Table 1 Baseline characteristics and clinical outcomes between the two groups before and after PSM

Before PSM

After PSM

Characteristic

Overall

N = 24,860

Ramelteon unexposed

N = 22,152

Ramelteon exposed

N = 2,708

SMD

Overall

N = 5,214

Ramelteon unexposed

N = 2,607

Ramelteon exposed

N = 2,607

SMD

Demographic parameters

 Gender(male), n (%)

14,492.0 (58.3%)

12,811.0 (57.8%)

1,681.0 (62.1%)

0.09

3,215.0 (61.7%)

1,604.0 (61.5%)

1,611.0 (61.8%)

0.01

 Race(white), n (%)

16,220.0 (65.2%)

14,541.0 (65.6%)

1,679.0 (62.0%)

0.08

3,279.0 (62.9%)

1,661.0 (63.7%)

1,618.0 (62.1%)

0.03

 Age (years), Median (Q1, Q3)

68.0 (57.0, 79.0)

68.0 (56.0, 79.0)

69.0 (59.0, 79.0)

0.07

69.0 (58.0, 79.0)

69.0 (58.0, 80.0)

69.0 (58.0, 79.0)

0.01

 Height(cm), Median (Q1, Q3)

170.0 (162.6, 178.0)

170.0 (161.3, 178.0)

170.0 (163.0, 178.0)

0.06

170.0 (163.0, 178.0)

170.0 (163.0, 178.0)

170.0 (163.0, 178.0)

0.02

 Weight(kg), Median (Q1, Q3)

80.0 (67.3, 95.7)

80.0 (67.2, 95.5)

80.9 (68.0, 96.9)

0.04

80.2 (67.3, 96.2)

80.0 (66.8, 96.0)

80.8 (68.0, 96.5)

0.04

Vital signs

 Heart rate(bpm), Median (Q1, Q3)

85.1 (75.4, 97.0)

85.2 (75.5, 97.0)

84.8 (74.5, 97.7)

0.00

84.8 (75.0, 97.6)

84.7 (75.3, 97.7)

84.8 (74.6, 97.5)

 < 0.01

 MBP (mmHg), Median (Q1, Q3)

75.7 (70.4, 82.4)

75.5 (70.2, 82.2)

77.1 (71.9, 84.0)

0.19

77.1 (71.7, 84.0)

77.2 (71.5, 84.3)

77.1 (71.8, 83.9)

0.01

 Respiratory rate(bpm), Median (Q1, Q3)

19.0 (16.8, 22.1)

18.9 (16.7, 22.0)

19.8 (17.5, 22.8)

0.19

19.7 (17.4, 22.8)

19.7 (17.3, 23.0)

19.8 (17.4, 22.7)

0.01

 Temperature(°C), Median (Q1, Q3)

36.9 (36.6, 37.2)

36.9 (36.6, 37.2)

36.9 (36.7, 37.2)

0.09

36.9 (36.6, 37.2)

36.9 (36.6, 37.2)

36.9 (36.7, 37.2)

0.03

 SPO₂(%), Median (Q1, Q3)

97.3 (95.8, 98.5)

97.3 (95.9, 98.6)

96.8 (95.3, 98.3)

0.19

96.9 (95.3, 98.3)

96.9 (95.3, 98.3)

96.8 (95.3, 98.3)

0.03

 Glucose(mg/dl), Median (Q1, Q3)

132.0 (114.8, 160.5)

131.8 (114.8, 159.7)

133.9 (114.0, 165.7)

0.03

133.3 (114.0, 167.3)

133.2 (114.0, 169.4)

133.7 (113.6, 165.3)

 < 0.01

 Urine output(ml), Median (Q1, Q3)

1,545.0 (935.0, 2,350.0)

1,560.0 (950.0, 2,368.0)

1,375.0 (800.0, 2,180.0)

0.12

1,372.5 (800.0, 2,170.0)

1,365.0 (800.0, 2,160.0)

1,375.0 (800.0, 2,175.0)

0.01

Laboratory

 Hemoglobin(g/dl), Median (Q1, Q3)

10.9 (9.3, 12.6)

10.9 (9.3, 12.6)

11.1 (9.2, 12.9)

0.05

11.1 (9.3, 12.8)

11.1 (9.4, 12.7)

11.1 (9.2, 12.8)

0.01

 Hematocrit (%), Median (Q1, Q3)

33.3 (28.4, 38.0)

33.2 (28.4, 37.9)

34.4 (28.8, 39.4)

0.15

34.3 (29.0, 39.1)

34.2 (29.4, 38.9)

34.4 (28.7, 39.3)

0.02

 WBC (× 10⁹), Median (Q1, Q3)

10.8 (7.5, 15.3)

10.8 (7.5, 15.3)

