Frequency of extra pulmonary complications in critically ill COVID-19 patients and their association with inflammatory markers and hypoxia: Retrospective analysis at a tertiary care hospital in Karachi, Pakistan

Background and Objective: This study aimed to determine the incidence of extra pulmonary complications among critically ill COVID-19 patients requiring invasive mechanical ventilation and association of these complications with various inflammatory markers and degree of hypoxia. Methods: A retrospective cohort study was conducted among 173 adults in Karachi having COVID-19 and were admitted to ICU in a tertiary care private hospital between August 2020 to July 2021. Results: The median age of patients included in the analysis was 61 years (IQR; 16). Acute kidney injury, septic shock, cardiac injury, and electrolytes imbalance were the most frequent extra pulmonary complications with proportion of 65.3% (n=113), 63.6% (n=110), 61.8% (n=107) and 33.5% (n=58). Statistically significant differences in the median serum levels of ferritin were observed among male versus female, critically ill covid patients with and without ICU mortality as well as patients with and without hospital mortality (p-value <0.05). Significantly higher serum levels of d-dimer were noted among patients who developed acute liver injury or NSTEMI, or had ICU stay of > 3 days or received mechanical ventilation for >2 days. Conclusion: Acute kidney injury, septic shock, cardiac injury, and electrolytes imbalance were the most common extra pulmonary complications among mechanically ventilated COVID-19 patients with ARDS. Higher serum d-dimer levels were associated with acute liver injury, NSTEMI, ICU stay longer >3 days and invasive mechanical ventilation >2 days. Higher serum ferritin levels are associated with male sex and serve as an important predictor of ICU as well as hospital mortality.


INTRODUCTION
Global evidence suggests that besides serious pulmonary manifestations COVID-19 also manifests as various extra pulmonary complications as result of inflammatory process or direct organ damage. 1 Acute liver injury, acute kidney injury, cardiac injury, neurological dysfunctions, and coagulopathy are among common extra pulmonary complication of COVID-19. 2,35][6] A systematic review of 27 cohort studies and six case series involving 42,219 participants from variety of populations concluded that critically ill COVID-19 patients are at risk high mortality rates. 7he study also reported mortality rate of 48% among South Asian population excluding China.The study also supported the role of clinical interventions like invasive mechanical ventilation, renal replacement therapy and vasopressors in improving the patients` survival during ICU stay. 7 study conducted in 2019 among COVID-19 patients in Karachi identified acute liver injury and acute kidney injury as the most common extra pulmonary complications with frequency of 58.9% and 24.4% respectively.The study reported significantly higher mortality among COVID-19 patients with ARDS as compared to patients without ARDS.The study showed higher morbidity and mortality among patients with complications like cardiomyopathy, renal impairment, and shock. 8However, there is lack of scientific evidence regarding the role of inflammatory markers and degree of hypoxia in development of extra pulmonary complications among COVID-19 patients requiring invasive mechanical ventilation.So, this study was conducted with the purpose to determine the frequency of extra pulmonary complications and possible association of the inflammatory markers and hypoxia with extra pulmonary complications among critically ill COVID-19 patients.Our study will help in identifying common extra pulmonary complications among critically ill COVID-19 patients, as well as help in understanding the role of inflammatory markers and hypoxia in occurrence of such complications.Such information can be useful in risk stratification among critically ill COVID-19 ICU patients with ARDS managed with invasive mechanical ventilation.

RESULTS
The median age of 173 critically COVID-ICU patients included in this study was 61 years (IQR=16 years).76.3% (n=132) of all the patients were male while 23.7% (n=41) were female.94.2% (n=163) of all the patients were found to receive mechanical ventilation for more than two days of duration, (Table-I).
The study calculated the incidence proportion for all the extrapulmonary complications among critically ill COVID-19 patients.Acute kidney injury, sepsis, cardiac complications, electrolyte imbalance, and acute liver injury were identified as the most frequent extrapulmonary complications followed by neurological complications and disseminated intravascular coagulation (DIC) (Fig. 1).
Our study found no statistically significant differences in the median levels of inflammatory markers based on different age groups, status for medical comorbid, and duration of hospital stay.Nevertheless, this study found significantly higher levels of serum ferritin among male patients as compared to female patients (p-value <0.05).The study also found significantly higher serum ferritin levels among those who either had ICU or hospital mortality as compared to those who did not have ICU or hospital mortality (Table II).Similarly, significantly higher serum levels of d-dimer were observed among patients who had an ICU stay of > three days and those who received invasive mechanical ventilation for > two days (Table II).
This study did not find any significant statistical differences in the serum levels of d-dimer among patients with or without extrapulmonary complication except for acute live injury.Likewise, significantly higher d-dimer levels were observed among patients who developed NSTEMI as compared to those with no NSTEMI (Table III).
The study didn't find statistically significant differences in the degree of hypoxia measured as PaO2/FiO2 ratio among patients with and without extrapulmonary complications or based on differences in sociodemographic characteristics.mechanical.The demographic characteristics of COVID-19 patients included in the study were comparable to the previous evidence from Karachi. 8 Moreover, acute kidney injury, sepsis, cardiac complications, and acute liver injury were identified as the most frequent extra-pulmonary complications.1][12][13][14] The local evidence also supports the considerably high burden of acute liver injury and acute kidney injury among COVID-19 patients with severe and prolonged disease. 15,16his study did not find any statistical differences in the serum levels for most of the inflammatory biomarkers i.e., CRP, LDH, ferritin, and d-dimer based on differences in age, sex, types, and number of previous medical comorbidity, ICU mortality, and hospital mortality.This can be explained by the previous local evidence where the rise in biomarkers among hypoxic COVID-19 patients was later followed by a decline and high mortality among patients with invasive ventilation. 12However, male patients were found to have significantly higher serum ferritin levels as compared to females.This finding is in line with the current evidence identifying the male sex as the major predictor of the worst prognosis and higher risk of mortality among COVID-19 patients.

