Optimal postoperative Pain management After Lung surgery (OPtriAL): multi-centre randomised trial

Adequate pain control after video-assisted thoracic surgery (VATS) for lung
resection is important to improve postoperative mobilisation and recovery, and
to prevent postoperative pulmonary complications. Thoracic epidural analgesia
(TEA) is the gold standard for postoperative pain management following thoracic
surgery. Although the analgesic effect of TEA is clear, failure rates are 9-30%
[1, 2, 3] and awake placement is stressful for patients. In addition, TEA is
associated with patient immobilisation, bladder dysfunction and hypotension
[4]. Based on the best available evidence and the recent guidelines by the
Enhanced Recovery After Surgery (ERAS) society, the European Society of
Thoracic Surgeons (ESTS) includes early mobilisation after surgery as one of
their key recommendations [5].

The disadvantages of the TEA initiated the development of unilateral regional
techniques for pain management. Single-shot and continuous paravertebral,
intercostal, serratus anterior and erector spinae blocks have shown to be safe
and effective [6]. A meta-analysis on single-shot versus continuous peripheral
nerve blockade showed improved pain control, decreased need for opioids and
greater patient satisfaction with the continuous infusion technique [7].
Another non-systematic review suggests poorer pain control in single-shot local
techniques, however this technique is easy to perform, has low costs compared
to the standard TEA care [8] and lower incidence of adverse events [9].
Unilateral regional techniques are not associated with patient immobilisation,
bladder dysfunction and hypotension [10].

So far, no consensus exists on optimal postoperative pain management after VATS
lung resection. A review of enhanced recovery after thoracic surgery (ERATS)
protocols strengthened the lack of unambiguity [11]. The five included
protocols all used different techniques for postoperative pain management:
oral, intravenous, intercostal, paravertebral and epidural anaesthesia. We
conducted a systematic review and found that TEA resulted in mean pain scores
of 1.8 (95%-CI 1.4-2.3) at 24 hours after surgery and 1.5 (95%-CI 1.2-1.8)
after 48 hours. Regional continuous analgesia resulted in mean pain scores of
2.6 (95%-CI 1.9-3.5) and 2.1 (95%-CI 1.6-2.8) respectively, whereas single-shot
regional analgesia resulted in mean pain scores of 2.2 (95%-CI 1.7-2.8) and 1.3
(95%-CI 0.9-1.7). The quality of recovery during the first 2 postoperative days
and postoperative analgesia was improved in patients after VATS undergoing
single-injection serratus plane block with ropivacaine compared to a placebo
control group [12].

The Dutch Societies of Lung Surgery (NVvL) and Thoracic Surgery (NVT) provide
no guidelines for postoperative pain management. The Dutch guideline database
and the ESTS guideline on ERATS all address TEA as well as other regional
techniques to be valid options for pain control after VATS. In January 2018,
the NVvL introduced 2 of the 28 knowledge gaps of the Dutch Society of Surgery.
The first addresses research on *optimal perioperative management after
minimally invasive thoracic surgery*, which should finally lead to a Dutch
ERATS protocol. Nationally, an ERATS working group is installed focusing on the
disadvantages of TEA: hypotension, the need for a urinary catheter,
immobilisation and stressful awake placement of the TEA catheter. There is much
interest in the implementation of a multi-modal analgesic regimen without TEA
and relying solely on single shot intercostal nerve block and systemic pain
control. On the other hand, anaesthesiologists regard TEA as the best current
analgesic technique. A survey among Dutch lung and thoracic surgeons indeed
pointed out that 69% of hospitals currently use TEA for pain control after VATS
lung resection. Of all new regional analgesic techniques, the paravertebral
block (PVB) is the only technique with central blockade of both the intercostal
and sympathetic nerves. Therefore, next to TEA, PVB fits best in the concept of
anaesthesiologists for pain control after VATS lung resection. Internationally,
PVB has therefore much attention as regional analgesic technique after VATS.
In addition to studying pain, patient satisfaction and postoperative quality of
recovery (QoR) are crucial factors in the decision making of patient selected
analgesic techniques. The *Standardised Endpoints in Perioperative
Medicine* (StEP) initiative seeks to provide guidance for researchers in their
selection of patient-centred outcomes used in clinical effectiveness trials
related to anaesthetic-specific interventions [13]. Quality of health is
multidimensional and involves QoR as a whole, taking into account physical and
mental well-being. Pain assessment continues to be a challenge due to its
subjective nature and relation to various outcomes related to QoR, therefore,
anaesthesia and pain studies strongly recommend using a patient related outcome
measure reporting QoR to assess postoperative pain [14, 15]. To our knowledge,
only two articles are published [12, 16] about pain and QoR after VATS using
the QoR-40 item questionnaire. Recently, Stark and colleagues [17] developed a
QoR-15 item questionnaire, which is proven to be an easy to use short version
and is a validated and relevant tool for measuring QoR. The QoR-15
questionnaire contains the most relevant questions regarding physical and
mental well-being after surgery and focuses on the following five domains:
pain, physical comfort, physical independence, psychological support and
emotional state.

