Volatile anaesthesia and peri-operative outcomes related to cancer: a feasibility and pilot study for a large randomised control trial.

Published data suggest that the type of general anaesthesia used during surgical resection for cancer may impact on patient long-term outcome. However, robust prospective clinical evidence is essential to guide a change in clinical practice. We explored the feasibility of conducting a randomised controlled trial to investigate the impact of total intravenous anaesthesia with propofol vs. inhalational volatile anaesthesia on postoperative outcomes of patients undergoing major cancer surgery. We undertook a randomised, double-blind feasibility and pilot study of propofol total intravenous anaesthesia or volatile-based maintenance anaesthesia during cancer resection surgery at three tertiary hospitals in Australia and the USA. Patients were randomly allocated to receive propofol total intravenous anaesthesia or volatile-based maintenance anaesthesia. Primary outcomes for this study were successful recruitment to the study and successful delivery of the assigned anaesthetic treatment as per randomisation arm. Of the 217 eligible patients approached, 146 were recruited, a recruitment rate of 67.3% (95%CI 60.6-73.5%). One hundred and forty-five patients adhered to the randomised treatment arm, 99.3% (95%CI 96.2-100%). Intra-operative patient characteristics and postoperative complications were comparable between the two intervention groups. This feasibility and pilot study supports the viability of the protocol for a large, randomised controlled trial to investigate the effect of anaesthesia technique on postoperative cancer outcomes. The volatile anaesthesia and peri-operative outcomes related to cancer (VAPOR-C) study that is planned to follow this feasibility study is an international, multicentre trial with the aim of providing evidence-based guidelines for the anaesthetic management of patients undergoing major cancer surgery.

Dexmedetomidine promotes metastasis in rodent models of breast, lung, and colon cancers.

BACKGROUND: Perioperative strategies can significantly influence long-term cancer outcomes. Dexmedetomidine, an α2-adrenoceptor agonist, is increasingly used perioperatively for its sedative, analgesic, anxiolytic, and sympatholytic effects. Such actions might attenuate the perioperative promotion of metastases, but other findings suggest opposite effects on primary tumour progression. We tested the effects of dexmedetomidine in clinically relevant models of dexmedetomidine use on cancer metastatic progression. METHODS: Dexmedetomidine was given to induce sub-hypnotic to sedative effects for 6-12 h, and its effects on metastasis formation, using various cancer types, were studied in naïve animals and in the context of stress and surgery. RESULTS: Dexmedetomidine increased tumour-cell retention and growth of metastases of a mammary adenocarcinoma (MADB 106) in F344 rats, Lewis lung carcinoma (3LL) in C57BL/6 mice, and colon adenocarcinoma (CT26) in BALB/c mice. The metastatic burden increased in both sexes and in all organs tested, including lung, liver, and kidney, as well as in brain employing a novel external carotid-artery inoculation approach. These effects were mediated through α2-adrenergic, but not α1-adrenergic, receptors. Low sub-hypnotic doses of dexmedetomidine were moderately beneficial in attenuating the deleterious effects of one stress paradigm, but not of the surgery or other stressors. CONCLUSIONS: The findings call for mechanistic translational studies to understand these deleterious effects of dexmedetomidine, and warrant prospective clinical trials to assess the impact of perioperative dexmedetomidine use on outcomes in cancer patients.

Anesthetic Considerations for Mediastinal Staging Procedures for Lung Cancer.

Tumor staging is critical for the treatment of lung malignancies. Invasive techniques of lung tumor staging can be accomplished via mediastinoscopy, endobronchial ultrasound, and video-assisted thoracoscopy. Anesthesiologists taking care of patients undergoing mediastinal staging procedures might face different challenges. In this narrative review, the authors summarize the literature on the anesthetic considerations for mediastinal staging procedures.

Investigating the association between perioperative blood transfusions and outcomes in children undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND AND OBJECTIVES: Studies indicate the perioperative transfusion of red blood cells during oncologic surgery may be associated with worse outcomes. In this study, we evaluated the impact of red blood cell transfusions on the short- and long-term outcomes of children undergoing a major oncologic surgery. MATERIALS AND METHODS: A retrospective review of the medical records of children ≤18 years of age who had undergone cytoreductive surgery with hyperthermic intraperitoneal chemotherapy was performed. Univariate and multivariate analyses were performed to identify factors influencing survival, complications and length of stay. RESULTS: Seventy-five children were identified, 80% of whom had received a red blood cell transfusion. Children who received a red blood cell transfusion had a significantly longer length of stay (P = 0·0003). However, the association between red blood cell transfusions and recurrence-free survival (HR: 1·307, 95% CI: 0·547-3·124; P = 0·55), overall survival (HR: 1·487, 95% CI: 0·585-3·780; P = 0·40) or the incidence of major complications (27·8 vs. 0% in non-transfused children, P = 0·18) was not statistically significant. CONCLUSION: This retrospective study of children undergoing major oncologic surgery did not demonstrate a significant association between red blood cell transfusions and worse outcomes.

