Attention to Immortal Time Bias in Critical Care Research

Vail, Emily A.; Gershengorn, Hayley B.; Wunsch, Hannah; Walkey, Allan J.

doi:10.1164/rccm.202008-3238cp

Cited by 23 publications

(20 citation statements)

References 45 publications

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“…In our study, BSI patients infected with unknown pathogen and those infected with an identified micro-organism had similar outcomes, and should be both similarly considered. Fourth, as BSI occurred during ICU stay, we should acknowledge immortal time bias [ 25 ]. However, this bias would lead to underestimation of mortality risk associated with BSI, since patients experiencing this event are those surviving longer enough, whereas those who died early have short time of exposition but were even included in control group.…”

Section: Discussionmentioning

confidence: 99%

Characteristics and prognosis of bloodstream infection in patients with COVID-19 admitted in the ICU: an ancillary study of the COVID-ICU study

Massart

Maxime²,

Amara

et al. 2021

Ann. Intensive Care

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Background Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-COV 2) and requiring intensive care unit (ICU) have a high incidence of hospital-acquired infections; however, data regarding hospital acquired bloodstream infections (BSI) are scarce. We aimed to investigate risk factors and outcome of BSI in critically ill coronavirus infectious disease-19 (COVID-19) patients. Patients and methods We performed an ancillary analysis of a multicenter prospective international cohort study (COVID-ICU study) that included 4010 COVID-19 ICU patients. For the present analysis, only those with data regarding primary outcome (death within 90 days from admission) or BSI status were included. Risk factors for BSI were analyzed using Fine and Gray competing risk model. Then, for outcome comparison, 537 BSI-patients were matched with 537 controls using propensity score matching. Results Among 4010 included patients, 780 (19.5%) acquired a total of 1066 BSI (10.3 BSI per 1000 patients days at risk) of whom 92% were acquired in the ICU. Higher SAPS II, male gender, longer time from hospital to ICU admission and antiviral drug before admission were independently associated with an increased risk of BSI, and interestingly, this risk decreased over time. BSI was independently associated with a shorter time to death in the overall population (adjusted hazard ratio (aHR) 1.28, 95% CI 1.05–1.56) and, in the propensity score matched data set, patients with BSI had a higher mortality rate (39% vs 33% p = 0.036). BSI accounted for 3.6% of the death of the overall population. Conclusion COVID-19 ICU patients have a high risk of BSI, especially early after ICU admission, risk that increases with severity but not with corticosteroids use. BSI is associated with an increased mortality rate.

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Section: Discussionmentioning

confidence: 99%

Characteristics and prognosis of bloodstream infection in patients with COVID-19 admitted in the ICU: an ancillary study of the COVID-ICU study

Massart

Maxime²,

Amara

et al. 2021

Ann. Intensive Care

View full text Add to dashboard Cite

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“…Additionally, we included laboratory-confirmed COVID-19 PCR tests, thereby minimizing selection or surveillance bias at each center. Lastly, prior observational studies could be biased by immortal time and indication bias [ 25 , 34 ]. We used a novel statistical analysis to overcome these limitations and application of target trial design, which is likely a better approach to reduce immortal time bias and best resembling clinical practice.…”

Section: Discussionmentioning

confidence: 99%

“…Patients who died within first 48 h were excluded. Those who get treatment of interest after day 1 were classified by treatment exposure in first 48 h [similar to intention-to-treat analysis in randomized controlled trial (RCT)] [ 25 ]. The outcomes of interest in target trial approach were VFDs and 28-day mortality.…”

Section: Methodsmentioning

confidence: 99%

Clinical characteristics and outcomes of critically ill mechanically ventilated COVID-19 patients receiving interleukin-6 receptor antagonists and corticosteroid therapy: a preliminary report from a multinational registry

