Trial Outcomes & Findings for Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis (NCT NCT00464204)

Last Updated: 2012-01-11

Results Overview

Initial hemodynamic stabilization (HDS) was defined as normalization of mean arterial pressure (MAP) and at least two of the three parameters central venous pressure (CVP), urine output and central venous oxygen saturation and maintaining this normalization over a period of four hours, with no increase in the infusion of vasopressors, or ionotropic therapy and with no more than 1 L of additional study drug administration within these four hours.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

196 participants

Primary outcome timeframe

until hemodynamic stabilization (up to 48 hours)

Results posted on

2012-01-11

Participant Flow

Participants were recruited in 24 intensive care units of hospitals in France and Germany from July 2007 until February 2010 and were followed up until May 2010.

Participants were screened in intensive care units of the participating study sites in France and Germany.

Participant milestones

Participant milestones
Measure	Voluven® Arm 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Overall Study STARTED	100	96
Overall Study Completed Treatment	81	83
Overall Study Day 30 Follow-up Performed	89	83
Overall Study Day 90 Follow-up Performed	69	74
Overall Study Withdrawal Due to Discharge From ICU	18	11
Overall Study COMPLETED	51	64
Overall Study NOT COMPLETED	49	32

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Effects of Voluven on Hemodynamics and Tolerability of Enteral Nutrition in Patients With Severe Sepsis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Voluven® Arm n=100 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=96 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day	Total n=196 Participants Total of all reporting groups
Age Continuous	65.8 years STANDARD_DEVIATION 15.4 • n=93 Participants	65.9 years STANDARD_DEVIATION 14.7 • n=4 Participants	65.8 years STANDARD_DEVIATION 15.0 • n=27 Participants
Sex: Female, Male Female	36 Participants n=93 Participants	39 Participants n=4 Participants	75 Participants n=27 Participants
Sex: Female, Male Male	64 Participants n=93 Participants	57 Participants n=4 Participants	121 Participants n=27 Participants
Region of Enrollment France	87 participants n=93 Participants	84 participants n=4 Participants	171 participants n=27 Participants
Region of Enrollment Germany	13 participants n=93 Participants	12 participants n=4 Participants	25 participants n=27 Participants
Origin of sepsis Lungs	53 participants n=93 Participants	58 participants n=4 Participants	111 participants n=27 Participants
Origin of sepsis Abdomen	24 participants n=93 Participants	18 participants n=4 Participants	42 participants n=27 Participants
Origin of sepsis Urogenital	8 participants n=93 Participants	14 participants n=4 Participants	22 participants n=27 Participants
Origin of sepsis Skin, bone and soft tissue	6 participants n=93 Participants	4 participants n=4 Participants	10 participants n=27 Participants
Origin of sepsis Other	5 participants n=93 Participants	2 participants n=4 Participants	7 participants n=27 Participants
Origin of sepsis Unknown	4 participants n=93 Participants	2 participants n=4 Participants	6 participants n=27 Participants
Origin of sepsis Neurological system	3 participants n=93 Participants	2 participants n=4 Participants	5 participants n=27 Participants
Origin of sepsis Ears-nose-throat system	2 participants n=93 Participants	0 participants n=4 Participants	2 participants n=27 Participants

PRIMARY outcome

Timeframe: until hemodynamic stabilization (up to 48 hours)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization.

Outcome measures

Outcome measures
Measure	Voluven® Arm n=88 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=86 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Amount of Study Drug Required to Achieve Initial Hemodynamic Stabilization	1379 Milliliter Standard Deviation 886	1709 Milliliter Standard Deviation 1164

SECONDARY outcome

Timeframe: until hemodynamic stabilization (up to 48 hours)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

Time from start of fluid resuscitation with study drug to the initial hemodynamic stabilization

Outcome measures

Outcome measures
Measure	Voluven® Arm n=88 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=86 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Time From Start of Fluid Resuscitation With Study Drug to the Initial Hemodynamic Stabilization	11.8 Hours Standard Deviation 10.1	14.3 Hours Standard Deviation 11.1

SECONDARY outcome

Timeframe: 4 days

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

Total quantity of study drug infused over four consecutive days in the ICU

Outcome measures

Outcome measures
Measure	Voluven® Arm n=88 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=86 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Quantity of Study Drug in 4 Days	2615 Milliliter Standard Deviation 1499	2788 Milliliter Standard Deviation 1799

SECONDARY outcome

Timeframe: Until start of enteral nutrition (up to 48 hours)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

Time from start of fluid resuscitation with study drug to start of enteral nutrition.

