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25th May 2022
A multi-inflammatory index (MII) biomarker have been shown to have good predictive power for mortality among COVID-19 patients admitted to an intensive care unit (ICU). This was the main finding of a study by a team of Turkish researchers.
It is common among patients with severe COVID-19 to develop acute respiratory distress syndrome (ARDS) which represents a life-threatening form of respiratory failure and after the initial infection, neutrophils, which form part of the innate immune system, rapidly infiltrate the lungs. However, lymphocytes also have an important role in both immune homeostasis and inflammatory responses throughout the body and lymphopenia has been shown to be an effective and reliable indicator of the severity and hospitalisation in COVID-19 patients. Nevertheless, infection with COVID-19 produces several biochemical abnormalities including elevation of C-reactive protein in patients with severe disease, together with hyper-inflammation and a cytokine storm. In fact, alterations in the level of several markers has been shown to be of value in predicting the prognosis of patients infected with the virus.
One particular biomarker, the multi-inflammatory index (MMI), which includes the neutrophil to lymphocyte ratio (NLR) and C-reactive protein (CRP), has been shown to have good prognostic mortality value when originally examined in patients with metastatic colorectal cancer undergoing first-line chemotherapy.
As other research has found that both the neutrophil-lymphocyte ratio and C-reactive protein are significantly higher in patients with COVID-19 and who subsequently die, the Turkish team wondered if the MII – which includes both measures – would have prognostic value for identifying which critically ill patients with COVID-19, were at a higher risk of mortality.
The team retrospectively analysed data on COVID-19 patients admitted to an ICU and compared the prognostic value of MII with a range of inflammatory biomarkers including the urea to albumin ratio, CRP to albumin ratio and the D-dimer to albumin ratio.
Multi-inflammatory index and COVID-19 mortality
A total of 348 patients with a median age of 74 years (59% male) were admitted to ICU due to COVID-19 and included in the analysis.
Overall, 24.7% of patients survived and the remainder died. While co-morbidities such as hypertension, diabetes and COPD were numerically higher among those who died, these differences were not statistically different.
Using multiple logistic regression, among all the inflammatory measures used, only MII was found to be an independent predictor of mortality (odds ratio, OR = 0.99, 95% CI 0.99 – 0.99, p = 0.03). Other significant predictors included age (OR = 1.07), the NLR (OR = 1.07).
Commenting on their results, the authors suggested that the likely reason why the NLR ratio was elevated in COVID-19 patients was because of an increased neutrophil count and a corresponding lymphopenia. They concluded that MII represents a simple and practical biomarker which could help identify COVID-19 patients with a poor prognosis and called for further studies to validate these retrospective findings.
Gozdas HT et al. Multi-inflammatory Index as a Novel Mortality Predictor in Critically Ill COVID-19 Patients J Intensive Care Med 2022
12th May 2022
Cancer patients with COVID-19 have been found to be at a greater risk of hospitalisation and 30-day all-cause mortality compared to those without the disease according to the results of a study by a US team from Texas.
The presence of cancer has become a recognised factor that is associated with a higher risk for severe outcomes in those infected with COVID-19 and which is largely due to the presence of a compromised immune system. During the early course of the pandemic, studies observed that a higher proportion of cancer patients infected with COVID-19 were both hospitalised and subsequently died, compared to those without the disease. In contrast, however, other studies have suggested that cancer and non-cancer patients have comparable COVID-19 outcomes after adjusting for age, sex, and comorbidity. Furthermore, the impact of factors such as cancer treatments, different cancer types on COVID-19 related outcomes has been less well studied. For the present study, the US researchers examined the association between cancer-specific characteristics and COVID-19 outcomes. They turned to the Optum de-identified COVID-19 electronic health record, which is derived from over 700 hospitals and 7000 clinics across the USA. Using these data, the researchers examined the outcome of those with a laboratory confirmed COVID-19 and a recorded cancer diagnosis. The primary objective was to determine the effect of cancer on COVID-19 outcomes including 30-day all-cause mortality, hospitalisation, intensive care unit (ICU) admission and ventilator use. These outcomes were also analysed by the nature and type of cancer in comparison to patients without cancer. The authors the explored if there were any other specific factors in those with cancer which impacted on COVID-19 outcomes.
