Association Between Statin Use on Delirium and 30-day Mortality in Patients with Chronic Obstructive Pulmonary Disease

doi:10.21203/rs.3.rs-3122371/v1

Background: Delirium occurs frequently in patients with chronic obstructive pulmonary disease(COPD) in the intensive care unit(ICU).Effective prevention and treatment strategies for delirium remain limited. We aimed to assess delirium and 30-day mortality in patients with COPD who were statin and non-statin users.

Methods: In this retrospective study,patients with COPD were identified from the Medical Information Mart for Intensive Care database(MIMIC-IV).The primary exposure variable was the use of statins 3 days after entering the ICU and the primary outcome measure was the presence of delirium. The secondary outcome measure was 30-day mortality. Since the cohort study was retrospective, we used an inverse probability weighting derived from the propensity score matching to balance different variables.

Results: Among a cohort of 2738 patients, 1493 (55%) were statin users. Before propensity score matching, the prevalence of delirium was 16% and the 30-day mortality was 18% in patients with COPD. Statin use was significantly negatively correlated with delirium, with an odds ratio of 0.69 (95% CI,0.56~0.84, P < 0.001) in the inverse probability weighted cohort and 30-day mortality of 0.7 (95% CI,0.58~0.85, P < 0.001).

Conclusions: Statins administered in the ICU can significantly reduce the incidence of delirium and 30-day mortality in patients with COPD.

Delirium

Mortality

Chronic obstructive pulmonary disease

Statin

Propensity analysis

Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease, which is characterized by persistent respiratory symptoms and airflow limitations due to airway and/or alveolar abnormalities usually caused by significant exposure to dangerous particles or gases. Exacerbations negatively impact health status, hospitalization rates, and disease progression [1]. COPD is currently the third leading cause of deaths worldwide [2]. Many patients in the intensive care unit (ICU) present with comorbid COPD. Delirium is common in patients with COPD and in those with respiratory failure receiving mechanical ventilation [2]. Furthermore, the probability of survival in patients with COPD undergoing coronary artery bypass grafting (CABG) who developed postoperative delirium is significantly lower [4]. Delirium manifests itself as acute state of attention, cognitive impairment and mental disorder that can be related to potential physiological disorders [5]. Delirium is often accompanied by increased morbidity, prolonged hospitalization, higher medical costs and mortality[6]. However, the treatment of delirium is limited, so prevention is critical.

Recently, contradictory evidence has been provided on the role of statins in preventing delirium. Some studies have found that statins can reduce the occurrence of delirium, including in the ICU and in cases of postoperative delirium [7, 8]. Other studies have contrary findings that the effect of statins on delirium is related to the severity of the disease and not to its occurrence [9, 10]. A meta-analysis that included both cohort studies and randomized clinical trials (RCT) showed that treatment with statins was associated with a significant reduction in all-cause mortality in patients with COPD[11]. Although the meta-analysis that included only RCTs did not show benefits for patients with COPD [12, 13]. The role of statins on mortality in patients with COPD is controversial.

To date, no studies have examined the effects of statin use on delirium in patients with COPD. We used the Medical Information Mart for Intensive Care IV (MIMIC-IV) database (version 2.2) to investigate the relationship between statins and delirium and 30-day mortality in patients with COPD admitted to the ICU. In this study, we use weighted analysis according to the propensity score. Propensity score matching (PSM) was used to appropriately adjust for confounding factors, reduce the impact of these deviations and confounding variables, to allow a more reasonable comparison between the statin-exposed group and non-statin-exposed group.

Data Sources

This retrospective cohort study was based on the MIMIC-IV database (version 2.2)[14], which contains data from patients admitted to the ICU of the Beth Israel Deaconess Medical Centre in Boston, Massachusetts, between 2008 and 2019. One author (JLX) obtained access to the database and was responsible for data extraction. The establishment of the MIMIC-IV database was approved by the institutional review boards of Beth Israel Deaconess Medical Centre and the Massachusetts Institute of Technology Affiliates. The informed consent requirement was waived because the data from all patients in the database were anonymized.

