulation profile, C-reactive protein, liver function, D-dimer, troponin, and arterial blood gases were also determined. All patients underwent chest radiography or computed tomography. When there was clinical suspicion of DVT, the patient underwent a full bilateral lower limb venous duplex ultrasound scan (11 MHz linear transducer, Logic P6, GE Healthcare, Milwaukee, Wisconsin, United States). In cases of acute arterial occlusion, an additional arterial duplex ultrasound scan of the affected lower limb was performed to confirm clinical suspicion.

Statistical analysis
Categorical variables were described as frequency rates (number of events and %), and continuous variables were described as mean or median values, in addition to standard deviation (SD) or minimum and maximum ranges when appropriate. For dichotomous variables, researchers calculated the odds ratio (OR), adjusted odds ratio (aOR), and 95% confidence intervals (CIs) by comparing baseline characteristics and outcomes of interest or by comparing different groups of patients. Age > 70 years and sex were used as confounding parameters to calculate the adjusted values. Mean differences (MD) and 95% CIs were used for continuous data and were compared using the t-test. Categorical variables were compared using the Pearson chi-square or Wald chi-square independence test, and multivariate analysis using States) was used for forest plot graph development.

General characteristics
All 305 included patients were treated in the ICU due to the development of organ dysfunction; 193 (63.3%) were male, and the mean age was 59.94 (SD = 14.34) years. The mean age was higher in non-survivors than in survivors (MD 9.32, 95% CI 6.23-12.42, P < 0.00001), but there was no sex-related difference. All patients had at least one previous medical condition, and there was a mean of three comorbidities per patient (mean were the most common in all samples. However, when adjusted for age and sex, hypertension (aOR 1.78, 95% CI 1.06-2.96, P = 0.028) and chronic kidney disease (aOR 1.89, 95% CI 1.14-3.12, P = 0.013) were significantly more prevalent in the non-survivors than in the survivors group ( Table 1). The most common  Table 1).

Clinical manifestations
Of  Table 2). DVT, necrosis of the extremities, acute arterial occlusion, and rhabdomyolysis were also more common in the non-survivor group, but the difference was not significant ( Table 2).
Investigating the association between baseline characteristics and clinically relevant outcomes, there was more death in patients older than 70 years (aOR 3.31, 95% CI 1.83-5.99, P < 0.0001) and in those who presented with two or more comorbidities (aOR 2.00, 95% CI 1.06-3.78, P = 0.033) (Figure 1). Among all assessed baseline risk factors, only the previous use of heparin was associated with a decreased incidence of vascular complications (aOR 0.46, 95% CI 0.22-0.98; P = 0.043) (Figure 2). There was a greater need for IMV in patients who were hospitalized for surgical reasons (aOR 3.72, 95% CI 1.05-13.19, P = 0.042) (Figure 3). None of the baseline risk factors evaluated (age, sex, comorbidities, reason for hospitalization, use of heparin, and heparin dose used during hospitalization) were associated with any difference in the necessity of vasopressor agents during hospitalization (Figure 4).

Laboratory findings
Laboratory tests were performed on all patients. See        5). Notably, the baseline D-dimer count was significantly higher in all 305 patients during the study period (Figure 6).
According to the ISTH diagnostic criteria for DIC, 33 patients (10.8%) matched the grade of overt DIC (≥ 5 points). The criteria were matched in the later stages of COVID-19. In our enrolled patients with DIC, all had a high D-dimer count, that is, more than five times the upper normal limit.

DISCUSSION
Patients with confirmed COVID-19 are commonly prone to in-hospital mortality and an elevated rate of thromboembolic events, including other vascular complications. 8,9,23  period. One patient (0.3 %) presented rhabdomyolysis, which is not a frequent complication related to novel coronavirus infection, but has already been described in the literature. 21 Another study reported rates of 6.6% pulmonary embolism and 11.6% other cardiac complications in hospitalized patients with COVID-19. 22 We reported other clinically relevant and highly prevalent vascular complications such as DIC, acrocyanosis, necrosis of extremities, acute arterial occlusion, and rhabdomyolysis. Our symptomatic DVT rate (8.2%) was similar to previous venous thromboembolism (VTE) rates of 11.2% in hospitalized patients, but was less than the rates (31% to 49%) reported for ICU patients. 8,9,23 Thromboembolic events have been frequently described in patients with COVID-19, but the actual incidence of these events    5 ; therefore, it is considered a typical marker related to hypercoagulability and thrombotic events, and it also has the potential to be used as an indicator for prognosis and progression of the disease. 27 28 Cheng et al. found a higher in-hospital death rate for patients with kidney abnormalities, showing that acute kidney injury or even chronic renal disease can contribute as a risk factor for a poor prognosis in COVID-19 patients. 29 Benson et al. 30 emphasized a high mortality rate of 11% after vascular and endovascular procedures (elective or urgent) during the pandemic period, even at lower rates (4%) of confirmed COVID-19 cases. COVIDSurg Collaborative et al. 31 found that 30-day mortality in patients with COVID-19 increased from 7.4% to 40.8% in those with VTE, and Kollias et al. 32 reported that severely ill patients with COVID-19 had high rates of pulmonary embolism (32%) and DVT (27%) despite prophylactic anticoagulation. In our study, the death rate was even higher: 55.1% in those hospitalized for clinical reasons and 77.8% in those hospitalized for surgical reasons. Most deaths also occurred during the first two weeks after admission to the ICU, which demonstrates that the length of stay in the ICU can be long, demanding more resources and meaning a longer time of intubation for these patients.
Our study had some limitations. First, this was a retrospective observational study based on the analysis of medical records.
Although laboratory tests were performed for all patients, not all laboratory tests, including D-dimer and fibrinogen, were performed.
Hence, their importance in the poor outcomes of these patients could be underestimated. However, establishing the incidence of highly relevant vascular complications is essential for providing better treatment for all patients with COVID-19.
Even more than two years after its outbreak, the COVID-19 pandemic is a global health issue. However, non-transmissible circulatory diseases remain the leading cause of disease burden worldwide. 33 The high prevalence of related risk factors, such as hypertension (69.8%), diabetes (40.7%) and smoking (27.5%), reaffirmed their burden. Additionally, severely ill patients with COVID-19 are often followed by cardio-, cerebral-, and peripheral vascular complications, and clinicians prescribe pharmacological and non-pharmacological interventions to avoid complications such as VTE, acute limb ischemia, amputation, and death. 8,12,22,26 However, there is no consensus regarding the impact of vascular complications on managing severely ill patients with COVID- 19. The high prevalence of vascular complications (23.6%) in our study suggests that this impact may also be observed in severely ill patients with COVID-19.

CONCLUSION
The high death rate (56.3%) and the relatively high incidence of all vascular complications (23.6%) demonstrate the need to improve specific diagnostic and prevention strategies to manage COVID-19 complications.