Trial Outcomes & Findings for Effect & Safety of Inhaled Isoflurane vs IV Midazolam for Sedation in Mechanically Ventilated Children 3-17 Years Old (NCT NCT04684238)

Last Updated: 2025-05-25

Results Overview

Percentage of time of adequately maintained sedation within the COMFORT-B interval (light, moderate or deep sedation) prescribed at randomisation, monitored every 2 h for a minimum of 12 h (up to 48 h ± 6 h)

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

94 participants

Primary outcome timeframe

Minimum of 12 hours up to 48 hours (± 6 hours).

Results posted on

2025-05-25

Participant Flow

96 patients were randomised in total, 2 patients randomised to isoflurane did not receive treatment and 3 patients receiving treatment did not complete (1 patient receiving isoflurane and 2 patients receiving midazolam)

Participant milestones

Participant milestones
Measure	Drug: Midazolam Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the Anaesthetic Conserving Device (ACD), i.e., Sedaconda ACD-S.
Overall Study STARTED	33	61
Overall Study COMPLETED	31	60
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Data missing for 1 patient in the Isoflurane group. Safety set

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=61 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the Sedaconda ACD-S device	Total n=94 Participants Total of all reporting groups
Age, Customized Children (2-11 years)	28 Participants n=33 Participants	47 Participants n=61 Participants	75 Participants n=94 Participants
Age, Customized Adolescents (12-17 years)	5 Participants n=33 Participants	14 Participants n=61 Participants	19 Participants n=94 Participants
Sex: Female, Male Female	13 Participants n=33 Participants	23 Participants n=61 Participants	36 Participants n=94 Participants
Sex: Female, Male Male	20 Participants n=33 Participants	38 Participants n=61 Participants	58 Participants n=94 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	10 Participants n=33 Participants	13 Participants n=61 Participants	23 Participants n=94 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants n=33 Participants	28 Participants n=61 Participants	41 Participants n=94 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	10 Participants n=33 Participants	20 Participants n=61 Participants	30 Participants n=94 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=33 Participants	0 Participants n=61 Participants	0 Participants n=94 Participants
Race (NIH/OMB) Asian	0 Participants n=33 Participants	1 Participants n=61 Participants	1 Participants n=94 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=33 Participants	0 Participants n=61 Participants	0 Participants n=94 Participants
Race (NIH/OMB) Black or African American	1 Participants n=33 Participants	1 Participants n=61 Participants	2 Participants n=94 Participants
Race (NIH/OMB) White	22 Participants n=33 Participants	41 Participants n=61 Participants	63 Participants n=94 Participants
Race (NIH/OMB) More than one race	0 Participants n=33 Participants	0 Participants n=61 Participants	0 Participants n=94 Participants
Race (NIH/OMB) Unknown or Not Reported	10 Participants n=33 Participants	18 Participants n=61 Participants	28 Participants n=94 Participants
Weight	21.60 kg n=33 Participants • Data missing for 1 patient in the Isoflurane group. Safety set	20.00 kg n=60 Participants • Data missing for 1 patient in the Isoflurane group. Safety set	20.00 kg n=93 Participants • Data missing for 1 patient in the Isoflurane group. Safety set
Height	112.5 cm n=32 Participants • Missing data for 3 patients in Isoflurane group and from 1 patient in Midazolam group. Safety set.	123.0 cm n=58 Participants • Missing data for 3 patients in Isoflurane group and from 1 patient in Midazolam group. Safety set.	117.0 cm n=90 Participants • Missing data for 3 patients in Isoflurane group and from 1 patient in Midazolam group. Safety set.

PRIMARY outcome

Timeframe: Minimum of 12 hours up to 48 hours (± 6 hours).