Study Population and Data Extraction

We included all patients who were first admitted to the ICU diagnosed with COPD [15]in the MIMIC-IV database. We excluded (i) patients with dementia, (ii) patients younger than 18 years, (iii) patients without a CAM-ICU estimate, (iiii) patients with a duration of stay in the ICU stay < 2 days. Navicat Premium (version 16.0) was used to extract raw data relative to patients diagnosed with COPD from the MIMIC-IV database (version 2.2). The data extracted included demographics, laboratory tests results, vital signs, comorbidities, and administered drugs. The following demographic information was extracted: age, sex, length of hospitalization, and duration of stay in the ICU. Vital signs such as systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), respiratory rate (RR), and oxygenated hemoglobin saturation (SpO₂) were collected. Comorbidities including diabetes, asthma, coronary artery disease (CAD), peripheral vascular disease (PVD), congestive heart failure (CHF), malignant cancer, cerebrovascular disease (CVD), liver disease, and renal disease were extracted. Laboratory data included white blood cell (WBC) count, hemoglobin (HGB) level, platelets (PLT), blood glucose, anion gap, potassium, sodium, and calcium levels. We also extracted whether the patient received mechanical ventilation. The use of vasoactive drugs (norepinephrine, vasopressin, epinephrine) and antibiotics was also included. Whether the patient received oral or intravenous glucocorticoids was also determined. Whether the patient received ACEI/ARB, β-blockers, and statins three days after entering the ICU were extracted. A Simplified Acute Physiology Score (SAPS II), Charlson Comorbidity Index (CCI), and the Oxford Acute Severity of Illness Score (OASIS), which represents the severity of the disease, were also included.

Statin Use

We defined patients with records of 3 days of statin use after admission to the ICU as statin-exposed and others as non-statin-exposed. We searched drug ILIKE “statin” and NOT ILIKE “nystatin,” “mycostatin,” “imipenem-cilastatin,” “pentostatin,” and “sandostatin” in Navicat Premium (version 16.0). The medication prescriptions were recorded in the MIMIC-IV table (version 2.2) under “mimic-hospital, prescription.”

Outcomes

The primary outcome was the occurrence of delirium during the stay in the ICU. The secondary outcome was the 30-day mortality rate. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) method was used to assess delirium in patients[16].

Statistical analysis

The characteristics of the patients are described in general and by group (statin-exposed and non-statin-exposed). The measured data are expressed as mean (standard deviation) or median (interquartile interval) according to whether they were normally distributed. A one-way analysis of variance (ANOVA) or Kruskal Wallis H test was performed depending on whether the data were normally distributed. Categorical variables were expressed as percentages and treated with chi-square tests.

Propensity score matching (PSM) was used to adjust for confounders between the non-statin and statin groups. The following prognostic variables related to the outcome at P < 0.2 in the univariate analysis (Supplementary Table 1) were included in the propensity score: age, HGB, WBC, anion gap, sodium and calcium, CHF, asthma, liver disease, SBP, DBP, HR, and SpO₂ on the first day of admission, ACEI/ARB, antibiotic and glucocorticoids after admission to the ICU, and norepinephrine, vasopressin, epinephrine, and scores such as SAPII, OASIS for delirium were forced in the PSM. The variables that were included in the 30-day mortality analysis are shown in Supplementary Table 2. Reverse probability treatment weighting (IPTW) was used. The probability of being exposed to statin was estimated using a logistic regression for each patient. We matched the two groups in a 1:1 ratio with a caliper width of 0.2. The standardized mean difference (SMD) was used to examine the degree of PSM.

