A randomised trial of bilateral erector spinae plane block vs. no block for thoracolumbar decompressive spinal surgery.

Major spinal surgery causes significant postoperative pain. We tested the efficacy and safety of bilateral erector spinae block on quality of recovery and pain after thoracolumbar decompression. We randomly allocated 60 adults to standard care or erector spinae block. Erector spinae block improved the mean (SD) quality of recovery-15 score at 24 postoperative hours, from 119 (20) to 132 (14), an increase (95%CI) of 13 (4-22), p = 0.0044. Median (IQR [range]) comprehensive complication index was 1 (0-3 [0-5]) in the control group vs. 1 (0-1 [0-4]) after block, p = 0.4. Erector spinae block reduced mean (SD) area under the curve pain during the first 24 postoperative hours: at rest, from 78 (49) to 50 (39), p = 0.018; and on sitting, from 125 (51) to 91 (50), p = 0.009. The cumulative mean (SD) oxycodone consumption to 24 h was 27 (18) mg in the control group and 19 (26) mg after block, p = 0.20. In conclusion, erector spinae block improved recovery and reduced pain for 24 h after thoracolumbar decompression surgery.

The role of regional anaesthesia in the emerging subspecialty of onco-anaesthesia: a state-of-the-art review.

Cancer accounts for millions of deaths globally each year, predominantly due to recurrence and metastatic disease. The majority of patients with primary solid organ cancers require surgery, however, some degree of tumour dissemination related to surgery is inevitable. The surgical stress response and associated immunosuppression, pain, inflammation, tissue hypoxia and angiogenesis have all been implicated in promoting tumour survival, proliferation and recurrence. Regional anaesthesia was hypothesised to reduce the surgical stress response and immunosuppression, minimise the need for volatile anaesthesia and reduce pain and opioid requirements, thus mitigating pro-tumour pathways associated with the peri-operative period and improving long-term oncological outcomes. While some retrospective studies suggested an association between regional anaesthesia and reduced cancer recurrence, the first large randomised controlled trial on the effect of anaesthetic technique on cancer outcome found no significant difference between paravertebral regional anaesthesia and volatile anaesthesia with opioid analgesia in patients undergoing breast cancer surgery. Randomised controlled trials on the long-term oncological outcomes of regional anaesthesia in other tumour types are ongoing. The focus on how peri-operative interventions, especially regional anaesthesia, during cancer resection surgery, may enhance short-term recovery and perhaps influence long-term outcome has spawned the global emergence of the subspecialty of onco-anaesthesia. This review aims to discuss the most recent evidence on the use of regional anaesthesia in cancer surgery and the significance of its role in onco-anaesthesia.

Perioperative factors associated with postoperative morbidity after emergency laparotomy: a retrospective analysis in a university teaching hospital.

Emergency Laparotomy (EL) is associated with significant morbidity and mortality. Variation in practice and patient outcomes for patients undergoing emergency laparotomy has been identified through the UK National Emergency Laparotomy Audit (NELA), with 30-day mortality ranging from 11 to 15%. A correlation between preoperative haemodynamic parameters and increased postoperative mortality has been demonstrated by both NELA and other observational studies. The association between intraoperative haemodynamic parameters and overall postoperative morbidity has not been evaluated in EL patients. The aims of our study were to investigate the association between perioperative haemodynamic and logistic parameters and postoperative morbidity in a tertiary referral university hospital; and to compare our outcomes to that of the NELA data. A retrospective analysis correlating a range of perioperative parameters with Comprehensive Complication Index (CCI) among 86 patients who underwent EL during 2018 was conducted. Mean age was 64 years (SD 16). Median CCI was 27 [9-45], and 30-day mortality was 11.7%. Several intraoperative parameters correlated with CCI on univariate analysis. On multivariate analysis, ASA status (P = 0.005) and unplanned escalation to postoperative intensive care (P = 0.03) were independently associated with CCI. Our study shows a correlation between ASA status and unplanned escalation to ITU with increased postoperative morbidity in patients undergoing emergency laparotomy. We did not demonstrate an independent correlation between intraoperative parameters and postoperative morbidity. These findings warrant confirmation in a larger scale observational study. Outcomes in our institution are comparable to those seen in the NELA.

Influence of perioperative anaesthetic and analgesic interventions on oncological outcomes: a narrative review.