Population: Full Analysis set (FAS): The FAS included all randomised patients who received IMP and had at least a 6-hour sedation period and at least 3 blinded COMFORT-B-assessments. The FAS followed the intention-to-treat principle, i.e., patients were analysed according to the treatment group they were assigned to at randomisation. The main statistical analysis was performed on this population.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=59 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Percentage of Time of Adequately Maintained Sedation Depth up to 48 Hours (± 6 Hours)	62.37 Percentage of time Interval 44.7 to 80.04	68.94 Percentage of time Interval 52.83 to 85.05

PRIMARY outcome

Timeframe: Minimum of 12 hours up to 48 hours (± 6 hours).

Population: The PP analysis set included all patients in the FAS without any major protocol deviation affecting the primary analysis. To be included in the PP analysis patients had to have been sedated for at least 12h (which was interpreted as 12 h of study sedative treatment from start of IMP), with at least 50% of the planned COMFORT-B assessments performed.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=29 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=56 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Percentage of Time of Adequately Maintained Sedation Depth up to 48 Hours (± 6 Hours)	65.57 Percentage of time Interval 44.03 to 87.11	70.91 Percentage of time Interval 50.75 to 91.07

SECONDARY outcome

Timeframe: From first blinded COMFORT-B assessment (at +2 h from start of study drug initiation) to end of the study treatment period

Population: The FAS included all randomised patients who received IMP and had at least a 6-hour sedation period and at least 3 blinded COMFORT-B-assessments. The FAS followed the intention-to-treat (ITT) principle, i.e., patients were analysed according to the treatment group they were assigned to at randomisation.

Dose of opioids from first blinded COMFORT-B assessment (at +2 h from start of study drug) to end of study treatment period. This was a key secondary efficacy endpoint. Dose of opioids was expressed as fentanyl IV equivalents.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=59 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Compare the Use of Opioids	4.6 μg/kg/h Interval 3.5 to 5.6	2.1 μg/kg/h Interval 1.3 to 2.9

SECONDARY outcome

Timeframe: Last 4 hours of study treatment compared to first 4 hours of study treatment after first blinded COMFORT-B assessment (at +2 h from start of study drug initiation).

Population: FAS: Patients with 8 hours or more of study treatment from first blinded COMFORT-B assessment.

Dose of opioids during the last 4 h of study treatment, as compared to the first 4 h of study treatment after first blinded COMFORT-B assessment. This was a key secondary efficacy endpoint. Dose of opioids is expressed as fentanyl IV equivalents.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=59 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Compare the Use of Opioids	0.58 μg/kg/h Interval -0.16 to 1.32	-0.19 μg/kg/h Interval -0.74 to 0.35

SECONDARY outcome

Timeframe: From end of study drug administration to extubation or end of extubation attempt

Population: Subgroup of patients with endotracheal tube where wake-up was initiated at end of study treatment

Time from end of study drug administration to extubation if study drug was terminated for extubation

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=20 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=35 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Compare Time From End of Study Drug Administration to Extubation	1.09 hour Interval 0.49 to 5.5	0.75 hour Interval 0.25 to 1.5

SECONDARY outcome

Timeframe: From initiation of study drug treatment to End of study treatment (up to 48h +/- 6h)

Population: Full Analysis Set

Proportion of observations with spontaneous breathing efforts during study treatment. This was a key secondary safety endpoint.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=59 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Compare the Proportion of Time With Spontaneous Breathing	0.44 proportion of time Interval 0.28 to 0.59	0.48 proportion of time Interval 0.36 to 0.6

SECONDARY outcome

Timeframe: From start of study treatment to end of study treatment (up to 48h +/- 6h)