To adjust for the covariates of PSM, we used logistic regression for the subgroup analysis to investigate the association between statin use and delirium and 30-day mortality, as it differed between various subgroups classified by age, sex, CAD, CHF, antibiotic and glucocorticoids use, and the CCI score. The R software packages (http://www.R-project.org, The R Foundation) and Free Statistics software versions 1.7 were used to perform all statistical analyses. Statistical differences were considered significant at P values < 0.05.

Baseline Characteristics

Among the 50,920 patients who were admitted to the ICU and included in the MIMIC-IV database, 2738 patients had COPD and were evaluated using CAM-ICU methods. The patient selection process is shown in Fig. 1. Table 1 summarizes the characteristics of the statin and non-statin groups. In total, 1493 (55%) patients were exposed to statins. The median age of the patients was 72 years (range, 64 to 80), and 53.5% were male. The total incidence of delirium was 16% (438/2738) and that of 30-day mortality was 18% (494/2738). Patients in the statin group had a higher age, a higher rate of diabetes, CAD, CHF, PVD, renal disease, and CVD. Moreover, they also received treatment with more ACEI/ARB and vasoactive drugs than those in the non-statin group (all P < 0.05). However, they had a lower use of antibiotics and glucocorticoids and the incidence of delirium (13.4%-19.1%) and 30-day mortality was lower (15–21.7%) (for all P < 0.05).

Table 1

Baseline characteristics
Variables	Total (n = 2738)	non-statins	statins	p
Variables	Total (n = 2738)	(n = 1245)	(n = 1493)	p
Number
Age(year)	72.0 (64.0, 80.0)	69.0 (61.0, 78.0)	73.0 (67.0, 80.0)	< 0.001
Gender(male)	1465 (53.5)	646 (51.9)	819 (54.9)	0.121
ICU days	3.0 (2.0, 6.0)	4.0 (2.0, 7.0)	3.0 (2.0, 6.0)	< 0.001
Hospital days	8.0 (5.0, 13.0)	8.0 (5.0, 14.0)	8.0 (5.0, 13.0)	0.092
Vitals