The main objective is to compare regional continuous paravertebral block (PVB),
single shot multi-level intercostal nerve block (ICNB) and thoracic epidural
analgesia (TEA) as pain relief techniques in order to provide safe, effective
and efficient pain management after thoracoscopic lung surgery. This study will
provide the evidence for an ERATS protocol to be implemented for the optimal
analgesic technique after VATS anatomic lung resection taking into account pain
scores and QoR.

The proposed multi-centre randomised trial is a three-arm trial comparing PVB,
single shot ICNB and TEA in a 1:1:1 ratio for pain (non-inferiority) and for
QoR (superiority) in patients who have undergone a thoracoscopic anatomical
lung resection. The CONSORT 2010 flow diagram is shown in Figure 1.

Intervention 1: continuous regional PVB
The PVB catheter is placed after general anaesthesia at the beginning of the
VATS/RATS procedure under direct thoracoscopic vision. If placement cannot be
achieved at the beginning of the operation as a result of poor thoracoscopic
vision the catheter will be placed at the end of surgery. It is strongly
preferred to place the PVB at the beginning of the VATS procedure to benefit
from the advantages of administering local anaesthetics from the beginning of
the operation. If the PVB is placed at the end of the procedure, patients will
need more intravenous opioids during the operation which can interfere with
reliable data collection of pain scores and opioid use in the recovery room.
In order to place the PVB catheter, identify the paravertebral space (an
additional option is to use the thorax CT scan for an overview of the
landmarks) with the following landmarks: the height of the paravertebral block
is at T4-T5 or T5-T6 (carina height), 2-3 cm lateral from the midline and 3-6
cm of depth measured perpendicularly from the skin. After induction of
anaesthesia the patient is positioned in lateral decubitus and the relevant
landmarks are identified. Optionally, placement of the PVB catheter can be
achieved with the aid of ultrasonography. For this, start laterally from the
vertebral column and identify the rib and the pleura. Move medially and
identify the processus transversus. Locate the middle between two processus
transversi and mark the puncture site. Under thoracoscopic vision, identify the
sympathetic chain. In all cases the surgeon will identify the paravertebral
space under thoracoscopic vision. A Tuohy needle is inserted at the before
mentioned marked location and a syringe with NaCl is placed. After feeling a
*fascial pop* penetrating the intercostal ligament, feel the loss of resistance
when entering the subpleural space. At the same time, observe the appearance of
the needle tip under the pleura thoracoscopically. Once the needle is placed in
the paravertebral space, create hydrodissection with a minimal amount of NaCl
to reach the adequate paravertebral plane for placement of the catheter. Insert
the catheter under thoracoscopic vision. Remove the Tuohy needle. Join the
connector to the catheter and inject a bolus of local anaesthetic of 15-20 mL
ropivacaine 7.5 mg/mL or levobupivacaine 2.5 mg/mL. A ropivacaine 2 mg/mL pump
for continuous infusion is given with a infusion rate of 4-10ml/hour, in case
of insufficient pain control (NRS >=4) a bolus of 4-5 mL is given (in case a
patient controlled (epidural) anaesthesia pump is available with a lockout of
20 minutes). No opioid additives or opioids will be administered through the
paravertebral catheter. A provisional stop of the administration of local
anaesthetics is planned on the second postoperative day after which removal is
considered based on the effect on pain intensity, comparable to the TEA group.
No mobility restrictions are needed in this group.

Intervention group 2: single shot ICNB
At the end of the surgery a single shot ICNB will be placed at 6 levels (T3-T8)
with bupivacaine 2.5 mg/mL or levobupivacaine 2.5mg/mL and 2-3mL per site under
direct thoracoscopic vision. The injection site will be chosen in the
intercostal space, just lateral adjacent to the sympathetic trunk. This group
will have no analgesic catheters for continued analgesia with local
anaesthetics. No mobility restrictions are needed in this group.

According to a survey we conducted among lung surgeons and anaesthesiologists
in the Netherlands in 2019 asking about the preferred analgesic technique used
during VATS anatomic lung resection; 69% performed a TEA, 5.4% used a PVB and
18.2% used an ICNB. The variability, also confirmed through our literature
review, indicates no guideline in standard care. Taking into account that TEA
is the most performed technique, benefits in the patients undergoing the
intervention techniques will be the omitted epidural related complications
(according to our pilot study [18]): 1 day longer immobilisation, 2 days
urinary bladder catheter and hypotension (reported to be present in 26% of the
patients during POD 1-3).
To the best of our knowledge, the interventions used do not expose participants
to additional risks compared to TEA. PVB en ICNB are not experimental and
already implemented (inter)nationally. The PVB group has an equal or reduced
risk of bleeding, nerve damage, insertion site infection, hypotension, post
puncture spinal headache and failure of the analgesic technique compared to
TEA. The ICNB group has the lowest risk of complications as it is the most
peripheral analgesic technique without the insertion of a catheter. Nonetheless
aforementioned risks also apply.
It is realistic to expect that patients in the intervention groups will have
more episodes of NRS >=4, therefore, we expect these patients to use more
morphine to control pain.