Population: Safety analysis set

Need for additional inotropic/vasopressor agent defined by change in Vasoactive-Inotropic Score (VIS) during study treatment period compared to baseline. The VIS quantifies the amount of cardiovascular support required by infants postoperatively according to the below calculation: VIS = dopamine (µg/kg/min) + dobutamine (µg/kg/min) + 100 × epinephrine (µg/kg/min) + 100 × norepinephrine (µg/kg/min) + 10 × milrinone (µg/kg/min) + 10,000 × vasopressin (U/kg/min). An increased VIS score correlates to an increase in inotropic/vasopressor agents.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=61 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Evaluate Haemodynamic Effect as Indicated by Need for Additional Inotropic/Vasopressor Agent ≤24 hours	5.4 Change from baseline in VIS Standard Deviation 19.3	3.4 Change from baseline in VIS Standard Deviation 19.9
Evaluate Haemodynamic Effect as Indicated by Need for Additional Inotropic/Vasopressor Agent >24 hours	1.9 Change from baseline in VIS Standard Deviation 9.7	8.8 Change from baseline in VIS Standard Deviation 44.4

SECONDARY outcome

Timeframe: From > 96 hours sedation (including pre-study sedation period) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first.

Evaluate the frequency of withdrawal symptoms in isoflurane- vs midazolam-treated patients according to SOS-PD.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=61 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Evaluate the Number of Patients With Withdrawal Symptom	2 Participants	3 Participants

SECONDARY outcome

Timeframe: Patients admitted to the ICU ≥48 hours (including period prior to study enrolment) until the end of the 48-hour post study treatment monitoring or ICU discharge, whichever comes first.

Evaluate the frequency of delirium in isoflurane- vs midazolam-treated patients

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=61 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Evaluate the Frequency of Delirium	5 Participants	12 Participants

SECONDARY outcome

Timeframe: During study treatment and up to 48 hours after discontinuation of isoflurane and midazolam

Evaluate the frequency of neurological symptoms or psychomotor dysfunction during and up to 48 hours after discontinuation of isoflurane and midazolam treatment, and the association with duration of treatment, and total exposure (MAC hours and midazolam doses) over time.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=61 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Evaluate the Frequency of Neurological Symptoms or Psychomotor Dysfunction	6 Participants	16 Participants

SECONDARY outcome

Timeframe: From start of study treatment up to 30 days

Compare the 30 days/hospital mortality in isoflurane- vs midazolam-treated patients

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=61 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Compare the 30 Days/Hospital Mortality	2 Participants	0 Participants

SECONDARY outcome

Timeframe: From start of study treatment up to 30 days

Population: Safety analysis set (only patients not withdrawn prior to day 30)

Ventilator-free days at 30 days from start of study treatment period.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=60 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Compare Ventilator-free Days	22.55 Number of ventilator-free days Standard Deviation 10.62	25.00 Number of ventilator-free days Standard Deviation 6.74

SECONDARY outcome

Timeframe: From start of study treatment up to 30 days

Population: Safety analysis set (only patients not withdrawn prior to day 30)

Compare the time in ICU at 30 days from start of study treatment period. This was a secondary safety endpoint. Patients that were withdrawn prior to day 30 were excluded from the analysis. Patients who died before day 30 were not considered withdrawals. For these patients, the days in ICU until day of death were considered ICU days.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=60 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Compare the Time in ICU/Hospital	10.21 Number of ICU days Standard Deviation 9.13	9.65 Number of ICU days Standard Deviation 7.87

SECONDARY outcome

Timeframe: From start of study treatment up to 30 days

Population: Safety analysis set (only patients not withdrawn prior to day 30). This was a secondary safety endpoint. Patients who died before day 30 were not considered withdrawals. For these patients, the days in ICU until day of death were considered ICU days.

Compare ICU-free days up to 30 days in isoflurane- vs midazolam-treated patients.