Outcome measures

Outcome measures
Measure	Voluven® Arm n=62 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=67 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Time From Start of Study Drug to Start of Enteral Nutrition in the Subgroup of Patients Who Received Enteral Nutrition	24.6 Hours Standard Deviation 32.7	26.9 Hours Standard Deviation 33.8

SECONDARY outcome

Timeframe: up to 48 hours

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

Administration of enteral nutrition before initial hemodynamic stabilization was ignored in this analysis.

Outcome measures

Outcome measures
Measure	Voluven® Arm n=62 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=67 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Time From Start of Fluid Resuscitation With Study Drug to Start of Enteral Nutrition After Hemodynamic Stabilization	25.9 Hours Standard Deviation 32.1	27.6 Hours Standard Deviation 33.6

SECONDARY outcome

Timeframe: 7 days

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

This amount will be calculated from start of enteral nutrition until 7 am of day 8

Outcome measures

Outcome measures
Measure	Voluven® Arm n=62 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=67 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Total Amount of Enteral Calories During the First Seven Days of Enteral Nutrition	6877 kcal Standard Deviation 5008	7429 kcal Standard Deviation 4381

SECONDARY outcome

Timeframe: Until discharge from ICU (up to day 90)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization. Calculated for patients who did not die before end of study of the individual patient

Length of stay was analysed in two approaches. First, it was calculated and analysed only for patients who did not die before end of study of the individual patient. As a sensitivity analysis, the analysis was carried out including patients who died with the maximum possible length of stay (i.e., the worst possible value).

Outcome measures

Outcome measures
Measure	Voluven® Arm n=58 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=61 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Length of Stay in the Intensive Care Unit (ICU)	15.4 Days Standard Deviation 11.1	20.2 Days Standard Deviation 22.2

SECONDARY outcome

Timeframe: Until discharge from ICU (up to Day 90)

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization. Imputed with the longest possible duration for patients who died before end of the study of the individual patient.

Outcome measures

Outcome measures
Measure	Voluven® Arm n=88 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=86 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Length of Stay in the ICU	40.0 Days Standard Deviation 36.5	39.6 Days Standard Deviation 36.3

SECONDARY outcome

Timeframe: Until discharge from hospital (up to day 90)

Outcome measures

Outcome measures
Measure	Voluven® Arm n=58 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=61 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Length of Stay in the Hospital	37.7 Days Standard Deviation 26.5	42.7 Days Standard Deviation 31.6

SECONDARY outcome

Timeframe: Until discharge from hospital (up to Day 90)

Outcome measures

Outcome measures
Measure	Voluven® Arm n=88 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=86 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Length of Stay in the Hospital	56.1 Days Standard Deviation 33.5	56.9 Days Standard Deviation 34.7

SECONDARY outcome

Timeframe: From Screening to Day 4

Population: Full analysis set (FAS) = all randomized patients treated with study drug who reached hemodynamic stabilization

The Sepsis-related Organ Failure Assessment (SOFA) score in this study is reported for entire days, not for exact time points on a day. Potentially, more than one SOFA score may be available for the same day. In this case, the mean of the respective total scores was used for that day for calculation of Area Under the Curve (AUC). The SOFA score includes sub-scores for Respiration, Coagulation, Liver, Cardiovascular, Central Nervous System and Renal function and may range from 0 (worst outcome) to 4 (best outcome).

Outcome measures

Outcome measures
Measure	Voluven® Arm n=82 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=74 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Area Under the Curve (AUC) of Sepsis-related Organ Failure Assessment (SOFA) Score Per Day From Screening to Day 4	6.9 Scores on a scale Standard Deviation 3.3	7.6 Scores on a scale Standard Deviation 3.1

OTHER_PRE_SPECIFIED outcome

Timeframe: From Screening to end of Follow-up

Population: Treated population (TRT) = all randomized patients treated with study drug. Two patients in the Voluven® arm died due to non-treatment emergent SAEs.

Mortality was reported for the time period from Screening until the end of follow-up.

Outcome measures

Outcome measures
Measure	Voluven® Arm n=100 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=96 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Mortality From screening until (and including) Day 28	31 Participants	24 Participants
Mortality From screening until end of follow-up	40 Participants	32 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From screening to end of follow-up (up to day 90)

Population: Treated population (TRT) = all randomized patients treated with study drug. Patients without ARF were excluded from analysis if they had no creatinine value at Screening or no post-screening creatinine value.

