Surgery (Austin & Northern Health) - Theses
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ItemIntravenous lignocaine followed by a 24-hour postoperative subcutaneous infusion shortens length of hospital stay after open radical retropubic prostatectomy: a blinded, randomised, placebo-controlled multicentre trial( 2014)Introduction: An alternative method of administering lignocaine for its beneficial anti-inflammatory and analgesic effects to improve and accelerate postoperative recovery is to administer the local anaesthetic solution by a continuous intravenous infusion. However, in patients undergoing major abdominal surgery, intravenous lignocaine combined with a 24-hour continuous subcutaneous infusion has not been systematically examined for efficacy and safety. A subcutaneous infusion of lignocaine may be an effective strategy to continue systemic lignocaine into the early postoperative period. Subcutaneous delivery may be more advantageous than an intravenous infusion, being technically easier to deliver, safer and cost-effective. Drug tolerance may also be less likely to develop. A significant advantage of subcutaneous infusions over intravenous drug delivery methods is that plasma levels are more stable, and symptom control may be achieved without the toxic effects of peaks and troughs resulting from episodic drug administration or a prolonged continuous intravenous infusion. However, it is unknown whether this intervention will impact clinically on important postoperative outcomes, such as length of hospital stay and accelerated postoperative rehabilitation. Before a combination of intravenous lignocaine and subcutaneous lignocaine is adopted as a feasible and efficacious technique for patients undergoing major abdominal surgery, it needs to be investigated in a randomised controlled clinical trial to measure its benefits and harm, and to better define its role in therapy. Study aims: The aims of this study are to evaluate whether a combination of intravenous lignocaine followed by a postoperative 24-hour subcutaneous infusion is beneficial in decreasing length of hospital stays, improving analgesia, and reducing opioid consumption compared to placebo. This study will also quantify the safety of this technique in a perioperative setting. The study was designed to test the hypothesis that perioperative systemic lignocaine infusion in this combination enhances recovery and shortens length of hospital stay after an open radical retropubic prostatectomy. Methods: The Austin and Box Hill Human Research Ethics Committees approved this study. This was a blinded, randomised, placebo-controlled, multicentre trial at two university teaching hospitals. Patients undergoing open radical retropubic prostatectomy were randomised to receive intravenous lignocaine (bolus injection 1.5 mg/kg), then an intravenous infusion (1.5 mg/kg/hr) during surgery, followed by iv subcutaneous infusion for 24 hours (1.5 mg/kg/hr) (Lignocaine group), or a Placebo group who received an equal volume of normal saline delivered at the same infusion rates and over the same time period. General anaesthesia, including the use intraoperative opioids, was standardized, and no patient received regional analgesia or anaesthesia, surgical wound catheters, or infiltration of the surgical wound with local anaesthetic solutions. All patients received morphine patient-controlled analgesia postoperatively in a standardized dosing regime. The primary aim of this study is to evaluate whether a combination of intravenous lignocaine followed by a postoperative 24-hour subcutaneous infusion is beneficial in decreasing the length of hospital stay compared to placebo. Important secondary outcomes included comparing intraoperative haemodynamics (heart rate, blood pressure), Bispectral index (BIS), and end-tidal sevoflurane concentrations required to maintain 1 MAC of anaesthesia. In addition, postoperative pain using a Visual Analogue Scale at the incision site measured at rest and with coughing, morphine and rescue analgesia consumption, need for rescue anti-emetic therapy, and patient satisfaction were also evaluated. Opioid-related and lignocaine-related side effects were critically examined including the measurement of plasma lignocaine levels performed in the immediate postoperative period and at 24 hours prior to the discontinuation of the lignocaine subcutaneous infusion. Results: The Lignocaine group had 37 patients and the control group had 38 patients. Patient demographics were similar between groups. The mean duration for surgery was 155.7 minutes (SD: 34.2) for the Lignocaine group and 141.6 minutes (SD: 44.6) for the Placebo group (estimated difference: 14.1 minutes, 95% CI: -4.27 to 32.47, p = 0.13). In the Lignocaine group, the mean highest heart rate recorded was 97.5 beats/minute vs. 103.8 beats/minute in the Placebo group (estimated difference: 6.3 beats/minute; 95% CI: 2.4 to 10.3 beats/minute, p = 0.001). Intraoperatively, the Lignocaine group had lower heart rates [52.1 beats/minute vs. 59.0 beats/minute; estimated difference: 6.8 beats/minute; 95% CI: 3.3 to 10.3 beats/minute, p = 0.001]. The mean BIS is the Lignocaine group was lower than that in the Placebo group (43.4% vs. 49.8%; estimated difference 6.3%, 95% CI: 3.0% to 9.7%, p = 0.001). Despite the BIS being lower in the Lignocaine group, the average concentration of sevoflurane required to maintain 1 MAC of anaesthesia was lower in the Lignocaine group [1.49% vs. 1.89%; estimated difference 0.39%, 95% CI: 0.26% to 0.5%, p = 0.001]. The Lignocaine group had a shorter length of hospital stay [3.3 days (SD: 0.8) vs. 4.7 days (SD: 3.2), estimated difference 1.3 days; 95% CI: 0.2 to 2.4, p = 0.02]. The Lignocaine group required less morphine during the first 24 hours [mean 38 mg (SD: 24) vs. 52 mg (SD: 27); estimated difference 14 mg; 95% CI 2 to 26 mg, p = 0.02]. The mean Visual Analogue Scores for pain at rest