10.8 (7.8, 15.5)

0.06

10.9 (7.7, 15.5)

10.9 (7.6, 15.6)

10.8 (7.8, 15.4)

0.03

 Platelet (× 10¹²), Median (Q1, Q3)

190.0 (135.0, 256.0)

189.0 (134.0, 255.0)

199.0 (143.0, 266.0)

0.10

196.0 (141.0, 264.0)

194.0 (137.0, 263.0)

197.0 (143.0, 265.0)

0.01

 BUN (mg/dl), Median (Q1, Q3)

20.0 (14.0, 34.0)

20.0 (14.0, 33.0)

22.0 (15.0, 37.0)

0.09

22.0 (15.0, 37.0)

22.0 (15.0, 37.0)

22.0 (15.0, 37.0)

0.01

 Creatinine(mg/dl), Median (Q1, Q3)

1.0 (0.8, 1.6)

1.0 (0.8, 1.5)

1.1 (0.8, 1.7)

0.11

1.1 (0.8, 1.7)

1.1 (0.8, 1.7)

1.1 (0.8, 1.7)

0.01

 Sodium(mmol/L), Median (Q1, Q3)

139.0 (136.0, 141.0)

139.0 (136.0, 141.0)

138.0 (135.0, 141.0)

0.10

138.0 (135.0, 141.0)

138.0 (135.0, 141.0)

138.0 (135.0, 141.0)

0.03

 Potassium(mmol/L), Median (Q1, Q3)

4.1 (3.8, 4.6)

4.1 (3.7, 4.6)

4.2 (3.8, 4.7)

0.15

4.2 (3.8, 4.7)

4.2 (3.8, 4.7)

4.2 (3.8, 4.7)

0.01

 Calcium(mg/dl), Median (Q1, Q3)

8.5 (7.9, 9.0)

8.4 (7.9, 8.9)

8.5 (8.0, 9.0)

0.14

8.5 (7.9, 9.0)

8.4 (7.9, 8.9)

8.5 (8.0, 9.0)

0.14

 Anion gap(mmol/L), Median (Q1, Q3)

14.0 (12.0, 17.0)

14.0 (12.0, 17.0)

14.0 (11.0, 16.0)

0.16

14.0 (11.0, 17.0)

14.0 (12.0, 17.0)

14.0 (11.0, 16.0)

0.02

 Bicarbonate(mmol/L), Median (Q1, Q3)

23.0 (20.0, 26.0)

23.0 (20.0, 26.0)

22.0 (19.0, 25.0)

0.14

22.0 (19.0, 25.0)

22.0 (19.0, 25.0)

22.0 (19.0, 25.0)

 < 0.01

Source of infection, n (%)

0.47

0.04

 Blood

10,651.0 (42.8%)

9,271.0 (41.9%)

1,380.0 (51.0%)

2,693.0 (51.6%)

1,366.0 (52.4%)

1,327.0 (50.9%)

 Others/Uncertain

8,853.0 (35.6%)

8,366.0 (37.8%)

487.0 (18.0%)

926.0 (17.8%)

447.0 (17.1%)

479.0 (18.4%)

 Pulmonary

477.0 (1.9%)

384.0 (1.7%)

93.0 (3.4%)

170.0 (3.3%)

81.0 (3.1%)

89.0 (3.4%)

 Stool

142.0 (0.6%)

128.0 (0.6%)

14.0 (0.5%)

26.0 (0.5%)

12.0 (0.5%)

14.0 (0.5%)

 Urine

4,737.0 (19.1%)

4,003.0 (18.1%)

734.0 (27.1%)

1,399.0 (26.8%)

701.0 (26.9%)

698.0 (26.8%)

co-morbidities

 Myocardial infarct, n (%)

4,310.0 (17.3%)

3,668.0 (16.6%)

642.0 (23.7%)

0.18

1,207.0 (23.1%)

607.0 (23.3%)

600.0 (23.0%)

0.01

 Congestive heart failure, n (%)

7,181.0 (28.9%)

6,131.0 (27.7%)

1,050.0 (38.8%)

0.24

1,972.0 (37.8%)

986.0 (37.8%)

986.0 (37.8%)

 < 0.01

 Peripheral vascular disease, n (%)

2,976.0 (12.0%)

2,624.0 (11.8%)

352.0 (13.0%)

0.03

659.0 (12.6%)

324.0 (12.4%)

335.0 (12.9%)

0.01

 Cerebrovascular disease, n (%)

3,800.0 (15.3%)

3,324.0 (15.0%)

476.0 (17.6%)

0.07

904.0 (17.3%)

454.0 (17.4%)

450.0 (17.3%)

 < 0.01

 Chronic pulmonary disease, n (%)

6,289.0 (25.3%)

