Dexmedetomidine (Precedex®) for Severe Alcohol Withdrawal... | NCT01362205

NCT01362205

Status Module

Description Module

Detailed Description

Severe alcohol withdrawal syndrome (AWS) and alcohol withdrawal delirium (AWD) are frequent principal indication/s for admission to intensive care units. Additionally, unanticipated alcohol withdrawal complicates other critical illnesses and peri-operative states. Alcohol intoxication and withdrawal syndrome are characterized by classic symptoms of adrenergic activation, psychiatric agitation including seizures, as well as metabolic and respiratory dysfunction. The majority of patients with severe AWS are effectively managed with combinations of benzodiazepine (BZD) sedatives (e.g. lorazepam) and butyrophenone antipsychotics (e.g. haloperidol) and require intensive care admission for 2-3 days. However, almost 25% of patients with SAWS have a prolonged critical care course, often complicated by respiratory failure and associated with excessive sedation and risk for complications such as ventilator-associated pneumonia (VAP). AWS is frequently difficult to manage with usual care including benzodiazepines. Additionally, while intermittent bolus dose sedation is recommended for AWS, high dose BZD alone is associated with excessive respiratory suppression and metabolic acidosis. Such therapy increases the likelihood of respiratory failure with its attendant complications of hospital acquired pneumonia and sepsis. Further, patients with underlying chronic liver disease are at greater risk for prolonged sedative effects of BZD and progression of hepatic encephalopathy. The requirement for mechanical ventilation additionally prolongs the course of treatment for AWD because of the need for prolonged sedation. Strategies to control AWS/AWD that control symptoms but avoid adverse effects of excessive respiratory suppression are anticipated to improve the short and medium-term outcomes of AWS.

BZD infusions have also been shown by several investigators to result in excessive and prolonged sedation. However, reasonable alternatives for effective control of psychomotor and adrenergic activation have until recently, been unavailable. The centrally acting alpha-2 receptor agonist, clonidine has been suggested as a useful adjunctive therapy to BZD. However, clonidine is only a mild sedative and can result in significant hemodynamic compromise. By contrast, dexmedetomidine (Precedex), a more potent alpha-2 receptor agonist, is potentially a more effective adjunctive therapy. Precedex is currently marketed in the USA for short-term use as a potent peri-operative sedative and analgesic. This agent has a short circulating half-life and has significantly fewer hemodynamic side effects than clonidine. In addition to its cardiovascular properties, dexmedetomidine possesses anxiolytic, hypnotic/sedative, anesthetic-sparing and analgesic actions and is devoid of significant respiratory depressant effects.

Precedex has been shown to be a safe and effective single agent sedative for critically ill medical and surgical patients in prolonged infusions up to thirty days and is associated with significantly lower incidence of delirium than sedation with the benzodiazepine, midazolam. Preclinical experience and case reports suggest anecdotally Precedex may be of particular benefit in patients with SAWS.

Measures of sedation and delirium will be assessed with the Minnesota Detoxification Scale (MINDS) derived for use in critically ill adults from the validated Clinical Institute Withdrawal Assessment (CIWA-r) scale.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Dexmedetomidine	Experimental	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician.	Drug: Dexmedetomidine
Placebo	Placebo Comparator	Blinded placebo study drug administration in equal volume per hour as active study medication arm.	Drug: Placebos

Name	Type	Description	Arm Group Labels	Other Names
Dexmedetomidine	Drug		Dexmedetomidine	Precedex
Placebos

Measure	Description	Time Frame
The Length of ICU Stay Defined as the Time Between Randomization and ICU Transfer Orders.		up to 28 days in hours