Assessing the impact of perioperative blood transfusions on the survival of adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for appendiceal carcinomatosis.

BACKGROUND AND OBJECTIVES: Perioperative red blood cell transfusions (PBT) may be associated with worse survival. In this study of adults undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), we investigated whether there was an association between PBT and survival. MATERIALS AND METHODS: A retrospective study of adults who had undergone CRS-HIPEC for appendiceal carcinomatosis was conducted. Univariate and multivariate analyses were used to identify factors associated with survival. RESULTS: Of the 270 patients analysed, 170 (63%) received PBT. A PBT was not significantly associated with recurrence-free survival (RFS) (HR = 1·03; 95% CI: 0·7-1·51; P = 0·879) or overall survival (OS) (HR = 0·65; 95% CI: 0·38-1·11; P = 0·116). Higher number of PBT units (≥5) was not associated with worse RFS (P = 0·077) or OS (P = 0·079). Independent predictors of poor survival included as follows: estimated blood loss and high tumour grade for RFS (both P < 0·001), and male gender (P = 0·029) and high tumour grade (P < 0·001) for OS. Higher preoperative haemoglobin was independently associated with better RFS (P = 0·011) and OS (P = 0·006). CONCLUSIONS: In this retrospective study of adults who had undergone CRS-HIPEC for appendiceal carcinomatosis, PBT was not significantly associated with survival.

Non-steroidal anti-inflammatory drugs in the oncological surgical population: beneficial or harmful? A systematic review of the literature.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesic drugs. Recent studies have indicated a potential beneficial effect on long-term survival outcomes after cancer surgery but a negative impact on anastomotic leaks. The objective of this study was to objectively assess the implications of the perioperative NSAIDs use on anastomotic leaks and cancer recurrence. METHODS: We searched PubMed, MEDLINE, Embase and Cochrane Library for publications up to mid-January 2017. Randomized controlled trials (RCTs) and observational studies in adults undergoing cancer surgery were included for quality assessment. We excluded animal studies, in vitro experiments and case reports. The selected sudies were graded using the Jadad score or Newcastle-Ottawa scale for RCTs and observational retrospective studies, respectively. RESULTS: The systematic review identified 25 trials that explored the impact of NSAIDs on anastomotic leaks and 16 trials that assessed the association between perioperative NSAIDs and cancer recurrence. Meta-analyses were not performed because of high heterogeneity and low quality of the included studies. CONCLUSIONS: The literature is not conclusive on whether the use of NSAIDs is associated with anastomotic leaks after gastrointestinal cancer surgery. Also, the current evidence is equivocal regarding the effects of short-term NSAIDs on cancer recurrence after major cancer surgery. Three RCTs are being conducted to assess the impact of NSAIDs on cancer recurrence. There are no registered RCTs that are testing the hypothesis of whether the perioperative use of NSAIDs increases the rate of anastomotic leaks.

Inflammatory response, immunosuppression, and cancer recurrence after perioperative blood transfusions.

Debate on appropriate triggers for transfusion of allogeneic blood products and their effects on short- and long-term survival in surgical and critically ill patients continue with no definitive evidence or decisive resolution. Although transfusion-related immune modulation (TRIM) is well established, its influence on immune competence in the recipient and its effects on cancer recurrence after a curative resection remains controversial. An association between perioperative transfusion of allogeneic blood products and risk for recurrence has been shown in colorectal cancer in randomized trials; whether the same is true for other types of cancer remains to be determined. This article focuses on the laboratory, animal, and clinical evidence to date on the mechanistic understanding of inflammatory and immune-modulatory effects of blood products and their significance for recurrence in the cancer surgical patient.

Intraoperative tissue oxygenation and postoperative outcomes after major non-cardiac surgery: an observational study.