Surgery is an important treatment modality for the majority of solid organ cancers. Unfortunately, cancer recurrence following surgery of curative intent is common, and typically results in refractory disease and patient death. Surgery and other perioperative interventions induce a biological state conducive to the survival and growth of residual cancer cells released from the primary tumour intraoperatively, which may influence the risk of a subsequent metastatic disease. Evidence is accumulating that anaesthetic and analgesic interventions could affect many of these pathophysiological processes, influencing risk of cancer recurrence in either a beneficial or detrimental way. Much of this evidence is from experimental in vitro and in vivo models, with clinical evidence largely limited to retrospective observational studies or post hoc analysis of RCTs originally designed to evaluate non-cancer outcomes. This narrative review summarises the current state of evidence regarding the potential effect of perioperative anaesthetic and analgesic interventions on cancer biology and clinical outcomes. Proving a causal link will require data from prospective RCTs with oncological outcomes as primary endpoints, a number of which will report in the coming years. Until then, there is insufficient evidence to recommend any particular anaesthetic or analgesic technique for patients undergoing tumour resection surgery on the basis that it might alter the risk of recurrence or metastasis.

The effect of anesthetic technique on µ-opioid receptor expression and immune cell infiltration in breast cancer.

BACKGROUND: Clinical histological studies demonstrate that the distribution of natural killer (NK) cells, other immune cells and µ-opioid receptors (MOR) within cancer tissue can predict cancer prognosis. No clinical study has evaluated whether anesthetic technique influences immune cell and MOR expression within human breast cancer. METHODS: Excised preoperative biopsies and intraoperative breast cancer specimens from 20 patients randomly chosen from patients previously enrolled in an ongoing, prospective, randomized trial (NCT00418457) investigating the effect of anesthetic technique on long-term breast cancer outcome were immunohistochemically stained and microscopically examined by two independent investigators, masked to randomization, to quantify MOR and immune cell infiltration: CD56, CD57 (NK cells), CD4 (T helper cells), CD8 (cytotoxic T cells) and CD68 (macrophages). Patients had been randomized to receive either a propofol-paravertebral anesthetic with continuing analgesia (PPA, n = 10) or balanced general anesthetic with opioid analgesia (GA, n = 10). RESULTS: There were no differences between the groups in staining intensity in preoperative biopsy specimens. Expression intensity values (median 25-75%) for MOR in intraoperative resected biopsy were higher in GA 8.5 (3-17) versus PPA 1 (0-10), p = 0.04. The numbers of MOR-positive cells were also higher in GA patients. Expression and absolute numbers of CD56, CD57, CD4 and CD68 were similar in resected tumor in both groups. CONCLUSION: General anesthesia with opioid analgesia increased resected tumor MOR expression compared with propofol-paravertebral anesthetic technique, but the anesthetic technique did not significantly influence the expression of immune cell markers.

Systematic review and consensus definitions for standardised endpoints in perioperative medicine: postoperative cancer outcomes.

BACKGROUND: The Standardising Endpoints for Perioperative Medicine group was established to derive an appropriate set of endpoints for use in clinical trials related to anaesthesia and perioperative medicine. Anaesthetic or analgesic technique during cancer surgery with curative intent may influence the risk of recurrence or metastasis. However, given the current equipoise in the existing literature, prospective, randomised, controlled trials are necessary to test this hypothesis. As such, a cancer subgroup was formed to derive endpoints related to research in onco-anaesthesia based on a current evidence base, international consensus and expert guidance. METHODS: We undertook a systematic review to identify measures of oncological outcome used in the oncological, surgical, and wider literature. A multiround Delphi consensus process that included up to 89 clinician-researchers was then used to refine a recommended list of endpoints. RESULTS: We identified 90 studies in a literature search, which were the basis for a preliminary list of nine outcome measures and their definitions. A further two were added during the Delphi process. Response rates for Delphi rounds one, two, and three were 88% (n=9), 82% (n=73), and 100% (n=10), respectively. A final list of 10 defined endpoints was refined and developed, of which six secured approval by ≥70% of the group: cancer health related quality of life, days alive and out of hospital at 90 days, time to tumour progression, disease-free survival, cancer-specific survival, and overall survival (and 5-yr overall survival). CONCLUSION: Standardised endpoints in clinical outcomes studies will support benchmarking and pooling (meta-analysis) of trials. It is therefore recommended that one or more of these consensus-derived endpoints should be considered for inclusion in clinical trials evaluating a causal effect of anaesthesia-analgesia technique on oncological outcomes.

Effect of perioperative lidocaine on metastasis after sevoflurane or ketamine-xylazine anaesthesia for breast tumour resection in a murine model.

