Usefulness of a selective neutrophil elastase inhibitor, sivelestat, in acute lung injury patients with sepsis

Figures & data

Table 1 New scoring system for disseminated intravascular coagulation (DIC) by the Japanese Association for Acute Medicine¹⁹

Criterion	Score
Systemic inflammatory response syndrome criteria
≥3	1
0–2	0
Platelet count (× 10^9/L)
<80 or >50% decrease within 24 hours	3
≥80 and <120 or >30% decrease within 24 hours	1
≥120	0
Prothrombin time (value of patient/normal value)
≥1.2	1
<1.2	0
Fibrin/fibrinogen degradation products (mg/L)
≥25	3
≥10 and <25	1
<10	0

Note: A score of four points or more is considered to indicate DIC.

Table 2 Characteristics of systemic inflammatory response syndrome (SIRS) patients at the time of acute lung injury (ALI) diagnosis

Characteristic	Control	Sivelestat	P-value
Patients	40	70
Sex (male/female)	23/17	48/22	0.243
Age (yrs)	71 (60–77)	73 (62–79)	0.358
Administration of steroid (yes/no)	15/25	36/34	0.159
Etiology of ALI
Direct/indirect	19/21	31/39	0.745
Infection (sepsis) (yes/no)	27/13	47/23	0.969
Non-infection (non-sepsis)
Operation (yes/no)	2/38	7/63	0.357
Aspiration (yes/no)	6/34	11/59	0.921
Others (yes/no)	5/35	5/65	0.347
Number of failed organs	2 (1–2)	2 (1–2)	0.124
SOFA score	10 (7–14)	9 (6–10)	0.212
GOCA score	6 (5–8)	5 (4–7)	0.219
SIRS score	3 (3–4)	3 (2–3)	0.063
DIC score	4 (2–5)	3 (1–5)	0.182
PaO2/FIO2 ratio (mmHg)	174.1 (130.1–233.1)	142.9 (110.0–205.0)	0.110
WBC (×10^3/μL)	12.75 (7.15–15.95)	12.15 (7.29–17.04)	0.857
CRP (mg/dL)	12.00 (5.64–20.42)	16.29 (6.26–20.68)	0.452

Note: Results are median values (interquartile ranges in parentheses).

Abbreviations: ALI, acute lung injury; SOFA score, sequential organ failure assessment score; GOCA score, gas exchange, organ failure, cause, associated disease score; SIRS, systemic inflammatory response syndrome; DIC, disseminated intravascular coagulation; WBC, white blood cell; CRP, C-reactive protein.

Table 3 Types of infections and causative pathogens in acute lung injury patients with sepsis

Parameter	N (%)
Infectious types
Pneumonia	33 (44.6)
Abdominal infection	14 (18.9)
Urinary tract infection	12 (16.2)
Bacterial pleuritis	8 (10.8)
Others (neck abscess, gas gangrene, etc)	7 (9.5)
Causative pathogens
Pseudomonas aeruginosa	15 (20.3)
Staphylococcus aureus	13 (17.6)
Escherichia coli	9 (12.2)
Enterococcus species	9 (12.2)
Streptococcus pneumonia	7 (9.5)
Klebsiella pneumonia	5 (6.8)
Prevotella species	4 (5.4)
Corynebacterium species	4 (5.4)
Stenotrophomonas maltophilia	3 (4.1)
Staphylococcus epidermidis	2 (2.7)
Haemophilus influenzae	1 (1.4)
Chryseobacterium meningosepticum	1 (1.4)
Acinetobacter species	1 (1.4)

Figure 1 Clinical efficacy of sivelestat for acute lung injury patients with systemic inflammatory response syndrome. (A) Kaplan–Meier curves for acute lung injury patients with systemic inflammatory response syndrome who did or did not receive sivelestat. Statistical analysis was performed using the log-rank test. Solid line, sivelestat patients; dashed line, control patients. (B and C) Clinical efficacy of sivelestat based on ventilator-free days (VFDs) and changes in PaO₂/F_IO₂ (ΔP/F) before and 7 days after diagnosis of acute lung injury.

Note: Statistical analysis was performed using the Mann–Whitney U test.

Figure 2 Hazard ratios and 95% confidence intervals for survival based on the Cox proportional hazards model for assessing acute lung injury patients with systemic inflammatory response syndrome.