et al. 2021

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Background Interleukin-6 receptor antagonists (IL-6RAs) and steroids are emerging immunomodulatory therapies for severe and critical coronavirus disease (COVID-19). In this preliminary report, we aim to describe the epidemiology, clinical characteristics, and outcomes of adult critically ill COVID-19 patients, requiring invasive mechanical ventilation (iMV), and receiving IL-6RA and steroids therapy over the last 11 months. Materials and methods International, multicenter, cohort study derived from Viral Infection and Respiratory Illness University Study registry and conducted through Discovery Network, Society of Critical Care Medicine. Data were collected between March 01, 2020, and January 10, 2021. Results Of 860 patients who met eligibility criteria, 589 received steroids, 170 IL-6RAs, and 101 combinations. Patients who received IL-6RAs were younger (median age of 57.5 years vs. 61.1 and 61.8 years in the steroids and combination groups, respectively). The median C-reactive protein level was > 75 mg/L, indicating a hyperinflammatory phenotype. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (interquartile range: 6–14 mg); 80.8% and 19.2% received low-dose and high-dose steroids, respectively. Of the patients who received IL-6RAs, the majority received one dose of tocilizumab and sarilumab (dose range of 600–800 mg for tocilizumab and 200–400 mg for sarilumab). Regarding the timing of administration, we observed that steroid and IL-6RA administration on day 0 of ICU admission was only 55.6% and 39.5%, respectively. By day 28, when compared with steroid use alone, IL-6RA use was associated with an adjusted incidence rate ratio (aIRR) of 1.12 (95% confidence interval [CI] 0.88, 1.4) for ventilator-free days, while combination therapy was associated with an aIRR of 0.83 (95% CI 0.6, 1.14). IL-6RA use was associated with an adjusted odds ratio (aOR) of 0.68 (95% CI 0.44, 1.07) for the 28-day mortality rate, while combination therapy was associated with an aOR of 1.07 (95% CI 0.67, 1.70). Liver dysfunction was higher in IL-6RA group (p = 0.04), while the bacteremia rate did not differ among groups. Conclusions Discordance was observed between the registry utilization patterns (i.e., timing of steroids and IL-6RA administration) and new evidence from the recent randomized controlled trials and guideline recommendations. These data will help us to identify areas of improvement in prescribing patterns and enhance our understanding of IL-6RA safety with different steroid regimens. Further studies are needed to evaluate the drivers of hospital-level variation and their impact on clinical outcomes. Trial registration ClinicalTrials.gov: NCT04486521. Registered on July 2020

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“…In the NHIS database, it is not feasible to temporally associate diagnoses (sepsis) with prescription charges (vitamin C) during hospitalization due to lack of time stamps, and immortal time bias may be a significant concern. To minimize bias, two analytical approaches were employed, namely, (1) an analysis excluding patients who died or were discharged within 2 days of ICU admission to prevent patients who died early in their hospital course from introducing bias and (2) an analysis assessing outcomes with stratification according to the follow-up period given the study intervention is not temporally defined [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

Vitamin C for ≥ 5 days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study

et al. 2022

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Background Previous randomized trials of vitamin C, hydrocortisone, and thiamine on sepsis were limited by short-term vitamin C administration, heterogeneous populations, and the failure to evaluate each component’s effect. The purpose of this study was to determine whether vitamin C alone for ≥ 5 days or in combination with corticosteroids and/or thiamine was associated with decreased mortality across the sepsis population and subpopulation. Methods Nationwide population-based study conducted using the Korean National Health Insurance Service database. A total of 384,282 adult patients with sepsis who were admitted to the intensive care unit were enrolled from January 2017 to December 2019. The primary outcome was hospital mortality, while the key secondary outcome was 90-day mortality. Results The mean [standard deviation] age was 69.0 [15.4] years; 57% were male; and 36,327 (9%) and 347,955 did and did not receive vitamin C, respectively. After propensity score matching, each group involved 36,327 patients. The hospital mortality was lower by − 0.9% in the treatment group (17.1% vs 18.0%; 95% confidence interval, − 1.3 to − 0.5%; p < 0.001), a significant but extremely small difference. However, mortality decreased greater in patients who received vitamin C for ≥ 5 days (vs 1–2 or 3–4 days) (15.8% vs 18.8% vs 18.3%; p < 0.001). Further, vitamin C was associated with a lower hospital mortality in patients with older age, multiple comorbidities, pneumonia, genitourinary infection, septic shock, and mechanical ventilation. Consistent findings were found for 90-day mortality. Moreover, vitamin C alone or in combination with thiamine was significantly associated with decreased hospital mortality. Conclusions Intravenous vitamin C of ≥ 5 days was significantly associated with decreased hospital and 90-day mortality in sepsis patients. Vitamin C combined with corticosteroids and/or thiamine in specific sepsis subgroups warrants further study.

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Attention to Immortal Time Bias in Critical Care Research

Cited by 23 publications

References 45 publications

Characteristics and prognosis of bloodstream infection in patients with COVID-19 admitted in the ICU: an ancillary study of the COVID-ICU study

Characteristics and prognosis of bloodstream infection in patients with COVID-19 admitted in the ICU: an ancillary study of the COVID-ICU study

Clinical characteristics and outcomes of critically ill mechanically ventilated COVID-19 patients receiving interleukin-6 receptor antagonists and corticosteroid therapy: a preliminary report from a multinational registry

Vitamin C for ≥ 5 days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study

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