Mild and deep hypothermia differentially affect cerebral neuroinflammatory and cold shock response following cardiopulmonary bypass in rat.

INTRODUCTION: Targeted temperature management (TTM) is considered to be a neuroprotective strategy during cardiopulmonary bypass (CPB) assisted procedures, possibly through the activation of cold shock proteins. We therefore investigated the effects of mild compared with deep hypothermia on the neuroinflammatory response and cold shock protein expression after CPB in rats. METHODS: Wistar rats were subjected to 1 hr of mild (33 °C) or deep (18 °C) hypothermia during CPB or sham procedure. PET scan analyses using TSPO ligand [11C]PBR28 were performed on day 1 (short-term) or day 3 and 7 post-procedure (long-term) to assess neuroinflammation. Hippocampal and cortical samples were obtained at day 1 in the short-term group and at day 7 in the long-term group. mRNA expression of M1 and M2 microglia associated cytokines was analysed with RT-PCR. Cold shock protein RNA-binding motive 3 (RBM3) and tyrosine receptor kinase B (TrkB) receptor protein expression were determined with Western Blot and quantified. RESULTS: In both groups target temperature was reached within an hour. Standard uptake values (SUV) of [11C]PBR28 in CPB rats at 1 day and 3 days were similar to that of sham animals. At 7 days after CPB the SUV was significantly higher in amygdala and hippocampal regions of the CPB 18 °C group as compared to the CPB 33 °C group. No differences were observed in the expression of M1 and M2 microglia-related cytokines between TTM 18 °C and 33 °C. RBM3 protein levels in cortex and hippocampus were significantly higher in CPB 33 °C compared to CPB 18 °C and sham 33 °C, at day 1 and day 7, respectively. CONCLUSIONS: TTM at 18 °C increased the neuroinflammatory response in amygdala and hippocampus compared to TTM at 33 °C in rats undergoing a CPB procedure. Additionally, TTM at 33 °C induced increased expression of TrkB and RBM3 in cortex and hippocampus of rats on CPB compared to TTM at 18 °C. Together, these data indicate that neuroinflammation is alleviated by TTM at 33 °C, possibly by recruiting protective mechanisms through cold shock protein induction.

The Impact of Different Anesthetics on the Distribution and Cytotoxic Function of NK Cell Subpopulations: An In Vitro Study.

Only some subpopulations of natural killer (NK) cells have cytotoxic functionality, and the effects of anesthetics on these subpopulations are unknown. This study aimed to evaluate the in vitro effects of various anesthetics, both alone and in combination, on the distribution and cytotoxic function of NK cells and their subpopulations. Peripheral blood mononuclear cells (PBMCs) from eight healthy volunteers were treated for 4 h in vitro with dexmedetomidine, remifentanil, lidocaine, propofol, sevoflurane, and combinations in clinically relevant concentrations or left untreated. Flow cytometry was used to quantify the percentage of sampled NK cells and evaluate their distribution (CD56brightCD16neg, CD56brightCD16dim, CD56dimCD16neg, CD56dimCD16bright, and CD56negCD16bright) and cytotoxicity (Granzyme B (GrzB) and perforin) of NK cell subpopulations. Although the percentage of total NK cells did not change following exposure to anesthesia, the most important cytotoxic subpopulation (CD56dimCD16bright NK cells) decreased after exposure to both propofol (-3.58%, p = 0.045) and sevoflurane (-16.10%, p = 0.008) alone, and most combinations, especially in combination with lidocaine (propofol with lidocaine (-9.66%, p = 0.002) and sevoflurane with lidocaine (-21.90%, p < 0.001)). Dexmedetomidine and remifentanil had no effect on CD56dimCD16bright NK cells. Furthermore, no anesthetic regimen or combination altered the expression of GrzB and perforin in NK cells or NK cell subpopulations. In short, propofol and sevoflurane suppressed the highly cytotoxic phenotype (CD56dimCD16bright) of NK cells, with those exposed to sevoflurane combinations showing greater reductions. Immunosuppression was intensified with the inclusion of lidocaine in the anesthetic regimen.

Ex Vivo Optimization of Donor Lungs with Inhaled Sevoflurane during Normothermic Ex Vivo Lung Perfusion (VITALISE): A Pilot and Feasibility Study in Sheep.

