key: cord-0686130-f3v1xezr
authors: Taylor, E. H.; Marson, E. J.; Elhadi, M.; Macleod, K. D. M.; Yu, Y. C.; Davids, R.; Boden, R.; Overmeyer, R. C.; Ramakrishnan, R.; Thomson, D. A.; Coetzee, J.; Biccard, B. M.
title: Factors associated with mortality in patients with COVID‐19 admitted to intensive care: a systematic review and meta‐analysis
date: 2021-06-29
journal: Anaesthesia
DOI: 10.1111/anae.15532
sha: 499a4d07d46f6e6b06a0456608f02f3c3b8781fa
doc_id: 686130
cord_uid: f3v1xezr

Identification of high‐risk patients admitted to intensive care with COVID‐19 may inform management strategies. The objective of this meta‐analysis was to determine factors associated with mortality among adults with COVID‐19 admitted to intensive care by searching databases for studies published between 1 January 2020 and 6 December 2020. Observational studies of COVID‐19 adults admitted to critical care were included. Studies of mixed cohorts and intensive care cohorts restricted to a specific patient sub‐group were excluded. Dichotomous variables were reported with pooled OR and 95%CI, and continuous variables with pooled standardised mean difference (SMD) and 95%CI. Fifty‐eight studies (44,305 patients) were included in the review. Increasing age (SMD 0.65, 95%CI 0.53–0.77); smoking (OR 1.40, 95%CI 1.03–1.90); hypertension (OR 1.54, 95%CI 1.29–1.85); diabetes (OR 1.41, 95%CI 1.22–1.63); cardiovascular disease (OR 1.91, 95%CI 1.52–2.38); respiratory disease (OR 1.75, 95%CI 1.33–2.31); renal disease (OR 2.39, 95%CI 1.68–3.40); and malignancy (OR 1.81, 95%CI 1.30–2.52) were associated with mortality. A higher sequential organ failure assessment score (SMD 0.86, 95%CI 0.63–1.10) and acute physiology and chronic health evaluation‐2 score (SMD 0.89, 95%CI 0.65–1.13); a lower PaO(2):F(I)O(2) (SMD −0.44, 95%CI −0.62 to −0.26) and the need for mechanical ventilation at admission (OR 2.53, 95%CI 1.90–3.37) were associated with mortality. Higher white cell counts (SMD 0.37, 95%CI 0.22–0.51); neutrophils (SMD 0.42, 95%CI 0.19–0.64); D‐dimers (SMD 0.56, 95%CI 0.43–0.69); ferritin (SMD 0.32, 95%CI 0.19–0.45); lower platelet (SMD −0.22, 95%CI −0.35 to −0.10); and lymphocyte counts (SMD −0.37, 95%CI −0.54 to −0.19) were all associated with mortality. In conclusion, increasing age, pre‐existing comorbidities, severity of illness based on validated scoring systems, and the host response to the disease were associated with mortality; while male sex and increasing BMI were not. These factors have prognostic relevance for patients admitted to intensive care with COVID‐19.

COVID-19 requiring admission to ICU has been associated with a high mortality [1] , with data reporting a mortality of 41.6% [1] . A more recent meta-analysis which included the African COVID-19 Critical Care Outcomes Study reported ICU mortality of 31.5% [2] . Despite the poor outcomes, the current clinical problem remains that the factors associated with ICU mortality are poorly described [3] . Understanding the factors associated with mortality may allow for appropriate risk stratification and management of these critically ill patients.

With the large volume of peer-reviewed publications relating to COVID-19 patient outcomes, it may be possible to describe the factors associated with mortality among patients admitted to ICU. Currently, we are only aware of systematic reviews which have described factors associated with mortality with unselected cohorts of COVID-19 patients 

This study is reported in accordance with the PRISMA statement [5] . We included all observational studies (prospective and retrospective) of adult patients with COVID-19 admitted to ICU, reporting mortality or survival outcomes stratified by patient factors, risk scores and haematological results of interest. We excluded studies with mixed cohorts (i.e. not limited to patients admitted to ICU); ICU cohorts restricted to a specific patient sub-group; studies investigating drug efficacy; and review articles. We used a modified Newcastle-Ottawa Scale to assess the methodological quality of each included study [6] , and this is shown in the online Supporting Information (Appendix S2). Studies scoring 7-9 points were considered high quality, with studies scoring ≤ 6 considered low quality. Modified Newcastle-Ottawa Scale assessments were conducted independently by two reviewers.

We summarised cohort characteristics for dichotomous variables by calculating the proportion of those with each factor in the overall cohort, survived and died groups; for continuous variables, we calculated the pooled estimate mean and 95%CI for the overall cohort, survived and died groups. To assess the association of the factors of interest with mortality we calculated the pooled OR and 95%CI for dichotomous variables and the pooled standardised mean difference (SMD) and 95%CI for continuous variables. Data reported as median and IQR or range were converted to mean and SD using the formula described by Wan et al. [7] . We assessed the s² and I² statistics as measures of statistical inconsistency and heterogeneity, respectively. A random-effects model was adopted if there was moderate (25-50%) or high (> 50%) between-study heterogeneity as assessed by the I² test.