Cancer patient with COVID-19 and related outcomes
A total of 271,639 patients with confirmed COVID-19 of whom 18,460, with a mean age of 66 years (45.3% male) had a cancer diagnosis were analysed. Among those with cancer, 8034 patients had a history of cancer for longer than 12 months and 10,426 had a more recent diagnosis, i.e., within 1 year before COVID-19.
30-day all-cause mortality was more than three times higher among those with cancer (6.8% vs 1.9%) compared to non-cancer patients. After adjustment for age, sex, ethnicity and risk factors, the presence of cancer was associated with a 7% higher risk of death (relative risk, RR = 1.07, 95% CI 1.01 – 1.14, p = 0.028) compared to those without the disease. Similarly, there was a 4% higher risk of hospitalisation (RR = 1.04, 95% CI 1.01 – 1.07, p = 0.006). When comparing the duration of cancer, those with a recent diagnosis had both a significant (p < 0.001) increased risk of mortality (RR = 1.17) and hospitalisation (RR = 1.10) although this risk was non-significant for those who had cancer for much longer.
There was also an increased mortality risk for those with recent metastatic (RR = 2.09), solid tumour (RR = 1.12) and haematological (RR = 1.48) cancers compared with those without the disease. Individual cancers with a significantly elevated risk were leukaemia (RR = 1.58), liver (RR = 2.46), lung (RR = 1.85) and pancreatic (RR = 1.94).
When exploring the factors related to COVID-19 mortality in those with recent cancer, both chemotherapy (RR = 1.37) and radiotherapy (RR = 1.83) within 3-months before COVID-19, were significantly associated with a higher risk of death as was increasing age (i.e., > 75 years) (RR = 6.69). In addition, the only significant co-morbidities were cardiovascular disease (RR = 1.72), diabetes (RR = 1.39) and renal disease (RR = 1.51).
Kim Y et al. Characterizing cancer and COVID-19 outcomes using electronic health records PLoS One 2022
11th February 2022
Multi-organ ultrasound might be of value in ruling out a pulmonary embolism (PE) in critically ill patients with COVID-19 and potentially reduce the need for computed-tomography pulmonary angiography (CTPA). This was the conclusion of a study by researchers from the department of Acute Internal Medicine, Amsterdam UMC, the Netherlands.
Among those who are critically ill with COVID-19, studies suggest an increased risk of thrombo-embolism and subsequent death. In fact, the incidence of PE is reported to be around 2.6 – 8.9% of COVID-19 in hospitalised patients and up to one-third of those requiring intensive care unit (ICU) admission, despite standard prophylactic anticoagulation. In a 2010 survey, the majority of the radiologists indicated that CTPA is the new reference standard for the diagnosis of pulmonary embolism. However, in cases where CTPA is unavailable, a 2020 meta-analysis has indicated that cardiopulmonary ultrasound may be useful in areas where CTPA is unavailable or unsuitable, as this modality can help detect right ventricular strain (RVS) which has a high degree of specificity for a PE. In addition, an emergency department study concluded that the use of multi-organ ultrasound is more sensitive than single-organ ultrasonography and increases the accuracy of clinical pre-test probability estimation in patients with suspected PE.
However, whether multi-organ ultrasound would be of value in ruling out a PE among critically ill patients with COVID-19 is unclear and was the objective of the current study by the Dutch team. They set out to compare the diagnostic value of lung, deep vein and cardiac ultrasound both separately and in combination for the detection of PE. Included patients were adults (> 18 years) admitted to an intensive care unit and for whom a multi-organ ultrasound scan was performed within 24 hours of a CTPA.
Multi-organ ultrasound scan results and pulmonary embolism
A total of 140 CTPA scans were performed in 70 consecutive patients with a mean age of 67.5 years (80% male) and patients underwent 126 lung, 123 deep vein and 125 cardiac ultrasound scans.
The diagnostic accuracy of sub-pleural consolidations was 42.9% (95% CI 34.1 – 52), and 75.6% (95% CI 67.1 – 82.9%) for deep vein ultrasound and 74.4% (95%CI 65.8 – 81.8%) for RVS on cardiopulmonary ultrasound.
