Patients
From September 27, 2018, to February 12, 2020, we screened 277 patients with sepsis at the two study sites, resulting in the enrollment of 100 patients (80 patients in Zhengzhou and 20 patients in Kunming), including 50 patients in the aminophylline group and 50 patients in the usual-care group. In the usual-care group, 4 patients with septic shock were missing repeated measurements (2 died and 2 had discharge requests) and were not involved in repeated data ANOVA. We assessed the 4 patients' survival status at 28 days and 60 days (Fig. 1).
The two groups were well-matched at baseline (Table 1). The most common site of infection in the aminophylline and usual-care groups was the lung (58%, 52%, respectively), and there was no statistical difference between the two groups. The criterion for septic shock was met in 28 patients (28/50, 56.0%) in the aminophylline group and 27 patients (27/50, 54.0%) in the usual-care group, showing no statistical difference.
Table 1. Characteristics of the Participants at Baselinea
|
|
Characteristics
|
Aminophylline group
(n = 100)
|
Usual-care group
(n = 100)
|
Age, median (IQR), y
|
51.5 (40.0 - 64.3)
|
51.5 (42.3 - 60.5)
|
Male sex, no. (%)
|
36 (72.0%)
|
35 (70.0%)
|
Underlying disease, no. (%)b
|
|
|
Hypertension
|
15 (30.0%)
|
11 (22.0%)
|
Coronary heart disease
|
3 (6.0%)
|
3 (6.0%)
|
Liver disease
|
4 (8.0%)
|
2 (4.0%)
|
Chronic obstructive pulmonary disease
|
3 (6.0%)
|
1 (2.0%)
|
Nervous system disease
|
5 (10.0%)
|
4 (8.0%)
|
Diabetes mellitus
|
12 (24.0%)
|
7 (14.0%)
|
Trauma
|
3 (6.0%)
|
2 (4.0%)
|
Tumor
|
1 (2.0%)
|
4 (8.0%)
|
Other diseases
|
9 (18.0%)
|
8 (16.0%)
|
Site of infection, no. (%)
|
|
|
Lungs
|
29 (58.0%)
|
26 (52.0%)
|
Abdomen
|
16 (32.0%)
|
16 (32.0%)
|
Urogenital tract
|
5 (10.0%)
|
4 (8.0%)
|
Blood
|
10 (20.0%)
|
12 (24.0%)
|
Other sites
|
13 (26.0%)
|
12 (24.0%)
|
Mechanical ventilation, no. (%)
|
22 (44.0%)
|
22 (44.0%)
|
Shock, no. (%)
|
28 (56.0%)
|
27 (54.0%)
|
a There were no significant difference between the two groups. IQR denotes interquartile range, CHD denotes coronary heart disease, and COPD denotes chronic obstructive pulmonary disease.
b Underlying diseases were self-reported and assessed by the physician.
Analysis of variance for repeated data
At the baseline of repeated measurements, patients in the aminophylline group had higher platelet counts and fibrinogen (Table 2). The data for repeated measurements were analyzed by multivariate analysis of variance because they did not conform to the spherical test. The results showed that platelet, fibrinogen, creatinine, total protein, albumin, PH, C-reactive protein, procalcitonin, SOFA scores, 24-hour fluid intake, oxygenation index, and other indicators improved gradually with the extension of treatment time (P < 0.05). The groups did not show any statistical significance for each repeated measurement index. There was an interaction between the group and time on the SOFA score, oxygenation index, and vasopressor dose in the shock subgroup. With the extension of treatment time, the aminophylline group showed a greater improvement in SOFA score, oxygenation index, and dose of vasopressors in the shock subgroup than in the usual-care group. The aminophylline group showed a greater 24-hour urine output than the usual-care group, but this difference was not statistically significant (Fig. 2).