Volatile anesthetics have been shown in different studies to reduce ischemia reperfusion injury (IRI). Ex vivo lung perfusion (EVLP) facilitates graft evaluation, extends preservation time and potentially enables injury repair and improvement of lung quality. We hypothesized that ventilating lungs with sevoflurane during EVLP would reduce lung injury and improve lung function. We performed a pilot study to test this hypothesis in a slaughterhouse sheep DCD model. Lungs were harvested, flushed and stored on ice for 3 h, after which EVLP was performed for 4 h. Lungs were ventilated with either an FiO2 of 0.4 (EVLP, n = 5) or FiO2 of 0.4 plus sevoflurane at a 2% end-tidal concentration (Cet) (S-EVLP, n = 5). Perfusate, tissue samples and functional measurements were collected and analyzed. A steady state of the target Cet sevoflurane was reached with measurable concentrations in perfusate. Lungs in the S-EVLP group showed significantly better dynamic lung compliance than those in the EVLP group (p = 0.003). Oxygenation capacity was not different in treated lungs for delta partial oxygen pressure (PO2; +3.8 (-4.9/11.1) vs. -11.7 (-12.0/-3.2) kPa, p = 0.151), but there was a trend of a better PO2/FiO2 ratio (p = 0.054). Perfusate ASAT levels in S-EVLP were significantly reduced compared to the control group (198.1 ± 93.66 vs. 223.9 ± 105.7 IU/L, p = 0.02). We conclude that ventilating lungs with sevoflurane during EVLP is feasible and could be useful to improve graft function.

Association between anaesthesia-related factors and postoperative neurocognitive disorder: a post-hoc analysis.

BACKGROUND: Postoperative neurocognitive disorder (pNCD) is common after surgery. Exposure to anaesthetic drugs has been implicated as a potential cause of pNCD. Although several studies have investigated risk factors for the development of cognitive impairment in the early postoperative phase, risk factors for pNCD at 3 months have been less well studied. The aim of this study was to identify potential anaesthesia-related risk factors for pNCD at 3 months after surgery. METHODS: We analysed data obtained for a prospective observational study in patients aged ≥ 65 years who underwent surgery for excision of a solid tumour. Cognitive function was assessed preoperatively and at 3 months postoperatively using 5 neuropsychological tests. Postoperative NCD was defined as a postoperative decline of ≥ 25% relative to baseline in ≥ 2 tests. The association between anaesthesia-related factors (type of anaesthesia, duration of anaesthesia, agents used for induction and maintenance of anaesthesia and analgesia, the use of additional vasoactive medication, depth of anaesthesia [bispectral index] and mean arterial pressure) and pNCD was analysed using logistic regression analyses. Furthermore, the relation between anaesthesia-related factors and change in cognitive test scores expressed as a continuous variable was analysed using a z-score. RESULTS: Of the 196 included patients, 23 (12%) fulfilled the criteria for pNCD at 3 months postoperatively. A low preoperative score on Mini-Mental State Examination (OR, 8.9 [95% CI, (2.8-27.9)], p < 0.001) and a longer duration of anaesthesia (OR, 1.003 [95% CI, (1.001-1.005)], p = 0.013) were identified as risk factors for pNCD. On average, patients scored higher on postoperative tests (mean z-score 2.35[± 3.13]). CONCLUSION: In this cohort, duration of anaesthesia, which is probably an expression of the complexity of the surgery, was the only anaesthesia-related predictor of pNCD. On average, patients' scores on cognitive tests improved postoperatively.

Immune Modulatory Effects of Nonsteroidal Anti-inflammatory Drugs in the Perioperative Period and Their Consequence on Postoperative Outcome.

Nonsteroidal anti-inflammatory drugs are among the most commonly administered drugs in the perioperative period due to their prominent role in pain management. However, they potentially have perioperative consequences due to immune-modulating effects through the inhibition of prostanoid synthesis, thereby affecting the levels of various cytokines. These effects may have a direct impact on the postoperative outcome of patients since the immune system aims to restore homeostasis and plays an indispensable role in regeneration and repair. By affecting the immune response, consequences can be expected on various organ systems. This narrative review aims to highlight these potential immune system-related consequences, which include systemic inflammatory response syndrome, acute respiratory distress syndrome, immediate and persistent postoperative pain, effects on oncological and neurologic outcome, and wound, anastomotic, and bone healing.

