Sevoflurane- Safety in Long-term Sedation Procedures

Study Overview
=================
Brief Summary
-----------------
Patients needing intensive care often require sedative drugs to reduce anxiety and agitation during ventilator care and invasive therapeutic and diagnostic procedures. At present there is no optimal sedative agent for these patients. The most commonly used sedative agents in intensive care units are midazolam and propofol. Both drugs have side effects of clinical importance. At present, a viable alternative to intravenous sedation is inhalatory sedation. Sevoflurane, as other inhaled anesthetic agents, is sedative in low doses. A new simplified method of administration of isoflurane or sevoflurane has been developed. The Anesthetic Conserving Device is a modified heat-moisture exchanger (HME) that permits direct infusion of sevoflurane to the airway, where it is vaporized in an evaporator rod in the device. However, the use of sevoflurane is limited to anesthesia and sedation lasting no more than 12 hours, since the possible renal problems posed by inorganic fluoride in prolonged operations remain the subject of controversy. The primary aim (and primary hypothesis) of the current trial is to determine whether sevoflurane can be administered as a sedative drug for more than 48 hours without clinically relevant physiopathological effects on kidney and liver function. Other end-points of the trial are to evaluate the quality of sedation of sevoflurane, in terms of sedation control, the rapidity and predictability of awakening, and the incidence of delirium in critical care patients.

Official Title
-----------------
Study of the Safety of Administration of Sevoflurane for Long-term Critically Ill Patients Sedation Undergoing Mechanical Ventilation. Prospective, Controlled, Randomized, Multicenter, Clinical Trial.

Conditions
-----------------
Poisoning by Inhaled Anaesthetic, Fluoride Poisoning, Recovery From Sedation, Renal Function, Hepatic Function

Intervention / Treatment
-----------------
* Drug: Sevoflurane
* Drug: Midazolam


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Signing of the informed consent document (patient or relatives). Patient age 18 years or older. Expected minimum duration of sedation: 48 hours. Exclusion Criteria: Chronic renal failure treated with replacement therapy (hemodialysis or peritoneal dialysis). Acute kidney injury in Stage 3 of AKIN classification Grade C hepatic Child-Pugh classification Established Acute Respiratory Distress Syndrome (ARDS). Central nervous system pathology with cognitive disorders that not allow performing the test of the study: severe dementia, Alzheimer's disease, depression, schizophrenia, acute stroke. Head trauma with Glasgow <12. Patient treated with antiepileptic drugs that must be maintained during the study period Patients requiring the use of neuromuscular blocking agents during the infusion of study drug, except for the insertion of the endotracheal tube. Epidural or spinal analgesia Allergy or known hypersensitivity to any of the study drugs Patients with known or suspected genetic susceptibility to malignant hyperthermia Previous participation in this trial Participation in another clinical trial within 4 weeks prior to selection. Pregnant women

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Inhalatory sedation<br>Sevoflurane given via AnaConDa for sedation minimum 48 hours | Drug: Sevoflurane<br>* Sedation with inhaled anesthetic via AnaConDa.<br>* Other names: Sevorane, Ultane, Sojourn;|
| Active Comparator: Intravenous sedation<br>Midazolam given intravenously for sedation minimum 48 hours | Drug: Midazolam<br>* Intravenous sedation.<br>* Other names: Versed;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintenance of renal function. | Measurements in plasma: creatinine and cystatin levels. | Baseline. Posteriorly, every 12 hours for the full length of sedation. After sedation, every 24 hours up to one week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of liver function | Measurements in plasma: SGOT (aspartate aminotransferase, AST), SGPT (alanine aminotransferase, ALT), LDH (lactate dehydrogenase) alkaline phosphatase, conjugated and total bilirubin, cholesterol, triglycerides, albumin, total proteins, electrolytes and glycogen. | Baseline. Posteriorly, every 12 hours for the full length of sedation. After sedation, every 24 hours up to one week | 
| Plasma pharmacokinetics of fluoride | Determine evolutionary plasmatic levels of fluorides. | Baseline. Posteriorly, every 12 hours for the full length of sedation. After sedation, every 24 hours up to one week | 
| Incidence of delirium | The incidence of delirium will be evaluated by the CAM-ICU method. | Baseline. Posteriorly, every 12 hours for the full length of sedation. After sedation, every 24 hours up to one week | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatotoxicity, Midazolam, Propofol, Inhalatory sedation, Sevoflurane, AnaConDa, Nephrotoxicity