Table 2
Comparison of laboratory and clinical indexes between the two groups
| Aminophylline group (n = 50) | Usual-care group (n = 50) | P Value |
Dose of vasopressors, median (IQR), µg/kg/mina | 0.05 (0.00–0.32) | 0.00 (0.00–0.28 ) | 0.652 |
White blood cell count, median (IQR), ×103/µL | 12.08 (8.79–16.77) | 12.82 (7.55–18.87 ) | 0.730 |
Red blood cell count, median (IQR), ×106/µL | 3.55 (2.85–4.13) | 3.30 (2.74–3.79 ) | 0.301 |
Hemoglobin, mean (SD), g/L | 103.08 (32.16) | 102.14 (26.04) | 0.873 |
Platelet count, median (IQR), ×103/µL | 158.50 (86.25–242.75) | 112.50 (28.50–213.50 ) | 0.046 |
Prothrombin time, median (IQR), sec | 13.40 (11.48–15.15) | 14.25 (11.78–15.73 ) | 0.274 |
Activated partial thromboplastin time, median (IQR), sec | 31.20 (28.10–40.30) | 33.40 (28.28–41.70 ) | 0.539 |
Fibrinogen, median (IQR), g/L | 4.59 (3.26–6.92) | 3.65 (2.67–4.99 ) | 0.037 |
D-Dimer, median, (IQR), mg/L | 1.94 (0.85–3.28) | 2.36 (1.05–3.95 ) | 0.282 |
Blood urea nitrogen, median, (IQR), mmol/L | 8.64 (5.11–15.67) | 10.00 (5.07–18.89 ) | 0.725 |
Serum creatinine, median, (IQR), µmol/L | 79.00 (58.98–154.03) | 79.75 (53.75–149.00 ) | 0.992 |
Glomerular filtration rate, median, (IQR), ml/min | 76.75 (43.46–105.79) | 81.88 (42.51–108.36 ) | 0.942 |
Alanine aminotransferase, median, (IQR), U/L | 25.50 (11.75–76.75) | 35.85 (21.75–63.50 ) | 0.197 |
Aspartate aminotransferase, median, (IQR), U/L | 32.50 (22.75–76.75) | 40.50 (19.53–97.25 ) | 0.588 |
Total protein, median, (IQR), g/L | 56.80 (50.65–62.20) | 56.40 (46.33–62.75 ) | 0.754 |
Albumin protein, median, (IQR), g/L | 25.55 (22.95–31.58) | 25.75 (21.50–30.90 ) | 0.756 |
Total bilirubin, median, (IQR), µmol/L | 16.25 (8.18–29.15) | 14.45 (10.65–35.90 ) | 0.408 |
Direct bilirubin, median, (IQR), µmol/L | 8.20 (4.65–16.28) | 8.95 (5.28–27.78 ) | 0.224 |
Indirect bilirubin, median, (IQR), µmol/L | 4.80 (3.03–10.18) | 6.25 (3.20–10.58 ) | 0.414 |
pH value, median, (IQR) | 7.42 (7.36–7.46) | 7.41 (7.36–7.46 ) | 0.664 |
Blood lactate, median, (IQR), mmol/L | 1.50 (1.10–2.23) | 1.60 (1.10–2.83 ) | 0.617 |
C-reactive protein, median, (IQR), mg/L | 156.91 (104.07–236.40) | 136.25 (73.50–217.19 ) | 0.343 |
Procalcitonin, median, (IQR), ng/mL | 7.77 (1.04–18.65) | 3.03 (0.88–13.70 ) | 0.212 |
Urine specific gravity, median, (IQR) | 1.02 (1.02–1.02) | 1.02 (1.01–1.02 ) | 0.157 |
APACHE Ⅱ score, median, (IQR) | 17.00 (11.75–21.00) | 14.00 (11.00–20.00 ) | 0.165 |
SOFA score, median, (IQR) | 8.00 (6.00–11.00) | 8.00 (5.00–11.25 ) | 0.906 |
24-hour liquid intake, median, (IQR), ml | 4238.00 (3178.00–5371.50) | 4052.00 (3259.00–5308.00 ) | 0.777 |
24-hour urine output, median, (IQR), ml | 2380.00 (1714.29–4066.07) | 2950.00 (1440.00–4065.00 ) | 0.989 |
Oxygenation index, median, (IQR) | 211.00 (170.75–274.98) | 249.50 (172.25–305.25 ) | 0.190 |
a: The only vasopressor used in shock patients at the two centers was noradrenaline. |
Mortality
A total of 23 patients died on the 28th day, including 20 (20/55) in the shock subgroup. The mortality of the aminophylline group was lower than that of the usual-care group (28-day mortality rate, 14.0 vs. 32.0%; 60-day mortality rate, 16.0 vs. 36.0%). In the shock subgroup, the 28-day and 60-day mortality of the aminophylline group were significantly lower than those of the control group (28-day mortality rate, 25.0 vs. 48.2%; 60-day mortality rate, 28.6 vs. 51.9%), but there was no statistical difference between the two groups (Fig. 3).