SBP(mmHg)	117.1 ± 16.0	116.6 ± 15.7	117.5 ± 16.3	0.165
DBP(mmHg)	61.9 ± 10.9	63.1 ± 11.0	60.9 ± 10.6	< 0.001
HR( beats/min)	85.9 ± 15.6	87.7 ± 16.4	84.4 ± 14.7	< 0.001
RR( beats/min)	19.8 ± 3.7	19.9 ± 3.9	19.7 ± 3.5	0.256
Spo2(%)	96.2 ± 2.3	96.2 ± 2.3	96.2 ± 2.2	0.794
Comorbidities, n (%)
Asthma	115 ( 4.2)	56 (4.5)	59 (4)	0.478
CAD	458 (16.7)	117 (9.4)	341 (22.8)	< 0.001
CHF	1221 (44.6)	423 (34)	798 (53.4)	< 0.001
PVD	520 (19.0)	168 (13.5)	352 (23.6)	< 0.001
CVD	434 (15.9)	161 (12.9)	273 (18.3)	< 0.001
Diabetes	945 (34.5)	317 (25.5)	628 (42.1)	< 0.001
Liver desease	315 (11.5)	220 (17.7)	95 (6.4)	< 0.001
Renal disease	696 (25.4)	216 (17.3)	480 (32.2)	< 0.001
Malignant cancer	447 (16.3)	255 (20.5)	192 (12.9)	< 0.001
Laboratory events
WBC(10^9/L)	14.7 ± 11.2	15.0 ± 14.1	14.5 ± 7.9	0.248
HGB(g/L)	11.3 ± 2.2	11.5 ± 2.3	11.3 ± 2.1	0.013
PLT(10^9/L)	209.0 (156.0, 277.0)	206.0 (147.0, 284.0)	211.0 (161.0, 272.0)	0.166
Glucose(mg/dL)	147.0 (119.0, 196.0)	144.0 (118.0, 190.0)	149.0 (120.0, 199.0)	0.036
Calcium(mg/dL)	8.6 ± 0.7	8.6 ± 0.8	8.6 ± 0.7	0.055
Sodium(mmol/L)	139.6 ± 4.9	139.6 ± 5.3	139.7 ± 4.6	0.394
Potassium(mmol/L)	4.7 ± 0.9	4.7 ± 0.9	4.7 ± 0.8	0.474
Aniongap(mmol/L)	16.4 ± 4.5	16.5 ± 4.6	16.3 ± 4.3	0.136
Treatment, n (%)
Glucocorticoid	971 (35.5)	485 (39)	486 (32.6)	< 0.001
Antibotic	2290 (83.6)	1076 (86.4)	1214 (81.3)	< 0.001
Vasopressin	286 (10.4)	115 (9.2)	171 (11.5)	0.059
Norepinephrine	578 (21.1)	239 (19.2)	339 (22.7)	0.025
Epinephrine	130 ( 4.7)	56 (4.5)	74 (5)	0.574
ACEI/ARB	417 (15.2)	122 (9.8)	295 (19.8)	< 0.001
β-blocker	1444 (52.7)	546 (43.9)	898 (60.1)	< 0.001
VENT	876 (32.0)	387 (31.1)	489 (32.8)	0.351
Scores
CCI	7.4 ± 2.6	7.0 ± 2.6	7.8 ± 2.5	< 0.001
SAPII	39.8 ± 12.8	40.4 ± 14.0	39.2 ± 11.6	0.017
OASIS	34.3 ± 9.0	35.5 ± 9.4	33.3 ± 8.4	< 0.001
Outcomes,n (%)
Delirium	438 (16.0)	238 (19.1)	200 (13.4)	< 0.001
30-day mortality	494 (18.0)	270 (21.7)	224 (15)	< 0.001

