Toll-like receptor 9 and the inflammatory response to surgical trauma and cardiopulmonary bypass.

OBJECTIVES: Cardiac surgery can lead to post-operative end-organ complications secondary to activation of systemic inflammatory response. We hypothesize that surgical trauma or cardiopulmonary bypass (CPB) may initiate systemic inflammatory response via release of mitochondrial DNA (mtDNA) signaling Toll-like receptor 9 (TLR9) and interleukin-6 production (IL-6). MATERIALS AND METHODS: The role of TLR9 in systemic inflammatory response in cardiac surgery was studied using a murine model of sternotomy and a porcine model of sternotomy and CPB. mtDNA and IL-6 were measured with and without TLR9-antagonist treatment. To study ischemia-reperfusion injury, we utilized an ex-vivo porcine kidney model. RESULTS: In the rodent model (n = 15), circulating mtDNA increased 19-fold (19.29 ± 3.31, p < 0.001) and plasma IL-6 levels increased 59-fold (59.06 ± 14.98) at 1-min post-sternotomy compared to pre-sternotomy. In the murine model (n = 11), administration of TLR-9 antagonists lowered IL-6 expression post-sternotomy when compared to controls (59.06 ± 14.98 vs. 5.25 ± 1.08) indicating that TLR-9 is a positive regulator of IL-6 after sternotomy. Using porcine models (n = 10), a significant increase in circulating mtDNA was observed after CPB (Fold change 29.9 ± 4.8, p = 0.005) and along with IL-6 following renal ischaemia-reperfusion. Addition of the antioxidant sulforaphane reduced circulating mtDNA when compared to controls (FC 7.36 ± 0.61 vs. 32.0 ± 4.17 at 60 min post-CPB). CONCLUSION: CPB, surgical trauma and ischemic perfusion injury trigger the release of circulating mtDNA that activates TLR-9, in turn stimulating a release of IL-6. Therefore, TLR-9 antagonists may attenuate this response and may provide a future therapeutic target whereby the systemic inflammatory response to cardiac surgery may be manipulated to improve clinical outcomes.

Microlobectomy: A Novel Form of Endoscopic Lobectomy.

OBJECTIVE: Microlobectomy is a novel form of videoscopic-assisted thoracic surgery lobectomy. Strict inclusion criteria consist of the following: no intercostal incisions greater than 5 mm, 12 mm subxiphoid port, subxiphoid removal of the specimen, total endoscopic technique with CO2 insufflation, vision through a 5-mm camera, stapling via the subxiphoid port, or with 5-mm stapling devices. METHODS: The combined early experiences of six hospitals from three countries were combined from September 2014 to May 2016. During that time, the study represents a consecutive cohort study of this technique. RESULTS: Seventy-two patients underwent microlobectomy. The median (range) age was 66 (27-82). Half of the patients were female. There were 48 right-sided resections and 24 on the left. There were four segmental resections and there was one right pneumonectomy. Four operations were performed robotically (with 8-mm intercostal incisions). The median (range) operative time was 180 (94-285) minutes and the blood loss was 118 (5-800) mL. There were three conversions to thoracotomy and two conversions to videoscopic-assisted thoracic surgery by means of an intercostal utility incision to complete the operation. The median (range) length of stay was 3 (1-44) days and 30 patients (42%) when home by day 2 and 16 patients (22%) were discharged on day 1. There were no deaths. Five patients (7%) had a prolonged airleak. There were no wound infections and there was one incisional hernia. CONCLUSIONS: We believe that microlobectomy is an interesting novel form of videoscopic-assisted thoracic surgery lobectomy and has several theoretical advantages. We have presented our early results and hope that this will stimulate others to investigate this type of videoscopic-assisted thoracic surgery lobectomy further.

Pulse wave velocity and neutrophil gelatinase-associated lipocalin as predictors of acute kidney injury following aortic valve replacement.

BACKGROUND: Accurate prediction, early detection and treatment of acute kidney injury (AKI) are essential for improving post-operative outcomes. This study aimed to examine the role of aortic stiffness and neutrophil gelatinase-associated lipocalin (NGAL) as predictors of AKI or need for early medical renal intervention following aortic valve replacement (AVR). METHODS: Aortic pulse wave velocity and plasma NGAL were measured pre-operatively in recruited patients undergoing AVR for aortic stenosis (AS). Plasma NGAL was also measured at 3 and 18-24 hours after cardiopulmonary bypass (CPB). AKI was defined using RIFLE criteria. Early medical renal intervention included diuretics or dopamine infusion exclusively for renal causes. RESULTS: Fifty-three patients aged 71 ± 9 years were included. Sixteen (30%) developed AKI (AKI-Yes) and 24 patients (45%) received early medical intervention (Intervention-Yes). There was no significant difference in the demographic, clinical or operative characteristics between the two groups for either outcome. PWV did not significantly correlate with AKI (r = 0.12, P = 0.13) or early intervention (r = 0.18, P = 0.18). At 3 h post-CPB, plasma NGAL was a much stronger predictor of both AKI and the need for early medical intervention than conventional markers such as creatinine (AKI: AUC 83%, 95% CI 0.70-0.95 vs. AUC 65%, 95% CI 0.47- 0.82; Medical intervention: AUC 84%, 95% CI 0.72-0.96 vs. AUC 56%, 95% CI 0.38-0.73). Post-CPB (3 hr) plasma NGAL was also significantly associated with AKI (r = 0.68, P < 0.001) at levels above 150 ng/ml; and significantly associated with early intervention (r = 0.64, P < 0.001) above 136 ng/ml. Simple linear regression showed no relationship between PWV and NGAL levels. CONCLUSION: Aortic PWV does not correlate significantly with post-operative AKI or plasma NGAL levels in surgical AS patients. Post-operative NGAL is however an early and powerful predictive biomarker of both post-operative AKI and the need for early medical renal intervention and should consequently be considered in prediction models for AKI after cardiac surgery.

