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Effects of Noradrenaline Administration Combined With Restrictive Intraoperative Fluid Substitution on Blood Loss and Perioperative Outcome in Patients Undergoing Open Radical Cystectomy

18 Years
Not Enrolling
Bladder Cancer, Urinary Diversion

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Trial Information

Effects of Noradrenaline Administration Combined With Restrictive Intraoperative Fluid Substitution on Blood Loss and Perioperative Outcome in Patients Undergoing Open Radical Cystectomy


Perioperative fluid management in abdominal surgery is a subject of controversy and current
standard fluid therapy is not evidence based. Standard fluid therapy includes replacement of
basic fluid requirements, loss by perspiration, by exsudation through the surgical wound,
and loss into the third space.

Fluid preload before spinal or just after epidural anaesthesia is a common and recognized
practice in clinical anaesthesia. Vasodilatation is a well-known side effect of halogenics,
of most hypnotics and opiates. Compensating decreasing blood pressure by volume substitution
is common praxis. Alternatively the fall in blood pressure due to vasodilatation can be
corrected by applying vasoactive agents. A review of the data on the effect of "high volume"
perioperative fluid therapy suggests that overhydration may have deleterious effects on
cardiopulmonary function (excessive shift to the right on the Starling myocardial
performance curve, pneumonia and respiratory failure) as well as on recovery of
gastrointestinal motility (prolonged postoperative ileus (PI)), tissue oxygenation and wound
healing (anastomosis leakage). A postoperative weight gain of 3-7 kg in patients after major
elective surgery therefore seems to represent a genuine fluid overload. Delay in bowel
motility may be due to the presence of excess fluid in the intestinal wall resulting from
excess perioperative fluid therapy. Increased gut permeability after surgical trauma may
also contribute to the development of PI because of enhanced uptake of luminal bacterial
products. Postoperative complications were significantly reduced by restricted fluid
therapy. A dose response relation between administrated fluid volume and postoperative
complications (cardiopulmonary and tissue healing) was found in a randomised assessor
blinded multicenter trial for colorectal surgery 11,12. The restricted fluid regimen did not
lead to haemodynamic instability and the amount of vasoactive substances administered was
similar. No significant difference in urinary output was demonstrated on days 1 and 6.
Restrictive fluid administration in fast-track surgery led to no differences in all-over
recovery after colonic surgery. Goal-directed intraoperative fluid administration using the
oesophageal Doppler monitor to maintain maximal stroke volume has been shown to reduce the
length of hospital stay, lower the incidence of postoperative nausea and vomiting and to
encourage an early return of bowel function. Oesophageal Doppler monitor permits rapid,
minimally invasive and continuous estimation of cardiac output. It can be easily inserted
and is not associated with major complications. The investigators will use oesophageal
Doppler monitoring for intraoperative monitoring of stroke volume and cardiac output.

In animal experiments on pigs, high (18ml/kg/h) or low (3ml/kg/h) volume crystalloid fluid
treatment had no effect on colon tissue oxygenation tension. Three different fluid volume
regimens (3ml/kg/h, 7 ml/kg/h and 20ml/kg/h) tested did not affect tissue oxygen pressure in
the jejunum and colon, suggesting efficient autoregulation of intestinal blood flow in
healthy pigs undergoing uncomplicated abdominal surgery 25. Noradrenaline increased systemic
blood flow (mean arterial pressure and cardiac index) and failed to increase
microcirculatory blood flow in most abdominal organs in septic pigs. Thoracic epidural
anesthesia per se does not affect intravascular volume. Therefore, vasopressors are
preferable for treatment of hypotension after epidural anesthesia.

The incidence of postoperative cognitive dysfunction varies greatly with reported rates of
10% to 55%. Patient characteristics such as age, education, type and length of surgical
procedure and preoperative cognitive status have been found to affect the incidence and
severity of postoperative cognitive dysfunction. The influence of intraoperative volume
management on cognitive function has not been assessed.

It seems of interest and safe to use a noradrenaline perfusor combined with a low volume
regimen during open radical cystectomy. The low volume regimen, as described in this study
protocol, is well established in our institution, which has a large experience in


The aim of this study is to compare intraoperative blood loss, quality of the surgical field
(defined later), metabolic response, pain relief, fatigue score, gastrointestinal function,
cardiovascular, pulmonary, infectious and surgical complications and cognitive function in
two groups of patients undergoing radical cystectomy. The first group will be treated
according to an internationally accepted standard fluid regimen (6 ml/kg/h of crystalloids
and correction of the hypotony with fluid boluses); the second one will be treated with a
restrictive fluid regimen of 2ml/kg/h of crystalloids in combination with


Prospective, randomised, controlled, single-centre study. Randomly assigned in equal
proportion by computer to receive the dry regimen 2ml/kg/h combined with sympathicomimetics
or the standard fluid management.

An advanced balanced electrolyte solution will be used containing acetate/malate instead of
lactate. Substantial advantages are a base excess of +/- O mmol/l, that it is isotonic, and
contains anions acetate and malate.

208 patients with open radical cystectomy Duration: 36 months Setting: University Department
of Urology , Inselspital Bern, Switzerland Study sample and power calculation

A power analysis for postoperative complication rate as primary outcome has been done with
the NCSS PASS programme:

Power: 80% Significance: 0.05% or lower Complication rate for the restrictive volume regimen
group: 20% Complication rate for the control group: 38% 83 patients will be required in each
group. Assuming a 20% drop-out rate 104 patients per group will be enrolled.

Inclusion Criteria:

- Written informed consent

- ASA 1 to 3

- Radical cystectomy with ileal neobladder/ileum conduit

Exclusion Criteria

- Coagulopathies

- - Significant hepatic dysfunction (liver enzymes > 50% upper normal value)

- - Significant renal dysfunction: GFR< 60 ml/min/1,73 m² (Kidney Disease Outcomes
Quality Initiative stade 3 or more )

- Congestive heart failure

- Oesophageal pathology

- Pregnancy

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Outcome Measure:

Complications (morbidity score)

Outcome Time Frame:

during hospitalisation, at 30 days postoperative

Safety Issue:


Principal Investigator

Patrick Y Wuethrich, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dep. of Anesthesiology and Pain Therapy, University Hospital Beern, Switzerland


Switzerland: Independent Local Research Ethic Commission (Ethikkommission)

Study ID:




Start Date:

November 2009

Completion Date:

December 2012

Related Keywords:

  • Bladder Cancer
  • Urinary Diversion
  • Bladder cancer
  • urinary diversion
  • Postoperative Complications
  • Fluid Therapy
  • Norepinephrine
  • Urinary Bladder Neoplasms