Propensity Score Matching Analysis

We used PSM to balance the baseline characteristics. After matching, 959 and 888 patients with delirium and 30-day mortality, respectively, were included in each group. The SMD of all covariates after matching was less than 0.1, indicating that the balance was sufficient after matching (Table 2, Table 3). We also reported variables in the subject operating characteristic (ROC) curve for delirium (Fig. 2(A)) and 30-day mortality (Fig. 2B). The area under the curve (AUC) was calculated to assess the relationship between statin use and delirium (70.4%) and 30-day mortality (72.9%).

Table 2

Imbalance of patient characteristics before and after propensity score matching in the assessment of delirium
Item	UnMatched			SMD	Matched			SMD
Item	non-Statins	Statins	SMD	-0.1	non-Statins	Statins	SMD	-0.1
n	1245	1493			959	959
Age(year)	69.47 (11.78)	73.11 (9.78)	0.337	> 0.1	71.59 (11.32)	71.54 (9.54)	0.004	< 0.1
SBP(mmHg)	116.60 (15.66)	117.46 (16.34)	0.053	< 0.1	116.80 (15.37)	117.48 (16.26)	0.043	< 0.1
DBP(mmHg)	63.13 (11.01)	60.95 (10.62)	0.202	> 0.1	62.26 (10.68)	62.24 (10.81)	0.002	< 0.1
HR( beats/min)	87.69 (16.35)	84.38 (14.71)	0.213	> 0.1	86.19 (15.99)	85.98 (15.35)	0.013	< 0.1
Spo2(%)	96.15 (2.34)	96.18 (2.20)	0.01	< 0.1	96.14 (2.35)	96.17 (2.15)	0.011	< 0.1
Asthma	56 ( 4.5)	59 ( 4.0)	0.027	< 0.1	44 ( 4.6)	46 ( 4.8)	0.01	< 0.1
CAD	117 ( 9.4)	341 (22.8)	0.372	> 0.1	110 (11.5)	121 (12.6)	0.035	< 0.1
Liver desease	220 (17.7)	95 ( 6.4)	0.353	> 0.1	82 ( 8.6)	87 ( 9.1)	0.018	< 0.1
Malignant cancer	255 (20.5)	192 (12.9)	0.206	> 0.1	163 (17.0)	156 (16.3)	0.02	< 0.1
PLT(10^9/L)	225.07 (114.55)	227.22 (99.29)	0.02	< 0.1	231.21 (111.42)	230.09 (104.91)	0.01	< 0.1
HGB(g/L)	11.46 (2.27)	11.25 (2.10)	0.095	< 0.1	11.36 (2.20)	11.42 (2.14)	0.028	< 0.1
Calcium(mg/dL)	8.59 (0.81)	8.64 (0.68)	0.073	< 0.1	8.63 (0.80)	8.62 (0.69)	0.012	< 0.1
Sodium(mmol/L)	139.55 (5.27)	139.71 (4.63)	0.033	< 0.1	139.68 (4.99)	139.76 (4.56)	0.017	< 0.1
Glucose(mg/dL)	169.49 (96.60)	177.26 (104.65)	0.077	< 0.1	171.87 (103.28)	172.22 (92.44)	0.004	< 0.1
Glucocorticoid	485 (39.0)	486 (32.6)	0.134	> 0.1	366 (38.2)	356 (37.1)	0.022	< 0.1
Antibotic	1076 (86.4)	1214 (81.3)	0.139	> 0.1	804 (83.8)	809 (84.4)	0.014	< 0.1
Norepinephrine	115 ( 9.2)	171 (11.5)	0.073	< 0.1	103 (10.7)	92 ( 9.6)	0.038	< 0.1
Epinephrine )	239 (19.2)	339 (22.7)	0.086	< 0.1	205 (21.4)	192 (20.0)	0.033	< 0.1
Vasopressin	56 ( 4.5)	74 ( 5.0)	0.022	< 0.1	48 ( 5.0)	41 ( 4.3)	0.035	< 0.1
ACEI/ARB	122 ( 9.8)	295 (19.8)	0.283	> 0.1	116 (12.1)	125 (13.0)	0.028	< 0.1
SAPII	40.40 (14.02)	39.24 (11.59)	0.091	< 0.1	39.86 (13.03)	39.75 (12.23)	0.009	< 0.1
OASIS	35.49 (9.39)	33.26 (8.45)	0.249	> 0.1	34.62 (9.15)	34.52 (8.60)	0.011	< 0.1
Notes:An absolute MSD < 10% was considered to support the assumption of a balance between the groups. SMD: standardized mean differences. Data are presented
as medians [interquartile ranges] ,mean[SD]or as numbers (percentages).
Abbreviations:SBP:Systolic blood pressure.DBP:Diastolic blood pressure.HR:heart rate .RR: respiratory rate, CAD:coronary artery disease.CVD:cerebrovascular disease.HGB:Hemoglobin.WB:white blood Cell count.ACEI/ARB:Angiotensin-converting enzyme inhibitors/Angiotensin II inhibitors.SAPS II: Simplified Acute Physiology Score.OASIS:Oxford acute severity of illness score.

