Perioperative epidural analgesia reduces cancer recurrence after gastro-oesophageal surgery.

BACKGROUND: Recent interest has focused on the role of perioperative epidural analgesia in improving cancer outcomes. The heterogeneity of studies (tumour type, stage and outcome endpoints) has produced inconsistent results. Clinical practice also highlights the variability in epidural effectiveness. We considered the novel hypothesis that effective epidural analgesia improves cancer outcomes following gastro-oesophageal cancer surgery in patients with grouped pathological staging. METHODS: Following institutional approval, a database analysis identified 140 patients, with 2-year minimum follow-up after gastro-oesophageal cancer surgery. All patients were operated on by a single surgeon (2005-2010). Information pertaining to cancer and survival outcomes was extracted. RESULTS: Univariate analysis demonstrated a 1-year 14% vs. 33% (P = 0.01) and 2-year 27% vs. 40% [hazard ratio (HR)=0.59; 95% CI, 0.32-1.09, P = 0.087] incidence of cancer recurrence in patients with (vs. without) effective (> 36 h duration) epidural analgesia, respectively. Multivariate analysis demonstrated increased time to cancer recurrence (HR = 0.33; 95% CI: 0.17-0.63, P < 0.0001) and overall survival benefit (HR = 0.42; 95% CI: 0.21-0.83, P < 0.0001) at 2-year follow-up following effective epidural analgesia. Subgroup analysis identified epidural-related cancer recurrence benefit in patients with oesophageal cancer (HR = 0.34; 95% CI: 0.16-0.75, P = 0.005) and in patients with tumour lymphovascular space infiltration (LVSI), (HR = 0.49; 95% CI: 0.26-0.94, P = 0.03). Effective epidural analgesia improved estimated median time to death (2.9 vs. 1.8 years, P = 0.029) in patients with tumour LVSI. CONCLUSIONS: This study found an association between effective post-operative epidural analgesia and medium-term benefit on cancer recurrence and survival following oesophageal surgery. A prospective study that controls for disease type, stage and epidural effectiveness is warranted.

A pilot study evaluating predictors of postoperative outcomes after major abdominal surgery: Physiological capacity compared with the ASA physical status classification system.

BACKGROUND: This pilot study compared the risk predictive value of preoperative physiological capacity (PC: defined by gas exchange measured during cardiopulmonary exercise testing) with the ASA physical status classification in the same patients (n=32) undergoing major abdominal cancer surgery. METHODS: Uni- and multivariate logistic regression models were fitted to measurements of PC and ASA rank data determining their predictive value for postoperative morbidity. Receiver operating characteristic (ROC) curves were used to discriminate between the predictive abilities, exploring trade-offs between sensitivity and specificity. RESULTS: Individual statistically significant predictors of postoperative morbidity included the ASA rank [P=0.038, area under the curve (AUC)=0.688, sensitivity=0.630, specificity=0.750] and three newly identified measures of PC: PAT (% predicted anaerobic threshold achieved, <75% vs > or =75%), DeltaHR1 (heart rate response from rest to the anaerobic threshold), and HR3 (heart rate at the anaerobic threshold). A two-variable model of PC measurements (DeltaHR1+PAT) was also shown to be statistically significant in the prediction of postoperative morbidity (P=0.023, AUC=0.826, sensitivity=0.813, specificity=0.688). CONCLUSIONS: Three newly identified PC measures and the ASA rank were significantly associated with postoperative morbidity; none showed a statistically greater association compared with the others. PC appeared to improve predictive sensitivity. The potential for new unidentified measures of PC to predict postoperative outcomes remains unexplored.

Coronary revascularization in transition from on-pump to off-pump: the effect of the off-pump coronary artery bypass on medium-term outcome.

AIM: We previously reported that early patient outcome, chiefly ischaemic injury, was reduced in patients allocated to off pump coronary artery bypass (OPCAB) surgery. This report concerns the medium-term outcome for this cohort of patients. METHODS: A prospective observational study was carried out in a single cardiothoracic specialty hospital. Forty-four patients scheduled for elective multivessel coronary artery bypass grafting (CABG) surgery using either off pump (OPCAB) (n=21) or on pump (cardiopulmonary bypass, CPB) (n=23) were included in the study. Data on the symptoms, quality of life, need for cardiovascular therapy, and occurrence of cardiovascular events or death among patients at 6- and 12-months after surgery were collected by a patient questionnaire and reviewing the medical charts. RESULTS: Compared with patients who underwent CPB surgery, OPCAB patients required a smaller increase in cardiovascular medication (5.6% versus 47.1%; P=0.007) at the 6-month follow-up and demonstrated a trend toward improved symptoms (dyspnea at 6 months, 0, range 0-4 versus 1, range 0-4; P=0.03) and quality of life (Duke Activity Status Index at 6 months, 20.8+5.6 versus 19+6.8; P=0.13). No differences in the incidence of cardiologic intervention or mortality were observed between groups. CONCLUSIONS: The trend toward improved medium-term outcome variables among patients treated with OPCAB may have owed to the reduced cardiac ischemic injury associated with OPCAB compared with CPB.

