Pain, Postoperative Clinical Trial
Official title:
Intraluminal Ureteric Injection of High Concentration Alkalinised Long-acting Local Anaesthetic and STeroid Post urEteroscopy: A Prospective Double Blinded Randomised Controlled Trial (LASTE Trial)
Précis:
Randomised control trial to evaluate safety and efficacy of intraluminal injection of high
pH-high concentration of a long-acting local anesthetic and long-acting glucocorticoid in the
ureter after ureteroscopy.
Objectives:
To evaluate a novel method to ameliorate post-ureteroscopy pain in all patients (with and
without stents)
Endpoints:
Primary endpoint: mean visual analog pain scale (VAS) post-operatively starting at 1 hour, 4
hours, 8 hours, 24 hours and 7 days post-procedure (minimum of 3 VAS scores). VAS pain,
ureteral stent symptoms and analgesic requirement will be assessed at different points during
this time period.
Secondary endpoint: Postoperative Nausea/Vomiting (PONV), safety of intraluminal injection of
high concentration alkalinized local anaesthetic solution by comparing adverse events between
placebo and treatment arms. In addition, rehospitalisation rates and postoperative length of
stay will be compared between the three groups.
Population:
150 adult patients undergoing ureteroscopy for ureteric stone disease stratified into
negative ureteroscopy and those treated for a stone with or without stent insertion
postoperatively Number of Sites: Tallaght Hospital Study Duration: 8 months
Study Rationale Ureteroscopy is a widely performed procedure in urology. Pain is one of the
commonest complications after ureteroscopy and one of the common reasons for re-admission
after this procedure. Insertion of a stent post-ureteroscopy can cause pain affecting daily
activities in 80% of the patients. Pain post ureteroscopy is multi-factorial and currently
there is no specific method used clinically to treat this. Intraluminal injection of local
anesthetic solution in the ureter has been extensively studied in the animal model with
positive results. Intraluminal injection steroids has also been studied previously and
steroids have also been used in medical expulsive therapy for ureteric stones previously. The
investigators are proposing the use of high concentration alkalinized long-acting local
anaesthetic levo-bupivicaine and long-acting steroid dexamethasone for post-ureteroscopy
pain. It is simple, cheap, safe, easy to perform and widely available.
Background Intraluminal injection of local anesthetics (LA) in the ureter has been studied
previously in animal models. Burdgya et al in 1986, USSR examined effects of LA on guinea pig
ureters . Action potential of ureteric smooth muscle has initial fast component consisting of
repeated gradually decaying spikes and a subsequent slow component i.e plateau. This action
potential is accompanied by a brief contraction. Two opposite effects of LA occur on ureteric
smooth muscle: Low concentrations of procaine, lignocaine and tetracaine (0.1-1 mM) at pH 7.4
increased duration of slow plateau of the evoked action potentials. At higher concentrations
lignocaine (5mM) and tetracaine (0.5mM) caused complete inhibition of evoked action
potentials and phasic contractions. Procaine 5mM predominantly inhibited contractile
responses. High pH (9) significantly increased while low pH (pH 6) decreased the inhibitory
action of procaine and lignocaine. Tetracaine had the most potent inhibitory action on ureter
smooth muscle with the weakest stimulant action while lignocaine had stronger inhibitory
effect on ureter smooth muscle than procaine. Ross et al in 1972 reported intraluminal
injection of 2% lignocaine reduced peristaltic activity in 5 out of 15 ureters in their
patients with no effect in the remaining group.
Andersson and Ulmsten found that local instillation of 4% lignocaine in their patients caused
an initial brief stimulation followed by reduced activity. Tsuchida in 197 studied dog
ureters to report prompt inhibitory effect of 4% lignocaine applied to mucosa invivo with no
effect when applied to adventitia.
Struthers in 1976 in his invivo dog studies found both systemic and intraluminal
administration of lignocaine, procaine and mepivacaine caused only hyperperistalsis and never
inhibition. Sur et al published a study with intravesical injection of ropivacaine before
ureteroscopic surgery demonstrated trends toward decreased pain and voiding symptoms.
Patients received five injections of 2 mL 0.5% ropivacaine around the ureteral orifice or to
the control cohort, who received five injections of 2 mL of 0.9% normal saline in identical
locations. A pilot study suggested that PSD597 (intravesical alkalinized lidocaine) is
effective for treating interstitial cystitis/painful bladder syndrome (IC/PBlS) , providing
short-term amelioration of symptoms in a substantial proportion of patients, with a strong
suggestion that repeating the treatment has a potentially cumulative effect. A randomized
controlled trial comparing injection of non-irritating salt water (placebo), and half an
injection of pH buffered lidocaine before the stent placement in patients undergoing
ureteroscopy is currently being conducted. Till date there is no human study assessing the
efficacy and safety of high concentration alkalinised long-acting LA injection for
post-ureteroscopy pain based on the results of the animal studies outlined above.
The anaesthetic drug chosen for this study is levobupivacaine (Chirocaineā¢ -): it is S-isomer
of bupivacaine, an amino-amide local anaesthetic widely used in regional anaesthesia, in
postoperative analgesia and in treatment of acute and chronic pain. This drug produces
sensory and motor nerve conduction block, acting on sodium channels of the cell membrane -
sensitive to electric stimulus - but also on potassium and calcium channels. Moreover, it is
remarkable for a rapid onset time and a long duration. In vitro and in vivo pharmacodynamic
studies show that levobupivacaine has the same potency as bupivacaine, though the former is
less likely to cause cardio- and neurotoxicity.
The effect of steroids on ureteric motility has previously been studied in in-vitro sheep
models. Glucocorticoids inhibit the release of phospholipase A2 enzyme which catalyses the
release of arachidonic acid from membrane phospholipids and thereby can have a spasmolytic
action on the ureter by a prostaglandin-inhibitory action. Dexamethasone has shown the most
potent dose dependant effect on the ureteral motility, it blocks ureteral motility in high
concentrations within 24 minutes of instillation. Being a long-acting steroid, its duration
of action in previous studies on nerve blocks and intra-articular injections is demonstrated
at 12 weeks.
Study population: 150 patients undergoing ureteroscopy for ureteric stones:
1. Ureteric stone treatment (including proximal, mid and distal ureteric stones) with or
without JJ stent insertion OR
2. Negative ureteroscopy (no stone found)
Pre and intraop: Obtain informed written consent pre-operatively with a pre-operative pain
score, and rule out any allergies. Standardised uniform anesthetic regimen in all
ureteroscopies.Post-ureteroscopy: drain the renal pelvis
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