Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00722709 |
| Other study ID # |
LAstudy |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1
|
| First received |
July 23, 2008 |
| Last updated |
January 12, 2010 |
| Start date |
September 2008 |
| Est. completion date |
January 2010 |
Study information
| Verified date |
January 2010 |
| Source |
University of Auckland, New Zealand |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
New Zealand: Health Research Council |
| Study type |
Interventional
|
Clinical Trial Summary
Aim:
The general aim of this research group is to improve the recovery of patients after
abdominal surgery. The specific aim of this study is to conduct a randomized, double
blinded, controlled trial to investigate the effect of intra-peritoneal local anaesthesia
application on postoperative pain and post-operative fatigue. This will be conducted in the
setting of an enhanced recovery after surgery program (ERAS).
Methods:
Patients will be randomised by computer generated random numbers and opaque envelope method.
In the treatment arm patients will receive 10ml 0.75% ropivacaine diluted to 50mls with 0.9%
saline soon after the creation of the laparotomy . In the placebo arm, 50mls of 0.9% normal
saline will be used in a similar fashion. At closure, two small 2mm catheter belonging to
the On-Q pain buster system will be placed in the peritoneal cavity. This will be attached
to a pump which will contain either a 0.2% ropivacaine solution or 0.9% saline placebo
running at 4mls/hr for 68 hours. All members involved in patient care (with the exception of
one nurse) will be blinded to the above. After 68 hours the pump will be stopped and the
catheter will be removed. Assessment of postoperative pain will be performed by visual
analogue scale, and fatigue assessment will be done using the Identity Consequence Fatigue
Scale (ICFS) at various intervals post-operatively. Blood tests for inflammatory markers
including glucose, cortisol, CRP, albumin and several cytokines as well as local anaesthetic
levels will be taken.
Significance to health:
This method of analgesia administration has not been investigated in open major colonic
surgery. This trial has wide reaching implications, with the potential to improve pain and
thus recovery after abdominal surgery.
Description:
Scientific Background:
Postoperative fatigue (POF) is a common phenomenon following abdominal surgery and is
currently under investigation at the department of surgery, Middlemore hospital, Auckland.
POF in patients undergoing major abdominal procedures is very common. It has been reported
that 92% of patients who have undergone abdominal surgery report increased fatigue reports
immediately after the procedure, dropping to about 10% in 3 months. POF comprises of
unpleasant symptoms that impact on the patient's quality of life.
1. It can create difficulties in performing activities of daily living.
2. The symptoms of POF include tiredness, lack of energy and sense of debilitating muscle
weakness.
3. POF is thought to be associated with poor physical, psychological and functional
outcomes.
4. The aetiology of POF is thought to be multi-factorial. Biological, psychological and
social factors all contribute.
The biological aspect of POF can be divided into the physiological stress response to the
trauma of surgery, postoperative nutritional deficits and the loss of previous
cardiovascular fitness subsequently after surgery. Various methods have been investigated
over the last two decades to address and "dampen" the physiological response in order to
enhance postoperative recovery.
There are two possible ways of communication between the periphery and the brain. One is the
hormonal route and the other is the neural route. The later route is projected via paracrine
action of local cytokines on the afferent nerve endings 5. In the abdominal cavity, there
are two types of afferent endings 6. These are the vagal afferents and spinal afferents.
Vagal and spinal afferent fibres transmit sensory information from the GI tract to the CNS.
Afferents from the vagus nerve conduct neuronal messages from the intra-peritoneal cavity to
the CNS.
Vagal afferents have cell bodies in nodose ganglia and enter via the brainstem. In
comparison cell bodies of the spinal afferents are located in the dorsal root ganglion and
project to the dorsal horn of the cord. They follow the paths of the sympathetic and
parasympathetic efferents to the gut wall.
Vagal afferents are either intramuscular or intraganglionic. Spinal afferents on the other
hand are located in the serosa, mesenteric attachments and the submucosa of the tract.
The surgical stress response produces alterations in the haemodynamic, metabolic and immune
response of patients 7. The biochemical cytokine response to surgical trauma is well
understood and summarised well by Ni Choileain.
