Abstract
Background
Despite great advancement in treatment of sepsis, mortality of sepsis remains unacceptably high, even with the modern antibiotic and intensive care technologies. Considering the key role of immune dysfunction in sepsis pathophysiology, different treatments were evaluated, but failed to improve survival of patients. Natural remedies have been tested in various studies to overcome sepsis. In this study, we aim to review some of the evidence from clinical, in vitro and in vivo studies about the effect of alternative medicine on sepsis management.
Methods
The following databases were searched up to March 2014: PubMed, Scopus, Web of Science, Ovid and Google Scholar using combination of Mesh term. All in vitro and in vivo studies, also clinical trials, published in English, which evaluated alternative medicine in management of sepsis were included.
Results
Out of 95 relevant studies, the inclusion criteria were met for 79 cases. Among them, 18 studies were performed on humans. The most herbal medicine, including Xubijing (n=10) and then Rhubarb (n=3). Most of the reviewed botanical medicines modulate the immune system. Reduction of mortality was also reported in studies.
Conclusions
Modulation of immune system, anti-inflammatory activities and improvement of survival were the action of herbal medicine. A monovalent approach is not enough for treatment of sepsis, we recommend further studies to identify active component of herbal and use them in combination. Also an animal model of sepsis does not exactly mimic human sepsis, so more clinical studies should be performed. With no new drug on the horizon, herbal medicine will be promising for treatment of sepsis.
Introduction
Sepsis is a systemic inflammatory response to infection that is initiated by bacteria and their related toxins. Ranging from the systemic inflammatory response syndrome (SIRS) and its complication septic shock and multiple organ dysfunction syndrome (MODS), sepsis represents the leading cause of death in intensive care patients [1, 2]. SIRS leads to endothelial dysfunction, impairment of microcirculation, tissue hypoxia, apoptosis and finally multiple organ failure and death [3]. Following the initial host and microbial interaction, inflammatory cytokines (such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6 and IL-8) are released by activating macrophages and CD4 T cell within the first hour after infection. To prevent severe damage, anti-inflammatory mediators (such as IL-10, IL-13, IL-14 and transforming growth factor-β (TGF-β)) are released [4, 5]. With advances in the understanding of the pro-inflammatory versus anti-inflammatory immune responses during sepsis in recent years, studies have demonstrated that both types of cytokines are regulated simultaneously at the onset of sepsis [7, 8]. These findings implicate that drugs, multi-targeting inflammatory mediators will provide a promising strategy in treatment of sepsis or even protect hosts from sepsis. Several immunomodulatory therapies have been evaluated in sepsis. Corticosteroids [9], anti-TNF-α antibodies [10], anti-interleukin antibodies [11], platelet activating factor (PAF) antagonists [12], antioxidants, especially selenium [13, 14], modulation of coagulation and complement pathway [15] are examples of immunotherapy in sepsis, and some of them show a positive effect on survival [16]. It is likely that multiple immunomodulatory strategies will be necessary to achieve clinical success. Owing to numerous and redundant pathways are involved in sepsis.
Alternative medicine, especially herbal medicine, usually provides multiple activities including anti-infection, anti-inflammation or immunomodulation, which provide a promising strategy in treatment of sepsis or even protect the host from sepsis [17, 18]. Thus, in this study, we aim to review some of the evidence from clinical in vitro and in vivo studies about the efficacy of alternative medicine (especially herbs) on sepsis.
Methods
Search strategy
A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, Ovid and Google Scholar from 1966 to March 2104 using the following Mesh keywords: (1) “Alternative medicine”, (2) “Herbal medicine”, (3) “Complementary medicine”, (4) “Homeopathy”, (5) “Phytotherapy”, (6) “Organotherapy”, (7) “Sepsis”, (8) “Septic shock”. All keywords from 1 to 6 separately combined with each keyword from 7 to 8 in all databases without narrowing or limiting search items. Publications with available abstracts were reviewed. The reference list of each eligible study was also checked to identify additional studies.
Inclusion/exclusion criteria
All in vitro and in vivo studies, and also randomized and quasi-randomized clinical trials, both in animal and human studies were included. The main outcomes were defined as efficacy of alternative medicine in management of sepsis (both changes in inflammatory mediators and also survival) and safety of interventions.
The following were excluded: review, letters and editorials, and unpublished documents; report published as meeting abstracts only; where insufficient data were reported to allow conclusion.
Data from eligible studies were extracted individually and compared by two authors using standard form that included study design, types of participants, type of sepsis model, sample size, age, gender, types of intervention (treatment and control group), route of administration, duration of treatment and follow-up, dosing regimen and outcomes (measured biomarkers and survival). Disagreements were resolved through discussion; if necessary, they consulted a third person. A narrative synthesis was conducted, and data were extracted into tables and summarized.
Results
Following initial screening of mentioned databases, a total of 126 citations (12 duplicates) were extracted, but only 95 of them were potentially eligible to include for investigation of objectives (according to our proposed inclusion criteria) based on title and abstract. The full text searching excluded another 16 citations, and the remaining 79 papers were considered relevant for data extraction and following analysis. Table 1 lists the characteristics of the included studies.
