Donal J. Buggy

Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis

Background: Regional anesthesia is known to prevent or attenuate the surgical stress response; therefore, inhibiting surgical stress by paravertebral anesthesia might attenuate perioperative factors that enhance tumor growth and spread. The authors hypothesized that breast cancer patients undergoing surgery with paravertebral anesthesia and analgesia combined with general anesthesia have a lower incidence of cancer recurrence or metastases than patients undergoing surgery with general anesthesia and patient-controlled morphine analgesia. Methods: In this retrospective study, the authors examined the medical records of 129 consecutive patients undergoing mastectomy and axillary clearance for breast cancer between September 2001 and December 2002. Results: Fifty patients had surgery with paravertebral anesthesia and analgesia combined with general anesthesia, and 79 patients had general anesthesia combined with postoperative morphine analgesia. The follow-up time was 32 ± 5 months (mean ± SD). There were no significant differences in patients or surgical details, tumor presentation, or prognostic factors. Recurrence- and metastasis-free survival was 94% (95% confidence interval, 87–100%) and 82% (74–91%) at 24 months and 94% (87–100%) and 77% (68–87%) at 36 months in the paravertebral and general anesthesia patients, respectively (P = 0.012). Conclusions: This retrospective analysis suggests that paravertebral anesthesia and analgesia for breast cancer surgery reduces the risk of recurrence or metastasis during the initial years of follow-up. Prospective trials evaluating the effects of regional analgesia and morphine sparing on cancer recurrence seem warranted.

Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis.

Background:Regional anesthesia and analgesia attenuate or prevent perioperative factors that favor minimal residual disease after removal of the primary carcinoma. Therefore, the authors evaluated prostate cancer recurrence in patients who received either general anesthesia with epidural anesthesia/analgesia or general anesthesia with postoperative opioid analgesia. Methods:In a retrospective review of medical records, patients with invasive prostatic carcinoma who underwent open radical prostatectomy between January 1994 and December 2003 and had either general anesthesia–epidural analgesia or general anesthesia–opioid analgesia were evaluated through October 2006. The endpoint was an increase in postoperative prostate-specific antigen. Results:After adjusting for tumor size, Gleason score, preoperative prostate-specific antigen, margin, and date of surgery, the epidural plus general anesthesia group had an estimated 57% (95% confidence interval, 17–78%) lower risk of recurrence compared with the general anesthesia plus opioids group, with a corresponding hazard ratio of 0.43 (95% confidence interval, 0.22–0.83; P = 0.012) in a multivariable Cox regression model. Gleason score and tumor size (percent of prostate involved) were also independent predictors of recurrence (hazards ratios of 1.19 [1.08, 1.52], P = 0.004, and 1.17 [1.03, 1.34] for 10% size difference, P = 0.01, respectively). A similar association between epidural use and recurrence was obtained by comparing patients matched on the propensity to receive epidural versus general anesthesia. Conclusions:Open prostatectomy surgery with general anesthesia, substituting epidural analgesia for postoperative opioids, was associated with substantially less risk of biochemical cancer recurrence. Prospective randomized trials to evaluate this association seem warranted.

Gabapentin in postamputation phantom limb pain: A randomized, double-blind, placebo-controlled, cross-over study

Background and Objectives Severe phantom limb pain after surgical amputation affects 50% to 67% of patients and is difficult to treat. Gabapentin is effective in several syndromes of neuropathic pain. Therefore, we evaluated its analgesic efficacy in phantom limb pain. Methods Patients attending a multidisciplinary pain clinic with phantom limb pain were enrolled into this randomized, double-blind, placebo-controlled, cross-over study. Other anticonvulsant therapy was discontinued. Each treatment was 6 weeks separated by a 1-week washout period. Codeine/paracetamol was allowed as rescue analgesia. The daily dose of gabapentin was titrated in increments of 300 mg to 2,400 mg or the maximum tolerated dose. Patients were assessed at weekly intervals. The primary outcome measure was visual analog scale (VAS) pain intensity difference (PID) compared with baseline at the end of each treatment. Secondary measures were indices of sleep interference, depression (Hospital Anxiety and Depression [HAD] scale), and activities of daily living (Bartel Index). Results Nineteen eligible patients (mean age, 56 years; range, 24 to 68 years; 16 men) were randomized, of whom 14 completed both arms of the study. Both placebo and gabapentin treatments resulted in reduced VAS scores compared with baseline. PID was significantly greater than placebo for gabapentin therapy at the end of the treatment (3.2 ± 2.1 v 1.6 ± 0.7, P = .03). There were no significant differences between placebo and gabapentin therapy in terms of the number of tablets of rescue medication required, sleep interference, HAD scale, or Bartel Index. The medication was well tolerated with few reports of adverse effects. Conclusions After 6 weeks, gabapentin monotherapy was better than placebo in relieving postamputation phantom limb pain. There were no significant differences in mood, sleep interference, or activities of daily living, but a type II error cannot be excluded for these variables.

