Unfractionated Heparin Improves the Clinical Efficacy in Adult Sepsis Patients

A Systematic Review and Meta-analysis

Sifeng Fu; Sihan Yu; Liang Wang; Xiaochun Ma; Xu Li

BMC Anesthesiol. 2022;22(28)

Conclusion

UFH may reduce 28 d mortality and improve the clinical efficacy for sepsis patients without bleeding complications. We call for large multicenter RCTs to evaluate the clinical value of UFH in sepsis patients because of the moderate quality of this body of evidence.

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Abbreviations
Ang: Angiopoietin; APACHE II: Acute Physiology and Chronic Health Evaluation II; APC: Activated protein C; APTT: Activated partial thromboplastin time; AT: Antithrombin; CIs: Confidence intervals; CMeSH: Chinese Medical Subject Headings; CRRT : Continuous Renal replacement therapy; DIC: Disseminated intravascular coagulation; F: Factor; IQR: Interquartile range; ISTH: International Society on Thrombosis & Haemostasis; KLF-5: Kruppel-like factor 5; LMWH: Low molecular weight heparin; LOS: Length of stay; MeSH: Medical Subject Headings; MD: Mean differences; MODS: Multiple organ dysfunction syndrome; NF-kB: Nuclear factor-κB; PLT: Platelet; PRISMA: Preferred Reporting Items for the Systematic Reviews and Meta-Analyses; PT: Prothrombin time; RCTs: Randomized controlled trials; RevMan: Review Manager; rhAPC: Recombinant human APC; rhTM: Recombinant human thrombomodulin; RoB2: Risk of Bias tool 2; RR: Relative risk; SIRS: Systemic inflammatory response syndrome; SSC: Surviving Sepsis Campaign; TFPI: Tissue factor pathway inhibitor; TM: Thrombomodulin; UFH: Unfractionated heparin.

Acknowledgements
We acknowledge all staff who helped perform this study.

Funding
This work was supported by the National Natural Science Foundation of China (Grant No. 81671936).

Availability of data and materials
Not applicable.

Declarations
Ethics approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Table 1. The basic characteristics of the included studies
Article, year	Number of researches centers	Total (n), UFH/Control	Population	Age (Yr)		P value
Article, year	Number of researches centers	Total (n), UFH/Control	Population	UFH	Control	P value
Deng et al, 2017 [22]	1	118, 62/56	Sepsis and septic shock	62.5 ± 13.9	61.5 ± 15.2	P > 0.05
Gu et al, 2014 [23]	1	42, 21/21	Sever sepsis	64.6 ± 12.7	69.7 ± 16.3	P > 0.05
Guo et al, 2019 [24]	1	90,45/45	Sepsis with pre-DIC	64.75 ± 7.88	68.87 ± 6.16	P > 0.05
Hou et al, 2011 [25]	1	40, 20/20	Sever sepsis	58.6 ± 15.4	57.7 ± 12.6	P > 0.05
Jaimes et al, 2009 [26]	1	319, 159/160	Sepsis	57 (IQR: 39–70)	55 (IQR: 40–72)	P > 0.05
Levi et al, 2007 [27]	224	1440, 485/955	Sever sepsis	59.6 ± 16.1	58.4 ± 16.0	P = 0.90 > 0.05
Liu et al, 2014 [28]	1	37, 22/15	Sepsis	48.86 ± 14.3	47.47 ± 14.68	P = 0.935 > 0.05
Liu et al, 2009 [29]	1	27, 12/15	Sepsis	47.4 ± 16.8	48.3 ± 14.1	P = 0.708 > 0.05
Peng et al, 2013 [30]	1	112, 56/56	Sepsis with pre-DIC	63.5 ± 7.8	63.5 ± 7.8	P > 0.05
Wang et al, 2012 [31]	1	48, 24/24	Sepsis	52.7 ± 9.4	54.3 ± 8.6	P > 0.05
Wu et al, 2011 [32]	1	85, 45/40	Sepsis	68 ± 13	67 ± 14	P = 0.684 > 0.05
Zhang et al, 2006 [33]	1	22, 11/11	Sever sepsis	59.55 ± 6.15	59.36 ± 8.05	P > 0.05
Zhao et al, 2009 [34]	1	79, 37/42	Sepsis	61.5 ± 11.9	60.6 ± 15.9	P > 0.05
Zhao et al, 2007 [35]	1	52, 27/25	Sever sepsis	NR	NR	P > 0.05
Zhang et al, 2016 [36]	1	106, 53/53	Sepsis	43.5 ± 6.6	43.5 ± 6.6	P > 0.05