BACKGROUND: Breast cancer accounts for 7% of female cancer deaths, usually attributable to metastasis. While surgery is a mainstay of treatment, perioperative interventions may influence risk of metastasis during breast tumour resection. Amide local anaesthetics influence cancer cell biology via numerous mechanisms in vitro, but in vivo data is lacking. We aimed to test the hypothesis that perioperative lidocaine reduces pulmonary metastasis after inhalation and i.v. anaesthesia in the 4T1 murine breast cancer model. METHODS: 4T1 Cancer cells were injected into the mammary fat-pad of immunocompetent BALB/c female mice. After 7 days, the resultant tumour was excised under either sevoflurane or ketamine/xylazine anaesthesia with or without perioperative i.v. lidocaine (1.5 mg kg-1 bolus followed by 25 min infusion 2 mg kg-1 h-1). Fourteen days post-surgery, posthumous lung and liver specimens were examined for metastasis. Pro-inflammatory and pro-metastatic cytokines were profiled in post-mortem serum from a small number of the mice. RESULTS: Primary tumour diameter was similar between groups. Lidocaine reduced lung metastatic colony count vs sevoflurane alone; median (inter-quartile range) 0 (0-2) compared with 22.5 (0-481), P=0.02 and reduced the proportion of animals with pulmonary metastasis (28.5% compared with 52.5%, P=0.04). In mice receiving ketamine-xylazine, lidocaine did not decrease the overall colony count: 60 (26-123) compared with 23.5 (0-225), P=0.43, but increased the proportion of animals with pulmonary metastasis (100% compared with 50%, P<0.01). Post-mortem serum analysis demonstrated reduced pro-inflammatory and angiogenic cytokine expression in animals without metastasis which received lidocaine with sevoflurane. CONCLUSIONS: In this 4T1 murine model of breast cancer, lidocaine decreased pulmonary metastasis when combined with sevoflurane anaesthesia, perhaps via anti-inflammatory and anti-angiogenic effects. It had no such effect in mice given ketamine anaesthesia.

Single-shot pectoral plane (PECs I and PECs II) blocks versus continuous local anaesthetic infusion analgesia or both after non-ambulatory breast-cancer surgery: a prospective, randomised, double-blind trial.

BACKGROUND: Pectoral plane blocks (PECs) are increasingly used in analgesia for patients undergoing breast surgery, and were recently found to be at least equivalent to single-shot paravertebral anaesthesia. However, there are no data comparing PECs with the popular practice of continuous local anaesthetic wound infusion (LA infusion) analgesia for breast surgery. Therefore, we compared the efficacy and safety of PECs blocks with LA infusion, or a combination of both in patients undergoing non-ambulatory breast-cancer surgery. METHODS: This single-centre, prospective, randomised, double-blind trial analysed 45 women to receive either PECs blocks [levobupivacaine 0.25%, 10 ml PECs I and levobupivacaine 0.25%, 20 ml PECs II (PECs group); LA infusion catheter (levobupivacaine 0.1% at 10 ml h-1 for 24 h (LA infusion group); or both (PECs and LA infusion)]. The primary outcome measure was area under the curve of the pain verbal rating score whilst moving vs time (AUC) over 24 h. Secondary outcomes included total opioid consumption at 24 h. RESULTS: AUC moving was mean (SD) 71 (34) mm h-1vs 58 (41) vs 23 (20) in PECs, LA infusion, and both, respectively; P=0.002. AUC at rest was also significantly lower in patients receiving both. The total 24 h opioid consumption [median (25-75%)] was 14 mg (9-26) vs 11 (8-24) vs 9 (5-11); P=0.4. No adverse events were observed. CONCLUSIONS: The combination of both pre-incisional PECs blocks and postoperative LA infusion provides better analgesia over 24 h than either technique alone after non-ambulatory breast-cancer surgery. CLINICAL TRIAL REGISTRATION: NCT 03024697.

The effect of anaesthetic technique during primary breast cancer surgery on neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and return to intended oncological therapy.

Inflammation and immunosuppression contribute to the pathogenesis of cancer. An increased neutrophil-lymphocyte ratio reflects these processes and is associated with adverse cancer outcomes. Whether anaesthetic technique for breast cancer surgery influences these factors, and potentially cancer recurrence, remains unknown. We conducted a secondary analysis in patients enrolled in an ongoing trial of anaesthetic technique on breast cancer recurrence. The primary hypothesis was that postoperative neutrophil-lymphocyte ratio is lower in patients allocated to receive propofol-paravertebral rather than inhalational agent-opioid anaesthesia for primary breast cancer surgery. Among 397 patients, 116 had differential white cell counts performed pre-operatively and postoperatively. Pre-operative neutrophil-lymphocyte ratio was similar in the propofol-paravertebral 2.3 (95%CI 1.8-2.8) and inhalational agent-opioid anaesthesia 2.2 (1.9-3.2) groups, p = 0.72. Postoperative neutrophil-lymphocyte ratio was lower (3.0 (2.4-4.2) vs. 4.0 (2.9-5.4), p = 0.001) in the propofol-paravertebral group. Propofol-paravertebral anaesthesia attenuated the postoperative increase in the neutrophil-lymphocyte ratio.