Effects of isoflurane, pentobarbital, and urethane on apoptosis and apoptotic signal transduction in rat kidney.

BACKGROUND: Renal cell apoptosis contributes significantly to the pathogenesis of acute renal failure. Anesthetic agents have been shown to modulate apoptotic signal transduction in various tissues. We examined the effects of 6 h of different general anesthetic techniques on renal cell apoptosis in rat kidneys. METHODS: Twenty-one male Sprague-Dawley rats were randomly allocated into four groups: (i) control, non-anesthetized rats (n= 3) and rats anesthetized with (ii) inhaled isoflurane (n= 6), (iii) intraperitoneal pentobarbital (n= 6), and (iv) intraperitoneal urethane (n= 6). Animals were sacrificed 6 h after the induction of anesthesia. RESULTS: Apoptosis was assessed by terminal deoxynucleotidyl transferase-fluorescein end-labeling analysis. RNA was extracted from the left kidney to probe cDNA microarrays. Gene expression was measured as a percentage of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and subsequently confirmed using reverse transcriptase-polymerase chain reaction (RT-PCR). Compared with the control (no anesthesia), urethane significantly (P < 0.001) induced apoptosis in both the renal cortex and medulla. Isoflurane significantly (P < 0.001) inhibited apoptosis in the medulla. Microarray analysis revealed that urethane up-regulated more (74) genes than pentobarbital (16) and isoflurane (10). Isoflurane down-regulated more genes (85) than pentobarbital (74) and urethane (12). These anesthetic-induced modulations were significant (P < 0.05) for 60 isoflurane-, 30 pentobarbital- and 4 urethane-modulated genes. CONCLUSION: Our results suggest that general anesthetic drugs have an effect on renal cell apoptosis and apoptotic signal transduction, and thus may potentially affect the risk of subsequent acute renal failure.

Transcriptional responses of rat skeletal muscle following hypoxia-reoxygenation and near ischaemia-reperfusion.

AIM: The effect of ischaemia/reperfusion or hypoxia/reoxygenation on gene expression has not been extensively studied. We hypothesized that in skeletal muscle, tissue hypoxia of similar magnitude but induced by different mechanisms would lead to different transcriptional responses. METHODS: Muscle gene transcription was assessed using microarray analysis and reverse transcriptase polymerase chain reaction in 18 rats exposed to regional hind limb near ischaemia/reperfusion (n = 6), hypoxia/reoxygenation (n = 6) or sham operation (n = 6). Hypoxic burden was measured by the area under the PtO(2)-time curve. RESULTS: PtO(2) was reduced in both the near ischaemia/reperfusion and hypoxia/reoxygenation groups. Although the hypoxic burden was similar, the genomic response was different for each condition. Near ischaemia/reperfusion had a greater effect on gene expression than hypoxia/reoxygenation. Using stringent criteria for changes in gene expression (i.e. more than or equal to twofold change vs. control) unique patterns of gene expression could be identified suggesting individualized transcriptional responses to each of these injuries. Several genes, including insulin-like growth factor 1 (IGF-1) and cyclin-dependent kinase inhibitor (p27(Kip1)) were induced by both injury types and these may have potential clinical application as markers of tissue damage. In contrast, no single gene was downregulated by both injury conditions. CONCLUSIONS: The mechanism of skeletal muscle hypoxia has a profound effect on its subsequent transcriptional response. We identified several potential candidates as markers of skeletal muscle ischaemic damage.

[Effect of fructose-1,6-diphosphate on myocardial purin and pyrimidin metabolism during coronary artery bypass grafting surgery]. / A fruktóz-1,6-difoszfát hatása a szívizom purinés pirimidin-metabolizmusára koszorúérmútét közben.