BACKGROUND: The relationship between tissue oxygen saturation (StO(2)) and serious postoperative complications remains unclear. We tested the hypothesis that perioperative in patients undergoing major non-cardiac surgery is inversely related to serious surgical outcomes. METHODS: We enrolled 124 patients, ASA physical status ≤IV, having elective major non-cardiac surgeries with general anaesthesia. An InSpectra Model 650 StO(2) monitor (Hutchinson Technology, Hutchinson, MN, USA) was used to measure at the thenar eminence throughout surgery and for two postoperative hours. Our primary outcome was a composite of 30 day mortality and serious in-hospital complications. The secondary outcome was an a priori subset of the primary composite outcome representing infectious and wound-healing complications. Multivariable logistic regression was used to evaluate the associations between our primary and secondary outcomes and time-weighted average (TWA) and minimum . RESULTS: Patients were 61 (12), mean (SD) yr old. The minimum was inversely associated with our primary composite outcome (P=0.02). The estimated odds ratio (97.5% CI) of having any major postoperative morbidity was 0.82 (0.67, 1.00) for a 5% increase in the minimum . In contrast, TWA was not significantly associated with major postoperative morbidity (P=0.35). Furthermore, neither TWA (P=0.65) nor minimum (P=0.70) was significantly associated with wound complications. CONCLUSIONS: Minimum perioperative peripheral tissue oxygenation predicted a composite of major complications and mortality from major non-cardiac surgery. This is an observational association and whether clinical interventions to augment tissue oxygenation will improve outcomes remains to be determined.

Neurological biomarkers in the perioperative period.

The rapid detection and evaluation of patients presenting with perioperative neurological dysfunction is of great clinical relevance. Biomarkers have been defined as biological molecules that can be used as an indicator of new onset or progression of a biological process or effect of treatment. Biomarkers have become increasingly important in this setting to supplement other modalities of diagnosis such as EEG, sensory- or motor-evoked potential, transcranial Doppler, near-infrared spectroscopy, or imaging methods. A number of neuro-proteins have been identified and are currently under investigation for potential to provide insights into injury severity, outcome, and the ability to monitor cellular damage and molecular events that occur during neurological injury. S100B is a protein released by glial cells and is considered a marker of blood-brain barrier dysfunction. Clinical studies in patients undergoing cardiac and non-cardiac surgery indicate that serum levels of S100B are increased intraoperatively and after operation. The neurone-specific enolase has also been extensively investigated as a potential marker of neuronal injury in the context of cardiac and non-cardiac surgery. A third biomarker of interest is the Tau protein, which has been linked to neurodegenerative disorders. Tau appears to be more specific than the previous two biomarkers since it is only found in the central nervous system. The metalloproteinase and ubiquitin C terminal hydroxylase-L1 (UCH-L1) are the most recently researched markers; however, their usefulness is still unclear. This review presents a comprehensive overview of S100B, neuronal-specific enolase, metalloproteinases, and UCH-L1 in the perioperative period.

Anesthetic care influences long-term outcomes: What is the evidence?

Despite advances in cancer therapy surgery remains one of the most important treatments for solid tumors; however, even with the development of better and less invasive surgical techniques, surgery is characterized by the increased risk of tumor metastasis, accelerated growth of pre-existing micrometastasis and cancer recurrence. Total intravenous anesthesia (TIVA) and regional anesthesia have been proposed to improve long-term outcomes after cancer surgery by different mechanisms, including attenuation of the neuroendocrine response, immunosuppression, decreased opioid requirements (opioids promote angiogenesis and tumor growth) and avoidance of volatile inhalational agents. Much of the data that support these ideas originate from laboratory studies, while there is no clear consensus from the retrospective cohort studies to date. Several randomized controlled trials (RCTs) are in progress and may provide a better understanding regarding the role of the anesthesiologist in cancer surgery. The purpose of this review is to summarize the experimental and human data regarding the effect of anesthesia agents and anesthesia techniques on cancer outcomes.

The use of isoflurane and desflurane as inhalational agents for glioblastoma surgery. A survival analysis.

BACKGROUND: Several studies have examined the impact of anesthetics on cancer recurrence. Isoflurane but not desflurane has protumoral effects. We hypothesize the use of isoflurane but not desflurane during surgery for primary GBM is an independent predictor of disease progression and mortality. METHODS: 378 adult patients were included in the study. The progression free survival (PFS) and overall survival (OS) rates at 1 and 5years were compared in patients who had either desflurane or isoflurane alone or in combination with propofol infusion. Multivariate analyses were conducted to test the association between preoperative, intraoperative and postoperative hyperglycemia with PFS and OS. RESULTS: Kaplan-Meier curves demonstrated similar survival in patients who had either desflurane or isoflurane. The use of a propofol infusion during surgery did not affect survival. Univariate analysis demonstrated that age, body mass index and the adjusted Charlson comorbidity score were associated with reduced survival. The multivariate analysis confirmed that age and BMI but not the type volatile anesthetic use were independent prognostic factors for PFS (HR, 95%CI: 1.07, 0.85-1.37, 9=0.531) and OS (HR, 95%CI: 1.13, 0.86-1.48, p=0.531). CONCLUSION: The use of isoflurane or desflurane during GBM surgery is not associated with reduced PFS or OS.