Acute Renal Failure (ARF) was defined as a two fold increase in serum concentration over the value at screening at any time after screening.

Outcome measures

Outcome measures
Measure	Voluven® Arm n=98 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=95 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Changes in Renal Function: 1. Acute Renal Failure (ARF) at Any Time After Screening	24 Participants	19 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From screening to end of follow-up

Population: Treated population (TRT) = all randomized patients treated with study drug

Acute Kidney Injury Network (AKIN) Classification in this study is based on serum creatinine values and renal replacement therapy, i.e. ignoring criteria based on urine output, as fulfilment of urine output criteria cannot be determined from the data collected in the study. AKIN ranges from stage 1 to stage 3 (worst outcome). Stages differ in serum creatinine increase. Stage 1: Increase ≥ 0.3mg/dL or ≥ 150%-200% from reference; Stage 2: Increase ≥ 200%-300% from reference; Stage 3: Increase \>300% from reference with an acute increase of at least 0.5mg/dL or renal replacement therapy.

Outcome measures

Outcome measures
Measure	Voluven® Arm n=100 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=96 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Changes in Renal Function: 2. Acute Kidney Injury Network (AKIN) Classification AKIN Stage 1	21 Participants	21 Participants
Changes in Renal Function: 2. Acute Kidney Injury Network (AKIN) Classification None	52 Participants	52 Participants
Changes in Renal Function: 2. Acute Kidney Injury Network (AKIN) Classification AKIN Stage 2	5 Participants	6 Participants
Changes in Renal Function: 2. Acute Kidney Injury Network (AKIN) Classification AKIN Stage 3	22 Participants	17 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: From screening to end of follow-up

Population: Treated population (TRT) = all randomized patients treated with study drug

Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) Classification in this study is based on serum creatinine values and renal replacement therapy, i.e. ignoring criteria based on urine output, as fulfilment of urine output criteria cannot be determined from the data collected in the study. RIFLE comprises five categories: Risk (R), Injury (I), Failure (F), Loss (L), End-stage kidney disease (E) (worst outcome). R, I and F are based on increase in serum creatinine. L and E are based on administration of renal replacement therapy.

Outcome measures

Outcome measures
Measure	Voluven® Arm n=100 Participants 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=96 Participants NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Changes in Renal Function: 3. Risk, Injury, Failure, Loss, End-stage Kidney Disease (RIFLE) Classification None	77 Participants	73 Participants
Changes in Renal Function: 3. Risk, Injury, Failure, Loss, End-stage Kidney Disease (RIFLE) Classification Risk	13 Participants	11 Participants
Changes in Renal Function: 3. Risk, Injury, Failure, Loss, End-stage Kidney Disease (RIFLE) Classification Injury	4 Participants	5 Participants
Changes in Renal Function: 3. Risk, Injury, Failure, Loss, End-stage Kidney Disease (RIFLE) Classification Failure	5 Participants	7 Participants
Changes in Renal Function: 3. Risk, Injury, Failure, Loss, End-stage Kidney Disease (RIFLE) Classification Loss	1 Participants	0 Participants
Changes in Renal Function: 3. Risk, Injury, Failure, Loss, End-stage Kidney Disease (RIFLE) Classification End-stage kidney disease	0 Participants	0 Participants

Adverse Events

Voluven® Arm

Serious events: 53 serious events

Other events: 99 other events

Deaths: 0 deaths

NaCl 0.9 % Arm

Serious events: 44 serious events

Other events: 95 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Professor Dr. Martin Westphal

Fresenius Kabi Aktiengesellschaft

Phone: +49 6172 686

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee All investigators agreed that there will be one or more publications describing the study and the results. No center or combination of centers will submit their results for publication separately. Highest recruiting centers and Fresenius Kabi will contribute authors. The writing of the manuscript will be a collaborative effort.
Publication restrictions are in place

