Less opioids after major abdominal surgery in young infants using wound catheter infusion with local anesthetics: a randomized controlled trial.

Postoperative pain in infants
Treatment of pain in neonates and infants has much improved in the last
decades, when it became clear that young children respond to tissue injury with
specific behaviour and with autonomic and hormonal responses and signs of
metabolic stress.[1, 2] Pain may lead to several unwanted consequences, such as
discomfort and distress, but may also have long-term behavioural
consequences.[3-6]
Worldwide, the standard analgesic drug after major surgery in neonates and
infants is morphine, with or without paracetamol. However, young children are
vulnerable to the side effects of opioids, especially respiratory depression,
but also gastrointestinal dysfunction, delayed feeding and bladder retention.
Morphine administration may also prolong the need for ventilatory support in
infants.[7] Numerous experimental data have suggested long term neurobiological
sequelae of early opioid exposure in the offspring.[5,8]

Regional anesthesia
Regional anesthesia (RA) provides profound analgesia with minimal physiological
perturbations or side effects and is an effective alternative to systemic
analgesics.[9-11] Only a few prospective randomized controlled trials comparing
RA with systemic analgesics in children are available in the literature.[9-10]
According to the Guidelines for Postoperative Pain Treatment (page 176),
released in 2013 by the Dutch Society for Anesthesiology (Nederlandse
Vereniging voor Anesthesiologie), there is a lack of scientific evidence on RA
in children. More research is needed to show the advantage of RA over other
treatment modalities for postoperative pain (oral, rectal, intravenously).[12]
There are several regional analgesia techniques for the treatment of
postoperative pain after abdominal surgery, such as epidural catheters and
regional blocks of the abdominal wall.[13,14] In adults, epidural analgesia has
shown to be effective after abdominal surgery.[15] Pediatric epidural analgesia
is however associated with risks, especially in children < 6 months of age,
such as nerve root damage, dural puncture and accidental intrathecal
administration of drugs.[11,16] Although the risks are considered small in
experienced hands, a peripheral regional block is considered safer than a
neuraxial block.[11,16,17]
Peripheral blocks of the abdominal wall provide analgesia restricted to the
site of surgery, with a good safety record, especially when performed under
ultrasound guidance.[14] However, as these abdominal wall blocks are single
shot blocks, the analgesic effect is short-lived, and opioid use is not always
reduced.[14,17] Therefore, pediatric anesthesiologists are still in search of
regional anesthetic techniques, which can be performed safely in neonates and
infants, and with a longer duration of effect.