one hour postoperatively were 3.73 units for the Placebo group and 1.93 units for the Lignocaine group. On average, the Placebo group scored 1.80 units higher than the Lignocaine group at this time point (95% CI: 0.73 to 2.88, p = 0.001). There was no difference in rest pain at 24 hours. There were also no significant differences in pain on movement over the 24-hour period. Among secondary endpoints, the time taken to tolerate free fluids and a light ward diet were shorter in the Lignocaine group. Time to mobilize was also shorter in the Lignocaine group. Other secondary endpoints were similar. In the Lignocaine group, the mean plasma lignocaine level after surgery was 1.36 mcg/mL (SD: 0.48), range 0.5 mcg/mL to 2.19 mcg/mL; and at 24 hours postoperatively was 3.1 mcg/mL (SD: 0.95); range 1.1 mcg/mL to 4.96 mcg/mL. Lignocaine levels in the Placebo group were always less than 0.5 mcg/mL. No patient experienced complications associated with lignocaine infusion. Conclusions: Intravenous lignocaine followed by a 24-hour subcutaneous infusion resulted in a shorter length of hospital stay and accelerated acute rehabilitation after open radical retropubic prostatectomy. Furthermore, subcutaneous infusion of lignocaine was an effective strategy to continue systemic lignocaine into the early postoperative period. To date, this is the first randomised clinical trial evaluating the use of subcutaneous lignocaine in this setting, and therefore adds to the growing body of literature supporting the use of lignocaine via this route for open abdominal surgery.
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ItemPrognostic factors in urological malignancies( 2014)BACKGROUND: The management of urologic cancers relies heavily on the implicit or explicit application of prognostic models. This may range from the appropriate selection of diagnostic tests based upon the pre-test probability of a positive finding, to an informed decision on choice of treatment modality or enrolment in suitable clinical trials. While some prognostic factors such as stage and grade are time-tested, others such as molecular and immunohistochemical markers or surgical approach are new and evolving. Furthermore, the literature abounds with nomograms, models, risk tables or groups which utilize varying combinations of predictor variables to prognosticate on myriad outcomes of interest. The aim of this body of work was to enhance our understanding of prognostication in urologic malignancies, particularly prostate cancer, renal cancer and urothelial cancer of the bladder, in various clinical settings. METHODS: Details of methodology vary – specifics are outlined in the relevant chapters. In general terms, an appropriate study population was defined based upon the hypothesis. Variables of interest were extracted from suitable database and / or clinical records, or assessed in the laboratory. Associations between predictors and outcomes were analysed using univariate and (where suitable) multivariate regression techniques. PRINCIPAL RESULTS: • PSA kinetics provide important prognostic information in various clinical settings, including prior to surgical treatment and after hormonal therapy • A persistently detectable PSA following radical prostatectomy is associated with a greater risk of progression and death, but with a long natural history • Younger patients with prostate cancer have less aggressive features, but a proportionately greater risk of progression and death despite curative surgical treatment • Obese patients with prostate cancer have more adverse pathologic features, but similar oncological outcomes compared to those of normal weight • A positive family history is associated with an increased risk of developing prostate cancer, but similar oncologic outcomes following surgical treatment • Gleason scoring has evolved over time, with consequent changes in the prognostic implications thereof • So-called “insignificant” prostate cancer has similar oncological outcomes to low-risk cancers overall, following surgical treatment • Patient suitability for brachytherapy as a single modality can be judged based on the clinically assessed risk of lymph node or seminal vesicle involvement • Clinical factors can predict the risk of nodal metastasis, thus allowing the rational selection of patients for pelvic lymphadenectomy at the time of radical prostatectomy • RALRP is associated with a lower rate of +SM compared to ORP, even after adjusting for known clinical and pathological risk factors • Renal cancers in solitary kidneys associated with vena caval extension may be treated by nephron-sparing surgery where technically suitable, although a high risk of disease progression and death remains • The pre-operative erythrocyte sedimentation rate provides independent prognostic information in patients with renal cancer • Renal lesions with low nephrometry score as measured using the R.E.N.A.L. have a greater likelihood of having benign or indolent histology • Histologic coagulative tumour necrosis within renal cancers is associated with poorer oncological outcomes after surgical treatment • Expression of the oncogene c-kit is rare within high-grade or sarcomatoid renal cancers • Muscle invasive urothelial cancers of the bladder are often infiltrated by profuse numbers of lymphocytes with a variety of phenotypes, although they appear not to impact on the risk of progression or death after surgical treatment • Peri-operative chemotherapy has been increasing in its use over recent years, and appears to reduce the risk of recurrence after surgical treatment of urothelial cancer of the bladder CONCLUSIONS: Many of the findings summarized above have had important implications for practice. For instance: • PSA kinetics are now in widespread use at various stages of prostate cancer management • Gleason scores from patients treated some time ago are often re-interpreted according to revised criteria