Can regional analgesia reduce the risk of recurrence after breast cancer? ☆ Methodology of a multicenter randomized trial

Surgery is the primary and most effective treatment of breast cancer, but minimal residual disease is probably unavoidable. Whether residual disease results in clinical metastases depends on numerous factors, including anti-tumor cell mediated immunity and angiogenic and growth signals in sites of residual disease. At least three perioperative factors adversely affect these: 1) the neuroendocrine stress response to surgery, 2) volatile anesthetics, and 3) opioids. Animal studies indicate that regional anesthesia and optimum postoperative analgesia independently reduce the metastatic burden in animals inoculated with breast adenocarcinoma cells following surgery. Retrospective studies in humans also suggest that regional analgesia may reduce recurrence risk after cancer surgery. We will test the hypothesis that local or metastatic recurrence after breast cancer surgery is lower in patients randomized to paravertebral or high-thoracic epidural analgesia combined with sedation or light anesthesia than in patients given intraoperative volatile anesthesia and postoperative opioid analgesia. In a Phase III, multi-center trial, Stage 1-3 patients having mastectomies for cancer will be randomly assigned to thoracic epidural or paravertebral anesthesia/analgesia, or to sevoflurane anesthesia and morphine analgesia. The primary outcome will be cancer recurrence. Enrolling 1100 patients over 5 years will provide 85% power for detecting a 30% treatment effect at an alpha of 0.05. We plan four equally spaced interim analyses, each evaluating efficacy and futility. Confirming our hypothesis will indicate that a small modification to anesthetic management, one that can be implemented with little risk or cost, will reduce the risk of cancer recurrence - a complication that is often ultimately lethal.

Epidural anaesthesia and analgesia: better outcome after major surgery?

Major surgery induces profound physiological changes in the perioperative period, characterised by increases in sympathoadrenal and other neuroendocrine activity and also increased cytokine production Because epidural anaesthesia can attenuate this “stress response” to surgery, improve the quality of postoperative analgesia in comparison with systemic opioids, and hasten recovery of gut function, it has been suggested that conducting surgery under epidural anaesthesia (either as the sole anaesthetic or in combination with general anaesthesia) may reduce perioperative morbidity and mortality compared with general anaesthesia alone.1 Indeed, in a study of high risk patients undergoing major vascular surgery those who received combined general and epidural anaesthesia with postoperative epidural analgesia had significantly lower cardiac morbidity than those receiving general anaesthesia alone with postoperative systemic opioid analgesia.2 Unfortunately, subsequent studies have failed to confirm this finding. This uncertainty probably relates to the design, small size, and inadequate number of relevant studies for a meta-analysis of outcome; hence investigators in Australia are currently undertaking a large, multicentre study to address this question. Though the effects of epidural anaesthesia on mortality and cardiac morbidity have been disappointing so far, the evidence that epidural anaesthesia decreases thromboembolic, pulmonary, …