When the signs of multi-organ ultrasound scans were combined, the sensitivity was high at 87.5% (95% CI 67.6 – 97.3) although the specificity was low at 25%.
The authors concluded that while the use of individual single site ultrasounds were of limited value on their own, multi-organ ultrasound had a higher sensitivity and could therefore be of value at ruling out a PE. They described how these data suggested the use of multi-organ ultrasound has the potential to reduce the amount of CTPA’s undertaken adding that since devices were hand-held and hence more accessible, scanning could be undertaken by intensive care personnel.
Lieveld A et al. Multi-organ point-of-care ultrasound for detection of pulmonary embolism in critically ill COVID-19 patients – A diagnostic accuracy study J Crit Care 2022
27th January 2022
Intensive care unit (ICU) patients continue to frequently experience physical, mental and cognitive symptoms one year after their acute infection with COVID-19. This was the main finding from a study by researchers from the Radboud University Medical Center, Nijmegen, the Netherlands.
ICU patients who survive serious illnesses such as acute respiratory distress syndrome are known to have persistent functional disability one year after discharge from an intensive care unit. Moreover, during the current pandemic, patients recovering from severe COVID-19 have been found to present with early mild to moderate functional impairment, mildly reduced quality of life and a worsening of pain and depression/anxiety symptoms at 6 months. In addition, other work indicates frequent cognitive sequelae after infection with COVID-19.
However, longer-term outcome data among ICU patients admitted to these units due to COVID-19, is lacking. As a result, for the present study, the Dutch researchers set out to establish the extent of any long-term physical, mental and cognitive symptoms among this patient cohort. They recruited patients discharged from ICU due to COVID-19 but excluded individuals whose stay in ICU was less than 12 hours as well as those with a life expectancy of less than 48 hours. For the three main outcomes, the team assessed physical symptoms based on the Clinical Fragility Score (CFS) for which the cut-off score, indicative of frailty is 5. Mental symptoms such as anxiety and depression were measured using the Hospital Anxiety and Depression scale (HADS), which has a cut-off value of 8 and finally, cognitive symptoms were assessed using the abbreviated Cognitive Failure Questionnaire-14, for which the cut-off score was 43.
ICU patients mental, physical and cognitive scores
A total of 246 patients with a mean age of 61.2 years (71.5% male) completed the one-year follow-up questionnaires.
At 12 months 74.3% of ICU patients reported physical symptoms compared to 26.2% for mental and 16.2% for cognitive symptoms respectively. In addition, 30.6% of patients reported symptoms from at least two of these domains with 10.5% having symptoms from all three domains. For the CFS, the median value after one year was 2, with 6.1% of patients exceeding the cut-off score for frailty. Similarly, 18.3% exceeded the cut-off score for HADS, indicating anxiety and depression and 16.2% exceeded the cognitive failure score cut-off.
Among the range of new physical symptoms developed, 38.9% reported a weakened condition, 26.3% reported joint stiffness, followed by joint pain (25.5%) and muscle weakness (24.8%). Symptoms of anxiety and depression were reported by 17.9% and 18.3% respectively.
The authors concluded that among ICU patients, one year after treatment, physical, mental and cognitive symptoms continued to be reported.
Heesakkers H et al. Clinical Outcomes Among Patients With 1-Year Survival Following Intensive Care Unit Treatment for COVID-19 JAMA 2020
13th January 2022
Atorvastatin given to patients infected with COVID-19 and admitted to an intensive care unit (ICU) is not associated with a significant reduction in adverse outcomes according to research by a team from the Rajaie Cardiovascular Medical and Research Centre, Tehran, Iran.
Hydroxymethylglutaryl coenzyme A reductase inhibitors (or statins), are known to exert a direct antithrombotic effect in models of arterial and venous thrombosis via a mechanism unrelated to the cholesterol-lowering activity, as well as having anti-inflammatory properties. Furthermore, a 2021 systematic review also identified additional pleiotropic effects including antiviral and immunomodulatory that might help treat COVID-19.