Table 4 Clinical characteristics of non-septic patients and septic patients

	Non-septic			Septic
	Control	Sivelestat	P	Control	Sivelestat	P
Patients	13	23		27	47
Sex (male/female)	7/6	16/7	0.346	16/11	32/15	0.444
Age (yrs)	73 (62–76)	75 (64–81)	0.365	70 (56–79)	73 (61–77)	0.570
Etiology of ALI (direct/indirect)	6/7	8/15	0.501	13/14	23/24	0.948
Number of failed organs	2 (1–3)	2 (1–2)	0.805	2 (1–3)	1 (1–2)	0.105
Administration of steroid (yes/no)	5/8	13/10	0.298	10/17	23/24	0.322
SOFA score	9 (5–13)	8 (6–10)	0.542	10 (7–14)	9 (6–11)	0.259
GOCA score	5 (4–7)	6 (4–6)	0.730	6 (5–8)	5 (4–7)	0.213
SIRS score	3 (3–4)	3 (2–3)	0.753	3 (3–4)	3 (2–3)	0.312
DIC score	5 (3–5)	3 (2–4)	0.096	4 (2–5)	2 (1–5)	0.556
PaO2/FIO2 ratio (mmHg)	168.3 (115.9–178.8)	135.2 (103.7–222.2)	0.693	195.7 (138.5–250.5)	144.0 (120.8–197.8)	0.046
WBC (×10^3/μL)	12.70 (3.30–14.60)	11.44 (9.06–14.41)	0.521	12.80 (10.08–19.15)	12.20 (6.68–17.68)	0.419
CRP (mg/dL)	6.88 (3.28–16.01)	17.48 (4.81–20.29)	0.134	13.59 (7.16–24.98)	15.29 (6.91–21.62)	0.978

Note: Results are median values (interquartile ranges in parentheses).

Abbreviations: ALI, acute lung injury; SOFA score, sequential organ failure assessment score; GOCA score, gas exchange, organ failure, cause, associated disease score; SIRS, systemic inflammatory response syndrome; DIC, disseminated intravascular coagulation; WBC, white blood cell; CRP, C-reactive protein.

Figure 3 Clinical efficacy of sivelestat based on ventilator-free days (VFDs) and changes in PaO₂/F_IO₂ (ΔP/F) before and 7 days after sivelestat administration for acute lung injury patients with systemic inflammatory response syndrome who were non-septic, septic, negative for procalcitonin (PCT), and positive for PCT. (A and C) VFD for patients who were non-septic, septic, negative for PCT, and positive for PCT. (B and D) ΔP/F for patients who were non-septic, septic, negative for PCT, and positive for PCT.

Notes: PCT levels higher than 0.5 ng/mL were considered PCT positive. Statistical analysis was performed using the Mann–Whitney U test.
Abbreviations: Ctl, control patients; Si, sivelestat patients.

Table 5 The hazard ratios and 95% confidence intervals (CIs) for mortality based on univariate and multivariate Cox analysis in septic acute lung injury patients

Parameter	Hazard ratio	95% CI		P
		Low	High
Univariate
Male	1.260	0.607	2.617	0.535
Age	1.023	0.994	1.052	0.124
Indirect lung injury	1.364	0.662	2.809	0.400
Number of failed organs	2.704	1.699	4.305	<0.001
Administration of sivelestat	0.393	0.191	0.808	0.011
Administration of steroid	0.909	0.441	1.871	0.795
SOFA score	1.185	1.106	1.268	<0.001
GOCA score	1.553	1.303	1.851	<0.001
SIRS score	1.321	0.785	2.224	0.294
DIC score	1.317	1.136	1.526	0.003
PaO2/FIO2 ratio	1.004	0.998	1.011	0.145
WBC	1.000	1.000	1.000	0.550
CRP	0.969	0.936	1.005	0.087
Multivariate
Number of organ failures	1.185	0.604	2.323	0.621
Administration of sivelestat	0.366	0.171	0.783	0.010
SOFA score	1.000	0.876	1.143	0.995
GOCA score	1.448	1.042	2.012	0.028
DIC score	1.106	0.929	1.317	0.257

Abbreviations: SOFA score, sequential organ failure assessment score; GOCA score, gas exchange, organ failure, cause, associated disease score; SIRS, systemic inflammatory response syndrome; DIC, disseminated intravascular coagulation; WBC, white blood cell; CRP, C-reactive protein.

Table 6 The hazard ratios and 95% confidence intervals for mortality based on univariate and multivariate Cox analysis in non-septic acute lung injury patients

Parameter	Hazard ratio	95% CI		P
		Low	High
Univariate
Male	0.824	0.313	2.170	0.695
Age	1.023	0.984	1.064	0.250
Indirect lung injury	0.905	0.364	2.252	0.831
Number of failed organs	1.058	0.555	2.015	0.864
Administration of sivelestat	1.206	0.458	3.175	0.705
Administration of steroid	2.136	0.840	5.433	0.111
SOFA score	1.137	1.003	1.288	0.044
GOCA score	1.429	1.105	1.848	0.007
SIRS score	0.902	0.494	1.647	0.738
DIC score	1.184	0.965	1.453	0.106
PaO2/FIO2 ratio	0.991	0.982	1.001	0.070
WBC	1.000	1.000	1.000	0.391
CRP	0.986	0.935	1.041	0.618
Multivariate
SOFA score	0.958	0.787	1.167	0.670
GOCA score	1.530	1.023	2.288	0.038

Abbreviations: ALI, acute lung injury; SOFA score, sequential organ failure assessment score; GOCA score, gas exchange, organ failure, cause, associated disease score; SIRS, systemic inflammatory response syndrome; DIC, disseminated intravascular coagulation; WBC, white blood cell; CRP, C-reactive protein.

