Intraoperative hypotension is associated with decreased long-term survival in older patients after major noncardiac surgery: Secondary analysis of three randomized trials.

STUDY OBJECTIVE: To assess the association of intraoperative hypotension with long-term survivals in older patients after major noncardiac surgery mainly for cancer. DESIGN: A secondary analysis of databases from three randomized trials with long-term follow-up. SETTING: The underlying trials were conducted in 17 tertiary hospitals in China. PATIENTS: Patients aged 60 to 90 years who underwent major noncardiac thoracic or abdominal surgeries (≥ 2 h) in a single center were included in this analysis. EXPOSURES: Restricted cubic spline models were employed to determine the lowest mean arterial pressure (MAP) threshold that was potentially harmful for long-term survivals. Patients were arbitrarily divided into three groups according to the cumulative duration or area under the MAP threshold. The association between intraoperative hypotension exposure and long-term survivals were analyzed with the Cox proportional hazard regression models. MEASUREMENTS: Our primary endpoint was overall survival. Secondary endpoints included recurrence-free and event-free survivals. MAIN RESULTS: A total of 2664 patients (mean age 69.0 years, 34.9% female sex, 92.5% cancer surgery) were included in the final analysis. MAP < 60 mmHg was adopted as the threshold of intraoperative hypotension. Patients were divided into three groups according to duration under MAP < 60 mmHg (<1 min, 1-10 min, and > 10 min) or area under MAP <60 mmHg (< 1 mmHg⋅min, 1-30 mmHg⋅min, and > 30 mmHg⋅min). After adjusting confounders, duration under MAP < 60 mmHg for > 10 min was associated with a shortened overall survival when compared with the < 1 min patients (adjusted hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.09 to 1.57, P = 0.004); area under MAP < 60 mmHg for > 30 mmHg⋅min was associated with a shortened overall survival when compared with the < 1 mmHg⋅min patients (adjusted HR 1.40, 95% CI 1.16 to 1.68, P < 0.001). Similar associations exist between duration under MAP < 60 mmHg for > 10 min or area under MAP < 60 mmHg for > 30 mmHg⋅min and recurrence-free or event-free survivals. CONCLUSIONS: In older patients who underwent major noncardiac surgery mainly for cancer, intraoperative hypotension was associated with worse overall, recurrence-free, and event-free survivals.

Delirium in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: a multicentre randomised trial.

BACKGROUND: Delirium is a common and disturbing postoperative complication that might be ameliorated by propofol-based anaesthesia. We therefore tested the primary hypothesis that there is less delirium after propofol-based than after sevoflurane-based anaesthesia within 7 days of major cancer surgery. METHODS: This multicentre randomised trial was conducted in 14 tertiary care hospitals in China. Patients aged 65-90 yr undergoing major cancer surgery were randomised to either propofol-based anaesthesia or to sevoflurane-based anaesthesia. The primary endpoint was the incidence of delirium within 7 postoperative days. RESULTS: A total of 1228 subjects were enrolled and randomised, with 1195 subjects included in the modified intention-to-treat analysis (mean age 71 yr; 422 [35%] women); one subject died before delirium assessment. Delirium occurred in 8.4% (50/597) of subjects given propofol-based anaesthesia vs 12.4% (74/597) of subjects given sevoflurane-based anaesthesia (relative risk 0.68 [95% confidence interval {CI}: 0.48-0.95]; P=0.023; adjusted relative risk 0.59 [95% CI: 0.39-0.90]; P=0.014). Delirium reduction mainly occurred on the first day after surgery, with a prevalence of 5.4% (32/597) with propofol anaesthesia vs 10.7% (64/597) with sevoflurane anaesthesia (relative risk 0.50 [95% CI: 0.33-0.75]; P=0.001). Secondary endpoints, including ICU admission, postoperative duration of hospitalisation, major complications within 30 days, cognitive function at 30 days and 3 yr, and safety outcomes, did not differ significantly between groups. CONCLUSIONS: Delirium was a third less common after propofol than sevoflurane anaesthesia in older patients having major cancer surgery. Clinicians might therefore reasonably select propofol-based anaesthesia in patients at high risk of postoperative delirium. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR-IPR-15006209) and ClinicalTrials.gov (NCT02662257).

Long-term survival in older patients given propofol or sevoflurane anaesthesia for major cancer surgery: follow-up of a multicentre randomised trial.