Wound Catheter Infusion
The use of a subcutaneous wound catheter infusion (WCI) with local anesthetics
is a relatively new technique, which has shown to produce effective
postoperative analgesia in adults.[18-20] WCI was associated with low pain
scores comparable to epidural analgesia, decreased morphine consumption,
increased patient satisfaction, normal postoperative recovery and was not
associated with any adverse effects regarding to wound healing.[18,20] An
interesting aspect of WCI and postoperative wound healing is that local
anesthetics seem to have an antimicrobial effect, inhibit local inflammatory
response to injury and reduce the release of inflammatory mediators.[21,22]
In children, WCI has been described after iliac crest bone harvesting,
abdominal surgery, sternotomy, thoracotomy, and orthopaedic surgery.[23-29]
However, most of these studies included older children (> 3 years of age).
These studies show that WCI provides good postoperative analgesia, and is safe
to use in children. In one study, the lower requirement for IV morphine was
associated with earlier return of bowel function.[28] In a retrospective study
WCI led to a decreased rate and duration of postoperative urinary catheter
placement.[29] A reduction in opioid requirements could not always be
demonstrated.
So far, few studies have been published on the use of WCI in children < 1 year
old. One RCT published in 2013 investigated the efficacy of WCI after abdominal
surgery in children (6 months * 13 years old).[27] Thirty-three children
undergoing elective minor abdominal surgery were included. Patients were
randomized to receive bupivacaine or saline via WCI. All patients received
paracetamol. In case of pain, a bolus morphine was administered IV (0.05
mg/kg). Primary outcome was the number of postoperative rescue morphine doses.
Mean age of the children included in this study was 3.4 years in the
bupivacaine group (n=17) and 2.8 years in the saline group (n=16). On the first
postoperative day, patients in the bupivacaine group had significantly less
need for morphine compared to the saline group with a mean of 1.3 (SD 1.3) and
3.1 (SD 2.5) respectively (p< 0.05). No plasma bupivacaine concentrations were
measured. In this study, children < 9 kg received a lower dose of bupivacaine
(0.2 mg/kg/h) than children > 9 kg (0.4 mg/kg/h). No separate analysis of
morphine rescue doses was performed for the group < 9 kg, and the number of
patients included in this weight group is unknown. Also, they could not
demonstrate an opioid sparing effect of WCI in children < 6.3 kg. This group
was given the lowest dose of WCI, and may have been under dosed.
Another RCT published in 2009 was performed in 72 children after sternotomy for
open heart surgery.[28] The treatment group (n=35) received levobupivacaine
0.25% or bupivacaine 0.25% via WCI, the control group (n=37) saline. Children
aged > 3 months and < 17 years and weight > 5 kg were included. An elastomeric
bulb device filled with local anesthetic or saline was attached to the wound
catheter, and a continuous infusion of 0.5-5.0 ml/h was used, depending on the
weight of the patient. Rescue analgesia was IV morphine 0.05 mg/kg. Patients of
> 5 years old were given PCA morphine IV as rescue. Total morphine requirements
over the first 24 hours were significantly lower in the treatment group than in
the control group (p=0.007), but not on postoperative days two and three.
Levobupivacaine plasma levels remained below the toxic threshold (4 mcg/ml)
throughout the study period. However, the relationship between weight of the
child, dose of local anesthetic administered and level of local anesthetic
measured in the plasma was not investigated.
A group from the Karolinska University in Stockholm, Sweden published 2 studies
on the use of WCI in neonates after thoracotomy for ligation of ductus Botalli,
and plasma concentrations of local anesthetics (levobupivacaine) during WCI in
these patients. The WCI technique was associated with low pain scores,
apparently normal postoperative recovery and was not associated with any
adverse effects with regard to wound healing.[30] The levels of total and
unbound plasma concentrations of levobupivacaine remained within acceptable
safety limits during 72 hours in these studies.[30,31]

Ropivacaine * rationale for drug choice
Most studies regarding WCI in children have been performed with bupivacaine as
local anesthetic.[24-28]
However, levobupivacaine and ropivacaine are associated with a lower risk for
serious systemic toxicity compared with bupivacaine, and should therefore
preferably be used in children.[32]
Amide local anesthetics (such as (levo)bupivacaine and ropivacaine) bind to
serum AGP (a1-acid glycoprotein). AGP concentrations are very low at birth and
progressively increase during the first year of life. This is why neonates and
young infants have a much higher free fraction of local anesthetics than
adults.[33] Also, CYP1A2 activity, which metabolizes ropivacaine, is immature
before the age of 4-7 years.[33] Neonates and infants are therefore more prone
to develop toxicity.
Ropivacaine appears to be the least toxic of the available long-acting local
anesthetics, but is less potent than levobupivacaine and bupivacaine.[32] In
the ErasmusMC-Sophia, there is much experience with the use of ropivacaine in
children, as this is the local anesthetic of choice for continuous infusions in
epidural and locoregional catheters in children.

Conclusion
Further investigations are needed to determine the analgesic and opioid sparing
effect of WCI in children < 1 year of age. The technique seems promising,
however few data are available on the efficacy of WCI for treatment of
postoperative pain in neonates and infants, the group of children who would
benefit especially from the opioid sparing effect.
Since the data on the use of ropivacaine for WCI in children are sparse,
investigations are needed to determine the adequate dose to establish analgesia
and an opioid sparing effect, including measurements of plasma concentrations
to determine whether the dose used is safe for infants and neonates.

