Effect of post-operative goal-directed fluid therapy (GDFT) on organ function after orthotopic liver transplantation: Secondary outcome analysis of the COLT randomised control trial.

BACKGROUND: Goal-directed fluid therapy (GDFT) has been shown to reduce the complications following a variety of major surgical procedures, possibly mediated by improved organ perfusion and function. We have shown that it is feasible to randomise patients to GDFT or standard fluid management following liver transplant in the cardiac-output optimisation following liver transplantation (COLT) trial. The current study compares end organ function in patients from the COLT trial who received GDFT in comparison to those receiving standard care (SC) following liver transplant. METHODS: Adult patients with liver cirrhosis undergoing liver transplantation were randomised to GDFT or SC for the first 12 h following surgery as detailed in a published trial protocol. GDFT protocol was based on stroke volume (SV) optimisation using 250 ml crystalloid boluses. Total fluid administration and time to extubation were recorded. Hourly SV and cardiac output (CO) readings were recorded from the non-invasive cardiac output monitoring (NICOM) device in both groups. Pulmonary function was assessed by arterial blood gas (ABG) and ventilatory parameters. Lung injury was assessed using PaO2:FiO2 ratios and calculated pulmonary compliance. The KDIGO score was used for determining acute kidney injury. Renal and liver graft function were assessed during the post-operative period and at 3 months and 1-year. RESULTS: 60 patients were randomised to GDFT (n = 30) or SC (n = 30). All patients completed the 12 h intervention period. GDFT group received a significantly higher total volume of fluid during the 12 h trial intervention period (GDFT 5317 (2335) vs. SC 3807 (1345) ml, p = 0.003); in particular crystalloids (GDFT 3968 (2073) vs. SC 2510 (1027) ml, p = 0.002). There was no evidence of significant difference between the groups in SV or CO during the assessment periods. Time to extubation, PaO2: FIO2 ratios, pulmonary compliance, ventilatory or blood gas measurements were similar in both groups. There was a significant rise in serum creatinine from baseline (77 µmol/L) compared to first (87 µmol/L, p = 0.039) and second (107 µmol/L, p = 0.001) post-operative days. There was no difference between GDFT and SC in the highest KDIGO scores for the first 7 days post-LT. At 1-year follow-up, there was no difference in need for renal replacement therapy or graft function. CONCLUSIONS: In this randomised trial of fluid therapy post liver transplant, GDFT was associated with an increased volume of crystalloids administered but did not alter early post-operative pulmonary or renal function when compared with standard care.

The effects of cancer therapies on physical fitness before oesophagogastric cancer surgery: a prospective, blinded, multi-centre, observational, cohort study.

Background: Neoadjuvant cancer treatment is associated with improved survival following major oesophagogastric cancer surgery. The impact of neoadjuvant chemo/chemoradiotherapy on physical fitness and operative outcomes is however unclear. This study aims to investigate the impact of neoadjuvant chemo/chemoradiotherapy on fitness and post-operative mortality. Methods: Patients with oesophagogastric cancer scheduled for chemo/chemoradiotherapy and surgery were recruited to a prospective, blinded, multi-centre, observational cohort study. Primary outcomes were changes in fitness with chemo/chemoradiotherapy, measured using cardiopulmonary exercise testing and its association with mortality one-year after surgery. Patients were followed up for re-admission at 30-days, in-hospital morbidity and quality of life (exploratory outcomes). Results: In total, 384 patients were screened, 217 met the inclusion criteria, 160 consented and 159 were included (72% male, mean age 65 years). A total of 132 patients (83%) underwent chemo/chemoradiotherapy, 109 (71%) underwent chemo/chemoradiotherapy and two exercise tests, 100 (63%) completed surgery and follow-up. A significant decline in oxygen uptake at anaerobic threshold and oxygen uptake peak was observed following chemo/chemoradiotherapy: -1.25ml.kg -1.min -1 (-1.80 to -0.69) and -3.02ml.kg -1.min -1 (-3.85 to -2.20); p<0.0001). Baseline chemo/chemoradiotherapy anaerobic threshold and peak were associated with one-year mortality (HR=0.72, 95%CI 0.59 to 0.88; p=0.001 and HR=0.85, 0.76 to 0.95; p=0.005). The change in physical fitness was not associated with one-year mortality. Conclusions: Chemo/chemoradiotherapy prior to oesophagogastric cancer surgery reduced physical fitness. Lower baseline fitness was associated with reduced overall survival at one-year. Careful consideration of fitness prior to chemo/chemoradiotherapy and surgery is urgently needed.

BACKGROUND: Cancer treatments such as chemotherapy and radiotherapy given to people with oesophageal and gastric cancer (also known as cancer of the food pipe/stomach) before surgery can improve survival. However, the impact such treatments have on fitness and recovery after surgery is unclear. The aim of this research was to understand the impact cancer treatments has on fitness and any complications after surgery. METHODS: Patients with oesophageal and gastric cancer (also known as cancer of the food pipe/stomach) who were being treated by cancer treatment and surgery were recruited from different hospitals in the UK. All participants were asked to undertake an exercise test to measure fitness and fill out questionnaires to measure quality of life before and after cancer treatment. Complications patients experienced after surgery, the number of patients who had to be readmitted to hospital 30 days after surgery and one-year survival was recorded. RESULTS: A total of 160 consented to participate in this study and 159 were included in the study (72% male, average age 65 years). In total, 132 patients (83%) had cancer treatment, 109 (71%) had cancer treatment and the two exercise tests and 100 (63%) had surgery and were followed-up after surgery. Study findings show that fitness reduced after cancer treatment. Patient's fitness levels at the start of the study (or before cancer treatment) were linked to one-year survival. The fall in fitness after cancer treatment was not linked to death at the one-year follow-up. CONCLUSION: Cancer treatments before oesophageal and gastric cancer reduce fitness. Patients with a lower fitness level before cancer treatment had a reduced overall survival at one-year. Careful consideration of fitness prior to such cancer treatments and surgery is urgently needed.

Support of the histaminergic hypothesis in Tourette syndrome: association of the histamine decarboxylase gene in a large sample of families.

BACKGROUND: Gilles de la Tourette Syndrome is a neurodevelopmental disorder that is caused by the interaction of environment with a complex genetic background. The genetic etiology of the disorder remains, so far, elusive, although multiple promising leads have been recently reported. The recent implication of the histamine decarboxylase (HDC) gene, the key enzyme in histamine production, raises the intriguing hypothesis of a possible role of histaminergic dysfunction leading to TS onset. METHODS: Following up on the finding of a nonsense mutation in a single family with TS, we investigated variation across the HDC gene for association with TS. As a result of a collaborative international effort, we studied a large sample of 520 nuclear families originating from seven European populations (Greek, Hungarian, Italian, Polish, German, Albanian, Spanish) as well as a sample collected in Canada. RESULTS AND CONCLUSIONS: Interrogating 12 tagging SNPs (tSNP) across the HDC region, we find strong over-transmission of alleles at two SNPs (rs854150 and rs1894236) in the complete sample, as well as a statistically significant associated haplotypes. Analysis of individual populations also reveals signals of association in the Canadian, German and Italian samples. Our results provide strong support for the histaminergic hypothesis in TS etiology and point to a possible role of histamine pathways in neuronal development.