BACKGROUND: Experimental evidence indicates that i.v. anaesthesia might reduce cancer recurrence compared with volatile anaesthesia, but clinical information is observational only. We therefore tested the primary hypothesis that propofol-based anaesthesia improves survival over 3 or more years after potentially curative major cancer surgery. METHODS: This was a long-term follow-up of a multicentre randomised trial in 14 tertiary hospitals in China. We enrolled 1228 patients aged 65-90 yr who were scheduled for major cancer surgery. They were randomised to either propofol-based i.v. anaesthesia or to sevoflurane-based inhalational anaesthesia. The primary endpoint was overall survival after surgery. Secondary endpoints included recurrence-free and event-free survival. RESULTS: Amongst subjects randomised, 1195 (mean age 72 yr; 773 [65%] male) were included in the modified intention-to-treat analysis. At the end of follow-up (median 43 months), there were 188 deaths amongst 598 patients (31%) assigned to propofol-based anaesthesia compared with 175 deaths amongst 597 patients (29%) assigned to sevoflurane-based anaesthesia; adjusted hazard ratio 1.02; 95% confidence interval (CI): 0.83-1.26; P=0.834. Recurrence-free survival was 223/598 (37%) in patients given propofol anaesthesia vs 206/597 (35%) given sevoflurane anaesthesia; adjusted hazard ratio 1.07; 95% CI: 0.89-1.30; P=0.465. Event-free survival was 294/598 (49%) in patients given propofol anaesthesia vs 274/597 (46%) given sevoflurane anaesthesia; adjusted hazard ratio 1.09; 95% CI 0.93 to 1.29; P=0.298. CONCLUSIONS: Long-term survival after major cancer surgery was similar with i.v. and volatile anaesthesia. Propofol-based iv. anaesthesia should not be used for cancer surgery with the expectation that it will improve overall or cancer-specific survival. CLINICAL TRIAL REGISTRATIONS: ChiCTR-IPR-15006209; NCT02660411.

Protein-energy malnutrition worsens hospitalization outcomes of patients with pancreatic cancer undergoing open pancreaticoduodenectomy.

To assess the role of protein-energy malnutrition on perioperative outcomes in patients with pancreatic cancer undergoing open pancreaticoduodenectomy. We conducted a retrospective observational cohort study and investigated patients ≥ 18 years old with pancreatic cancer undergoing open pancreaticoduodenectomy within the National inpatient sample database during 2012-2014. The study population was divided into two groups based on the presence of protein-energy malnutrition. In-hospital mortality, length of stay, cost of hospitalization, and in-hospital complications were compared between the two groups. Logistic and linear regression analyses were used to adjust for potential confounders. A trend analysis was further conducted on the in-hospital outcomes. Of the 12,785 patients aged ≥ 18 years undergoing open pancreaticoduodenectomy during years 2012-2014, 9865 (77.0%) had no protein-energy malnutrition and 2920 (23.0%) had protein-energy malnutrition. Patients with protein-energy malnutrition were found to have significantly higher mortality rate, longer length of hospital stay, and higher total hospital cost compared to those without protein-energy malnutrition. The risks of gastroparesis, small bowel obstruction, intraoperative and postoperative hemorrhage, infectious complications, and several systemic complications were found to be significantly higher in the protein-energy malnutrition group in a multivariate regression model. A study of trends from 2009 to 2012 revealed an increasing prevalence of protein-energy malnutrition, a declining trend in mortality and length of stay and a stable total hospital cost in the protein-energy malnutrition group. Protein-energy malnutrition was found to be associated with higher mortality, longer length of hospital stay and greater hospital cost in pancreatic cancer patients undergoing open pancreaticoduodenectomy, as well as increased occurrence of various systemic complications. Attention should be paid to patients' nutritional status, which can be corrected before surgery as an effective means to optimize postoperative results.

Intraoperative Intravenous Mannitol Administration Failed to Provide Added Value on Renal Functional Preservation After Partial Nephrectomy in Patients with Chronic Kidney Disease: A Matched Cohort Study.

Background: Previous randomized-controlled trials have demonstrated that intraoperative intravenous mannitol administration shows no added value on renal functional preservation after partial nephrectomy (PN) in patients with normal renal function. However, the renoprotective effect of mannitol has not been fully evaluated in patients with preoperative chronic kidney disease (CKD). Materials and Methods: This was a retrospective cohort study with propensity score matching. Patients with a preoperative estimated glomerular filtration rate (eGFR) of <60 mL/minute/1.73 m2 undergoing PN were enrolled in the study between January 2012 and December 2019 in Peking University First Hospital. Participants were divided into two groups: patients who received 25 g of mannitol (group M+) or not (group M-). The primary endpoint was the decreased rate of eGFR at the 6-month follow-up. Results: A total of 244 patients were included in the analysis. After propensity score matching, 80 patients remained in each group. The percentage of decrease from baseline eGFR at postoperative 6-month follow-up showed no difference between the two patient groups (median 11.1 [interquartile range 5.3-25.3] in group M+ vs 12.2 [4.7-21.3] in group M-, median difference -0.7 [95% confidence interval -4.6 to 3.1]; p = 0.704). Postoperative acute kidney injury, renal replacement therapy during hospitalization, postoperative complications, incidence of >20% decrease from baseline eGFR at 6 months, and dialysis at 6 months showed no difference between the two patient groups. Conclusions: A 25 g dose of mannitol administration during PN failed to provide added value on renal functional preservation in CKD patients.