In this prospective, double-blind, randomized controlled trial, we investigate
the hypothesis that regional anesthesia provided by WCI with ropivacaine will
reduce pain postoperatively (as measured with COMFORT behavior scale and
Numeric Rating Scale Pain scores) and lead to a morphine-sparing effect of at
least 30% after major abdominal surgery in infants < 1 year of age.
In this investigation also plasma ropivacaine levels will be measured, during
the phase of continuous infusion via the wound catheter, to determine if levels
of ropivacaine remain below toxic thresholds.

Single center, prospective, randomized, double blind, placebo controlled study
where children < 1 year of age undergoing major abdominal surgery will be
randomized for the treatment with WCI with a bolus dose and continuous infusion
with ropivacaine 0.2% (R group) or with placebo (saline) (Control).
At the end of surgery, following closure of the muscle layers, the surgeon will
place a multi-hole wound catheter superficial to the muscle fascia under direct
vision (On Q® Soaker Catheter, Halyard*) in all patients. The subcutaneous
tissue is closed where after the skin is sutured.
Both groups will receive a bolus via the catheter: ropivacaine 2 mg/kg in the R
group, saline (NaCl 0.9%) in the same amount in the control group. Both groups
will receive a bolus intravenously: morphine 0.1 mg/kg in the control group,
and the same amount in ml/kg saline in the R group. A continuous infusion via
the wound catheter will be started in both groups: ropivacaine 0.2 mg/kg/h in
the R group, and saline in the control group.
Both groups will receive intermittent administration of paracetamol IV (as
primary analgesic) and titrated morphine IV in case of documented pain (rescue
therapy).

Wound catheter placement and medication
At the end of surgery, following closure of the muscle layers and subcutaneous
tissue, the surgeon will place a multi-hole wound catheter superficial to the
muscle fascia under direct vision (On Q® Soaker Catheter, Halyard) and tunneled
from a separate stab incision approximately 3 cm lateral to the wound.
Hereafter the skin is sutured. The catheter is fixated to the skin with a
plaster (Steri Strip* and Tegaderm*) and is connected to a syringe in a
perfusor pump, which is filled with either ropivacaine 0.2% or saline
(placebo). Before end of anesthesia, all children will receive a bolus dose via
the wound catheter: ropivacaine 2 mg/kg (R group) or the same amount in ml/kg
of saline (saline) in the control group. WCI is started postoperatively:
ropivacaine 0.2 mg/kg/h (R group) or saline (control group) in the same amount.
At the end of surgery, the control group will receive a bolus dose of morphine
100 mcg/kg IV, because this is standard of care after major surgery in the
Erasmus MC-Sophia (local pain protocol). Group R receives placebo (saline) in
the same amount as IV bolus dose. All patients receive a first dose of
paracetamol 20 mg/kg IV at the end of surgery. Paracetamol IV is continued as
standard analgesic, also according to local pain protocol.
Postoperatively, all children < 3 months of age (or 60 weeks PC age in
premature children) are admitted to the PICU or the recovery ward (> 3 months
of age, or > 60 weeks PC age). At the PICU or recovery ward, postoperative pain
is assessed in all children using the COMFORT behavior scale and NRS pain.
Based on these validated pain assessments, patients receive rescue morphine
doses, when needed, according to an algorithm. (Appendix 1)
Children will be followed up for 72 hours postoperatively, after which the
catheter will be removed.

Treatment of postoperative pain in both groups
All patients receive paracetamol IV postoperatively, according to a protocol
published by our group.[34]
Additional IV morphine is administered whenever the NRS is equal to or greater
than 4 and COMFORT > 16, which indicates pain. (Appendix 1) Doses of additional
morphine are administered every 10 minutes whenever needed, with a maximum of 3
times per hour. Ten minutes after each extra dose of morphine, pain is
re-assessed. If there is no improvement in the scores three additional (rescue)
doses, an additional dose of morphine 100 mcg/kg IV is administered and
continuous morphine infusion is started. This can be increased in total 2 times
if the child still needs extra doses of morphine.

