Anisodamine Critically Ill SeptIc Shock (ACIdoSIS)

Effectiveness of Anisodamine for the Treatment of Critically Ill Patients With Septic Shock: a Randomized Controlled Trial

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.

Study Overview

• Status: Completed
• Conditions: Septic Shock
• Intervention / Treatment: Drug: anisodamine

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.

• Study Type: Interventional
• Enrollment (Actual): 355
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Guangdong
    • Huizhou, Guangdong, China, 516000
      • Huizhou First Hospital
  • Hubei
    • Wuhan, Hubei, China
      • Union Hospital, Tongji medical collegue, Huazhong university of Science and Technology
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • The First Affiliated Hospital of Nanjing Medical University
    • Zhenjiang, Jiangsu, China
      • affiliated hospital, Jiangsu University
  • Shandong
    • Binzhou, Shandong, China
      • Binzhou People's hospital of Shandong province
  • Shanghai
    • Shanghai, Shanghai, China, 200001
      • department of critical care medicine, Ren Ji Hospital, School of medicine, Shanghai Jiao Tong University
  • Shanxi
    • Changzhi, Shanxi, China
      • Peace hospital of Changzhi medical college
  • Zhejiang
    • Hangzhou, Zhejiang, China
      • Sir Run Run Shaw Hospital
    • Hangzhou, Zhejiang, China, 310000
      • Zhejiang Hospital
    • Hangzhou, Zhejiang, China, 321000
      • Sir Run Run Shaw Hospital
    • Jinhua, Zhejiang, China, 321000
      • Jinhua Municipal Central Hospital
    • Lishui, Zhejiang, China, 323000
      • Department of critical care medicine, The central hospital of Lishui City
    • Ningbo, Zhejiang, China
      • Beilun People's hospital; The first affiliated hospital of Zhejiang university (Beilun Branch)
    • Taizhou, Zhejiang, China, 317000
      • Taizhou Hospital of Zhejiang Province
    • Yongkang, Zhejiang, China
      • The first People's hospital of Yongkang

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: anisodamine group; administration of the drug	Drug: anisodamine; Anisodamine will be given first as bolus of 10 mg, followed by 0.1-0.5mg/kg/hr. The adjustment of pump infusion rate is largely at the discretion of treating physician, with the aim of improving microcirculation and limit the side effect to a minimum. For example, if serum lactate continues to elevate, the infusion rate can be increased. Discontinuation on severe side effect or recovery of shock (normalized lactate, weaned from vasopressor) or death.; Other Names: 654-2
NO_INTERVENTION: control group; these arm do not use anisodamine, other resuscitation protocol is as usual.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
hospital mortality	the outcome will be assessed by using proportion of patients died, and relative risk will be reported.	from ICU admission to hospital discharge (participants will be followed for the duration of hospital stay, an expected average of 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
lactate levels	the value was measured in mmol/l, and they will be compared between both arms.	from ICU admission to hospital discharge (participants will be followed for the duration of hospital stay, an expected average of 28 days)

Collaborators and Investigators

• Sponsor: Jinhua Central Hospital
• Investigators: Study Director: kun chen, MSc, Jinhua Municipal Central Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (ACTUAL): October 1, 2020
• Study Completion (ACTUAL): October 1, 2020

Study Registration Dates

• First Submitted: April 30, 2015
• First Submitted That Met QC Criteria: May 12, 2015
• First Posted (ESTIMATE): May 13, 2015

Study Record Updates

• Last Update Posted (ACTUAL): September 29, 2021
• Last Update Submitted That Met QC Criteria: September 23, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: septic shock; anisodamine
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Shock, Septic; Shock; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Gastrointestinal Agents; Protective Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Anti-Ulcer Agents; Antioxidants; Free Radical Scavengers; Anisodamine
• Other Study ID Numbers: 2015-013