Molecular Aspects of Volatile Anesthetic-Induced Organ Protection and Its Potential in Kidney Transplantation.

Ischemia reperfusion injury (IRI) is inevitable in kidney transplantation and negatively impacts graft and patient outcome. Reperfusion takes place in the recipient and most of the injury following ischemia and reperfusion occurs during this reperfusion phase; therefore, the intra-operative period seems an attractive window of opportunity to modulate IRI and improve short- and potentially long-term graft outcome. Commonly used volatile anesthetics such as sevoflurane and isoflurane have been shown to interfere with many of the pathophysiological processes involved in the injurious cascade of IRI. Therefore, volatile anesthetic (VA) agents might be the preferred anesthetics used during the transplantation procedure. This review highlights the molecular and cellular protective points of engagement of VA shown in in vitro studies and in vivo animal experiments, and the potential translation of these results to the clinical setting of kidney transplantation.

Effects of propofol and dexmedetomidine with and without remifentanil on serum cytokine concentrations in healthy volunteers: a post hoc analysis.

BACKGROUND: Anaesthetic agents are likely to alter circulating cytokine concentrations. Because preceding studies have not been able to exclude the contribution of surgical trauma, perioperative stress, or both to circulating cytokine concentrations, the effects of anaesthesia remain unclear. The aim of this study was to quantify serum cytokines in healthy volunteers administered i.v. anaesthetic agents in the absence of surgical trauma and perioperative stress. METHODS: Serum samples obtained during previous standardised studies from healthy volunteers were compared before and 6-8 h after induction of anaesthesia with propofol (n=31), propofol/remifentanil (n=30), dexmedetomidine (n=17) or dexmedetomidine/remifentanil (n=15). Anaesthetic regimens were standardised and volunteers did not undergo any surgical intervention. Serum concentrations of interleukin (IL)2, IL4, IL6, IL10, IL17, IL18, IL21, IL22, IL23, C-X-C motif ligand 8, interferon gamma, E-selectin, L-selectin, major histocompatibility complex class I chain-polypeptide-related sequence (MIC)A, MICB, Granzyme A, and Granzyme B were quantified using a multiplexed antibody-based assay (Luminex). RESULTS: Samples were obtained from volunteers of either sex aged 18-70 yr. After anaesthesia with propofol alone, concentrations of IL4 (P=0.012), IL6 (P=0.027), IL21 (P=0.035), IL22 (P=0.002), C-X-C motif ligand 8 (P=0.004), MICB (P=0.046), and Granzyme A (P=0.045) increased. After anaesthesia with propofol and remifentanil, IL17 (P=0.013), interferon gamma (P=0.003), and MICA (P=0.001) decreased, but IL6 (P=0.006) and L-selectin (P=0.001) increased. After dexmedetomidine alone, IL18 (P=0.002), L-selectin (P=0.017), E-selectin (P=0.002), and Granzyme B (P=0.023) decreased. After dexmedetomidine with remifentanil no changes were observed. CONCLUSIONS: In healthy volunteers not undergoing surgery, different i.v. anaesthesia regimens were associated with differential effects on circulating cytokines.

Impact of neoadjuvant chemoradiotherapy on postoperative course after curative-intent transthoracic esophagectomy in esophageal cancer patients.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) improves locoregional control and overall survival in esophageal cancer patients. Although adverse events are relatively low during neoadjuvant CRT, severe postoperative adverse effects may occur, leading to morbidity and even mortality. We investigated the impact of a more frequently used neoadjuvant CRT regimen of 41.4 Gy/5 weeks radiotherapy with concurrent carboplatin and paclitaxel (CROSS schedule) on the postoperative course. METHODS: Between 2006 and 2012, a total of 96 esophageal cancer patients (staged cT1N+/T2-4a/N0-3 and M0) were treated according to the above neoadjuvant scheme. To reduce bias in this single-center study, we performed a propensity score-matched analysis with patients who underwent surgery alone (n = 230) from a prospectively maintained database (n = 326). RESULTS: Baseline characteristics between both groups were equally distributed in the matched cohort. In the neoadjuvant treated group, significantly more patients were diagnosed with pneumonia (27.1 vs. 51.0%; p = 0.001), pleural effusion (12.5 vs. 24.0%; p = 0.040), and arrhythmia (20.4 vs. 34.4%; p = 0.008). In addition, in the multivariate analysis, neoadjuvant CRT was significantly associated with an increased risk of pneumonia (p = 0.001, odds ratio 2.896), pleural effusion (p = 0.041, odds ratio 2.268), and arrhythmia (p = 0.023, odds ratio 2.215). Despite these outcomes, no differences were detected in duration of intensive care unit or hospital stay. Short-term mortality did not differ between both groups. CONCLUSIONS: We observed an increase of cardiopulmonary complications in the neoadjuvant CRT group, without any effect on hospital or intensive care unit stay and mortality. Further research is warranted on the limitation of chemoradiation-induced cardiopulmonary toxicity.