Table 3

Imbalance of patient characteristics before and after propensity score matching in the assessment of 30-day mortality
Item	UnMatched			SMD	Matched			SMD
Item	non-Statins	Statins	SMD	-0.1	non-Statins	Statins	SMD	-0.1
n	1245	1493			888	888
Age(year)	69.47 (11.78)	73.11 (9.78)	0.337	> 0.1	72.02 (11.08)	71.75 (9.80)	0.026	< 0.1
SBP(mmHg)	116.60 (15.66)	117.46 (16.34)	0.053	< 0.1	117.14 (15.80)	117.48 (16.23)	0.021	< 0.1
DBP(mmHg)	63.13 (11.01)	60.95 (10.62)	0.202	> 0.1	62.32 (10.76)	62.25 (10.91)	0.007	< 0.1
HR( beats/min)	87.69 (16.35)	84.38 (14.71)	0.213	> 0.1	86.01 (15.91)	85.76 (15.30)	0.016	< 0.1
RR( beats/min)	19.91 (3.86)	19.75 (3.47)	0.043	< 0.1	19.75 (3.60)	19.87 (3.53)	0.036	< 0.1
Spo2(%)	96.15 (2.34)	96.18 (2.20)	0.01	< 0.1	96.15 (2.34)	96.15 (2.19)	0.002	< 0.1
CHF	423 (34.0)	798 (53.4)	0.4	> 0.1	368 (41.4)	385 (43.4)	0.039	< 0.1
Asthma	56 ( 4.5)	59 ( 4.0)	0.027	< 0.1	38 ( 4.3)	46 ( 5.2)	0.042	< 0.1
Diabetes	317 (25.5)	628 (42.1)	0.357	> 0.1	271 (30.5)	282 (31.8)	0.027	< 0.1
Liver desease	220 (17.7)	95 ( 6.4)	0.353	> 0.1	83 ( 9.3)	86 ( 9.7)	0.012	< 0.1
Renal disease	216 (17.3)	480 (32.2)	0.348	> 0.1	191 (21.5)	193 (21.7)	0.005	< 0.1
Malignant cancer	255 (20.5)	192 (12.9)	0.206	> 0.1	151 (17.0)	143 (16.1)	0.024	< 0.1
WBC(10^9/L)	14.99 (14.09)	14.50 (7.94)	0.043	< 0.1	15.02 (14.89)	14.94 (8.20)	0.006	< 0.1
HGB(g/L)	11.46 (2.27)	11.25 (2.10)	0.095	< 0.1	11.36 (2.20)	11.45 (2.14)	0.041	< 0.1
PLT(10^9/L)	225.07 (114.55)	227.22 (99.29)	0.02	< 0.1	229.99 (111.92)	229.97 (103.99)	< 0.001	< 0.1
Glucose (mg/dl)	169.49 (96.60)	177.26 (104.65)	0.077	< 0.1	170.00 (99.03)	173.46 (104.75)	0.034	< 0.1
Sodium(mmol/L)	139.55 (5.27)	139.71 (4.63)	0.033	< 0.1	139.66 (4.92)	139.65 (4.50)	0.001	< 0.1
Potassium(mmol/L)	4.68 (0.90)	4.70 (0.83)	0.027	< 0.1	4.69 (0.88)	4.68 (0.80)	0.004	< 0.1
Aniongap(mmol/L)	16.51 (4.65)	16.26 (4.35)	0.057	< 0.1	16.11 (4.19)	16.23 (4.38)	0.029	< 0.1
Glucocorticoid	485 (39.0)	486 (32.6)	0.134	> 0.1	329 (37.0)	323 (36.4)	0.014	< 0.1
Antibotic	1076 (86.4)	1214 (81.3)	0.139	> 0.1	747 (84.1)	746 (84.0)	0.003	< 0.1
Vasopressin	115 ( 9.2)	171 (11.5)	0.073	< 0.1	89 (10.0)	83 ( 9.3)	0.023	< 0.1
Epinephrine	56 ( 4.5)	74 ( 5.0)	0.022	< 0.1	44 ( 5.0)	43 ( 4.8)	0.005	< 0.1
Norepinephrine	239 (19.2)	339 (22.7)	0.086	< 0.1	183 (20.6)	170 (19.1)	0.037	< 0.1
ACEI.ARB	122 ( 9.8)	295 (19.8)	0.283	> 0.1	114 (12.8)	119 (13.4)	0.017	< 0.1
β-blocker	546 (43.9)	898 (60.1)	0.331	> 0.1	462 (52.0)	466 (52.5)	0.009	< 0.1
CCI	6.98 (2.62)	7.82 (2.46)	0.329	> 0.1	7.27 (2.60)	7.29 (2.47)	0.007	< 0.1
SAPII	40.40 (14.02)	39.24 (11.59)	0.091	< 0.1	39.72 (12.66)	39.84 (12.48)	0.009	< 0.1
OASIS	35.49 (9.39)	33.26 (8.45)	0.249	> 0.1	34.40 (8.85)	34.53 (8.75)	0.015	< 0.1
Notes:An absolute MSD < 10% was considered to support the assumption of a balance between the groups. SMD: standardized mean differences. Data are presented
as medians [interquartile ranges] ,mean[SD]or as numbers (percentages).
Abbreviations:SBP:Systolic blood pressure.DBP:Diastolic blood pressure.HR:heart rate .RR: respiratory rate.HGB:Hemoglobin.WB:white blood Cell count.PLT:platelets.ACEI/ARB:Angiotensin-converting enzyme inhibitors/Angiotensin II inhibitors. CCI:Charlson Comorbidity Index.SAPS II: Simplified Acute Physiology Score.OASIS:Oxford acute severity of illness score.

