Clinical trial NCT03643367: Sevoflurane Sedation in Patients With Septic Shock
Official title: Sevoflurane Sedation: A Potentially Promising Immunomodulation in Patients With Septic Shock
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE2
Conditions: Shock, Septic
Keywords: Sepsis
Septic Shock
Sevoflurane Conditioning
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: Kantonsspital Münsterlingen
name: Triemli Hospital
name: Waid City Hospital, Zurich
First posted: 2018-08-22
Enrollment: 153
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Patients with septic shock are intubated and ventilated and therefore need sedation. So far, most ICU centers use intravenously applied sedatives in these patients. In the proposed study, we will switch sedation from an intravenous to a volatile anesthetic for a short period of time (4 hours) to explore if sepsis markers improve within the following 120 hours upon sevoflurane conditioning.
Primary purpose: TREATMENT

Brief summary: Recent in vivo studies from others as well as the investigators group demonstrated that volatile anesthetics immunomodulate sepsis and improve outcome. Also, several clinical trials have convincingly shown that application of a volatile anesthetic provides protection in patients undergoing major surgery.

Patients with sepsis are intubated and ventilated and therefore need sedation. So far, most ICU centers use intravenously applied sedatives in these patients. In the proposed study, we will switch sedation from an intravenous to a volatile anesthetic for a short period of time to explore if sepsis markers improve within the following 120 hours upon sevoflurane conditioning.

Detailed description: This randomized controlled trial (RCT) will be conducted over a period of 48 months, to investigate if volatile anesthetics have a positive effect on the prognostic sepsis marker IL-6. All patients with septic shock are intubated, ventilated and sedated with an intravenous anesthetic. In this study, eligible patients diagnosed with septic shock will be randomized 1:1 to the 'volatile group' with interruption of the propofol infusion, followed by a 4-hour sedation with the volatile anesthetic sevoflurane, or a continuous intravenous sedation ('intravenous' =control group). In both groups, 'intravenous' and 'volatile', the inflammatory markers as well as clinical parameters will be determined. The investigators will explore if there is a difference between the course of sepsis markers of the two groups within 5 days after intervention in favor of the volatile group.

Eligibility criteria: Inclusion Criteria:

* Male and female patients, age 18 to 80 years
* Intensive care Unit (ICU) patients with septic shock (despite fluid resuscitation vasopressors needed to maintain mean arterial pressure ≥65 millimeter of mercury (mmHg), and serum lactate \>2mmol/l even with fluid application)
* Treatment of septic shock on ICU with vasopressors not longer than 12 hours
* Sedation and mechanical ventilation on ICU
* Female patients of childbearing potential with negative pregnancy test
* Informed Consent as documented by signature

Exclusion Criteria:

* Previous surgery and/or anesthesia (within last 7 days)
* Application of nitric oxide (NO)
* Suspected or known intolerance by history to volatile anesthetics (malignant hyperthermia)
* Immunosuppressive agents
* Systemic corticosteroids in the phase before hospitalization (\> 10mg/d prednisone)
* Significant concomitant disease (acute cerebral vascular event, acute coronary syndrome, decompensated heart failure, acute pulmonary edema, major cardiac arrhythmia, seizure, burn, chronic kidney disease, end stage liver failure, neuromuscular disease)
* AIDS
* Autoimmune disease
* Organ transplant
* Subject with active malignancy receiving
* chemotherapy or radiation treatment within last 60 days
* Hepatitis B/C virus infection
* Anti-tumor necrosis factor (TNF) therapy
* Pregnancy and/or Breast feeding
* Use of cytokine absorber
* Enrollment in any other clinical trial during the course of this trial, 30 days prior to its beginning or 30 days after its completion

Primary outcomes:
measure: Concentration of interleukin-6 over time
timeFrame: 5 days
Secondary outcomes:
measure: Pro-/anti-inflammatory mediators
timeFrame: 5 days
measure: Vasopressor support
timeFrame: 5 days
measure: Sequential organ failure score (SOFA Score)
timeFrame: 5 days
measure: Richmond Agitation Sedation Scale
timeFrame: 5 days
measure: Duration of mechanical ventilation
timeFrame: 28 days
measure: Mortality
timeFrame: 28 days
Other outcomes:
Locations:
city: Münsterlingen
country: Switzerland
facility: Kantonasspital Münsterlingen
city: Zurich
country: Switzerland
facility: University Hospital of Zurich
city: Zürich
country: Switzerland
facility: Stadtspital Triemli
city: Zürich
country: Switzerland
facility: Waidspital Zürich
Study officials:
affiliation: University of Zurich
name: Martin Schlaepfer, PD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tang BM, McLean AS, Dawes IW, Huang SJ, Lin RC. The use of gene-expression profiling to identify candidate genes in human sepsis. Am J Respir Crit Care Med. 2007 Oct 1;176(7):676-84. doi: 10.1164/rccm.200612-1819OC. Epub 2007 Jun 15.
citation: Lu Y, Wang J, Yan J, Yang Y, Sun Y, Huang Y, Hu R, Zhang Y, Jiang H. Sevoflurane attenuate hypoxia-induced VEGF level in tongue squamous cell carcinoma cell by upregulating the DNA methylation states of the promoter region. Biomed Pharmacother. 2015 Apr;71:139-45. doi: 10.1016/j.biopha.2015.02.032. Epub 2015 Mar 3.
citation: Klag T, Cantara G, Sechtem U, Athanasiadis A. Interleukin-6 Kinetics can be Useful for Early Treatment Monitoring of Severe Bacterial Sepsis and Septic Shock. Infect Dis Rep. 2016 Mar 21;8(1):6213. doi: 10.4081/idr.2016.6213. eCollection 2016 Mar 21.
citation: Rios-Toro JJ, Marquez-Coello M, Garcia-Alvarez JM, Martin-Aspas A, Rivera-Fernandez R, Saez de Benito A, Giron-Gonzalez JA. Soluble membrane receptors, interleukin 6, procalcitonin and C reactive protein as prognostic markers in patients with severe sepsis and septic shock. PLoS One. 2017 Apr 5;12(4):e0175254. doi: 10.1371/journal.pone.0175254. eCollection 2017.
citation: Tschaikowsky K, Hedwig-Geissing M, Braun GG, Radespiel-Troeger M. Predictive value of procalcitonin, interleukin-6, and C-reactive protein for survival in postoperative patients with severe sepsis. J Crit Care. 2011 Feb;26(1):54-64. doi: 10.1016/j.jcrc.2010.04.011. Epub 2010 Jun 19.
citation: Gordon AC, Mason AJ, Thirunavukkarasu N, Perkins GD, Cecconi M, Cepkova M, Pogson DG, Aya HD, Anjum A, Frazier GJ, Santhakumaran S, Ashby D, Brett SJ; VANISH Investigators. Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial. JAMA. 2016 Aug 2;316(5):509-18. doi: 10.1001/jama.2016.10485.
citation: Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, Angus DC, Reinhart K; International Forum of Acute Care Trialists. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016 Feb 1;193(3):259-72. doi: 10.1164/rccm.201504-0781OC.
citation: Kellner P, Muller M, Piegeler T, Eugster P, Booy C, Schlapfer M, Beck-Schimmer B. Sevoflurane Abolishes Oxygenation Impairment in a Long-Term Rat Model of Acute Lung Injury. Anesth Analg. 2017 Jan;124(1):194-203. doi: 10.1213/ANE.0000000000001530.