During ischaemia, the glycolytic pathway (Embden-Meyerhof) is up regulated in an attempt to produce ATP anaerobically. However, this is short-lived due to negative feedback on the key glycolytic enzyme phosphofructokinase by accumulating lactate. Fructose-1,6-diphosphate (FDP), a high energy intermediary metabolite of this pathway, is unique in that is enters glycolysis distal to this inhibitory site. Exogenously administered FDP should therefore theoretically yield ATP independent of lactate accumulation and thereby ameliorate ischaemic injury. Clinical benefit has been shown in coronary artery bypass grafting (CABG) surgery, congestive cardiac failure and adult respiratory distress syndrome. Ischaemia-reperfusion injury induced by cardiopulmonary bypass (CPB) presents clinically as an impairment of myocardial function in the postoperative period. At a cellular level this reflects myocardial metabolic changes and nucleotide degradation (directly linked to high energy phosphate turnover). Quantification of myocardial nucleotide catabolite release therefore provides useful information regarding intermediary metabolism and cytoprotection conferred to myocardial (inosine, uridine) and endothelial (hypoxanthine) tissue. The authors investigated the myocardial cytoprotective effects of FDP in 16 patients scheduled for elective CABG surgery. Aortic and coronary sinus blood were collected directly into liquid nitrogen and analysed by high performance liquid chromatography prior to CPB and at different time points after reperfusion. FDP was administered intravenously in 8 patients and 5% dextrose was administered in 8 other patients. Analysis of transmyocardial (coronary sinus-aortic) nucleotide metabolite levels showed increased release of inosine, hypoxanthine and uridine in both the FDP and the control groups following reperfusion. However, compared to baseline (pre-aortic clamping) values, hypoxanthine and inosine concentrations were significantly elevated at 0, 1, 5 and 10 minutes following reperfusion in the control group. This was in contrast to earlier recovery to baseline levels (after 5 minutes of reperfusion) in the FDP group. Furthermore, when compared to control group, the hypoxanthine and inosine concentrations were significantly decreased by FDP treatment. Uridine concentrations were significantly elevated at 1 and 5 minutes in the control group and no significant change was observed in the FDP group. In conclusion, these data suggest that FDP, through an intermediary metabolic effect, may contribute to myocardial and endothelial cytoprotection during the ischaemic insult of cardiac surgery.

Potential therapeutic applications of fructose-1,6-diphosphate.

Ischaemia-related tissue injury is the leading cause of death in developed countries. Drugs that can reduce ischaemic injury would be beneficial in treatment of myocardial infarction (MI), surgical trauma and stroke. Fructose-1,6-diphosphate (FDP) is a key intermediate in anaerobic glycolysis and is the product of the major regulatory enzyme in the pathway (phosphofructokinase). Preclinical and clinical data suggest that FDP has substantial cytoprotective effects in a variety of ischaemia-reperfusion injury scenarios. Evidence indicates that FDP has a direct effect on ATP pools, reduces ischaemia-induced tissue damage and has positive inotropic effects on heart function. The clinical data suggest that FDP may be a useful drug in a variety of ischaemic and inflammatory clinical settings where acute management of tissue injury is desired. Potential uses include: iv. administration for the reduction of ischaemic injury in sickle cell anaemia, bypass surgery, congestive heart failure, myocardial infarction, as well as organ preservation in transplants.

Ischemic injury and its prevention.

Perioperative ischemia is common in patients at risk of or with known artery disease undergoing noncardiac or cardiac surgery. Resultant ischemic injury can lead to a delay in extubation and hospital discharge, impaired quality of life after surgery, and a disproportionate consumption of health resources. Our goal as anesthesiologists is to prevent this poor perioperative cardiac outcome, to continually strive for improved patient care, and to reduce medical resource consumption. These goals are the driving force behind the recent increased interest in the use of minimally invasive direct vision coronary artery bypass graft techniques. This report discusses the definition and etiology of ischemia and the perioperative management strategies available to prevent ischemic injury, with emphasis on cardioprotective strategies (ischemic reconditioning, regional anesthesia, substrate provision) for minimally invasive direct vision coronary artery bypass surgery. Brief mention is also made of ischemic injury to other organ systems that may delay patient recovery.

Epidural anesthesia in coronary artery bypass grafting surgery.

Thoracic epidural anesthesia may affect the outcome of patients undergoing coronary artery bypass graft surgery beneficially by producing superlative perioperative analgesia, stress response attenuation, and cardiac sympatholysis. The technique of instrumentation in combination with full intraoperative heparinization, however, may risk potentially serious adverse effects and undesirable drug effects. This article attempts to establish whether a favorable risk/benefit ratio exists and to clarify the role of sympatholysis by thoracic epidural anesthesia in cardiac surgery.