Measure	Description	Time Frame
Average MINDS Score	Minnesota Detoxification Scale (MINDS) min score 0, max score 46. The higher the score, the worse the symptoms of AWS/AWD.	up to 28 days
The Number of CAM-ICU Negative Days After Randomization.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male or female patients, 18 years or older, with severe AWS or AWD per DSM-IV definitions (below) requiring admission to the ICU for medical management
Ability to provide informed consent (via a proxy decision maker or patient).
Within 96 hours of ICU admission.
Meets DSM-IV diagnostic criteria for 291.8 Alcohol Withdrawal Syndrome:
- Cessation of (or reduction in) alcohol use that has been heavy and prolonged.
- Two (or more) of the following, developing within several hours to a few days after Criterion A:
  1. autonomic hyperactivity (e.g., sweating or pulse rate greater than 100)
  2. increased hand tremor
  3. insomnia
  4. nausea or vomiting
  5. transient visual, tactile, or auditory hallucinations or illusions
  6. psychomotor agitation
  7. anxiety
  8. grand mal seizures
The symptoms are not due to a general medical condition and are not better accounted for by another mental disorder.

AND Meets DSM-IV diagnostic criteria for 291.0 Alcohol Intoxication or Withdrawal Delirium

Disturbance of consciousness
A change in cognition
The disturbance develops over a short time and can fluctuate
Onset is temporal associated with Alcohol Withdrawal Syndrome

Exclusion Criteria:

Age < 18 years
Physician anticipates ICU transfer orders in less than 12 hours from time of consent.
Recent traumatic brain injury
Active status epilepticus
Pregnancy or lactation
Known allergy or adverse response to any of the study medications
Requiring glucocorticoid therapy for treatment of acute hepatitis or Stage III (advanced) decompensated liver failure and encephalopathy
Trauma or burns as admitting diagnoses
Neuromuscular blockade other than for intubation
Epidural or spinal analgesia
General anesthesia 24 hours prior to, or planned after, the start of study drug infusion
Serious central nervous system pathology (acute stroke, uncontrolled seizures, severe dementia),
Unstable angina or acute myocardial infarction
Left ventricular ejection fraction less than 30%
Heart rate less than 50/min
Second- or third degree heart block
Systolic blood pressure less than 90 mm Hg despite continuous infusions of 2 vasopressors before the start of study drug infusion.
Previous randomization into this study.

Name	Affiliation	Role
Ivor S Douglas, MD, FRCP	Denver Health Medical Center	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Memorial Hospital Central		Colorado Springs	Colorado	80909	United States
Memorial Hospital North

PubMed Identifier	Type	Citation	Retractions
19188334	Background	Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG; SEDCOM (Safety and Efficacy of Dexmedetomidine Compared With Midazolam) Study Group. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009 Feb 4;301(5):489-99. doi: 10.1001/jama.2009.56. Epub 2009 Feb 2.
18780809

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Arm/Group Information

ID	Title	Description
BG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
BG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00022 BG00127 BG00249

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00046.5± 11.54 BG00148.2± 11.82 BG00247.4± 11.61

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG0006 BG0013 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG0002 BG0018 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0000 BG0011 BG002

Region of Enrollment

Number

participants

Title

Denominators

Categories

United States

Title	Measurements
	BG00022 BG00127 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

The Length of ICU Stay Defined as the Time Between Randomization and ICU Transfer Orders.

Posted

Median

Inter-Quartile Range

hours

up to 28 days in hours

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Units	Counts
Participants	OG00022 OG00127

Title

Denominators

Categories

Title	Measurements
	OG00079.2(43.9 to 134.6) OG001104.9(63.7 to 183.1)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Wilcoxon (Mann-Whitney)		0.2454														Other

Secondary

Average MINDS Score

Minnesota Detoxification Scale (MINDS) min score 0, max score 46. The higher the score, the worse the symptoms of AWS/AWD.

Posted

Median

Inter-Quartile Range

units on a scale

up to 28 days

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Units	Counts
Participants

Secondary

The Number of CAM-ICU Negative Days After Randomization.

The Confusion Assessment Method (CAM)-ICU is a validated instrument used to detect the presence or absence of delirium in the ICU. A delirium free day is counted for any day a patient is negative by the CAM-ICU. The higher the number of CAM-ICU negative days indicates the more days a patient was able to think clearly.

Posted

Median

Inter-Quartile Range

days

up to 28 days

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Secondary

Number of Ventilator Free Days After Randomization.