Aortic stiffness as a marker of cardiac function and myocardial strain in patients undergoing aortic valve replacement.

BACKGROUND: Cardiac function and myocardial strain are affected by cardiac afterload, which is in part due to the stiffness of the aortic wall. In this study, we hypothesize that aortic pulse wave velocity (PWV) as a marker of aortic stiffness correlates with conventional clinical and biochemical markers of cardiac function and perioperative myocardial strain in aortic valve replacement (AVR). METHODS: Patients undergoing AVR for aortic stenosis between June 2010 and August 2012 were recruited for inclusion in this study. PWV, NYHA class and left ventricular (LV) function were assessed pre-operatively. PWV was analysed both as a continuous and dichotomous variable according to age-standardized reference values. B-type natriuretic peptide (BNP) was measured pre-operatively, and at 3 h and 18-24 h after cardiopulmonary bypass (CPB). NYHA class, leg edema, and LV function were recorded at follow-up (409 ± 159 days). RESULTS: Fifty-six patients (16 females) with a mean age of 71 ± 8.4 years were included, with 50 (89%) patients completing follow-up. The NYHA class of PWV-norm patients was significantly lower than PWV-high patients both pre- and post-operatively. Multiple logistic regression also highlighted PWV-cut off as an independent predictor of NYHA class pre- and post-operatively (OR 8.3, 95% CI [2.27,33.33] and OR 14.44, 95% CI [1.49,139.31] respectively). No significant relationship was observed between PWV and either LV function or plasma BNP. CONCLUSION: In patients undergoing AVR for aortic stenosis, PWV is independently related to pre- and post-operative NYHA class but not to LV function or BNP. These findings provisionally support the use of perioperative PWV as a non-invasive marker of clinical functional status, which when used in conjunction with biomarkers of myocardial strain such as BNP, may provide a holistic functional assessment of patients undergoing aortic valve surgery. However, in order for PWV assessment to be translated into clinical practice and utilised as more than simply a research tool, further validation is required in the form of larger prospective studies specifically designed to assess the relationship between PWV and these functional clinical outcomes.

Organ dysfunction in patients with left ventricular impairment: what is the effect of cardiopulmonary bypass?

OBJECTIVE: We have previously demonstrated that avoidance of cardiopulmonary bypass may reduce early mortality and cardiac related complications in patients with left ventricular dysfunction. This study examines the impact of cardiopulmonary bypass in the same subgroup in terms of organ dysfunction and non-cardiac related complications METHODS: A systematic literature review identified 24 studies including 7,976 patients. Data was extracted for the following outcomes of interest: stroke, renal failure, ventilation time, pulmonary complications and sternal wound infection. Random effects meta-analysis was used to aggregate the data. Sensitivity and heterogeneity were assessed. RESULTS: Meta-analysis through subgroup analysis of the highest quality studies revealed that the off-pump technique is associated with significantly lower incidence of stroke, renal failure, ventilation time and sternal wound infection. CONCLUSION: These results highlight an important link between cardiopulmonary bypass and the incidence of multi-organ dysfunction in patients with left ventricular dysfunction. The results add to the growing body of evidence that off-pump surgery is more beneficial in high-risk patients. Even in the light of mixed reports on graft patency and completeness of revascularisation, the technique may be justified in selected patients in attempt to reduce organ dysfunction.

Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass.

OBJECTIVES: Systemic inflammatory responses are a major cause of morbidity and mortality in patients undergoing cardiac surgery with cardiopulmonary bypass. However, the underlying molecular mechanisms for systemic inflammation in response to cardiopulmonary bypass are poorly understood. METHODS: A porcine model was established to study the signaling pathways that promote systemic inflammation in response to cardiac surgery with cardiopulmonary bypass under well-controlled experimental conditions. The influence of sulforaphane, an anti-inflammatory compound derived from green vegetables, on inflammation and injury in response to cardiopulmonary bypass was also studied. Intracellular staining and flow cytometry were performed to measure phosphorylation of p38 mitogen-activated protein kinase and the transcription factor nuclear factor-κB in granulocytes and mononuclear cells. RESULTS: Surgery with cardiopulmonary bypass for 1 to 2 hours enhanced phosphorylation of p38 (2.5-fold) and nuclear factor-κB (1.6-fold) in circulating mononuclear cells. Cardiopulmonary bypass also modified granulocytes by activating nuclear factor-κB (1.6-fold), whereas p38 was not altered. Histologic analyses revealed that cardiopulmonary bypass promoted acute tubular necrosis. Pretreatment of animals with sulforaphane reduced p38 (90% reduction) and nuclear factor-κB (50% reduction) phosphorylation in leukocytes and protected kidneys from injury. CONCLUSIONS: Systemic inflammatory responses after cardiopulmonary bypass were associated with activation of p38 and nuclear factor-κB pathways in circulating leukocytes. Inflammatory responses to cardiopulmonary bypass can be reduced by sulforaphane, which reduced leukocyte activation and protected against renal injury.