Intraoperative serum lactate is not a predictor of survival after glioblastoma surgery.

BACKGROUND: Cancer cells can produce lactate in high concentrations. Two previous studies examined the clinical relevance of serum lactate as a biomarker in patients with brain tumors. Patients with high-grade tumors have higher serum concentrations of lactate than those with low-grade tumors. We hypothesized that serum lactic could be used of biomarker to predictor of survival in patients with glioblastoma (GB). METHODS: This was a retrospective study. Demographic, lactate concentrations and imaging data from 275 adult patients with primary GB was included in the analysis. The progression free survival (PFS) and overall survival (OS) rates were compared in patients who had above and below the median concentrations of lactate. We also investigated the correlation between lactate concentrations and tumor volume. Multivariate analyses were conducted to test the association lactate, tumor volume and demographic variables with PFS and OS. RESULTS: The median serum concentration of lactate was 2.3mmol/L. A weak correlation was found between lactate concentrations and tumor volume. Kaplan-Meier curves demonstrated similar survival in patients with higher or lower than 2.3mmol/L of lactate. The multivariate analysis indicated that the intraoperative levels of lactate were not independently associated with changes in survival. On another hand, a preoperative T1 volume was an independent predictor PFS (HR 95%CI: 1.41, 1.02-1.82, p=0.006) and OS (HR 95%CI: 1.47, 1.11-1.96, p=0.006). CONCLUSION: This retrospective study suggests that the serum concentrations of lactate cannot be used as a biomarker to predict survival after GB surgery. To date, there are no clinically available serum biomarkers to determine prognosis in patients with high-grade gliomas. These tumors may produce high levels of lactic acid. We hypothesized that serum lactic could be used of biomarker to predictor of survival in patients with glioblastoma (GB). In this study, we collected perioperative and survival data from 275 adult patients with primary high-grade gliomas to determine whether intraoperative serum acid lactic concentrations can serve as a marker of prognosis. The median serum concentration of lactate was 2.3mmol/L. Our analysis indicated the intraoperative levels of lactate were not independently associated with changes in survival. This retrospective study suggests that the serum concentrations of lactate cannot be used as a biomarker to predict survival after GB surgery.

Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation.

Glutamate is a primary excitatory neurotransmitter in the mammalian CNS. Glutamate released from presynaptic neurons is cleared from the synaptic cleft passively by diffusion and actively by glutamate transporters. In this study, the role of glutamate transporters in sensory processing in the spinal cord has been investigated in behavioral, in vivo and in vitro experiments. Intrathecal application of a non-selective glutamate transport inhibitor, L-trans-pyrrolidine-2,4-dicarboxylic acid (10 microl of 100 microM solution) induced hypersensitivity to peripheral mechanical and thermal stimuli. Topical application of L-trans-pyrrolidine-2,4-dicarboxylic acid (100 microM) onto the dorsal surface of the L3-L6 spinal cord increased spontaneous activities, innocuous and noxious stimulus-evoked responses and after-discharges of wide dynamic range neurons in the L4-5 spinal segments. Whole cell recordings made from superficial dorsal horn neurons in an isolated whole spinal cord from newborn rats (2-3 weeks old) revealed that bath-applied L-trans-pyrrolidine-2,4-dicarboxylic acid (100 microM) produced partial membrane depolarization, increased spontaneous action potentials with decreased neuronal membrane resistance and time constant, but without significant changes of capacitance. Finally, the amplitude and duration of primary afferent evoked-excitatory postsynaptic currents recorded from neurons in the substantia gelatinosa in the spinal slices from young adult rats (6-8 weeks old) were increased in the presence of L-trans-pyrrolidine-2,4-dicarboxylic acid (100 microM). This study indicates that glutamate transporters regulate baseline excitability and responses of dorsal horn neurons to peripheral stimulation, and suggests that dysfunction of glutamate transporters may contribute to certain types of pathological pain.

Altered discharges of spinal wide dynamic range neurons and down-regulation of glutamate transporter expression in rats with paclitaxel-induced hyperalgesia.