Summary of findings and study characteristics.
| Author [reference] | Types of animal/participants | Types of sepsis model | Intervention group, n | Control group, n | Dose/route | Duration of treatment/follow-up | Laboratory data | Clinical data | Effect (conclusion) |
|---|---|---|---|---|---|---|---|---|---|
| Abdel-salam et al. [48] | Rats | LPS | Capsaicin (n=35), 7 groups (n=5) | (n=5) (vehicle of the administered drug) | 15, 1,500 μg/kg 10, 100, 400 μg/kg Oral & i.p. | 4 h | ↓MDA, ↓glutathione, ↓serum Na in liver & lung | – | Positive |
| Ahn et al. [44] | Rats | S. aureus induced sepsis | Ginsan (Panax ginseng) | – | ? | Pre-post | IL-1β, IL-6, INFγ, IL-2 and IL-8 decreased significantly | – | Positive |
| Alici et al. [49] | Rats | E. coli induced | Nigella sativa oil (n=24), 3 groups | n=8 (Normal saline) | 50 g/kg i.p. | 24 h | ↓ET-1, ↓MDA significantly ↑SOD (p: 0.02) | – | Positive |
| Bae et al. [50] | Rats | LPS | Nardostachys jatamansi | – | 1, 5,10 mg/kg, oral | Pre-post (1 h) | ↓IL-1β, ↓IL-6, ↓TNF-α, ↓INF-α/β | – | Positive |
| Barak et al. [31] | Blood (monocyte culture) | LPS | PADMA-28 (herbal combination) | – | 25/50 μg/well | 24 h | ↓IL-6, ↓TNF-α, ↓IL-8, ↓IL-β, ↑IL-10 | – | Positive (both) dose |
| Cai et al. [45] | Patient | Septic patient | Xuebijing (n=79) | Cefoperazon Sodium sulbactam Sodium (n=75) | 100 mL/BID | 7 days | ↓PCT, ↓CRP and ↓WBC | Improve clinical symptom, Reduce course of treatment, ↑curative effect | Positive (significant) |
| Canturk et al. [51] | Rats | E. coli induced | Ginco biloba (n=10) | Saline/ Indomethacin, PGE2 (n=10 each group) | – | – | – | Indomethacin do not decrease mortality | ? |
| Chen et al. [52] | Patients | Toxic paralytic ileus | Rhubarb | Placebo | Oral/Enema | 24, 48, 72 h | ↓TNF-α (p: 0.001) | SIRS improved in 44 % of patients after 72 h | Positive |
| Chiou et al. [53] | Rats | E. coli LPS | Evodia rataecarpa | – | 25, 50, 100 mg/kg | Pre-post (1 h) | ↓NO significantly (iNOS inhibition) | – | – |
| Dadkhah et al. [54] | Rats | CLP | Caraway extract | – | 50, 100 mg/kg i.p. | Pre-post (24 h) | ↓Lipid peroxidation in liver & kidney | – | Positive |
| Dadkhah et al. [55] | Rats | CLP | STWS (herbal combination) | – | 2.5, 5, 10 mg/kg i.p. | Pre-post (24 h) | No effect | – | Negative |
| Dipaola et al. [56] | Rats | Zymosan | Green tea extract | – | 25 mg/kg i.p. | 1 and 6 h treatment, 12 days F/O | ↓MPO, ↓iNOS significantly | – | Positive |
| Eslami et al. [19] | Patients | Severe sepsis | Septimeb® (n=16) | Conventional Therapy (n=13) | i.v. | 14 days treatment, 28 days F/O | No change of IL-2, TNF-α, PGF, MMP-2 | ↓mortality significantly (p: 0.048) | Positive |
| Fang et al. [57] | Patients | Sepsis | Raw rhubarb (n=18) | Conventional therapy (n=22) | 9 g/d, P.O | Pre-Post F/O: 6 days | ↓plasma d-lactate and procalcitonin | – | Positive |
| Frass et al. [58] | Patients | Severe sepsis | Globules (n=35) | Placebo (n=35) | 200 cm3, q12 h | During stay in ICU | – | ↑Survival after 30 days was not significant, but after 180 days was significant (p: 0.045) | Positive (adjunctive homeopathic treatment) |
| Gao et al. [59] | Rats | CLP | Astragalus membranaceus Roots | – | 100, 400 mg/kg oral | Pre-post (1 h) | ↓MPO, ↓LDH, ↓AST with dose of 400 mg/kg | ↑Survival (in 400 mg/kg) | Positive |
| Garrido et al. [60] | Rats | LPS | Mangifera indica L. (Vimang) | – | 20 mg/kg | – | ↓TNF-α, ↓NO | – | Positive |
| Han et al. [61] | Rats | LPS | Tongfu granules | Rhubarb or magnolia cortex | I: 28 g/kg/d p.o. C: 5 g/kg/d p.o. | T: 24, 48, 72 h, F/O: 72 h | ↓TNF-α, ↓IL-8 significantly | – | Positive |
| He et al. [62] | Rats | Acintobacter | Xuebijing (n=18) | Control (n=36) | 4 mL/kg q12 h i.v. | 6, 12, 24 h | ↓IL-8, TNF-α, ↑annexin A1 | – | Positive |