There are elements of immune over stimulation resulting in a cascade of cytokine activation
following surgery. These cytokines include tumour necrosis factor alpha (TNF-a) and
interleukin 1B (IL-1B). These can stimulate the production and release of other cytokines
including interleukin 6 (IL-6). IL-6 results in the production of C-reactive protein (CRP)
and other acute phase proteins through the hepatic component of this response.
Therapeutic strategies are aimed at restoring these physiological imbalances associated with
surgery.
In the rat sub diaphragmatic vagotomy has prevented the effects of intraperitoneal IL-1
administration which prevented increases in body temperature and the increase in secreted
hypothalamic norepinephrine (NE), and markedly attenuated the increases in plasma ACTH and
corticosterone 8. This is thought to have reduced the "sickness response" to intraperitoneal
cytokine administration. Similarly, administration of localised partial body exposure to
irradiation in vagotomised rats resulted in decreased hypothalamic, thalamic, hippocampal
and cortical IL-6, IL-1b and TNF-a compared with non-vagotomised rats 9. It is therefore
thought that the vagus plays a major role in the surgical stress response although it is
important to point that the vagus is not thought to be solely responsible for the activation
of hypothalamic activity 10.
A pro-inflammatory cytokine pathway after abdominal surgery, with direct action of cytokines
on the vagus nerve as a major vehicle in this response, is therefore, a feasible explanation
for contributing to POF.
In the clinical context, recent developments in elective large bowel surgery include the use
of Fast Track (FT) or Enhanced Recovery After Surgery (ERAS) protocols. The use of such
protocols is generally said to affect metabolic, neural and other organ activities in order
to reduce morbidity, increase recovery time and result in shorter hospital stays.
There are numerous elements to these protocols, given there are multiple contributors to
POF, as already discussed. In brief, some of these interventions include extensive
preoperative counseling and preparation psychologically, no preoperative fasting,
carbohydrate loading, use of epidural anaesthesia, avoidance of peri-operative fluid over
load, early removal of catheters, drains and early mobilisation with physiotherapist. 11.
Other interventions, such as pre-operative steroid administration, are currently being
trialed as part of an ERAS surgical protocol at the Manukau Surgery Centre (MSC), Middlemore
Hospital, Auckland. The purpose is to enhance recovery by decreasing the cascade of
pro-inflammatory post surgical response using the immunosuppressive properties of this
agent. As discussed earlier, pro-inflammatory responses are hypothesised to contribute to
POF.
Local anaesthetic (LA) agents, when applied in sufficient concentration at the site of
action, prevent conduction of electrical impulses by the membranes of nerve and muscle12. In
order to obtain a clear picture of the fundamental blocking mechanism, knowledge of the
channel-binding kinetics of the drug is necessary. The application of LA agents to the
intraperitoneal cavity has been investigated in several trials to decrease post operative
pain and enhance recovery 13-18. Unfortunately there are few studies if any looking at the
application of local anaesthesia in open procedures compared with laparoscopic
gastrointestinal procedures. It is therefore an area where trials are needed.
It is not unreasonable that the application of local anaesthesia to the intraperitoneal
cavity should play a role in ERAS protocols. In order to reduce postoperative pain and
reduce intra-abdominal to CNS signal transmission we will produce a transient "chemical
affarenectomy". As part of the already established ERAS protocol at the Manukau Surgical
Centre (MSC), my aim is to look at the effects of instillation of local anaesthesia to the
intra-peritoneal cavity immediately after opening the abdominal cavity and we propose an
ongoing LA infusion with an intraperitoneal catheter and external pump postoperatively.
Objectives:
1. To be involved in running the already established ERAS program at Manukau Surgical
Centre (MSC).
2. Conduct a randomised double blinded controlled trial to investigate the effect of
intra-peritoneal local anaesthesia application on postoperative pain and POF in
patients under the ERAS protocol.
Methods and Outcomes:
There is already an established ERAS perioperative care plan at the MSC. Patients are
usually recruited from surgical outpatients clinics at Manukau Super Clinic. Patients who
are undergoing colonic operations are recruited in the ERAS program under the supervision of
the primary consultant colorectal surgeon. My aim is to be involved in data gathering and
clinical aspects of maintaining this protocol.