Plasma concentrations of ropivacaine
To determine if plasma ropivacaine levels do not exceed toxic levels, blood
samples will be taken from an indwelling arterial line, or at the same time a
regular blood sample is taken by heel prick, concomitant with blood sampling
for clinical purposes (in case there is no arterial line). Patients will not
suffer extra heel pricks for only study purposes. With respect to the ethical
requirement that not more than 3% of the total blood volume (80-100 ml/kg) can
be drawn from a patient, sampling will be restricted to maximum three samples
per day (0.5 ml each) (maximum six samples over the whole study period (48
hours)). Weight of the patients will vary between approximately 3 and 10
kilograms, hence, in a 3 kg baby 6 x 0.5 ml = 3 ml is max 2% of TBV .

Worldwide, the standard analgesic drug after major surgery in neonates and
infants is morphine. However, young children are vulnerable to the side effects
of opioids, especially respiratory depression. Morphine administration may also
prolong the need for ventilator support in infants.
The use of a subcutaneous wound catheter infusion (WCI) with local anesthetics
is a relatively new technique, which produces effective postoperative analgesia
and is safe to use in adults and older children. WCI was associated with low
pain scores and decreased morphine consumption. However, most of these studies
included older children (> 3 years of age).
The WCI technique would provide postoperative analgesia without respiratory
depression associated with opioids, which would be a great advantage in young
children. Therefore we would like to conduct this study in children < 1 year of
age, who would benefit especially from the possible morphine-sparing effect.
Eligible children will be children < 1 year of age already undergoing major
abdominal surgery, elective or semi-urgent. These children will receive the
standard perioperative care, this will not be changed because of the
investigation.
All children will receive a woundcatheter during closure of the wound. The
child is still under anesthesia, at the end of the operation. This will be no
extra burden to the child. Ropivacaine (a local anesthetic) will be
administered via the woundcatheter, subcutaneously: first a bolus dose, and
then a continuous infusion in a lower dose. After a few days the woundcatheter
will be removed. This is a painless procedure, and therefore not a burden to
the child.
We exclude all children with an allergy to local anesthetics,
contra-indications for regional anesthesia techniques (such as infection of the
site of the wound) and also children with renal or hepatic dysfunction, as this
may cause a higher risk of local anesthetic toxicity or toxicity from
paracetamol or morphine administration.
Research on the woundcatheter in older children has shown that its use is safe:
sometimes leakage of the local anesthetic from the wound is described, or
redness of the skin around the wound. No increase of woundinfections or delayed
wound healing has been shown.

Ropivacaine is a local anesthetic, which is the local anesthetic of choice in
het Sophia Children's Hospital. It is registered for the use in young children:
from the age of 0 months for the use as epidural infusion, ans in children > 1
year of age for use for peripheral nerve blockade. Risks of the administration
of ropivacaine are accidental injection of the drug directly into a
bloodvessel, which could lead to cardiotoxic reactions (arrhythmia). This can
be prevented by aspiration of the catheter first, to see if blood is aspirated.
Also, an overdose of the drug can lead to toxicity ( arrhythmias, epileptic
insults). As ropivacaine is not a registered drug for continuous wound
infiltration in children < 1 year of age, we decided to stay on the safe side
of dosage and use the recommended (en registered) dose advice for ropivacaine
in epidural infusions in children < 6 months of age, which is 0.2 mg/kg/h for
72 hours.
To determine if plasma ropivacaine levels do not exceed toxic levels, blood
samples will be taken from an indwelling arterial line, or at the same time a
regular blood sample is taken by heel prick, concomitant with blood sampling
for clinical purposes (in case there is no arterial line). Patients will not
suffer extra heel pricks for only study purposes. Also a DSMB is established,
who will examine the results, including plasma concentrations of ropivacaine
per patient, after 10 and 30 patients have been included in the study. We
thereby hope to have taken sufficient measures to reduce the overall risks for
the children participating in this investigation.

A potential ethical concern of the study is that this is a placebo controlled
study investigating a new RA technique for the treatment of postoperative pain,
and special care must be taken that no child included in the study is
undertreated when having postoperative pain. We therefore have an extensive
postoperative pain protocol, which is our current protocol in the pediatric
intensive care unit, to guarantee that no child will suffer from severe
postoperative pain during this trial.