Outcome measures

Outcome measures
Measure	Drug: Midazolam n=33 Participants Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=60 Participants Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the AnaConDa-S (Anaesthetic Conserving Device)
Compare ICU-free Days	18.58 Number of days alive and not in the ICU Standard Deviation 10.26	20.35 Number of days alive and not in the ICU Standard Deviation 7.87

Adverse Events

Drug: Midazolam

Serious events: 8 serious events

Other events: 13 other events

Deaths: 2 deaths

Drug: Isoflurane

Serious events: 19 serious events

Other events: 32 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Drug: Midazolam n=33 participants at risk Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=61 participants at risk Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the Sedaconda ACD-S.
General disorders Hyperthermia	6.1% 2/33 • Number of events 2 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
General disorders Pyrexia	6.1% 2/33 • Number of events 2 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	13.1% 8/61 • Number of events 13 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
General disorders Hypoxia	3.0% 1/33 • Number of events 3 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	6.6% 4/61 • Number of events 12 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
General disorders Pleural effusion	3.0% 1/33 • Number of events 2 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	8.2% 5/61 • Number of events 6 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Psychiatric disorders Delirium	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	8.2% 5/61 • Number of events 5 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Cardiac disorders Bradycardia	9.1% 3/33 • Number of events 10 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	4.9% 3/61 • Number of events 12 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Cardiac disorders Tachycardia	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	6.6% 4/61 • Number of events 8 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Gastrointestinal disorders Constipation	12.1% 4/33 • Number of events 4 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	19.7% 12/61 • Number of events 12 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Skin and subcutaneous tissue disorders Pruritus	6.1% 2/33 • Number of events 2 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	0.00% 0/61 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.

Additional Information

Ida Sverud

Sedana Medical AB

Phone: +46 8 124 052 00

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Drug: Midazolam n=33 participants at risk Midazolam for sedation in the ICU Midazolam: Solution for Injection/Infusion	Drug: Isoflurane n=61 participants at risk Volatile for sedation in the ICU Isoflurane: Inhalation vapour, liquid. Isoflurane delivered by the Sedaconda ACD-S.
Investigations Magnetic resonance imaging head abnormal	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Injury, poisoning and procedural complications Anaesthetic complication neurological	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Injury, poisoning and procedural complications Complications of transplanted liver subjects affected / exposed	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	0.00% 0/61 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Injury, poisoning and procedural complications Gastrostomy tube site complication	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Injury, poisoning and procedural complications Postoperative thoracic procedure complication	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	0.00% 0/61 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Injury, poisoning and procedural complications Postpericardiotomy syndrome	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	0.00% 0/61 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Vascular disorders Hypotension	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Vascular disorders Shock haemorrhagic	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Cardiac disorders Cardiac arrest	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Cardiac disorders Pericardial effusion	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Nervous system disorders Cerebrovascular accident	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	0.00% 0/61 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Nervous system disorders Hemiparesis	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Nervous system disorders Hypoxic-ischaemic encephalopathy	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Nervous system disorders Intracranial pressure increased	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Nervous system disorders Seizure	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 2 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Nervous system disorders Vocal cord paralysis	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
General disorders Complication associated with device	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
General disorders Postoperative wound infection	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
General disorders Pseudomembranous colitis	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	0.00% 0/61 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
General disorders Pyelonephritis	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
General disorders Septic shock	6.1% 2/33 • Number of events 2 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	0.00% 0/61 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
General disorders Urinary tract infection	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Gastrointestinal disorders Gastric ulcer haemorrhage	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Gastrointestinal disorders Subileus	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Gastrointestinal disorders Vomiting	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Respiratory, thoracic and mediastinal disorders Chylothorax	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Respiratory, thoracic and mediastinal disorders Respiratory failure	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	0.00% 0/61 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Respiratory, thoracic and mediastinal disorders Tonsillar haemorrhage	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Psychiatric disorders Delirium	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Renal and urinary disorders Acute kidney injury	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	4.9% 3/61 • Number of events 3 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Infections and infestations Cellulitis	3.0% 1/33 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	0.00% 0/61 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Infections and infestations Meningitis bacterial	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.
Infections and infestations Peritonitis	0.00% 0/33 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.	1.6% 1/61 • Number of events 1 • Adverse events (AEs) were recorded during the study drug treatment period (up to 48h +/- 6h from start of IMP) and for 48 hours after end of study drug treatment. Mortality was monitored for up to 30 days.