DISCUSSION
Our study could not find any significant differences in the inflammatory markers among different age groups.This study estimated COVID-19-associated ICU mortality of 52.6% which is slightly higher than ICU mortality reported among COVID-19 patients from other parts of Asia except China. 7][6] Significantly higher levels of serum ferritin were observed among patients with ICU and hospital mortality in comparison to patients without ICU and hospital mortality respectively. 15][13] We observed significantly higher serum levels of d-dimer among patients who developed acute liver injury as well as among those who developed Non-ST Elevation Myocardial Infraction (NSTEMI) as compared to those who didn't develop the mentioned complications.Previous studies have been reporting a positive association of high levels of d-dimer with the development of kidney injury, liver injury, as well as COVID-19 associated mortality. 15-202][23] This study didn't observe any significant association between d-dimer and kidney injury which is contrary to the previous evidence; however, this can be explained by the differences in the study population as well as the severity of disease. 20n addition, patients who had ICU stay of > three days or received mechanical ventilation for > two days were also found to have significantly higher median levels of d-dimer than those patients with ICU stay of ≤ three or who received mechanical ventilation for ± two days.This finding is in line with previous evidence supporting the influence of high d-dimer levels at third day of hospital admission in predicting hospital mortality among COVID-19 patients. 17,24This finding is also supported by a study conducted by Tassiopoulos and colleagues which highlights the role of d-dimer-driven anticoagulation therapy in improving survival among intubated COVID-19 patients admitted to ICU. 25 Nevertheless, our study could not find any significant difference in the proportion of extrapulmonary complications among COVID-19 patients with and without ARDS based on the PaO2/FiO2 ratio.This finding is in contrast to previous studies identifying low PaO2/FiO2 ratio (OR=0.96,7][28] However, our study findings can be well explained and supported due to the inclusion of critically ill COVID-19 patients only.
This study provides evidence regarding the frequency of extrapulmonary complications in the local context as well as about the role of inflammatory markers among critically ill COVID-19 patients with ARDS requiring invasive mechanical ventilation.The study identified ARDS as an independent predictor of ICU and hospital mortality among critically ill COVID-19 patients in the local context.Moreover, this study also determined the association between serum ferritin levels and ICU and hospital mortality and the association of d-dimer levels with acute liver injury and NSTEMI.
Limitations: It notably focused on critically ill COVID-19 patients with ARDS, receiving invasive mechanical ventilation which has affected the utility of its findings.Moreover, this study couldn't find significant differences among most of the inflammatory markers among patients with and without extrapulmonary complications.This can be well explained by the high median age of the study sample, the limited sample size, and the specific inclusion of critically ill patients with ARDS.Furthermore, this study lacks the capacity to report extrapulmonary complications developed after hospital discharge.

CONCLUSION
Acute kidney injury, septic shock, cardiac injury, and electrolyte imbalance were the most common extrapulmonary complications among mechanically ventilated COVID-ICU patients with ARDS.However, higher serum levels of d-dimer were associated with acute liver injury, NSTEMI, ICU stay > three days, and mechanical ventilation > two days.Higher serum ferritin levels were associated with male sex and serve as an important predictor of ICU as well as hospital mortality.
Grant Support & Financial Disclosures: None.

History of Co-morbids
Table-II Difference in median levels of CRP, Ferritin, LDH and PaO2/FiO2 ratio across critically ill, COVID-19 patients on mechanical ventilation with different demographic and clinical characteristics (n =159).

Table -
III: Difference in median levels of CRP, Ferritin, D-dimer, LDH and PaO2/FiO2 ratio across critically ill, COVID-19 patients on mechanical ventilation with and without extra pulmonary complications (n =159) *P value <0.05-statistically significant difference in the median levels of d-dimer.