Survival analysis
The survival benefits seen in the aminophylline group were better than in the usual-care group. There was a significant difference in the duration of survival between the two groups (P = 0.039 by the log-rank test) (Fig. 4).
The COX proportional-hazards model adjusted imbalance baseline (platelet count and fibrinogen) showed the following: group (HR = 0.312, 95% CI: 0.129–0.753, P = 0.010), shock (HR = 4.695, 95% CI: 1.402–15.722, P = 0.012), bloodstream infection (HR = 3.290, 95% CI:1.332–8.126, P = 0.010), SOFA score (HR = 1.180, 95% CI:1.023–1.360, P = 0.023), D-dimer (per 1 mg/L, HR = 1.109, 95% CI:1.034–1.190, P = 0.004), and platelet count (per 10×103/µL, HR = 1.083, 95% CI:1.033–1.136, P = 0.001) were all independent risk factors for death events.
Further bivariate correlation analysis showed that the platelet count on day 0 was positively correlated with survival time (correlation coefficient = 0.025, P = 0.807) and mortality risk (correlation coefficient = 0.059, P = 0.475), but the association was not statistically significant. The change in platelet count on day 5 was positively correlated with survival time (correlation coefficient = 0.284, P = 0.005) and negatively correlated with risk of death (correlation coefficient = -0.279, P = 0.001); the association was statistically significant.
Other secondary outcomes
The length of stay in the hospital and ICU were similar in the two groups, and the difference was not statistically significant. In the aminophylline group, the median length of stay in the hospital and ICU were 18.50 days (11.75, 31.25) and 10.00 days (7.00, 16.00), respectively. In the usual-care group, the median length of stay in the hospital and ICU were 18.50 days (11.75, 31.25) and 10.00 days (7.00, 16.00), respectively. In the shock subgroup, the median length of stay in the hospital and ICU were 16.50 days (9.50, 28.75) and 9.00 days (7.00, 13.75), respectively, in the aminophylline group, and 17.00 days (9.00, 23.00) and 9.00 days (7.00, 16.00), respectively, in the usual-care group, showing no statistical significance in two groups.
According to the adjusted baseline APACHE II scores on day 0, the APACHE II scores on day 5 in the aminophylline group and usual-care group were 10.79 (95% CI: 9.20–12.38) and 12.84 (95% CI: 11.18–14.49), respectively. There was no statistically significant difference between the two groups (P = 0.083, F = 3.072, difference = -2.042, 95% CI: -4.356–0.272). In the shock subgroup, there was also no statistically significant difference in the adjusted APACHE II scores on day 5 between the aminophylline group and usual-care group (11.21, 95% CI: 8.96–13.45 vs. 13.58, 95% CI: 11.10–16.06, P = 0.166, F = 1.974, difference = -2.371, 95% CI: -5.763–1.022).
Adverse effects
No aminophylline-related adverse reactions were observed within 48 hours from enrollment to 48 hours afterward. Adverse reactions to aminophylline are closely related to the drug concentration. If the concentration of aminophylline exceeds 15 ug/ml, the risk of mild adverse reactions is increased; when it exceeds 20 ug/ml, tachycardia and other arrhythmias may occur; and over 40 ug/ml, fever, dehydration, convulsions, even cardiac arrest may occur. We monitored the concentrations of aminophylline on days 1, 3, and 5, and these were 6.66 ± 3.30 ug/ml, 8.09 ± 4.23ug /ml, and 7.74 ± 3.67ug/ml, respectively. The difference in aminophylline concentration at 3-time points was statistically significant (P = 0.024): at day 3, this was 1.425 ug/ml (95% CI: 0.191–2.659, P = 0.019) higher than on day 1. At day 5, the difference was 1.077 ug/ml (95% CI: -0.405–2.558) higher than on day 1 and not statistically significant (P = 0.233). The difference on day 5 was decreased by 0.348 ug/ml (95% CI: -1.575–0.880) compared to day 3, with no statistically significant difference (P = 1.000).
With the extension of aminophylline application time, the numbers of patients with an aminophylline concentration exceeding 15 ug/ml increased: one patient on day 1 (23.08 ug/ml), 3 patients on day 3 (19.60 ug/ml, 18.34 ug/ml, and 15.20 ug/ml), and 4 patients on day 5 (17.40 ug/ml, 15.60 ug/ml, 15.20 ug/ml, and 15.06 ug/ml).