Given this potential beneficial role for statins, the Iranian team sought to examine the impact of atorvastatin on thromboembolic events or death, in patients with the COVID-19, admitted to ICU. Their study was part of the INSPIRATION trial which had two arms: one that explored the effect of prophylactic anticoagulation and the other focusing on the use of atorvastatin.
The team recruited adult patients (> 18 years of age) with a PCR confirmed COVID-19 infection, admitted to ICU and in whom there was no baseline therapeutic need for a statin. Enrolled patients were then randomised 1:1 to atorvastatin 20 mg daily or matching placebo and followed for 30 days after randomisation. For patients requiring mechanical ventilation, the drug was delivered via a nasogastric or orogastric tube. The primary outcome of interest was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation or all-cause mortality within 30 days of randomisation.
A total of 587 patients with a median age of 57 years (44% female) were randomised to atorvastatin or placebo and treatment was used for a median of 21 days and slightly less, at 19 days for placebo. The median length of stay within ICU was 5 days in both groups.
After 30 days, the primary outcome had occurred in 95 (33%) of patients assigned to atorvastatin and 108 (36%) of those given placebo (odds ratio, OR = 0.84, 95% CI 0.58 – 1.21, p = 0.35). The results for the primary outcome were largely driven by mortality, with 31% and 35% of deaths in the atorvastatin and placebo groups respectively although no patients required extracorporeal membrane oxygenation.
The use of imaging tests such as computed tomography pulmonary angiograms and doppler, revealed a similar level of venous thromboembolism diagnoses in the two groups (20% vs 20%, p = 0.64). There was also no difference in the incidence of arterial thrombosis. In subgroup analysis, there were no sex-related differences, among patients older/younger than 65 years, smokers or in those with/without obesity or diabetes.
In trying to account for their findings, the authors speculated that atorvastatin may have had a small protective effect which was undetectable or that statins were only of benefit in the early stages of COVID-19 infection prior to the inflammatory response which led to irreversible damage.
INSPIRATION-S investigators. Atorvastatin versus placebo in patients with covid-19 in intensive care: randomized controlled trial. BMJ 2022
2nd December 2021
Inhibition of the renin-angiotensin-aldosterone system (RAAS inhibition) reduces mortality in those hospitalised with COVID-19 and admitted to an intensive care unit. This was the finding of a retrospective analysis presented at the American Heart Association (AHA) conference 2021.
Inhibition of the RAAS system can be achieved through the use of both angiotensin converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs). Although it has become widely accepted that the COVID-19 virus gains entry to cells via the angiotensin converting enzyme 2 receptor, whether existing use of drugs affecting the RAAS system affects the outcomes of those with more severe COVID-19 infection remains uncertain.
For the present study, researchers turned to the COVID-19 Critical Care Consortium which represents a global database of de-identified information on treatment outcomes of critically ill COVID-19 patients. The critical care consortium includes data from 354 centres in 54 countries and thus represents an important source of information for researchers as it generates a huge amount of clinical insight about the virus. The stated aim of the study was to examine the role of ACEi / ARB drug exposure (i.e., RAAS inhibition) on outcomes in COVID-19 patients with prior hypertension (HTN) and who had been admitted to intensive care units (ICU) due to the severity of their infection. For the analysis, researchers focused on adult patients (i.e., >18 years of age) and with pre-existing HTN. Outcomes of interest included the length of stay and in-hospital mortality to 90 days post ICU admission.
A total of 663 eligible patients were included in the analysis, of whom, 480 patients, with a median age of 65 years (67% male) had been prescribed an ACEi and / or ARB therapy in the 2 weeks before ICU admission. The average lengths of stays in both ICU and a general ward were longer in those prescribed ACEi / ARB drugs compared to non-users (20.8 days and 6.5 days vs. 15.5 and 6.0 days, respectively). However, RAAS inhibition treatment was associated with a decreased risk of death (Hazard ratio, HR = 0.69, 95% CI 0.54 — 0.88) which persisted after adjusting for propensity scores (HR = 0.67, 95% CI 0.53 — 0.86).
Based on these findings, the authors concluded that the use of ACEi/ARB’s for the management of pre-existing hypertension was associated with a reduced mortality risk in those admitted to an ICU after admission to hospital due to the severity of their COVID-19 infection.