| Hong et al. [63] | Rats | CLP | MADG (n=80) | (n=20) | 50 mg/kg oral | 24, 41, 72 h F/O: 10 days | ↓Cytokine levels | ↑Survival (p<0.05) | Positive |
| Ikezoe et al. [35] | Rat/Macrophage | LPS (E. coli) | PC-SPES (8 herbs) | – | 320 mg/cap, i.p. (160 mg) | t: 3 h, F/O: 72 h | ↓NF-κB, ↓TNF-α, ↓IL1-β, ↓IL-6 | – | Positive |
| Jiang et al. [64] | Rats | CLP | Xuebijing | – | – | – | ↓NF-ĸB production | ↓Mortality (p<0.05) | Positive |
| Jiang et al. [65] | Rats/Macrophage | CLP | Rosmarinic acid | Imipenem | i.v. | Pre-post | ↓TNF-α, ↓IL-6 (both group), ↑IL-10 (in vitro) | Improvement of hemodynamic, ↓in serum enzyme | Positive (NF-ĸB inhibition) |
| Jiang et al. [66] | Rats/Macrophage | CLP | Paeoniflorin | Imipenem | i.p. | Pre-post | ↓TNF-α, ↓IL-6, ↓NF-ĸB, ↑IL-10 | Improvement of hemodynamic, ↓in serum enzyme | Positive (NF-ĸB inhibition) |
| Jiang et al. [67] | Rats/Macrophage | CLP | Cornuside (secoiridoid glucoside compound) | Imipenem | i.v. | Pre-post | ↑IL-10, ↓IL-6, ↓NO | ↓Bacterial count | Positive |
| Jiang et al. [68] | Rats/Macrophage | CLP | Forsythoside B | Imipenem | i.v. | Pre-post | ↓TNF-α, ↓IL-6, ↓HMGB1, ↑IL-10 | ↓Mortality | Positive |
| Kawagnchi et al. [69] | Rats | Salmonella | Naringin | – | 1 mg | Pre-post (3 h) | ↓LPS, ↓TNF-α, ↓Fibrinogen, ↓CD14 | ↓Bacterial count in spleen& liver | Effect was time and dose dependent |
| Kim et al. [70] | Rats/Macrophage | LPS | Salvia miltiorrhiza Bunge | – | – | – | ↓NO, ↓PGE2, ↓CoX2 and ↓iNOS in both model | – | Positive |
| Kim et al. [71] | Rats | ALI (LPS) | Alisma orientale | – | Intratracheal | – | ↓Inflammatory cytokines | ↑Survival | Positive |
| Lee et al. [72] | Rats | LPS | Pulsatilla koreana | ? | ? | ? | ↓IL-IB, ↓IL-6, ↓TNF-α, ↓NO, ↓ICAM-1, ↓PGE2, ↑IL-10 | – | Positive |
| Lee et al. [73] | Rats | TNF-α induced | Illicium verum | – | 10 mg/kg | ? | ↓ALT | ↑Survival | Positive |
| Lee et al. [74] | Rats | LPS | Baicalein | – | 10 mg/kg i.v. | F/O: 6 h | ↑superoxide onion, ↓caspase-3 induce hemoxygenase-1, ↓oxidative stress (<0.05) | ↑Cardiac contractile function | Positive |
| Li et al. [75] | Patients | Sepsis | Xuebijing (n=52) | Normal saline | 100 mL i.v | t=7 days F/O=12 days | ↓Vcam-1, ↓ICAM-1, ↓NO | ↓Mortality (28 days) (p<0.05) | Positive |
| Li et al. [76] | Rats | LPS | NiupoZhibao | – | 3 mL (1 g/kg) p.o. | t: 7 days | ↓HMGB-1 in lungs | – | Positive (↓endotoxin shock) |
| Li et al. [77] | Rats/Macrophage | ? | Salvia miltiorrhiza | – | i.p. | Pre-post | ↓NO, ↓TNF-α, ↓IL-1β, ↓IL-6 | ↑Survival | Positive (inhibition of NF-κB, inhibition of ROS) |
| Li et al. [78] | Macrophage, monocyte culture/rats | LPS/CLP | Green tea (Camellia sinensis) and EGCC | Placebo | i.p. | t: 48 h, F/O: 2 weeks | ↓HMGB-1, ↓IL-6, ↓TNF-α | ↑Survival (<0.05) | Positive |
| Li et al. [79] | Rats | CLP | QRJD/LXHX (herbal combination) | Normal saline | 24 g/kg/day oral | – | ↓Metabolic biomarkers (fat, amino acid) | ↑Survival | Positive (QRJD was more effective than LxHx) |
| Li et al. [80] | Rats | CLP | Xuebijing (96) (4 groups) | – | – | – | ↓TNF-α, ↓protein C (<0.01) | – | Prevention of sepsis Positive |
| Lin et al. [36] | Rats | Intratracheal LPS (ALI) | SFYCT (13 medicinal plants) | – | 0.5, 1, 2 mg/kg | F/O: 24 h | ↓TNF-α, ↓IL-1β, ↓IL-6, ↓NO, ↓iNOS, ↓NFκB, ↑IL-4, ↑IL-10 | ↓Pulmonary edema, ↓neutrophil infiltration | Positive |
| Lin et al. [81] | Rats | LPS (E. coli) d-galactosamine | Acanthopanaxsenticosus | – | 100, 200, 400 mg/kg i.p. | Pre-post F/O: 6 h | ↓TNF-α, ↓NO, ↓iNOS, ↓NF-κB, ↑IL-10 | ↑Survival (<0.05) | Positive (full protection with 400 mg/kg) effect dose dependent |
| Lin et al. [82] | Patients | Severe sepsis | Yeng-Xuzheng (TCM) (n=126) | – | – | 3 years | ↓TNF-α, ↓IL-8, ↓IL-6, ↓IL-18 | ↓Mortality | Use a Chinese method for mortality prediction |
| Lo et al. [83] | Rats/Macrophage | LPS induced arterial hypotension | Coptidisrhizoma+Scutellariae radix+Rhei rhizome | – | 0.01, 0.03 mg/kg | Pre-post | ↓Cytokines, ↓PGE2, ↓Cox2 and ↓iNOS expression | ↑BP | Positive |