5,625.0 (25.4%)

664.0 (24.5%)

0.02

1,265.0 (24.3%)

634.0 (24.3%)

631.0 (24.2%)

 < 0.01

 Diabetes with complications, n (%)

2,547.0 (10.2%)

2,044.0 (9.2%)

503.0 (18.6%)

0.27

942.0 (18.1%)

476.0 (18.3%)

466.0 (17.9%)

0.01

 Renal disease, n (%)

5,367.0 (21.6%)

4,622.0 (20.9%)

745.0 (27.5%)

0.16

1,416.0 (27.2%)

710.0 (27.2%)

706.0 (27.1%)

 < 0.01

 Malignant cancer, n (%)

3,328.0 (13.4%)

2,948.0 (13.3%)

380.0 (14.0%)

0.02

717.0 (13.8%)

354.0 (13.6%)

363.0 (13.9%)

0.01

 Severe liver disease, n (%)

1,866.0 (7.5%)

1,725.0 (7.8%)

141.0 (5.2%)

0.10

291.0 (5.6%)

150.0 (5.8%)

141.0 (5.4%)

0.02

 Delirium, n (%)

2,289.0 (9.2%)

1,732.0 (7.8%)

557.0 (20.6%)

0.37

964.0 (18.5%)

469.0 (18.0%)

495.0 (19.0%)

0.03

 Sleep disorder, n (%)

1,995.0 (8.0%)

1,593.0 (7.2%)

402.0 (14.8%)

0.25

713.0 (13.7%)

343.0 (13.2%)

370.0 (14.2%)

0.03

Severity scores and clinical interventions

 Sofa score, Median (Q1, Q3)

3.0 (2.0, 4.0)

3.0 (2.0, 4.0)

3.0 (2.0, 5.0)

0.06

3.0 (2.0, 5.0)

3.0 (2.0, 5.0)

3.0 (2.0, 5.0)

0.01

 Respiration ≥ 1, n (%)

8,121.0 (32.7%)

7,417.0 (33.5%)

704.0 (26.0%)

0.16

1,346.0 (25.8%)

659.0 (25.3%)

687.0 (26.4%)

0.02

 Coagulation ≥ 1, n (%)

8,310.0 (33.4%)

7,410.0 (33.5%)

900.0 (33.2%)

0.00

1,766.0 (33.9%)

891.0 (34.2%)

875.0 (33.6%)

0.01

 Liver ≥ 1, n (%)

3,605.0 (14.5%)

3,179.0 (14.4%)

426.0 (15.7%)

0.04

825.0 (15.8%)

415.0 (15.9%)

410.0 (15.7%)

0.01

 Cardiovascular ≥ 1, n (%)

15,905.0 (64.0%)

14,246.0 (64.3%)

1,659.0 (61.3%)

0.06

3,173.0 (60.9%)

1,577.0 (60.5%)

1,596.0 (61.2%)

0.01

 CNS ≥ 1, n (%)

6,590.0 (26.5%)

5,807.0 (26.2%)

783.0 (28.9%)

0.06

1,497.0 (28.7%)

754.0 (28.9%)

743.0 (28.5%)

0.01

 Renal ≥ 1, n (%)

8,910.0 (35.8%)

7,677.0 (34.7%)

1,233.0 (45.5%)

0.22

2,355.0 (45.2%)

1,184.0 (45.4%)

1,171.0 (44.9%)

0.01

 SAPS II score, Median (Q1, Q3)

39.0 (31.0, 48.0)

38.0 (31.0, 48.0)

40.0 (31.0, 49.0)

0.06

39.0 (31.0, 49.0)

39.0 (31.0, 49.0)

40.0 (31.0, 49.0)

 < 0.01

 Charlson comorbidity index, Median (Q1, Q3)

5.0 (3.0, 7.0)

5.0 (3.0, 7.0)

5.0 (3.0, 8.0)

0.17

5.0 (3.0, 8.0)

5.0 (3.0, 8.0)

5.0 (3.0, 8.0)

0.01

 Aminoglycosides, n (%)

938.0 (3.8%)

862.0 (3.9%)

76.0 (2.8%)

0.06

149.0 (2.9%)

74.0 (2.8%)

75.0 (2.9%)

 < 0.01

 Beta lactams, n (%)

17,850.0 (71.8%)

15,812.0 (71.4%)

2,038.0 (75.3%)

0.09

3,913.0 (75.0%)

1,956.0 (75.0%)

1,957.0 (75.1%)

 < 0.01

 Macrolides, n (%)

3,017.0 (12.1%)

2,556.0 (11.5%)

461.0 (17.0%)

0.16

871.0 (16.7%)

437.0 (16.8%)

434.0 (16.6%)