Sato K et al. Abstract 10482: Renin-Angiotensin-Aldosterone System Inhibition is Associated with Reduced In-Hospital Mortality in Critically Ill Covid-19 Patients with Pre-Existing Hypertension. Circulation 2021
12th August 2021
Among critically ill patients, intravenous fluids (IV) are used for intravascular volume replacement. Administration of such fluids is extremely common and it has been estimated that every day, over 20% of patients within an intensive care setting receive fluid therapy. In general terms, fluid therapy is required for several indications including impaired tissue perfusion, low cardiac output and abnormal vital signs, e.g., blood pressure, heart rate or urine output. The most commonly used IV fluid is saline solution (0.9% sodium chloride) although in recent years, there has been emerging evidence that IV fluids other than saline in critically ill patients may have a more favourable impact on mortality. Balanced IV fluids, for example, have been designed to be more aligned with the composition of serum and may have some advantages over saline. For example, one study in patients with sepsis, concluded that resuscitation with balanced fluids was associated with a lower risk of in-hospital mortality. In a 2018 study among critically ill adults, the use of a balanced crystalloid rather than saline, produced a lower rate of death compared to saline. The use of a balanced solution rather than saline has several other potential advantages, particularly in relations to adverse effects, since saline contains a higher concentration of chloride ions and has been associated with a hyperchloraemic metabolic acidosis and acute kidney injury.
However, the overall benefit of using a balanced IV fluid rather than saline is not always superior. For instance, the use of a balanced crystalloid did not reduce the incidence of acute kidney injury compared to saline within an intensive care unit (ICU). In trying to provide much needed clarity, the Balanced Solution versus Saline in Intensive Care Study (BaSICS) by a Brazilian group of clinicians was undertaken to compare the effectiveness and safety of balanced crystalloids compared with saline in critically ill patients. This trial undertaken at 75 intensive care units in Brazil, randomised patients admitted to an ICU to either saline or a balanced solution and the primary outcome was 90-day survival.
A total of 10,520 critically ill patients with a mean age of 61.1 years (44.2% female), were randomised to either balanced fluids or saline and patients in both groups received a median of 1.5 litres of fluid during the first day of enrolment. Of the whole cohort, 60.6% of patients had hypotension or vasopressor use and 44.3% required mechanical ventilation at enrolment. Within 90 days of enrolment, 26.4% of those assigned to balance fluids died compared to 27.2% given saline (adjusted hazard ratio, aHR = 0.97, 95% CI 0.90 – 1.05, p = 0.47).
The authors concluded that despite the potential advantages of balanced crystalloids over saline, there were no apparent mortality benefits.
Zampieri F et al. Effect of Intravenous Fluid Treatment with a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients. The BaSICS Randomised Clinical Trial. JAMA 2021
9th August 2021
Patients are hospitalised with COVID-19 because of breathing difficulties due to a lack of oxygen as the virus induces damage in the lungs. Among those who deteriorate further, respiratory failure leads to the need for invasive ventilation within critical care units. Early in the pandemic, the increasing number of severely ill patients placed an enormous strain on critical care units, prompting the need to explore viable alternatives to invasive ventilation. Possible alternatives that could help to reduce the need for invasive mechanical ventilation include continuous positive airway pressure (CPAP) and high-flow nasal oxygen (HFNO). The use of CPAP and HFNO have been perceived as attractive alternative treatment options although there is a lack of data on whether either CPAP or HFNO are clinically effective in comparison to conventional oxygen in reducing the need for intubation. This led the Recovery-respiratory Support collaborators from Warwick Clinical Trials Unit, Warwick Medical School, Coventry, UK, to undertake an open-label, randomised trial among hospitalised patients with COVID-19. The study was designed to evaluate the effectiveness of either CPAP, HFNO or conventional oxygen, in hospitalised patients with acute respiratory failure caused by COVID-19. All adult patients (18 years and older) with acute respiratory failure, deemed suitable for tracheal intubation if treatment escalation was required, were included in the study. The treating clinician randomised between CPAP, HFNO or conventional oxygen and patients were followed-up throughout their hospital stay. The primary outcome was a composite of tracheal intubation or mortality within 30 days of randomisation.