Summary of ERAS perioperative care plan at MSC conducted by Zargar et al. (Table 1)
- Pre-Operative Information and counseling
- Carbohydrate Loading
- Avoidance of Mechanical Bowel Preparation
- Continuous Bupivacaine thoracic epidural analgesia
- Limited IV fluid therapy (ERAS anaesthetic protocol)
- Avoidance of prophylactic nasogastric tubes
- Early Post operative oral intake
- Dietary Supplementation
- Avoidance of opioids
- Early mobilisation according to mobilisation protocols
- Discharge Criteria
Research Design:
Randomised double blinded clinical trial to investigate the effects of washing and infusing
the intraperitoneal cavity with local anaesthesia on postoperative pain and fatigue scores
on patients undergoing open colonic procedures.
Ethics:
Ethics approval for this project has been obtained.
Sample size:
Using the data from a previous study in measuring post-operative fatigue following colonic
surgery, in order to detect a reduction of post-operative fatigue by 30% on day 7
post-operatively with alpha of 0.05 and power of 0.8, 21 patients are required in each
group, we will aim for 30 patients in each arm anticipating for possible drop outs.
Brief Method:
Patients will be randomised by computer generated random numbers and opaque envelope method.
In the treatment arm patients will receive 10mls 0.75% ropivacaine diluted to 50mls with
0.9% saline soon after the creation of the laparotomy or in the placebo arm, receive 50mls
of 0.9% normal saline in a similar fashion. One theatre staff nurse who will not be involved
in patient care will be given the blinded envelop and prepare the lidocaine or saline
mixtures in the theatre drug room. The mixtures will be unlabelled and appear similar in
color. These will be given to the surgeon during the procedure. All members of the staff
involved in patient care including the anaesthetist will be blinded to the solution
administered.
The theatre staff nurse will then prepare a small infusion pump. The mixture used in the
pump will be pre-mixed by one of the clinical pharmacists at Middlemore hospital who will
not be involved in patient care. The staff nurse will be un-blinded to the contents of the
mixtures. The nurse will prepare the pump and load either the anaesthetic or saline
solution. At closure, two small 2mm catheter will be placed in the peritoneal cavity at the
site of the operation to infuse local anaesthetic. This will penetrate through the skin once
closure is complete. This will be attached to a small infusion pump (On-Q pain buster). This
pump will contain either a 270mls of 0.2% ropivacaine or 270mls of 0.9% saline. All members
involved in patient care including surgical, anaesthetic and nursing teams will be blinded
to the contents of this pump. The pump will be activated at a set rate of 4mls/hr
immediately once the patient is in the post anaesthesia recovery room. The pump will run
continuously. The patient will continue recovery on the ward as per ERAS protocol. After 68
hrs the pump will be stopped and the catheter will be removed in a similar fashion as
routine drain removal.
Endpoints:
- Assessment of postoperative pain using Visual analogue scale (VAS) 1 hour, 2 hours, 4
hours, 6 hours, 8 hours, day 1, day 2 and day 3 post operatively.
- Forced expiratory volumes using a peak flow meter immediately pre-operatively in the
anaesthesia room and 1 hour, 2 hours, 4 hours, 8 hours, day 1, day 2 and day 3
postoperatively (best of 3 attempts for each measurement will be used)
- Fatigue assessment will be done using the Identity Consequence Fatigue Scale (ICFS)
pre-operatively and on day 1, 2 and 3, 7, 30 and 60 postoperatively respectively.
- Serum Glucose, cytokines and local anaesthetic level at 8, 20, 48, 72 hours post op.
- CRP, Albumin at 20, 48 and 72 hours post op.
Resources:
Consultant Colorectal Surgeons at Middlemore Hospital involved in the project: Associate
Professor Andrew Hill, Mr Andrew Connolly and Mr Lincoln Israel.
Consultant anaesthetist:
Matthew Taylor Patients- approximately 100 major colorectal resections are performed at MSC
per year.
Manukau Surgical Centre staff facilities University of Auckland facilities