NR not reported, UFH unfractionated heparin, IQR interquartile range

Table 2. Characteristics and physiological parameters of patients in the included studies
Article, year	APACHE II score		P value	Intervention		28 d Mortality (%)		P value
Article, year	UFH	Control	P value	UFH	Control	UFH	Control	P value
Deng et al, 2017 [22]	20.5 ± 4.2	21.8 ± 6.2	P > 0.05	UFH 7d (vein)	Usual care	21.7	30.9	P < 0.05
Gu et al, 2014 [23]	12 ± 9	16 ± 5	P > 0.05	UFH 5–10 U/(kg*h) 7d (vein)	Usual care	23.8	33.3	P > 0.05
Guo et al, 2019 [24]	15.22 ± 5.34	18.16 ± 5.53	P > 0.05	UFH 70 U/kg 5–7d (vein)	Usual care + saline	NR	NR	NR
Hou et al, 2011 [25]	11.8 ± 3.5	15.3 ± 6.4	P > 0.05	UFH 3–4 U/kg/h 7d (vein)	Usual care	15	25	P = 0.429 > 0.05
Jaimes et al, 2009 [26]	9 (IQR: 7–13)	10 (IQR: 6–14)	P > 0.05	UFH 500 U/h 5–7d (vein)	Usual care + saline	14	25	P = 0.652 > 0.05
Levi et al, 2007 [27]	23.8 ± 7.6	24.0 ± 7.4	P = 0.90 > 0.05	UFH 5000 units bid (subcutaneously)	Usual care + saline	29.3	31.9	P > 0.05
Liu et al, 2014 [28]	20.82 ± 6.5	21.0 ± 6.69	P = 0.935 > 0.05	UFH 70 U/kg/24 h 5–7d (vein)	Usual care + saline	31.8	40	P = 0.434 > 0.05
Liu et al, 2009 [29]	12.67 ± 4.27	15.73 ± 7.27	P = 0.708 > 0.05	UFH 70 U/kg/24 h 5–7d (vein)	Usual care + saline	33.3	36.4	P = 0.643 > 0.05
Peng et al, 2013 [30]	15.22 ± 5.34	18.46 ± 5.53	P > 0.05	UFH 70 U/kg/24 h 5–7d (vein)	Usual care + saline	12.5	28.6	P < 0.05
Wang et al, 2012 [31]	18.7 ± 6.9	15.2 ± 6.2	P > 0.05	UFH 3–4 U/kg/h 7d (vein)	Usual care	8.33	12.5	P > 0.05
Wu et al, 2011 [32]	16.69 ± 4.12	18.89 ± 5.23	P = 0.684 > 0.05	UFH 5 U/kg/h 7d (vein)	Usual care	17.78	37.5	P < 0.05
Zhang et al, 2006 [33]	NR	NR	P > 0.05	UFH 3–4 U/kg/h 7d (vein)	Usual care	27.3	27.3	P < 0.05
Zhao et al, 2009 [34]	14.5 ± 4.2	14.8 ± 6.2	P > 0.05	UFH 40–50 mg/kg/24 h 5–7d (vein)	Usual care	15.4	32.4	P = 0.03 < 0.05
Zhao et al, 2007 [35]	20.54 ± 4.8	18.19 ± 3.69	P > 0.05	UFH 300 U/h 5d (vein)	Usual care + saline	33.3	48	P > 0.05
Zhang et al, 2016 [36]	11.7 ± 3.1	13.7 ± 7.6	P > 0.05	UFH 5 U/kg/h 7d (vein)	Usual care	NR	NR	NR

NR not reported, UFH unfractionated heparin, APACHE II Acute Physiology and Chronic Health Evaluation II, IQR interquartile range

Table 3. The pooled RR values under various APACHE II scores
APACHE II cut-off	Studies	Participants	RR (95% CI)	P
APACHE II ≤ 13	3	399	0.81 [0.53, 1.26]	0.36
APACHE II > 13	9	1996	0.82 [0.71, 0.94]	0.006
APACHE II ≤ 15	5	498	0.74 [0.51, 1.07]	0.11
APACHE II > 15	7	1897	0.83 [0.72, 0.96]	0.01
APACHE II ≤ 17	7	695	0.63 [0.47, 0.86]	0.003
APACHE II > 17	5	1700	0.88 [0.76, 1.03]	0.10
APACHE II ≤ 19	8	743	0.64 [0.47, 0.86]	0.003
APACHE II > 19	4	1652	0.88 [0.76, 1.03]	0.11
APACHE II ≤ 13	4	419	0.82 [0.55, 1.24]	0.36
13 < APACHE II ≤ 17	3	276	0.46 [0.29, 0.74]	0.001
APACHEII > 17	5	1700	0.88 [0.76, 1.03]	0.10
Total	12	2395	0.82 [0.71, 0.94]	0.004