During a 13-month period, 1,272 patients were randomised, 380 (29.9%) to CPAP, 417 (32.8%) to HFNO and the remainder to conventional oxygen therapy. The mean age of participants was 57.4 years (66.4% male) and 65.3% were of white ethnicity. The need for tracheal intubation occurred in 36.3% of CPAP patients and 44.4% of those receiving conventional oxygen, giving an adjusted odds ratio (OR) of 0.72 (95% CI 0.53–0.96, p = 0.03). For HFNO in comparison to conventional oxygen, there was no significant difference with an adjusted OR of 0.97 (95% CI 0.73–1.29, p = 0.85). With respect to 30-day mortality, there was no difference between CPAP and conventional oxygen (OR = 0.91, 95% CI 0.59–1.39) or for HFNO and oxygen (OR = 0.96, 95% CI 0.64–1.45).
The authors concluded that their data clearly demonstrated that the use CPAP reduced the need for tracheal intubation compared with the use of conventional oxygen. However, they also noted that neither CPAP or HFNO led to a reduction in mortality.
Perkins GD et al. An adaptive randomised controlled trial of non-invasive respiratory strategies in acute respiratory failure patients with COVID-19. MedRxiv 2021
23rd July 2021
Healthcare workers are three times more likely to become infected with COVID-19 compared to community individuals. Nevertheless, during viral epidemic outbreaks, an additional burden to healthcare staff is the impact on their mental wellbeing that accompanies the associated increased workload, leading to stress and anxiety. With thousands of patients across the globe developing more severe infection, there has been much focus on management within intensive care units. Such units are a highly demanding environment with staff continually exposed to traumatic and stressful events and a study from 2007, revealed a higher incidence of post-traumatic stress disorder (PTSD) among intensive care nursing staff. Given the high levels of 28-day mortality among patients with COVID-19, this undoubtedly further increases the mental health burden of intensive care staff. However, there is a lack of data specifically examining the mental wellbeing of intensive care staff.
Using an online survey, a team from the Department of Surgery and Cancer, Imperial College Healthcare NHS Trust, Imperial College, London, UK, sought to gain a better understanding of the mental health burden experienced by intensive care staff. The overall aim was to establish the prevalence of indices of depression, insomnia, and PTSD, which the authors suspected would be high among intensive care staff. The survey was conducted among all healthcare professionals working within the intensive care environment and distributed across the UK, France, Italy, Belgium, Egypt, Taiwan and Mainland China.
For the survey, three previously validated questionnaires were included: the two-item patient health questionnaire (PHQ-2) which sought to grade depression severity, an 8-item Athens Insomnia scale (AIS-8) and the 10-item trauma screening questionnaire (TSQ). The corresponding cut-off values for these questionnaires are 3 (PHQ-2), 8 (AIS-8) and 6 (TSQ). As well as these questionnaires, the authors included a series of general questions on wellbeing.
The final cohort included 515 responses from seven different countries and the majority of respondents were female (73%), of white ethnicity (73%) and aged 31–40 years (43.3%). Interestingly, 5.8% of respondents reported a pre-existing mental health condition. Just over half (52.4%) were nurses, with the remainder being senior (13.8%), residents/fellows (8.9%) and junior (6.4%) doctors, physiotherapists and others. Furthermore, nearly two-thirds (60.2%) had been re-deployed from another specialty and only a third (33.8%) were normally based within an intensive care ward.
The median scores were 2, 10 and 3 for PHQ-2, AIS-8 and TSQ respectively. Overall, 37.3%, 78.6% and 27.7% of participants had scores for PHQ-2, AIS-8 and TSQ respectively, that were above the thresholds for each condition. Across the different countries, 16–44% of respondents exceeded the threshold for depression, 60–80% for insomnia and 17–35% for PTSD.
The authors concluded that the COVID-19 pandemic had created a significant mental health burden for intensive care staff and recommended that all such staff have access to mental wellbeing resources, especially given the possibility of further surges in the rates of infection in the future.
Ezzat A. The global mental health burden of COVID-19 on critical care staff. Br J Nurs 2021