A ventilator day is counted for any use of invasive mechanical ventilation during a calendar day

Posted

Median

Inter-Quartile Range

days

up to 28 days

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Units	Counts
Participants

Secondary

The Length in Days of the Hospital Stay

A hospital day is counted for any time on a calendar day the patient is admitted to the hospital. Hospital days are inclusive of ICU days.

Posted

Median

Inter-Quartile Range

days

up to 28 days

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Units	Counts
Participants

Secondary

Scores at Hospital Discharge on the Mini Mental Exam.

The Mini Mental State Examination or Folstein test is a validated 30-point questionnaire used to measure cognitive impairment (min score 0, max score 30). A score of 24 points (out of a max of 30) indicates normal cognition, less than or equal to 9 points indicates severe impairment, 10-18 indicates moderate impairment and 19-23 mild impairment.

Posted

Mean

Standard Deviation

units on a scale

up to 28 days

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Secondary

Scores at Hospital Discharge on the Beck Depression Inventory.

The Beck Depression Inventory is a validated questionnaire used to measure severity of depression (min score 0, max score 63). The higher the score the greater the severity of depression. A score of 30-63 indicates severe depression, 19-29 moderate depression, 10-18 mild depression and 0-9 minimal depression.

Posted

Mean

Standard Deviation

units on a scale

Up to 28 days.

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Secondary

Scores at Hospital Discharge on the Beck Anxiety Inventory

The Beck Anxiety Inventory is a validated questionnaire used to measure severity of anxiety (min score 0, max score 63). The higher the score the greater the severity of anxiety. A score of 30-63 indicates severe anxiety, 17-29 moderate anxiety, 10-16 mild anxiety and 0-9 minimal anxiety.

Posted

Mean

Standard Deviation

units on a scale

Up to 28 days.

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Secondary

Scores at Hospital Discharge on the PTSD Civilian Checklist

PTSD checklist consists of 17 questions graded on a scale of 1 to 5. The PTSD score is comprised from the sum of the scores 17 questions. The PTSD score has possible values from to 17 to 85 with higher values indicating greater symptom severity.

The number of participants analyzed was lower than the total included as many patients were discharged quickly upon resolution of altered mental status when a research team member was unavailable to administer the questionnaires.

Posted

Median

Inter-Quartile Range

units on a scale

Up to 28 days

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Secondary

Resource Utilization Costs Associated With This Hospitalization Billed by Physicians.

Posted

Median

Inter-Quartile Range

Dollar (United States)

up to 28 Days

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Units	Counts
Participants

Secondary

Resource Utilization Costs Associated With This Hospitalization Billed by Facility.

The overall number of participants analyzed is less than the number randomized as data was not available for research use at many of the participating institutions.

Posted

Median

Inter-Quartile Range

USD

Up to 28 days

ID	Title	Description
OG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details
OG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%

Units	Counts

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Dexmedetomidine	Dexmedetomidine titrated to achieve predefined goals on selected components of the MINDS score using the minimum amount of medication possible. Blinded study medication will be started at a rate determined by the MINDS score. The maximum infusion rate is 1.4 μg/kg per hour. Uncontrolled SAWS/D symptoms, will be treated with open label lorazepam according to the MINDS score algorithm. Persistent SAWS/D symptoms despite maximum infusion rate of study medication treatment limiting symptoms while receiving higher infusion rates of study medication, ancillary therapies will be administered according to the MINDS score algorithm, at the discretion of the treating physician. Dexmedetomidine: See arm details	0	21	5	21	12	21
EG001	Placebo	Blinded placebo study drug administration in equal volume per hour as active study medication arm. Placebo: Sterile, clear saline 0.9%	0	27	3	27	17	27