Figure 4 Kaplan–Meier curves for acute lung injury patients with systemic inflammatory response syndrome who were septic (A), non-septic (B), positive for procalcitonin (PCT) (C), and negative for PCT (D).

Notes: PCT levels higher than 0.5 ng/mL were considered PCT positive. Statistical analysis was performed using the log-rank test. Solid line, sivelestat patients; dashed line, control patients.

Table 7 Clinical characteristics of procalcitonin (PCT)-negative patients and PCT-positive patients

	PCT negative			PCT positive
	Control	Sivelestat	P	Control	Sivelestat	P
Patients	12	22		28	48
Sex (male/female)	5/7	16/6	0.075	18/10	32/16	0.833
Age (yrs)	71 (62–76)	74 (69–81)	0.387	70 (57–79)	73 (61–77)	0.576
Etiology of ALI (direct/indirect)	5/7	9/13	0.966	14/14	22/26	0.726
Number of failed organs	2 (1–3)	2 (1–2)	0.843	2 (1–3)	2 (1–2)	0.096
Administration of steroid (yes/no)	4/8	14/8	0.091	11/17	22/26	0.578
SOFA score	10 (5–14)	8 (6–10)	0.601	10 (7–13)	9 (6–10)	0.232
GOCA score	6 (4–8)	6 (4–8)	0.732	6 (5–8)	5 (4–7)	0.202
SIRS score	4 (3–4)	3 (2–3)	0.056	3 (3–4)	3 (2–3)	0.369
DIC score	4 (3–5)	3 (2–5)	0.221	4 (2–5)	2 (1–5)	0.383
PaO2/FIO2 ratio (mmHg)	170.8 (107.8–187.5)	130.4 (102.6–200.0)	0.829	184.6 (141.1–245)	150.1 (127.0–205.5)	0.090
WBC (×10^3/μL)	9.15 (3.20–14.90)	11.92 (9.00–14.50)	0.428	13.30 (10.25–17.25)	12.15 (6.75–17.60)	0.383
CRP (mg/dL)	5.94 (2.56–11.82)	16.88 (4.32–18.74)	0.066	14.6 (9.23–24.96)	15.22 (6.50–22.78)	0.667

Note: Results are median values (interquartile ranges in parentheses).

Abbreviations: ALI, acute lung injury; SOFA score, sequential organ failure assessment score; GOCA score, gas exchange, organ failure, cause, associated disease score; SIRS, systemic inflammatory response syndrome; DIC, disseminated intravascular coagulation; WBC, white blood cell; PLT, platelet; CRP, C-reactive protein.

Table 8 The hazard ratios and 95% confidence intervals (CIs) for mortality based on univariate and multivariate Cox analysis in procalcitonin-positive patients

Parameter	Hazard ratio	95% CI		P
		Low	High
Univariate
Male	1.246	0.583	2.682	0.570
Age	1.030	0.999	1.062	0.056
Indirect lung injury	1.289	0.610	2.725	0.506
Number of organ failure	2.616	1.616	4.234	<0.001
Administration of sivelestat	0.409	0.194	0.862	0.019
Administration of steroid	0.942	0.446	1.992	0.876
SOFA score	1.173	1.091	1.261	<0.001
GOCA score	1.511	1.253	1.822	<0.001
SIRS score	1.451	0.841	2.504	0.181
DIC score	1.269	1.092	1.475	0.002
PaO2/FIO2 ratio	1.003	0.997	1.010	0.323
WBC	1.000	1.000	1.000	0.582
CRP	0.981	0.947	1.017	0.295
Multivariate
Number of organ failure	1.275	0.635	2.561	0.494
Administration of sivelestat	0.422	0.194	0.919	0.030
SOFA score	1.001	0.868	1.154	0.992
GOCA score	1.365	0.959	1.941	0.084
DIC score	1.096	0.917	1.310	0.315

Abbreviations: ALI, acute lung injury; SOFA score, sequential organ failure assessment score; GOCA score, gas exchange, organ failure, cause, associated disease score; SIRS, systemic inflammatory response syndrome; DIC, disseminated intravascular coagulation; WBC, white blood cell; CRP, C-reactive protein.

Gando S Iba T Eguchi Y Japanese Association for Acute Medicine Disseminated Intravascular Coagulation (JAAM DIC) Study Group A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: comparing current criteria Crit Care Med 2006 34 3 625 631 16521260

 PubMed Web of Science ®Google Scholar