Restriction type: OTHER

Measure	Voluven® Arm n=100 participants at risk 6 % Hydroxyethylstarch 130/0.4; Voluven® rates were not to exceed 50 mL/kg/day on the first days and 25 mL/kg/day from the second to the fourth day	NaCl 0.9 % Arm n=96 participants at risk NaCl 0.9 %; NaCl 0.9 % rates were not to exceed 50 mL/kg/day on the first day and 25 mL/kg/day from the second to the fourth day
Blood and lymphatic system disorders Anaemia	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Cardiac disorders Acute right ventricular failure	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Cardiac disorders Bradyarrhythmia	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Cardiac disorders Cardiac arrest	5.0% 5/100 Regular assessment by Pharmacovigilance and Safety Assessor	6.2% 6/96 Regular assessment by Pharmacovigilance and Safety Assessor
Cardiac disorders Cardiac tamponade	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Cardiac disorders Pericardial haemorrhage	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Cardiac disorders Supraventricular tachycardia	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Gastrointestinal disorders Colitis ischaemic	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Gastrointestinal disorders Duodenal perforation	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Gastrointestinal disorders Intestinal ischaemia	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Gastrointestinal disorders Intestinal obstruction	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Gastrointestinal disorders Peritonitis	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
General disorders Condition aggravated	4.0% 4/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
General disorders Multi-organ failure	7.0% 7/100 Regular assessment by Pharmacovigilance and Safety Assessor	5.2% 5/96 Regular assessment by Pharmacovigilance and Safety Assessor
General disorders Oedema due to cardiac disease	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
General disorders Sudden death	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Infections and infestations Abdominal sepsis	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Infections and infestations Pneumonia	4.0% 4/100 Regular assessment by Pharmacovigilance and Safety Assessor	3.1% 3/96 Regular assessment by Pharmacovigilance and Safety Assessor
Infections and infestations Pseudomembranous colitis	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Infections and infestations Sepsis	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	3.1% 3/96 Regular assessment by Pharmacovigilance and Safety Assessor
Infections and infestations Septic shock	9.0% 9/100 Regular assessment by Pharmacovigilance and Safety Assessor	8.3% 8/96 Regular assessment by Pharmacovigilance and Safety Assessor
Injury, poisoning and procedural complications Haemodilution	8.0% 8/100 Regular assessment by Pharmacovigilance and Safety Assessor	9.4% 9/96 Regular assessment by Pharmacovigilance and Safety Assessor
Injury, poisoning and procedural complications Tracheal haemorrhage	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Investigations Blood chloride increased	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Investigations Venous oxygen saturation decreased	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Metabolism and nutrition disorders Hyperchloraemia	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Metabolism and nutrition disorders Hypernatraemia	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Metabolism and nutrition disorders Hypoproteinaemia	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Metabolism and nutrition disorders Lactic acidosis	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Metabolism and nutrition disorders Marasmus	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Metabolism and nutrition disorders Tumour lysis syndrome	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial carcinoma	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pleural carcinoma	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tonsil cancer	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Nervous system disorders Cerebral disorder	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Nervous system disorders Cerebrovascular accident	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Nervous system disorders Coma	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Nervous system disorders Haemorrhage intracranial	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Renal and urinary disorders Renal failure	3.0% 3/100 Regular assessment by Pharmacovigilance and Safety Assessor	3.1% 3/96 Regular assessment by Pharmacovigilance and Safety Assessor
Renal and urinary disorders Renal failure acute	3.0% 3/100 Regular assessment by Pharmacovigilance and Safety Assessor	2.1% 2/96 Regular assessment by Pharmacovigilance and Safety Assessor
Renal and urinary disorders Renal impairment	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	2.1% 2/96 Regular assessment by Pharmacovigilance and Safety Assessor
Reproductive system and breast disorders Acute pulmonary oedema	2.0% 2/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Respiratory, thoracic and mediastinal disorders Acute respiratory distress syndrome	2.0% 2/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	2.1% 2/96 Regular assessment by Pharmacovigilance and Safety Assessor
Respiratory, thoracic and mediastinal disorders Hypoxia	2.0% 2/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Respiratory, thoracic and mediastinal disorders Lung disorder	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Respiratory, thoracic and mediastinal disorders Pneumothorax	2.0% 2/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	2.1% 2/96 Regular assessment by Pharmacovigilance and Safety Assessor
Respiratory, thoracic and mediastinal disorders Respiratory failure	2.0% 2/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Respiratory, thoracic and mediastinal disorders Respiratory fatigue	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Skin and subcutaneous tissue disorders Toxic epidermal necrolysis	1.0% 1/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Surgical and medical procedures Withdrawal of life support	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Vascular disorders Hypotension	2.0% 2/100 Regular assessment by Pharmacovigilance and Safety Assessor	0.00% 0/96 Regular assessment by Pharmacovigilance and Safety Assessor
Vascular disorders Peripheral ischaemia	0.00% 0/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor
Vascular disorders Shock	2.0% 2/100 Regular assessment by Pharmacovigilance and Safety Assessor	1.0% 1/96 Regular assessment by Pharmacovigilance and Safety Assessor