| Ma H et al. [84] | Rats | CLP | Liu-shen wan | – | 30 mg/kg q12 h p.o. | F/O: 4 days | ↓TNF-α, ↓IL-1 ↓MDA | ↑Survival (p<0.05), ↓infection-degree, ↑immunity function | Positive (protective role in sepsis) |
| Mahmoudpoor et al. [39] | Patients | Severe sepsis | Septimeb® | – | 125 mg i.v. | t: 14 days, F/O: 28 days | ↓TNF-α, ↑total thiol molecules | Improvement of SAPS, SOFA and APACHE scores, ↑survival (p>0.05) | Positive |
| Meng et al. [85] | Rats | CLP | Antrodia comphorata (3 groups) | Saline | i.p. | Pre-post F/O: 16 h | ↓IL-6, ↓TNF-α, ↓monocyte chemotactic pro-1, ↑IL-10 | – | Positive (after 16 h) |
| Mingyu et al. [86] | Patients | SIRS | Rhubarb (n=40) | n=38 | NG | F/O: 3 days | ↓TNF-α, ↓CRP, ↓C3, C4 | ↑Cure rate (p<0.05) | Positive (antagonized the effect of pro-inflammatory cytokines |
| Motobu et al. [87] | Rats | Salmonella LPS d-galactosamin | Sugarcane extract | Saline | 500 mg/kg i.p. | Pre-post | No effect on TNF-α, AST, ALT | ↑survival of rats, ↓liver injury (p<0.05) | – |
| Oberboam et al. [88] | Rats | CLP | TraumeelS (n=15) | N/S (n=15) | i.p. | F/O: 6 h | ↓IL-1β (p: 0.03) | – | Protective effect |
| Qin et al. [89] | Septic patients with DIC | – | Xuebijing (n=88) | (n=83) | i.v. | t: 7 days, F/O: 28 days | – | ↓DIC, ↓APACHE II, ↓mortality (p: 0.034) | Positive |
| Qian et al. [24] | Rats | ALI | Shenfu (6 groups) | – | 1, 10, 100 mg/kg | F: 2 h | ↓TNF-α, ↓NFκB, ↓MPO | – | Positive effects with dose |
| >10 mg/kg | |||||||||
| Qiuz et al. [23] | Patients | Severe sepsis | Shenfu (n=36) | n=32 | i.v. | F/O: 7 days, 28 days | No effect on CRP, IL-6, IL-10, ↓IL-6, CRP after 7 days | ↓APACHE II and Marshall scores (p<0.05), no change in mortality | Positive |
| Rattmann et al. [30] | Rats | CLP | Eugenia uniflora (5 groups) | 75, 150, 300 mg/kg p.o. | Pre-post: 6 h, F/O: 7 days | ↓IL-1β, ↓TNF-α, ↓Cox, ↓iNOS | ↓Mortality (30 %) | Positive | |
| Ryu et al. [90] | Macrophage | LPS | Woody plants (83 kind) alcoholic extract | – | – | 20, 40, 20 μg/mL | Dose dependent, inhibitor of NO | – | Positive in vitro study |
| Sautebin et al. [91] | Rats | LPS (E. coli) | Blackberry | – | 5 mg/kg i.v. | Pre-post | ↓Cox, ↓iNOS, ↓MDA | ↓lung injury, ↓PMN infiltration | Positive |
| Scoparo et al. [92] | Rats | Polymicrobial sepsis | Green & black tea | – | 30, 50, 100 mg/kg, oral | – | ↓Neutrophil influx | ↓Mortality (both tea) | Positive |
| Shao et al. [93] | Rabbit | LPS | Ligustilide (n=42) (6 groups) | – | 20, 40, 80 mg/kg i.v. | q30 min | ↓TNF-α, ↓IL-1β, ↓NO (p<0.05) | ↓ALT, ↓AST↓ALP, ↓GGT↓CK, ↓LDH ↓Scr, ↓BUN | Restore, the function of vital organs |
| Su et al. [21] | Patients | Severe sepsis | QishenHouxue granule (n=82) | n=85 | – | – | ↓TNF-α-↓IL-6 (p<0.05) | ↓Mortality ↓ICU stay (p<0.01) | Positive |
| Sun et al. [94] | Rabbit | ALI by LPS | Xuebijing | Saline | – | – | ↓IL-23 Not significantly | ↑Pao2 (p<0.05) | Positive in ALI |
| Sun et al. [95] | Rat/Macrophage | LPS | Artemisia vestita | – | – | Pre-post | ↓TNF-α, ↓NF-ĸB, ↓COX-2 | ↑Survival | Positive |
| Tavasoli et al. [96] | Rat | CLP | Pomegranate extract | Sham | 250 mg/kg/d | 4 week before CLP, F/O: 10days | – | ↑Mortality ↓Bacterial load (p<0.01) | Negative |
| Teixeira et al. [97] | Patients | SIRS | – | – | – | – | – | Homeopathy | Favorable results in SIRS patients |
| Wang et al. [98] | Patients | Sepsis | Modified Liang GC san+western medicine | – | – | 0, 3, 5, 9 days | ↓TLR4, ↓TNF-α, ↓CD40L, ↓ALT, ↓AST (p<0.05, <0.01) | ↓ICU stay, ↓Bleeding, ↓APACHE II score, no effect on mortality (after 9 days) | Positive (TLR4 inhibition) |
| Wang et al. [99] | Rat | CLP | Xuebijing+Liangge san | 10 mg/kg oral | F/O: 72 h | – | ↑Survival (p<0.01) | Positive | |