Synovial tissue hypoxia and inflammation in vivo

Introduction Hypoxia is a microenvironmental feature in the inflamed joint, which promotes survival advantage for cells. The aim of this study was to examine the relationship of partial oxygen pressure in the synovial tissue (tPO2) in patients with inflammatory arthritis with macroscopic/microscopic inflammation and local levels of proinflammatory mediators. Methods Patients with inflammatory arthritis underwent full clinical assessment and video arthroscopy to quantify macroscopic synovitis and measure synovial tPO2 under direct visualisation. Cell specific markers (CD3 (T cells), CD68 (macrophages), Ki67 (cell proliferation) and terminal deoxynucleotidyl transferase dUTP nick end labelling (cell apoptosis)) were quantified by immunohistology. In vitro migration was assessed in primary and normal synoviocytes (synovial fibroblast cells (SFCs)) using a wound repair scratch assay. Levels of tumour necrosis factor α (TNFα), interleukin 1β (IL1β), interferon γ (IFNγ), IL6, macrophage inflammatory protein 3α (MIP3α) and IL8 were quantified, in matched serum and synovial fluid, by multiplex cytokine assay and ELISA. Results The tPO2 was 22.5 (range 3.2–54.1) mm Hg and correlated inversely with macroscopic synovitis (r=−0.421, p=0.02), sublining CD3 cells (−0.611, p<0.01) and sublining CD68 cells (r=−0.615, p<0.001). No relationship with cell proliferation or apoptosis was found. Primary and normal SFCs exposed to 1% and 3% oxygen (reflecting the median tPO2 in vivo) induced cell migration. This was coupled with significantly higher levels of synovial fluid tumour necrosis factor α (TNFα), IL1β, IFNγ and MIP3α in patients with tPO2 <20 mm Hg (all p values <0.05). Conclusions This is the first study to show a direct in vivo correlation between synovial tPO2, inflammation and cell migration, thus it is proposed that hypoxia is a possible primary driver of inflammatory processes in the arthritic joint.

Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis

Cancer is a leading cause of morbidity and mortality worldwide and the ratio of incidence is increasing. Mortality usually results from recurrence or metastases. Surgical removal of the primary tumour is the mainstay of treatment, but this is associated with inadvertent dispersal of neoplastic cells into the blood and lymphatic systems. The fate of the dispersed cells depends on the balance of perioperative factors promoting tumour survival and growth (including surgery per se, many anaesthetics per se, acute postoperative pain, and opioid analgesics) together with the perioperative immune status of the patient. Available evidence from experimental cell culture and live animal data on these factors are summarized, together with clinical evidence from retrospective studies. Taken together, current data are sufficient only to generate a hypothesis that an anaesthetic technique during primary cancer surgery could affect recurrence or metastases, but a causal link can only be proved by prospective, randomized, clinical trials. Many are ongoing, but definitive results might not emerge for a further 5 yr or longer. Meanwhile, there is no hard evidence to support altering anaesthetic technique in cancer patients, pending the outcome of the ongoing clinical trials.

Inhibition of the Stress Response to Breast Cancer Surgery by Regional Anesthesia and Analgesia Does Not Affect Vascular Endothelial Growth Factor and Prostaglandin E2

Angiogenesis is essential for breast cancer metastases formation and is mediated by vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2). We hypothesized that serum levels of VEGF and PGE2 are increased by the stress response to breast cancer surgery and attenuated by paravertebral anesthesia and analgesia (PVAA). Thirty women undergoing mastectomy were enrolled in this prospective, randomized study, to receive general anesthesia (GA) and postoperative opioid analgesia (morphine 0.1 mg/kg bolus and patient-controlled infusion) or GA and PVAA (72-h infusion). All patients received rectal diclofenac. Venous blood samples were taken preoperatively and at 4 and 24 h postoperatively for serum glucose, cortisol, C-reactive protein, VEGF, and PGE2. PVAA inhibited the surgical stress response, as indicated by significantly less plasma glucose, cortisol, and C-reactive protein. VEGF and PGE2 values did not differ significantly between the groups. Mean (sd) percentage change in VEGF at 4 and 24 h respectively were 3% ± 44% versus 9% ± 80%, P = 0.29 and 5% ± 43% versus −10% ± 63%, P = 0.41 for patients with combined general and PVAA and GA alone, respectively. Mean percentage change in postoperative PGE2 at 4 and 24 h respectively was 10% ± 17% versus 11% ± 69%, P = 0.29 and 34% ± 19% versus 47% ± 18%, P = 0.15. We conclude that despite inhibiting the surgical stress response, PVAA had no effect on serum levels of putative breast cancer angiogenic factors, VEGF and PGE2.