Longitudinal analysis of cytokine expression during neoadjuvant chemoradiotherapy and subsequent surgery in esophageal cancer patients.

BACKGROUND: The purpose of this study was to provide more insight in the course of cytokine concentrations related to pathologic response (pR) and complications after neoadjuvant chemoradiotherapy (NCRT) and esophagectomy in esophageal cancer patients. METHODS: Patients treated with NCRT followed by transthoracic esophagectomy (n = 35) or transthoracic esophagectomy alone (n = 8) were included. Eight different cytokine concentrations were determined during NCRT, esophagectomy, and the first postoperative week. RESULTS: Platelet-activating factor before NCRT was associated with pR (P = .011) and remained elevated in patients with a better response. Concentrations of intestinal fatty acid-binding protein and angiopoietin 1 (Ang-1) were different between patients with and without NCRT. Decreased concentrations of Ang-1 on the third postoperative day were associated with postoperative complications (P = .046). CONCLUSIONS: In this observational study, elevated platelet-activating factor concentrations before NCRT were associated with pR. NCRT is associated with decreased Ang-1 concentrations, whereas reduced Ang-1 concentrations were associated with postoperative complications.

Increased risk of thromboembolism in esophageal cancer patients treated with neoadjuvant chemoradiotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) in esophageal cancer (EC) patients may increase the formation of thromboembolic events (TEEs). We analyzed the incidence and impact of TEEs in EC patients treated with platinum-based CRT. METHODS: A total of 336 patients with EC underwent an esophagectomy, of which 110 patients received neoadjuvant CRT (41.4 Gy with concurrent Carboplatin/Paclitaxel). Patients were matched based on pre- and perioperative characteristics. RESULTS: Preoperatively, 9 (8.2%) patients with neoadjuvant CRT (P = .004) were diagnosed with TEEs. Despite delay until surgery (P = .021), the postoperative course did not differ. In multivariate analysis, a history of deep vein thrombosis (P = .005) and neoadjuvant CRT (P = .004) were identified as risk factors. Postoperatively, there were no differences in TEEs (P = .560) observed. In multivariate analysis, a history of pulmonary embolism (P = .012) was identified as a risk factor for postoperative TEEs. CONCLUSIONS: Preoperatively, EC patients treated with neoadjuvant CRT have an increased risk to develop a TEE, especially those with a previous history of TEE. After surgery no increased incidence was observed. We recommend secondary prophylaxis during neoadjuvant treatment in this high-risk group.

Comparison of different risk-adjustment models in assessing short-term surgical outcome after transthoracic esophagectomy in patients with esophageal cancer.

BACKGROUND: Different risk-prediction models have been developed, but none is generally accepted in selecting patients for esophagectomy. This study evaluated 5 most frequently used risk-prediction models, including the American Society of Anesthesiologists, Portsmouth-modified Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM), and the adjusted version for Oesophagogastric surgery (O-POSSUM), Charlson and the Age adjusted Charlson score to assess postoperative mortality after transthoracic esophagectomy. METHODS: Data were obtained from 278 consecutive esophageal cancer patients between 1991 and 2007. Performance in predicting postoperative mortality (in-hospital and 90-day mortality) were analyzed regarding calibration (Hosmer and Lemeshow goodness-of-fit test) and discrimination (area under the receiver operator curve). RESULTS: The Hosmer and Lemeshow goodness-of-fit test was applied to each model and showed a significant outcome for only the P-POSSUM score (P = .035). The receiver operator curve indicated discriminatory power for P-POSSUM (.766) and for O-POSSUM (.756), other models did not exceed the minimal surface of .7. CONCLUSIONS: Postoperative mortality after esophagectomy was best predicted by O-POSSUM. However, it still overpredicted postoperative mortality.