Association between statin exposure and outcomes

Before matching, regression analysis showed that statin exposure was significantly associated with delirium at an odds ratio of 0.65 (95% CI 0.53 ~ 0.8, P < 0.001) (Table 4). After IPW, the risk of delirium remained significantly associated with statin exposure with an odds ratio of 0.69 (95% CI 0.56 ~ 0.84, P < 0.001). Before matching, the risk of 30-day mortality was significantly related to statin exposure at an odds ratio of 0.64 (95% CI: 0.52 ~ 0.78, P < 0.001). After IPW, the risk of 30-day mortality remained significantly associated with statin exposure with a odds ratio of 0.7 (95% CI 0.58 ~ 0.85, P < 0.001). The results were similar to those obtained with the PSM model.

Table 4

Associations between statin use and the outcome in the crude analysis, multivariable analysis, and propensity-score analyses.
Analysis	Delirium(%)	p	30-day mortality(%)	p
No. of events/no. of patients at risk (%)
No statin use	238/1245(19.1)		270(21.7)
Statin use	200/1493(13.4)		224(15)
Crude analysis-hazard ratio (95% CI)	0.65 (0.53 ~ 0.8)	< 0.001	0.64 (0.52 ~ 0.78)	< 0.001
Multivariable analysis-hazard ratio (95% CI)	0.66 (0.52 ~ 0.84)	0.001	0.67 (0.52 ~ 0.85)	0.001
With matching	0.7 (0.54 ~ 0.9)	0.005	0.78 (0.61 ~ 0.99)	0.043
With inverse probability weighting	0.69 (0.56 ~ 0.84)	< 0.001	0.7 (0.58 ~ 0.85)	< 0.001
Adjusted for propensity score	0.7 (0.56 ~ 0.87)	0.001	0.73 (0.59 ~ 0.9)	0.004
CI: confidence interval.

Subgroup analyses

As shown in Fig. 3(the original form is in Supplementary Tables 3 and 4), we found that patients with CHF showed an interaction between statin exposure and delirium (P = 0.007) and CAD showed an interaction between statin exposure and 30-day mortality (P = 0.037). The p-value for the interaction in the other subgroups showed no interaction with delirium or mortality at 30 days. In addition, the subgroup analyses were adjusted variables as those used in the PSM.

In this observational study of patients with COPD, we used PSM and found that statin administration after admission to the ICU was significantly associated with a reduced risk of delirium and 30-day mortality. To our knowledge, this is the first observational study on the association between statin exposure and delirium and 30-day mortality in patients with COPD.

Previous studies have found that statins reduce delirium in critically ill patients in the ICU[17, 18], but there have been no studies on statins in ICU patients with COPD. Although COPD has been found to increase the incidence of postoperative delirium in patients undergoing CABG [4], delirium is more common in patients with COPD combined with respiratory failure undergoing mechanical ventilation[19]. In our study, the use of statins in the ICU significantly reduced the incidence of delirium, and a subgroup analysis found that statins had a more significant effect in patients without malignancy[19]and in patients not receiving glucocorticoids, which is consistent with studies reporting an association between statins and mortality in patients using glucocorticoids[21].

