Clinical trial NCT02442440: Anisodamine Critically Ill SeptIc Shock
Official title: Effectiveness of Anisodamine for the Treatment of Critically Ill Patients With Septic Shock: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Septic Shock
Keywords: anisodamine
septic shock
Lead sponsor: Jinhua Central Hospital
Sponsor class: OTHER
First posted: 2015-05-13
Enrollment: 355
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Anisodamine has been widely used in China for its pharmacological effect on improving microcirculation during shock. It has been reported that anisodamine is effective in reducing mortality rate in children with meningitis. however, its effectiveness in patients with septic shock has not been systematically investigated. The aim of the study is to investigate the effectiveness of anisodamine in the treatment of patients with septic shock.

Detailed description: Septic shock is an important contributor of mortality in the intensive care unit (ICU). The crude mortality is reported to be from 30% to 65% (1-5). Although there are significant advances in the management of septic shock in recent decades, the mortality rate was only marginally reduced. For example, the CUB-Réa Network study reported that the mortality rate of septic shock declined from 62.1% in 1993 to 55.9% in 2000 (6). The well-known Surviving Sepsis Campaign has also made every effort to reduce mortality rate of severe sepsis and septic shock. The organization recommended bundled strategies including early goal directed therapy (EGDT) for the management of septic shock (7,8). Although EGDT was once the mainstay therapy of septic shock, its efficacy has been questioned by recent several large randomized controlled trials (9,10). Therefore, the treatment of septic shock is still a global challenge and there is no well-established intervention that can reduce its mortality.

Anisodamine is an active agent isolated from a Chinese herb medicine. Both experimental and clinical studies have shown some potential beneficial effects of anisodamine in improving outcomes of shock (11-13). It was reported that anisodamine could reduce the mortality rate of fulminant epidemic meningitis from 66.9% to 12.4% (14). The efficacy of anisodamine might be mediated via the inhibition of thromboxane synthesis, granulocyte and platelet aggregation (15). Although anisodamine has been widely used in the treatment of septic shock in mainland China, there is no solid evidence from well designed clinical trials to support its efficacy. The aim of the study is to investigate the effectiveness of anisodamine in the treatment of critically ill patients with septic shock.

Eligibility criteria: Inclusion Criteria:

* patients with septic shock

Inclusion criteria included patients with sepsis plus use of vasopressors. Systemic inflammatory response syndrome (SIRS) is defined as meeting at least one of the following 3 criteria for a systemic inflammatory response. One of the SIRS criteria must be either the WBC criteria (a) or the body temperature criteria (b):

1. White blood cell count \>12,000 or \<4,000 or \>10% band forms
2. Body temperature \>38oC (any route) or \<36oC (accepting core temperatures only; indwelling catheter, esophageal, rectal)
3. Heart rate (\> 90 beats/min) or receiving medications that slow heart rate or paced rhythm.

Suspected or documented infection included the following sites: thorax, urinary tract, abdomen, skin, sinuses, central venous catheters, and bacterial meningitis.

Septic shock was defined as sustained arterial hypotension with systolic blood pressure (SBP) \< 90 mm Hg, mean arterial pressure (MAP) \< 70 mm Hg, or an SBP decrease \> 40 mm Hg, despite adequate fluid resuscitation. To ease clinical screening process, we defined septic shock as the requirement of vasopressors despite adequate fluid resuscitation. Vasopressors include norepinephrine, epinephrine, phenylephrine and dopamine\>5mcg/kg/min.

Patients with following conditions will be excluded:

1. Age\<15 years old
2. Moribund (expected to die within 24 hours)
3. Stay in ICU for more than 24 hours
4. Contraindications to anisodamine: elevated intracranial pressure, acute phase of intracranial hemorrhage, glaucoma, untreated bowel obstruction (surgically treated obstruction is not contraindicated), enlargement of prostate without urinary catheterization.

Primary outcomes:
measure: hospital mortality
timeFrame: from ICU admission to hospital discharge (participants will be followed for the duration of hospital stay, an expected average of 28 days)
Secondary outcomes:
measure: lactate levels
timeFrame: from ICU admission to hospital discharge (participants will be followed for the duration of hospital stay, an expected average of 28 days)
Other outcomes:
Locations:
city: Huizhou
country: China
facility: Huizhou first hospital
state: Guangdong
city: Wuhan
country: China
facility: Union Hospital, Tongji medical collegue, Huazhong university of Science and Technology
state: Hubei
city: Nanjing
country: China
facility: the First Affiliated Hospital of Nanjing Medical University
state: Jiangsu
city: Zhenjiang
country: China
facility: affiliated hospital, Jiangsu University
state: Jiangsu
city: Binzhou
country: China
facility: Binzhou People's hospital of Shandong province
state: Shandong
city: Shanghai
country: China
facility: department of critical care medicine, Ren Ji Hospital, School of medicine, Shanghai Jiao Tong University
state: Shanghai
city: Changzhi
country: China
facility: Peace hospital of Changzhi medical college
state: Shanxi
city: Hangzhou
country: China
facility: Zhejiang Hospital
state: Zhejiang
city: Hangzhou
country: China
facility: Sir Run Run Shaw hospital
state: Zhejiang
city: Hangzhou
country: China
facility: Sir Run Run Shaw hospital
state: Zhejiang
city: Jinhua
country: China
facility: Jinhua Municipal Central Hospital
state: Zhejiang
city: Lishui
country: China
facility: Department of critical care medicine, The central hospital of Lishui City
state: Zhejiang
city: Ningbo
country: China
facility: Beilun People's hospital; The first affiliated hospital of Zhejiang university (Beilun Branch)
state: Zhejiang
city: Taizhou
country: China
facility: Taizhou hospital of Zhejiang province
state: Zhejiang
city: Yongkang
country: China
facility: The first People's hospital of Yongkang
state: Zhejiang
Study officials:
affiliation: Jinhua Municipal Central Hospital
name: kun chen, MSc
role: STUDY_DIRECTOR
References:
citation: Yu Y, Zhu C, Hong Y, Chen L, Huang Z, Zhou J, Tian X, Liu D, Ren B, Zhang C, Hu C, Wang X, Yin R, Gao Y, Zhang Z. Effectiveness of anisodamine for the treatment of critically ill patients with septic shock: a multicentre randomized controlled trial. Crit Care. 2021 Sep 27;25(1):349. doi: 10.1186/s13054-021-03774-4.
citation: Zheng Y, Li Y, Liu X, Zhang R, Wang Z, Sun H, Liu S. A phase III, multicenter randomized controlled trial of neo-adjuvant chemotherapy paclitaxel plus cisplatin versus surgery alone for stage IIA-IIIB esophageal squamous cell carcinoma. J Thorac Dis. 2017 Jan;9(1):200-204. doi: 10.21037/jtd.2017.01.44.
citation: Zhang Z, Zhou J, Shang Y, Wang X, Yin R, Zhu Z, Chen W, Tian X, Yu Y, Zuo X, Chen K, Ji X, Ni H; Anisodamine Critically Ill SeptIc Shock (ACIdoSIS) study group. Effectiveness of anisodamine for the treatment of critically ill patients with septic shock (ACIdoSIS study): study protocol for randomized controlled trial. Ann Transl Med. 2015 Oct;3(17):246. doi: 10.3978/j.issn.2305-5839.2015.10.03.