Expression of anaesthetic and analgesic drug target genes in excised breast tumour tissue: Association with clinical disease recurrence or metastasis.

BACKGROUND: Retrospective analyses suggest anaesthetic-analgesics technique during cancer surgery may affect recurrence/metastasis. This could involve direct effects of anaesthetic-analgesic drugs on cancer cells. While µ-opioid receptor over-expression in lung tumours is associated with greater metastasis, other anaesthetic-analgesic receptor targets in cancer recurrence/metastasis remain unexplored. Therefore, we evaluated the association between genetic expression of anaesthetic-analgesic receptor targets and recurrence/metastasis, using a repository of breast cancer gene expression and matching clinical data. METHODS: A list of 23 genes encoding for the most prominent anaesthetic-analgesic receptor targets was compiled. This was processed through BreastMark- an algorithm integrating gene expression data from ~17,000 samples and clinical data from >4,500 breast cancer samples. Gene expression data was dichotomized using disease-free survival (survival without recurrence) and distant disease-free survival (survival without metastasis) as end points. Hazard ratios were calculated by Cox-regression analysis. Enrichment for prognostic markers was determined by randomly choosing 23-member gene lists from all available genes, calculating how often >5 significant markers were observed and adjusting p-values for multiple testing. This was repeated 10,000 times and an empirical p-value calculated. RESULTS: Of 23 selected genes, 9 were significantly associated with altered rates of metastasis and 4 with recurrence on univariate analysis. Adjusting for multiple testing, 5 of these 9 genes remained significantly associated with metastasis, non with recurrence. This ratio of genes (5/23) was not significantly enriched for markers of metastasis (p = 0.07). CONCLUSION: Several anaesthetic-analgesic receptor genes were associated with metastatic spread in breast cancer. Overall there was no significant enrichment in prognostic markers of metastasis, although a trend was observed.

Understanding STAT3 signaling in cardiac ischemia.

Cardiovascular disease is the leading cause of death worldwide. It remains one of the greatest challenges to global health and will continue to dominate mortality trends in the future. Acute myocardial infarction results in 7.4 million deaths globally per annum. Current management strategies are centered on restoration of coronary blood flow via percutaneous coronary intervention, coronary artery bypass grafting and administration of anti-platelet agents. Such myocardial reperfusion accounts for 40-50 % of the final infarct size in most cases. Signaling transducer and activator of transcription 3 (STAT3) has been shown to have cardioprotective effects via canonical and non-canonical activation and modulation of mitochondrial and transcriptional responses. A significant body of in vitro and in vivo evidence suggests that activation of the STAT3 signal transduction pathway results in a cardio protective response to ischemia and attempts have been made to modulate this with therapeutic effect. Not only is STAT3 important for cardiomyocyte function, but it also modulates the cardiac microenvironment and communicates with cardiac fibroblasts. To this end, we here review the current evidence supporting the manipulation of STAT3 for therapeutic benefit in cardiac ischemia and identify areas for future research.

Effects of supplemental oxygen and dexamethasone on surgical site infection: a factorial randomized trial‡.

BACKGROUND: Tissue oxygenation is a strong predictor of surgical site infection. Improving tissue oxygenation should thus reduce wound infection risk. Supplemental inspired oxygen can improve tissue oxygenation, but whether it reduces infection risk remains controversial. Low-dose dexamethasone is often given to reduce the risk of postoperative nausea and vomiting, but steroid-induced immunosuppression can increase infection risk. We therefore tested the hypotheses that supplemental perioperative oxygen reduces infection risk and that dexamethasone increases it. METHODS: Using a factorial design, patients having colorectal resections expected to last ≥2 h were randomly assigned to 30% (n=270) or 80% (n=285) inspired oxygen during and for 1 h after surgery, and to 4 mg intraoperative dexamethasone (n=283) or placebo (n=272). Physicians blinded to group assignments evaluated wounds postoperatively, using US Centers for Disease Control criteria. RESULTS: Subject and surgical characteristics were similar among study groups. Surgical site infection incidence was similar among groups: 30% oxygen 15.6%, 80% oxygen 15.8% (P=1.00); dexamethasone 15.9%, placebo 15.4%, (P=0.91). CONCLUSIONS: Supplemental oxygen did not reduce surgical site infection risk. The preponderance of clinical evidence suggests that administration of 80% supplemental inspired oxygen does not reduce infection risk. We did not observe an increased risk of surgical site infection with the use of a single low dose of dexamethasone, indicating that it can be used for nausea and vomiting prophylaxis without promoting wound infections. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT00273377.