 < 0.01

 Glycopeptides, n (%)

16,109.0 (64.8%)

14,203.0 (64.1%)

1,906.0 (70.4%)

0.13

3,668.0 (70.3%)

1,832.0 (70.3%)

1,836.0 (70.4%)

 < 0.01

 Sulfonamides, n (%)

200.0 (0.8%)

174.0 (0.8%)

26.0 (1.0%)

0.02

51.0 (1.0%)

27.0 (1.0%)

24.0 (0.9%)

0.01

 Tetracyclines, n (%)

648.0 (2.6%)

506.0 (2.3%)

142.0 (5.2%)

0.16

263.0 (5.0%)

134.0 (5.1%)

129.0 (4.9%)

0.01

 Quinolones, n (%)

4,939.0 (19.9%)

4,717.0 (21.3%)

222.0 (8.2%)

0.38

438.0 (8.4%)

216.0 (8.3%)

222.0 (8.5%)

0.01

 other Antibiotics use, n (%)

708.0 (2.8%)

613.0 (2.8%)

95.0 (3.5%)

0.04

183.0 (3.5%)

91.0 (3.5%)

92.0 (3.5%)

 < 0.01

 propofol, n (%)

14,785.0 (59.5%)

13,014.0 (58.7%)

1,771.0 (65.4%)

0.14

3,368.0 (64.6%)

1,675.0 (64.3%)

1,693.0 (64.9%)

0.01

 Dexmedetomidine, n (%)

5,733.0 (23.1%)

4,431.0 (20.0%)

1,302.0 (48.1%)

0.62

2,397.0 (46.0%)

1,187.0 (45.5%)

1,210.0 (46.4%)

0.02

 Benzodiazepines, n (%)

7,806.0 (31.4%)

6,996.0 (31.6%)

810.0 (29.9%)

0.04

1,550.0 (29.7%)

773.0 (29.7%)

777.0 (29.8%)

 < 0.01

 Neuromuscular blocking agents, n (%)

1,148.0 (4.6%)

1,023.0 (4.6%)

125.0 (4.6%)

0.00

248.0 (4.8%)

124.0 (4.8%)

124.0 (4.8%)

 < 0.01

 Vasoactive agent, n (%)

12,424.0 (50.0%)

11,324.0 (51.1%)

1,100.0 (40.6%)

0.21

2,148.0 (41.2%)

1,075.0 (41.2%)

1,073.0 (41.2%)

 < 0.01

 CRRT, n (%)

1,719.0 (6.9%)

1,449.0 (6.5%)

270.0 (10.0%)

0.12

510.0 (9.8%)

256.0 (9.8%)

254.0 (9.7%)

 < 0.01

 IMV, n (%)

13,221.0 (53.2%)

11,961.0 (54.0%)

1,260.0 (46.5%)

0.15

2,419.0 (46.4%)

1,193.0 (45.8%)

1,226.0 (47.0%)

0.03

 Duration of ramelteon exposure(days), Median (Q1, Q3)

0.0 (0.0, 0.0)

0.0 (0.0, 0.0)

8.0 (4.0, 14.0)

1.2

0.0 (0.0, 7.0)

0.0 (0.0, 0.0)

7.0 (4.0, 14.0)

1.2

Outcomes

Overall

N = 24,860

Ramelteon unexposed

N = 22,152

Ramelteon exposed

N = 2,708

P value

Overall

N = 5,214

Ramelteon unexposed

N = 2,607

Ramelteon exposed

N = 2,607

P value

In-hospital mortality, n (%)

3,885 (15.6%)

3,562 (16.1%)

323 (11.9%)

 < 0.001

816 (15.7%)

513 (19.7%)

303 (11.6%)

 < 0.001

30-day mortality, n (%)

4,612 (18.6%)

4,246 (19.2%)

366 (13.5%)

 < 0.001

954 (18.3%)

605 (23.2%)

349 (13.4%)

 < 0.001

90-day mortality, n (%)

6,187 (24.9%)

5,576 (25.2%)

611 (22.6%)

0.003

1,358 (26.0%)

781 (30.0%)

577 (22.1%)

 < 0.001

Length of hospital stay (days), Median (Q1, Q3)

9.3 (5.7, 16.7)

8.8 (5.4, 15.3)

16.9 (9.7, 28.9)

 < 0.001

13.4 (7.7, 23.8)

10.5 (6.3, 18.6)

16.8 (9.6, 28.8)

 < 0.001

Length of ICU stay (days), Median (Q1, Q3)

3.4 (1.9, 7.0)

3.2 (1.9, 6.6)

5.2 (2.6, 11.0)

 < 0.001

4.6 (2.3, 9.7)

4.1 (2.2, 8.6)

5.1 (2.6, 11.0)

 < 0.001