Changes in the signaling of wide dynamic range neurons and the expression of glutamate transporters in the lumbar spinal dorsal horn of rats with Taxol-induced hyperalgesia are detailed in this report. Deep spinal lamina neurons have significantly increased spontaneous activity and after-discharges to noxious mechanical stimuli, increased responses to both skin heating and cooling, and increased after-discharges and abnormal windup to transcutaneous electrical stimuli. The expression of glutamate transporter proteins in the dorsal horn is decreased at the time point corresponding to the physiological changes. These results suggest a state of increased excitability develops in spinal pain-signaling neurons as a consequence of decreased glutamate clearance. These changes in dorsal horn neurobiology likely in turn contribute to the hyper-responsiveness to sensory stimuli seen in animals treated with Taxol and may play a role in the pain seen in cancer patients receiving Taxol.

Preoperative statin use is not associated with improvement in survival after glioblastoma surgery.

Cohort studies have suggested that the use of statins is associated with decreased risk of glioma formation and mortality. Here, a cohort of patients with glioblastoma multiforme (GBM) was analyzed to further investigate associations between preoperative use of statins and recurrence, and progression free and overall survival. Patients who had surgery for GBM (N=284) were followed up for a median of 18.1months. Seventy-eight patients were taking statins preoperatively while the rest were not. Cox proportional hazards models adjusted for several covariates of interest were applied before and after propensity score matching. Compared with statin users, those not taking the lipid-lowering drugs had similar progression free survival before (hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.70-1.26; p=0.68) and after propensity score matching (HR 0.95, 95% CI 0.67-1.35; p=0.68). Mortality was similar between both groups of patients before (HR 0.94, 95% CI 0.70-1.22; p= 0.73) and after propensity score matching (HR 1.13, 95% CI 0.78-1.64; p=0.49). Age and dexamethasone use were independent prognostic factors of survival. Contrary to previously published evidence, this study could not find an association between preoperative statin use and longer survival in GBM patients. Due to the small number of patients and retrospective nature of the study, further work is needed to understand the role of perioperative statins in GBM patients.

Transfusions of blood products and cancer outcomes.

Approximately half of cancer patients scheduled for major surgery are anemic. Also, a significant number of patients will present to the operating room with low platelet counts and coagulopathic disorders. Unfortunately, administration of red blood cells, platelets concentrates and fresh-frozen plasma is associated with unwanted adverse effects including fever, hemolytic reactions and transfusion-related immunomodulation (TRIM). TRIM is a multifactorial immunologic phenomenon in the recipient mediated by donor leukocytes, microparticles such as ectosomes, and growth factors. As some of these molecules are secreted in a time-dependent manner, blood storage time may play an important in TRIM, although the evidence is limited. Perioperative administration of red blood cells and associated TRIM has also been associated with increased recurrence of certain solid tumors, such as colorectal, lung, and hepatobiliary tumors. In this continuing education article, we review the available evidence on how perioperative blood product transfusions can affect oncological outcomes, such as cancer recurrence.

Impact of anesthesia on cancer recurrence.

Surgery remains the mainstay treatment in the majority of solid cancers. Anesthetics and analgesics used during the perioperative period may modulate the innate and adaptive immune system, inflammation and angiogenesis, and have a direct effect on cancer cells that could ultimately modify oncological outcomes. For instance, volatile anesthetics and opioid analgesics have shown predominantly pro-tumor effects, while propofol, non-steroid anti-inflammatory drugs have mostly anticancer effects. Researchers have been especially interested in investigating the association between the use of regional anesthesia techniques and the postoperative survival of patients with cancers. Since the results of the current retrospective studies are conflicting, several researchers are conducting prospective randomized trials.

Cyclooxygenase inhibitors and thalidomide ameliorate vincristine-induced hyperalgesia in rats.

In this study ibuprofen (50.0 mg/kg, i.p.), rofecoxib (10.0 mg/kg, i.p.) and thalidomide (50.0 mg/kg, oral) were shown to prevent vincristine-induced mechanical hyperalgesia. Sprague-Dawley rats were injected every other day with vincristine (0.1 mg/kg) over 13 days. The animals were cotreated daily with vehicle (saline), ibuprofen, rofecoxib or thalidomide throughout the period of vincristine treatment. Mechanical withdrawal threshold to punctuate and radiant heat stimuli were determined prior to and then on alternate days throughout the treatment period. Vincristine vehicle-treated animals developed marked mechanical hyperalgesia from day 5 of chemotherapy and this lasted until the end of the experiment. Thermal thresholds were not altered by the administration of vincristine vehicle. Animals in the vincristine vehicle group neither gained nor lost weight during the treatment period. All three active drugs showed an antihyperalgesic effect on the responses to mechanical stimulation of the hind paw that was significant from day 5 for ibuprofen and thalidomide and from day 7 for rofecoxib. Thermal thresholds increased after the administration of both the NSAIDs and thalidomide. Rofecoxib was the only drug to show any beneficial effect in protecting the animals from failure to gain body weight.