Preoperative intravenous rehydration for patients with pheochromocytomas and paragangliomas: is it necessary? A propensity score matching analysis.

BACKGROUND: Preoperative intravenous rehydration for patients with pheochromocytomas and paragangliomas (PPGLs) is widely used in many medical centers, but its usefulness has not been well evaluated. The objective of this study was to compare the perioperative hemodynamics and early outcome between patients who received preoperative intravenous rehydration and those without for resection of PPGLs. METHODS: In this retrospective propensity score-matched cohort study, the data of patients who underwent surgery for PPGLs were collected. Patients were divided into two groups depending on whether they received or did not receive intravenous rehydration preoperatively. The primary endpoint was intraoperative hypotension, described as the cumulative time of mean arterial pressure < 65 mmHg averaged by surgery duration. RESULTS: Among 231 enrolled patients, 113 patients received intravenous rehydration of ≥2000 ml daily for ≥2 days before surgery and 118 patients who did not have any intravenous rehydration before surgery. After propensity score matching, 85 patients remained in each group. The median cumulative time of mean arterial pressure < 65 mmHg averaged by surgery duration was not significantly different between rehydrated patients and non-rehydrated patients (median 3.0% [interquartile range 0.2-12.2] versus 3.8% [0.0-14.2], median difference 0.0, 95%CI - 1.2 to 0.8, p = 0.909). The total dose of catecholamines given intraoperatively, volume of intraoperative fluids, intraoperative tachycardia and hypertension, percentage of patients who suffered from postoperative hypotension, postoperative diuretics use, and postoperative early outcome between the two groups were not significantly different either. CONCLUSIONS: For patients with PPGLs, preoperative intravenous rehydration failed to optimize perioperative hemodynamics or improve early outcome.

Molecular cloning and characterization of a Brassica juncea yellow stripe-like gene, BjYSL7, whose overexpression increases heavy metal tolerance of tobacco.

KEY MESSAGE: BjYSL7 encodes a plasma-localized metal-NA transporter and has transport Fe(II)-NA complexes activity. BjYSL7 is involved in the transport of Cd and Ni from roots to shoots. Heavy metal transporters play a key role in regulating metal accumulation and transport in plants. In this study, we isolated a novel member of the yellow stripe-like (YSL) gene family BjYSL7 from the hyperaccumulator Brassica juncea. BjYSL7 is composed of 688 amino acids with 12 putative transmembrane domains and is over 90 % identical to TcYSL7 and AtYSL7. Real-time PCR analysis revealed that BjYSL7 mRNA was mainly expressed in the stem under normal condition. The expression of BjYSL7 was found to be up-regulated by 127.1-, 12.7-, and 3.4-fold in roots and 6.5-, 4.3-, and 2.8-fold in shoots under FeSO4, NiCl2, and CdCl2 stresses, respectively. We have demonstrated that BjYSL7 is a Fe(II)-NA influx transporter by yeast functional complementation. Moreover, a BjYSL7::enhanced green fluorescent protein (EGFP) fusion localized to the plasma membrane of onion epidermal cells. The BjYSL7-overexpressing transgenic tobacco plants exhibited longer root lengths, lower relative inhibition rate of lengths and superior root hair development compared to that of wild-type (WT) plants in the presence of CdCl2 and NiCl2. Furthermore, the concentrations of Cd and Ni in shoots of BjYSL7-overexpressing plants are significantly higher than that of WT plants. Compared with WT plants, BjYSL7-overexpressing plants exhibited Fe concentrations that were higher in the shoots and seeds and lower in the roots. Taken together, these results suggest that BjYSL7 might be involved in the transport of Fe, Cd and Ni to the shoot and improving heavy metal resistance in plants.

[Antioxidative enzymes play key roles in cadmium tolerance of Phytolacca americana].