The random-effects meta-analysis was conducted using the Sidik-Jonkman method. The analysis was conducted Fig. 1 . In total, 6498 abstracts were screened, with 751 full-text reviews. There was moderate or high heterogeneity across all analyses, and therefore all analyses were conducted with random-effects models. Increasing age (SMD 0. 65 (Figures S24-S46) . These show asymmetry for BMI, cerebrovascular disease and serum ferritin. All other plots appear symmetrical. Sensitivity analyses are shown in the online Supporting Information (Figures S47-S53 ).

where it was clear that these were taken at the time of admission to ICU. The findings of the sensitivity analysis did not differ from the main findings, except for the neutrophil count which crossed the line of no effect (SMD 0.29, 95%CI À0.05 to 0.62).

The principal findings of this meta-analysis are that increasing age; smoking; hypertension; diabetes; cardiovascular disease; respiratory disease; renal disease; and malignancy were associated with ICU mortality in patients with COVID-19. At admission to ICU, higher SOFA and APACHE-2 scores, a lower PaO 2 :F I O 2 and the need for invasive mechanical ventilation were all associated with mortality. Higher white cell counts; neutrophils; D-dimers; ferritin; lower platelet; and lymphocyte counts were also associated with mortality.

The findings confirm the association between diabetes, cardiovascular and respiratory comorbidities with mortality in COVID-19 patients. However, the reported associations between male sex and increasing BMI are not supported by this meta-analysis [66] . This meta-analysis provides a large sample size with respect to these risk-factors and is a robust estimate of risk associated with male sex and BMI. The previously described obesity paradox in which patients admitted to ICU with higher BMI have more favourable outcomes [67] is not supported by our findings. The previously described association between male sex and mortality [68] [69] [70] may need to be questioned further in light of these findings, particularly in the context of those admitted to ICU.

The associations with ICU mortality demonstrated in this meta-analysis may provide direction for future COVID-19-specific prognostic research. Age may be a surrogate for frailty in patients with COVID-19 [71] . The risk-factors of hypertension, smoking and respiratory disease may all be partially related to increased risk associated with angiotensin-converting enzyme (ACE) receptors, as seen by the increased expression of ACE-2 receptors among smokers and patients with chronic obstructive pulmonary disease [72, 73] . The association between hypertension and cardiovascular disease, and increased mortality may potentially increase the risk of cardiac injury associated with the systemic inflammatory response to COVID-19 infection [74, 75] .

The inflammatory response associated with mortality appears to be dysregulated in response to COVID-19, and it is likely to drive the high mortality in critically ill patients with COVID-19 [76] . Previously, a smaller meta-analysis has shown that a higher neutrophil:lymphocyte ratio is associated with mortality [77] . Our meta-analysis supports this finding with a significantly higher neutrophil count and significantly lower lymphocyte count associated with mortality. Furthermore, the inflammatory effects of a high ferritin, high D-dimers and low platelet counts could both precipitate or be the result of thrombotic and coagulopathic effects [78] . Our meta-analysis suggests that there is little difference between the SOFA or APACHE-2 risk stratification scores at critical care admission in patients with COVID-19, although other studies have suggested that the APACHE-2 score may be better at predicting mortality among severely ill patients with COVID-19 than the SOFA score [64] . Simpler scores, such as the quick SOFA may not have equivalent prognostic performance to the SOFA or APACHE-2 scores [79] , but may have clinical utility in lower resource environments where access to a full blood profile is not universally available [2] .

One limitation of this meta-analysis is that it does not allow us to risk-adjust between risk factors associated with Fig. 3 ) were calculated using standardised mean difference, which accounts for variation in reported units.

importance of these risk-factors will be difficult to determine, especially as a recent meta-analysis of early vs.

late tracheal intubation in patients with COVID-19 requiring mechanical ventilation did not show a difference in outcome between the two strategies [80] .

This meta-analysis did not assess some factors that may be prognostically important in critically ill patients with COVID-19, such as a short duration of time between first symptoms and ICU admission [18] and HIV/AIDS [2] .

Furthermore, the association between C-reactive protein, Figure 2 Summary estimates of risk for mortality following critical care admission associated with dichotomous variables (patient characteristics; comorbidities; and invasive mechanical ventilation (IMV) on admission).

Summary estimates of risk for mortality following critical care admission associated with continuous variables (patient factors; risk scores; and haematological results at admission). SOFA, sequential organ failure assessment; APACHE, acute physiology and chronic health evaluation-2.

interleukin-6 or procalcitonin and mortality were also not evaluated [81] . The impact of therapies such as dexamethasone and tocilizumab were not examined in this meta-analysis [82, 83] .

Finally, this meta-analysis is characterised by high heterogeneity despite using random-effects models. This may be partly due to the different definitions used for the risk-factors across the included studies.

In conclusion, increasing age, pre-existing comorbidities and greater severity of illness are associated with mortality in patients admitted to ICU with COVID-19, but male sex and increasing BMI were not. The host response to disease as manifested by various inflammatory and thrombotic markers and the severity of respiratory failure also predicts outcome. Requiring invasive mechanical ventilation on admission to ICU was a significant predictor of mortality although resources, management strategies and preadmission deterioration may all modify this risk-factor.

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