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Atrial fibrillation	Cardiac disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected27 at risk
Cardiac arrest	Cardiac disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected27 at risk
Hepatitis alcoholic	Hepatobiliary disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected27 at risk
Bacteraemia	Infections and infestations	MedDRA 10.0	Systematic Assessment	EG0000 affected21 at risk EG0011 affected27 at risk
Enterococcal infection	Infections and infestations	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected27 at risk
Pneumonia	Infections and infestations	MedDRA 10.0	Systematic Assessment	EG0000 affected21 at risk EG0011 affected27 at risk
Septic shock	Infections and infestations	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0011 affected27 at risk
Haemorrhage intracranial	Nervous system disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected27 at risk
Osmotic demyelination syndrome	Nervous system disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected27 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0010 affected27 at risk
Aspiration	Respiratory, thoracic and mediastinal disorders	MedDRA 10.0	Systematic Assessment	EG0000 affected21 at risk EG0011 affected27 at risk
Respiratory failure	Respiratory, thoracic and mediastinal disorders	MedDRA 10.0	Systematic Assessment	EG0002 affected21 at risk EG0011 affected27 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Leukocytosis	Blood and lymphatic system disorders	MedDRA 10.0	Systematic Assessment	EG0003 affected21 at risk EG0011 affected27 at risk
Thrombocytosis	Blood and lymphatic system disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0014 affected27 at risk
Bradycardia	Cardiac disorders	MedDRA 10.0	Systematic Assessment	EG0002 affected21 at risk EG0011 affected27 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA 10.0	Systematic Assessment	EG0003 affected21 at risk EG0014 affected27 at risk
Oedema peripheral	General disorders	MedDRA 10.0	Systematic Assessment	EG0006 affected21 at risk EG00111 affected27 at risk
Pyrexia	General disorders	MedDRA 10.0	Systematic Assessment	EG0004 affected21 at risk EG0013 affected27 at risk
Urinary tract infection	Infections and infestations	MedDRA 10.0	Systematic Assessment	EG0000 affected21 at risk EG0012 affected27 at risk
Laceration	Injury, poisoning and procedural complications	MedDRA 10.0	Systematic Assessment	EG0000 affected21 at risk EG0012 affected27 at risk
Skin abrasion	Injury, poisoning and procedural complications	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0012 affected27 at risk
Alanine aminotransferase increased	Investigations	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0013 affected27 at risk
Haemoglobin decreased	Investigations	MedDRA 10.0	Systematic Assessment	EG0000 affected21 at risk EG0013 affected27 at risk
Platelet count decreased	Investigations	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0013 affected27 at risk
Protein total decreased	Investigations	MedDRA 10.0	Systematic Assessment	EG0000 affected21 at risk EG0013 affected27 at risk
Hyperkalaemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG0000 affected21 at risk EG0012 affected27 at risk
Hypermagnesaemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG0002 affected21 at risk EG0011 affected27 at risk
Hypernatraemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0014 affected27 at risk
Hyperphosphataemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0013 affected27 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0014 affected27 at risk
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0012 affected27 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG00010 affected21 at risk EG00116 affected27 at risk
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0014 affected27 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG0002 affected21 at risk EG0011 affected27 at risk
Hypophosphataemia	Metabolism and nutrition disorders	MedDRA 10.0	Systematic Assessment	EG0003 affected21 at risk EG0015 affected27 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 10.0	Systematic Assessment	EG0002 affected21 at risk EG0010 affected27 at risk
Ecchymosis	Skin and subcutaneous tissue disorders	MedDRA 10.0	Systematic Assessment	EG0001 affected21 at risk EG0013 affected27 at risk
Deep vein thrombosis	Vascular disorders	MedDRA 10.0	Systematic Assessment	EG0000 affected21 at risk EG0012 affected27 at risk
Hypertension	Vascular disorders	MedDRA 10.0	Systematic Assessment	EG0005 affected21 at risk EG00113 affected27 at risk
Hypotension	Vascular disorders	MedDRA 10.0	Systematic Assessment	EG0006 affected21 at risk EG0014 affected27 at risk

ID	Term
D020268	Alcohol-Induced Disorders, Nervous System
D020258	Neurotoxicity Syndromes
D009422	Nervous System Diseases
D011041	Poisoning
D064419	Chemically-Induced Disorders
D020751	Alcohol-Induced Disorders
D019973	Alcohol-Related Disorders
D019966	Substance-Related Disorders
D013375	Substance Withdrawal Syndrome
D001523	Mental Disorders

ID	Term
D007093	Imidazoles
D001393	Azoles
D006573	Heterocyclic Compounds, 1-Ring
D006571	Heterocyclic Compounds