| Wang et al. [100] | Rat/Macrophage | CLP | Angelica sinensis+Lipaeonia lactiflora+Atracytylodes macrocephalae | – | i.p. | t: 28, 52 h F/O: 2 weeks | ↓HMG B1, ↓TNF, ↓NO after 24 h (p<0.05) | ↑Survival | Positive |
| Wei et al. [37] | Rat | CLP | HLJDT (combination) | – | 120, 270 mg/kg oral | Pre-post F/O: 24 h | ↓TNF-α, ↓IL-1, ↓IL-6, ↓IL-17A | – | Positive (promote balance of Th1/Th2) |
| Xu et al. [101] | Rat/Macrophage | CLP | Protocatechuic aldehyde | Imipenem | i.v. | – | ↓HMGB1, ↓MPO, ↑IL-10 | ↓Lethality (+imipenem) | NF-ĸB and HMGB1 inhibition |
| Yalindag et al. [102] | Septic infants | – | Garlic | – | – | – | – | – | A case report |
| Yang et al. [103] | Piglet | ALI/ARDS by oleic acid | Sho-seiryu-to (TJ-19) | – | 3 g/kg single dose, 0.75 g/kg/bid oral | F/O: 2 weeks before drug | – | ↓PaO2, prevent airway vascular, hyperpermeability, ↓lung injury, ↓oxidative stress | Positive |
| Yang et al. [104] | Rat | CLP | AlpiniakatsamadaiHayata seeds (EAKH) | – | Oral | – | ↓ALT/↓TNF-α, ↓IL-1β, ↓NO | ↑Survival, ↓MAP | Improve, peritoneal bacterial clearance, ↓systemic inflammation |
| Yanli et al. [105] | Patients | Severe sepsis | Qishenhuoxue granule (n=82) | n=85 | – | – | ↓IL-6, ↓TNF-α, ↓d-dimer (p<0.05) | ↓ICU Stay, ↓Mortality (p>0.05) | Positive |
| Yokozawa et al. [106] | Rat | CLP | Acanthopanax radix | – | Oral | Pre-post, F/O: 30 day | ↓NO, ↓lipid peroxidation | – | Positive |
| Yun et al. [107] | Rat | CLP | Aloe vera | – | – | – | ↓TNF-α, ↓IL-1β,↑IL-6 | ↑Bacterial clearance | Positive |
| Zhang et al. [108] | Rat | Endotoxin | Aconiti tuber (Bushi) | – | – | – | – | ↑MAP<0.05 | Improve microcirculation |
| Zhang et al. [20] | Patients | Severe sepsis | Shenfu (n=36) | n=32 | 100 mL i.v. | t: 7 days, F/O: 28 days | ↓IL-6 | ↓APACHE II, ↓Mortality (p>0.05), ↑Survival time | Positive |
| Zhang et al. [109] | Rat | CLP | Xuebijing | Sham ciprofloxacin | – | T: 3, 24 h, F/O: 72 h | ↓TNF-α, ↑IL-10, ↓Th1 /TL2 After 72 h) | – | Improvement of immunological function |
| Zhang et al. [110] | Patients | Severe sepsis | Hengyan (n=22) herbal combination | – | Oral | F/O: 7 days | ↓IL-6, ↓TNF-α, ↓CD3, ↓CD4, ↓CD2,↑IL-10 (p<0.05) | ↓APACHE II | Positive (immune response) |
| Zha et al. [111] | Patients | Severe sepsis | Xuebijing (n=89) | LMWH | i.v. | – | – | ↓APACHE-II (p<0.05), ↓length of stay (p<0.05) | Improve blood coagulation factor |
| Zhu et al. [112] | Rat/Macrophage | CLP | Mung bean coat | – | Oral | – | ↓HMGB1, Levels in macrophage | ↑Survival <0.05 | Protection against sepsis |
ALT, alanine transaminase; ALI, acute lung injury; ALP, alkaline phosphatase; AST, aspartate aminotransferase; APACHE, acute physiology and chronic health evaluation; BID, twice daily; BP, blood pressure; BUN, blood urea nitrogen; CK, creatine kinase; CLP, cecal ligation puncture; COX, cyclooxygenase; CRP, C reactive protein; DIC, disseminated intravascular coagulation; CD40L, CD40 ligand; E. coli, Escherichia coli; ET, endothelin; F/O, follow-up; GGT, gamma-glutamyltransferase; HMBG, high-mobility group box; ICAM, intercellular adhesion molecule; ICU, intensive care unit; IL, interleukin; INF, interferon; iNOS, inducible nitric oxide synthase; i.p., intraperitoneal; i.v., intravenous; LDH, lactate dehydrogenase; LMWH, low-molecular-weight heparin; LPS, lipopolysaccharide; MDA, malondialdehyde; MMP, matrix metalloproteinases; MPO, myeloperoxidase; NO, nitric oxide; NF-ĸB, nuclear Factor kappa B; PCT, procalcitonin; PG, prostaglandin; p.o., per oral; PMN, polymorphonuclear leukocytes; QRJD, Qin–Re–Jie–Du; LXHX, Liang–Xue–Huo–Xue; SPA, simplified acute physiology score; SIRS, systemic inflammatory response syndrome; SOFA, sequential organ failure assessment; SOD, superoxide dismutase; TNF, tumor necrosis factor; TLR, toll-like receptors; T, treatment; VCAM, vascular cell adhesion protein; MADG, monoacetyldiglyceride.