Ondansetron given before induction of anesthesia reduces shivering after general anesthesia.

The neurotransmitter pathways involved in the mechanism of postanesthetic shivering (PAS) are poorly understood. Meperidine, clonidine, and physostigmine are all effective treatments, indicating that opioid, &agr;2-adrenergic, and anticholinergic systems are probably involved. We investigated the effect of ondansetron, a 5-HT3 antagonist used to treat postoperative nausea and vomiting, on intraoperative core and peripheral temperatures and PAS. Eighty-two patients (age, 18–60 yr) undergoing orthopedic, general, or urological surgery were randomized into three groups in this double-blinded, placebo-controlled, study: Group O4 (n = 27) received ondansetron 4 mg IV, Group O8 (n = 27) received ondansetron 8 mg IV, and Group C (n = 28) received saline IV immediately before the anesthetic induction. Core (tympanic) and fingertip temperature (dorsum of middle finger) were recorded. Anesthesia was induced with IV fentanyl 1 &mgr;g/kg and propofol 2.0–2.5 mg/kg and maintained with 1 minimum alveolar anesthetic concentration isoflurane in 70% nitrous oxide/oxygen. The occurrence of shivering was documented clinically during recovery by nursing staff, who were unaware of the group assignment. PAS occurred in 16 of 28 (57%) patients in Group C, compared with 9 of 27 (33%) in Group O4 (P = 0.13) and 4 of 27 (15%) patients in Group O8 (P = 0.003). Within each group, core temperature decreased and peripheral temperature increased significantly, but there were no significant differences among the groups at any time interval. We conclude that ondansetron 8 mg IV given during the induction of anesthesia prevents PAS without affecting the core-to-peripheral redistribution of heat during general anesthesia. This suggests that serotonergic pathways have a role in the regulation of PAS. Implications In a randomized, double-blinded, placebo-controlled, clinical study, ondansetron 8 mg IV, given just before the induction, reduced the incidence of postanesthetic shivering compared with saline. The anticipated core-to-peripheral redistribution of body temperature during general anesthesia was not affected. This implies that ondansetron probably acts by a central inhibitory mechanism, and that 5-hydroxytryptaminergic pathways have a role in regulating postanesthetic shivering.

Effect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitro

BACKGROUND Metastatic recurrence is the main cause of breast cancer-related deaths. Tumour cell proliferation and migration are crucial steps in the metastatic process. Several perioperative factors, including general anaesthesia and opioid analgesia, adversely affect immune function, potentially increasing metastatic recurrence. Regional anaesthesia-analgesia has been consistently shown to attenuate the stress response to surgery, and also reduce opioid and general anaesthesia requirements, thereby attenuating this perioperative immunosuppression. We investigated the effect of serum from breast cancer surgery patients who received different anaesthetic techniques on breast cancer cell function in vitro. METHODS Patients were randomized to receive propofol/paravertebral anaesthesia-analgesia (propofol/paravertebral, n=11) or sevoflurane general anaesthesia with opioid analgesia (sevoflurane/opioid, n=11). The ER-negative MDA-MB-231 cell line was treated with patient serum from both groups. The effects on proliferation and migration were measured. RESULTS Treatment groups were well balanced for age, weight, surgical procedure, and cancer pathology. Pain scores were lower at 1 and 2 h in the propofol/paravertebral analgesia group. Compared with preoperative values, proliferation of MDA-MB-231 cells treated with postoperative patient serum at 10% concentration from the propofol/paravertebral group was significantly reduced compared with the sevoflurane/opioid group (-24% vs 73%, P=0.01). There was no significant change in MDA-MB-231 cell migration after treatment with patient serum between the two groups. CONCLUSIONS Serum from patients receiving propofol/paravertebral anaesthesia for breast cancer surgery inhibited proliferation, but not migration, of ER-MDA-MB-231 cells in vitro, to a greater extent than that from patients receiving sevoflurane/opioid anaesthesia-analgesia. This implies that anaesthetic technique alters the serum molecular milieu in ways that may affect breast cancer cell function, possibly by altering anaesthetic and opioid drug administration and resultant pain scores.