In our study, 55% of patients with COPD received statins, and more than half of the patients were taking statins. Several studies have found that statins reduce hospitalization rates and acute exacerbations in patients with COPD [22–24] but do not influence 30-day or 1-year mortality[22] nor are they associated with the occurrence of COPD in the adult population [24]. However, it is interesting that observational studies have found that statins reduce COPD mortality [25], while a RCT did not find this effect of statins [12]. According to a previous retrospective analysis[26]of 574 individuals from the Copenhagen General Population Study, statin use was associated with a reduced probability of exacerbations only in individuals with COPD of the general population, but not in those with the most severe COPD without cardiovascular comorbidity. However, it is unknown whether the effects of statin on mortality are related to cardiovascular disease. Our subgroup analysis found that statins did not reduce mortality in patients with COPD with CAD.

COPD is considered a chronic systemic inflammatory syndrome that can often be accompanied by impaired blood oxygenation, and both inflammation and impaired blood oxygenation can lead to an increased incidence of delirium in patients with COPD. Decreased lung function is associated with increased oxidative stress and inflammation, and studies have shown that statins reduce serum levels of pro-inflammatory cytokines in patients with COPD [25] and slow the decline in lung function[27]. Statins have been prescribed for the primary prevention of atherosclerotic cardiovascular disease because they effectively lower low-density lipoprotein (LDL) cholesterol levels, and a recent study found that the use of atorvastatin relieved cerebral vasospasm and mediated structural and functional remodeling of vascular endothelial cells[28], which may be related to the fact that statins can prevent delirium and mortality.

This study has some limitations. First, baseline data before admission to the MIMIC-IV database may be incomplete, which could have affected specific data relative to delirium regarding preoperative cognitive status, psychiatric history, and educational level. We also excluded dementia because dementia patients are prone to delirium[29, 30]. Second, we did not classify the type of statin used, although lipophilic statins are found to be more effective against acute exacerbations of COPD in patients with cardiovascular disease [24]. Third, our study was a retrospective study. Although we used PSM to control for confounding, residual confounders cannot be completely excluded. Finally, we cannot be sure whether patients received statins before or after admission to the ICU and whether the long-term preventive effect of statins achieved superior outcomes, as has been concluded in a previous study [31].

In this retrospective analysis, we confirmed that statin use in the ICU was significantly associated with reduced delirium and 30-day mortality in patients with COPD.

COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; MIMIC-IV, Medical Information Mart for Intensive Care-IV; PSM, propensity score matching; CI, confidence interval.

Ethics statement

The MIMIC-IV database has received ethical approval from the institutional review boards (IRBs) at Beth Israel Deaconess Medical Center and Massachusetts Institute of Technology. Because the database does not contain protected health information, a waiver of the requirement for informed consent was included in the IRB approval.

Consent for publication

Not applicable.

Data availability statement

Publicly available datasets were analyzed in this study. These data can be found at https://physionet.org/content/mimiciv/2.2.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding

None

Author contributions

JX designed the study and wrote the manuscript, CH analyzed the data. LW reviewed the statistical analyses. YZ conducted data collection and data interpretation. All authors read and approved the ﬁnal manuscript.

Acknowledgments

None.

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No competing interests reported.

SupplementaryTable.doc

Association Between Statin Use on Delirium and 30-day Mortality in Patients with Chronic Obstructive Pulmonary Disease

Status:

Version 1

Abstract

Figures

Introduction

Method

Data Sources

Study Population and Data Extraction

Statin Use

Outcomes

Statistical analysis

Results

Baseline Characteristics

Propensity Score Matching Analysis

Association between statin exposure and outcomes

Subgroup analyses

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1