From the 79 studies, 20 of them were human studies, 15 studies were in vitro studies (mostly on macrophage culture) and the remaining were animal studies.
As summarized in Table 1, almost all of the studies used herbal medicine to deal with sepsis, the most of the herbal has a Chinese origin. The primary endpoints of most of the studies were changes in inflammatory markers including different types of interleukins and TNF-α. Some of them evaluate survival as secondary outcomes.
The cecal ligation puncture (CLP) model was the commonest way to induce sepsis in animal models. About 5.5 % of the studies reported a negative outcome regarding improvement of sepsis.
Xubijing was the most studied plants (n=10), Rhubarb, Ginko, Green tea, caraway were examples of other botanical studied interventions.
Discussion
Many studies report a positive effect of different herbal plants on sepsis and septic shock. Based on the theory of the role of systemic inflammatory response in sepsis, most of these studies selected plants which hypothesized to have anti-inflammatory or immunomodulatory effects. Also, considering sepsis as an infectious disease, some of these plants control bacterial infection in sepsis. The remarkable point about these studies (mostly animal studies) is that these plants increase survival of septic animal/patients.
The levels of most important cytokines (such as TNF-α, IL-6 and IL-1β) and also levels of oxidative stress, such as nitric oxide (NO), myeloperoxidase (MPO) and lipid peroxidation products were decreased after intervention in most of the studies.
As shown in Table 1, nine studies were clinical trials of herbal medicine in septic patients. Although those clinical trials, all have methodological issues (regarding sample size, methods of randomization, duration of treatment and follow-up), but all of them show a positive effect of adjunctive herbal treatments to conventional treatment sepsis therapies. Two of these studies used homeopathy for treatment of sepsis. The number of patients was from 40 to 90, not enough to draw a definite conclusion. It is not clear from the method of these studies that if all conditions are identical for both groups or not; because of the nonhomogeneous condition, it is difficult to reach a conclusion about the efficacy of an adjunctive therapy especially in an extreme disease like sepsis. Even decreasing of inflammatory biomarkers does not prove anything, since other sepsis treatment modalities, such as broad spectrum antibiotics or sometimes hydrocortisone, may be effective on these markers. Eslami et al. [19] performed a clinical trial on a patent herbal drug named Septimeb; the levels of inflammatory markers didn’t change significantly after the intervention, but survival of patients increased significantly (p: 0.04). Zhang et al. [20] also showed a significant increase in survival (p<0.01) after intervention with Shen Fu in 36 septic patients, the duration of treatment was 7 days, with a 28-day follow-up. Su et al. [21] also showed a significant decrease in mortality (p<0.01) after treatment with Qishen Houxue granules in 82 septic patients. The length of ICU stays and levels of TNF-α and IL-6 also decreased significantly in this study (p<0.05).
Shen Fu or with the Latin name Scierotium Pararadicis Poriae Cocos traditionally used in China for its calming effects on the mind, diuretic effects, antibacterial effects and also lowering blood sugar and strengthen cardiac mortality. This drug has not anti-inflammatory effects [22]. We found three studies were evaluated the effect of Shen Fu on sepsis, of which two of them were in human. In Qiu et al. [23] study, Shen Fu had no effect on inflammatory markers (such as IL-6 and C – reactive protein) and did not change mortality, but in the Zhang et al. [20] Shen Fu decreased IL-6 level and also increased survival time. Qian et al. [24] induced acute lung injury in rats and treated them with 1, 10 and 100 mg/kg of Shen Fu, two hours follow-up showed a decrease in levels of TNF-α, NF-ĸB and MPO with a dose greater than 10 mg/kg. The results of these studies are heterogeneous. Ji et al. [25] inject Shen Fu to a porcine model of cardiac arrest, they showed that Shen Fu could attenuate post resuscitation myocardial injury through beneficial effects on energy metabolism and antioxidant capacity. Regarding the complicated nature of sepsis, it might be possible that herbal medicine like Shen Fu affect some pathways in this disease that it is not exactly related to inflammatory or immunomodulatory mechanisms.
Xuebijing (XBJ) injection is traditional Chinese medicine preparations consist of extracts of five Chinese herbs (i. e. Carthamus tinctorius or safflower, Paeoniae radix or red poney root, Salvia divinorum or Diviner’s sage, Angelica sinensis or female ginseng and Lingusticumwallichiifranchet or chuanxiong in Chinese [26]). It shows satisfactory antioxidant, anti-inflammatory effects in a series of animal experiments and is widely used in the treatment of sepsis. We found 10 studies which evaluated this herbal combination in treatment of sepsis. Four clinical trials investigated the effect of XBJ in septic patients. In these trials (with an average sample size of 80 patients) mortality decreased. Some inflammatory mediators indicated endothelial dysfunction such as VCAM-1 and ICAM-1, improved with XBJ injection. Animal studies with XBJ showed decreased levels of inflammatory markers such as IL-6, TNF-α or an increase of IL-10 in septic rats or rabbits (induced by CLP method). XBJ is a component of five plants, with the latest analysis of its component showed it is including amino acids, phenolic acids, flavonoid glycoside, terpene glycoside and phthalide [27]. These component especially flavonoids and terpens poses anti-inflammatory actions and through this mechanism modulate the inflammatory pathway in sepsis [28]. In vitro experimental systems showed that flavonoids possess anti-inflammatory, antiviral, antioxidant and anti-carcinogenic properties [29]. Rattmann et al. [30] extracted flavonoids from Eugenia uniflora and treated septic rats with this flavonoid-rich fraction. The 7-day follow-up of mice showed that oral administration of extract reduced the late mortality by 30 %. Serum analysis showed reduced levels of TNF-α and IL-1β. The results of this study indicate that inhibition of pro-inflammatory process in sepsis, which not only reduced levels of inflammatory cytokines but also delay mortality.
We found five studies that use combination of plants for treatment of sepsis including: PADMA, STWS, PC-SPES, SFYCT and HLJDT. PADMA 28 is a multicomponent, traditional Tibetan herbal plant remedy comprising 20 specific herbs and 2 nonherbal ingredients. The main PADMA’s active substances are bioflavonoids, tannins, phenolic acids, phenolic alcohols and terpenoids. Which claim that has anti-inflammatory, anti-oxidant, antimicrobial, angioprotecting and wound healing properties [31, 32]. These entire mentioned characteristic might be useful in sepsis. From 20 herbs present in PADMA, 13 of them have well-documented antimicrobial activity (e. g. Azadirachtaindica active against Gram-negative bacteria, or Aeglemarmelos has antifungal activity) [33]. We found an in vitro study on human blood monocytes which stimulated by endotoxine, this study shows that an aqueous extract of PADMA 28 significantly decreased cytokines released such as IL-1β, IL-6, IL-8 and TNF-α [31].
PC-SPES, a commercially available combination of eight herbs (Chrysanthemum, Isatis, Licorice, Gandoderma lucidum, Panax pseudo-ginseng, Rabdosia rubescense, Saw plalmetto and Scutellaria) is used for prostate health and strengthening of the immune system [34]. Ikezoa et al. showed that PC-SPES reduced NF-κB activity in LPS-induced macrophage and consequently inhibits production of TNF-α, IL-1β, IL-6 and COX-2 [35]. The same effect was shown in septic mice. Therefore, it is obvious that drug with a combination of several plant extracts has multiple mechanisms of action and might be effective in multiple pathway (inflammatory or immune) in sepsis.
SFYCT (Sheng–Fei–Yu–Chuan–Tang) is a traditional Chinese medicine formula consisting of 13 medicinal plants, was used to treat patients with lung disease. Lin et al. [36] showed an inhibition of oxidative stress pathway and the increase in inflammatory cytokines after SFYCT injection in rats with acute lung. Wei et al. showed same results with HLJDT (Huanglian–Jie–Du–Tang) in a pre-post study. HLJDT is a famous traditional Chinese formula that has been widely used clinically to treat cerebral ischemia, toxic heat syndrome and infectious diseases [37].
In Iran, we had an experience with an herbal drug named IMOD® (also Septimeb®, and Seratud®, Pars Roos, Iran). IMOD is a mixture of urtica carotenoids, urea and selenium that can regulate TNF-α, interferon-γ (IFN-γ) and IL-2. This drug has been patented in Europe with code of WO/2007/087825 for its immunomodulation and anti-TNF-α capacities and improving CD4 in HIV positive patients [38]. In a two randomized controlled trials [19, 39] in patients with severe sepsis, 50 patients enrolled (in total), IMOD was injected for 14 days and patients followed up for 28 days. All patients received standard treatment for sepsis based on sepsis campaign guideline. Inflammatory biomarkers such as IL-1, IL-2, IL-6, Plasminogen activator inhibitor (PAI-1), NO, lipid peroxidation and total antioxidant power did not change significantly between groups, except for the level of TNF-α, and total thiol molecules which improved significantly. The ICU score including SAPS (p: 0.029), SOFA (p: 0.003) and APACHE II (p: 0.008) reduced significantly after intervention. The 28-day mortality also decreased significantly with IMOD (p: 0.04). Although the sample size was small in these trials, but improvement of clinical scores and also survival confirms potential of herbal remedies in alleviation of sepsis severity.
Immune system and inflammatory cytokines have a key role in pathogenesis of sepsis, it has been suggested that the first response to infection is hyper inflammatory, which is followed by a hypo-immune state [6, 7, 40]. Regarding the pathogenesis of sepsis, immunomodulatory and anti-inflammatory therapy proposed as treatment for sepsis; but fail to improve survival of patients [16, 41]. The latest approved immunumodulatory agent was activated protein C, which has been withdrawn from the market, because of the latest meta-analysis showed the ineffectiveness of APC [42, 43]. Regarding the persisting very high mortality rate of sepsis, searches for new options in the treatment of sepsis is ongoing. Some of these, such as antioxidant therapies and stem cell and gene therapies, are still in the experimental stages, while others, such as high-volume hemofiltration, use of high cut-off membranes, non-selective adsorption like coupled plasma filtration adsorption, selective adsorption of endotoxin with polymyxin-B column, are approaches supported by randomized, controlled studies [17, 18]. These strategies, also have immunomodulation effect and in addition to the main forms of treatment of sepsis, such as antibiotics, these characteristics make it possible for successful outcomes to be achieved.
The active components of herbal medicine usually have one or more of the following properties: (1) direct attack and suppression on bacterial pathogens, (2) modulation of the host’s immune system which resulting in suppression of inflammatory response, (3) neutralization of toxic free radicals.
Examples of herbal and extract with antibacterial activity include Panax ginseng, Pomegranate extract, A. sinensis, Garlic, Grean tea, XBJ, Naringin and Alpinia katsumadai hyata seeds. Ahn et al. [44] found that Panax ginseng extract active against Staphylococcus aureus. In contrast, XBJ was effective on Gram-negative, resistant Acintobacter baumani [45]. So regarding the polymicrobial nature of sepsis, these herbal medicines could augment the antimicrobial activity of synthetic antibiotics.
As we mentioned the majority of herbal medicine modulate inflammatory and immune response. The mechanism of action is diverse. Anti-inflammatory effects, including decrease release of cytokines, including TNF-α, IL-6, IL-1β, IFN-γ, decrease level markers of endothelial dysfunction such as ICAM-1 and VCAM-1, also increase of anti-inflammatory mediators such as IL-4 and IL-10. Other mechanisms of action including decrease production of reactive oxygen species (ROS), anti-lipid production, scavenge free radicals and reduction of super oxide dismutase (SOD) activity. Spelman et al. [46] reported in an informal review that they found at least 17 herbs with immunomodulator activity. Most of them affect the immune system by regulation of cytokine release.
As we mentioned, in sepsis, the inflammatory response is partly mediated by innate immune cells (such as macrophages, monocytes and neutrophils), which not only ingest and eliminate invading pathogens but also initiate an inflammatory response upon recognition of pathogen-associated molecular patterns. The first phase response is crucial in fighting against the initial infection and drug or herbal medicine that suppresses these responses nonspecifically may worsen the sepsis process. Pro-inflammatory mediators such as high mobility group box 1 (HMGB1) functions as a late mediator of lethal endotoxaemia and sepsis. HMGB1 can be passively released from pathologically damaged cells, thereby converging infection and injury on commonly dysregulated inflammatory responses. Administration of anti-HMGB1 antibodies or inhibitors (e. g. ethyl pyruvate, nicotine, stearoyl lysophosphatidylcholine and Chinese herbs such as A. sinensis) protects mice against lethal endotoxaemia, and rescues mice from lethal experimental sepsis even when the first doses are given 24 h after onset of sepsis. So, targeting the early and late inflammatory responses specifically in sepsis, could dramatically decrease injury-elicited inflammatory responses without compromising the infection-mediated innate immunity. Bao et al. [113] review evidence that supports extracellular HMGB1 as a late mediator of inflammatory diseases and discuss the potential of several Chinese herbal components as HMGB1-targeting therapies. The found that herbals such as Radix Glycyrrhizae, Green tea, Radix Salviae Miltiorrhizae (Danshen in Chinese) could inhibit HMGB1 release or its cytokine/chemokine activities and all of them rescued mice from lethal sepsis and significantly increasing animal survival rates. Also they mentioned in their review that a combination herbal medicine named XBJ (as we discussed before) has proven to be protective in animal models of sepsis or in patients with sepsis and one of the mechanism of this herbal cocktails is HMGB1 inhibition. Therefore targeting sepsis treatment to mediators which induced injury in spite of protective mediators against infection, could be a better approach for sepsis management. Future clinical studies are anticipated to test this strategy in the clinical management of human inflammatory diseases.
The last point is that most of these research were animal based. Severe inflammatory responses in mice, does not accurately mimic sepsis in human. So drugs that help mice could make thing worse for patients [47]. There may be large differences between what is seen in vitro and clinical efficacy. When the in vitro findings do not correlate with clinical findings, clinical investigation should question the degree to which we really understand the biochemical mechanisms by which these extracts exert their clinical effects or if we are even taking the left approach to investigations.
Summary and conclusions
The treatment of sepsis remains challenging even with the development of modern antibiotics and intensive care technologies. Reliance on antibiotics and other methods targeting modulation of the systemic inflammatory response such as steroids, hemofiltration and cytokine antagonist has not led to reliable successful treatment for inflammation and infection-related shock. So researchers continue to search for treatments that could halt sepsis. Among them alternative or complementary medicine, especially herbal medicine has greatest interest. Although many of the plants listed in this review appear to be effective in sepsis, but the majority of research was performed in vitro or in animal models. There is a great need for rigorous, basic scientific investigation as well as controlled trials to examine the efficacy of herbal medicine in the treatment of septic patients. The in vitro and in vivo research suggests that the most of the reviewed botanical medicines modulate the immune system and such modulation may provide the mechanism of action for many of their therapeutic effects. Another point is that because of the complex interplay between pathways in sepsis, a monovalent approach in isolation are unlikely to attain the status of complete therapy, so it is likely that multiple modulation strategies will be necessary to achieve clinical success. Botanical extracts provide cytoprotection, anti-inflammatory and anti-infective activities in addition to immunomodulatory properties. Therefore, with no new drugs on the horizon, further research (particularly clinical trials) is indicated to elucidate the effects of botanical extracts also provided the active ingredients of the herbs. These two approaches together may provide a valuable adjunct to modern medicine and improved outcomes in patients with sepsis.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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