Phytolacca americana L. has the capacity to take up and accumulate to very high levels heavy metals such as Mn and Cd, and is used for phytoextraction of heavy metal contaminated soils. The role of antioxidative enzyme of Phytolacca americana in response to Cd stress is unknown. The 6-week-old seedlings of Phytolacca americana were exposed to half strength Hoagland solution with 200 micromol/L CdCl2 or 400 micromol/L CdCl2 for 4 days. The content of H2O2 and MDA, and electrolyte leakage increased, while the photosynthetic rate decreased, indicated that the oxidative damage induced by Cd stress in Phytolacca americana was one of the metal toxicity mechanism. The activities of SOD and POD increased rapidly with elevated Cd concentration and exposure time, CAT activity was stable in response to 200 micromol/L CdCl2 stress, and increased only at 3 d later upon 400 micromol/L CdCl2, treatment. Suggested that the enzymatic antioxidation capacity played important role in Cd tolerance of hyperaccumulator plant.

Phytochelatin synthase of Thlaspi caerulescens enhanced tolerance and accumulation of heavy metals when expressed in yeast and tobacco.

Phytochelatin synthase (PCS) is key enzyme for heavy metal detoxification and accumulation in plant. In this study, we isolated the PCS gene TcPCS1 from the hyperaccumulator Thlaspi caerulescens. Overexpression of TcPCS1 enhanced PC production in tobacco. Cd accumulation in the roots and shoots of TcPCS1 transgenic seedlings was increased compared to the wild type (WT), while Cd translocation from roots to shoots was not affected under Cd treatment. The root length of the TcPCS1 transgenic tobacco seedlings was significantly longer than that of the WT under Cd stress. These data indicate that TcPCS1 expression might increase Cd accumulation and tolerance in transgenic tobacco. In addition, the malondialdehyde content in TcPCS1 plants was below that of the wild type. However, the antioxidant enzyme activities of superoxide dismutase, peroxidase and catalase were found to be significantly higher than those of the WT when the transgenic plant was exposed to Cd stress. This suggests that the increase in PC production might enhance the Cd accumulation and thus increase the oxidative stress induced by the cadmium. The production of PCs could cause a transient decrease in the cytosolic glutathione (GSH) pool, and Cd and lower GSH concentration caused an increase in the oxidative response. We also determined TcPCS1 in Thlaspi caerulescens was regulated after exposure to various concentrations of CdCl(2) over different treatment times. Expression of TcPCS1 leading to increased Cd accumulation and enhanced metal tolerance, but the Cd contents were restrained by adding zinc in Saccharomyces cerevisiae transformants.

[Antioxidative response of Phytolacca americana and Nicotiana tabacum to manganese stresses].

Plant species capable of accumulating heavy metals are of considerable interest for phytoremediation and phytomining. The mechanism of Mn tolerance/hyperaccumulate in Phytolacca americana L. is less known. To elucidate the role of antioxidative enzyme in response to Mn, the 6-week-old seedling of Mn hyperaccumulator P. americana and non-accumulator-tobacco (Nicotiana tabacum) were exposed to half strength Hoagland solution with 1 mmol x L(-1) or 3 mmol x L(-1) MnCl2 for 4 days. The photosynthetic rate in P. americana decreased more slowly than that in tobacco, while the MDA content and electrolyte leakage in tobacco increased more rapidly than that in P. americana. For example, after exposure to 1 mmol x L(-1) Mn for 4 days, the photosynthetic rates of P. americana and tobacco in comparison to the control reduced by 13.3% and 75.5%, respectively. The MDA content and electrolyte leakage in tobacco increased by 347.3% and 120.1%, respectively, whereas Mn had no marked effect on both of it in P. americana, indicated that the oxidative damage in tobacco was more serious than that in P. americana. The activities of SOD and POD of both species increased rapidly with elevated Mn concentration and exposure time in both species, the increase of SOD activity in P. americana was higher than that in tobacco. CAT activity in tobacco declined rapidly, while the activity of CAT in P. americana was increased. The activities of SOD, POD and CAT in P. americana upon 1 mmol x L(-1) Mn exposure increased by 161.1%, 111.3% and 17.5%, respectively. The activities of SOD and POD in tobacco increased by 55.5% and 206.0%, respectively, while CAT activity decreased by 15.6%, indicating that the antioxidative enzymes in P. americana, particularly in CAT,could fully scavenge the reactive oxygen species generated by Mn toxicity. These results collectively indicate that the enzymatic antioxidation capacity is one of the important mechanisms responsible for Mn tolerance in hyperaccumulator plant species.

Characterization of the novel gene BjDREB1B encoding a DRE-binding transcription factor from Brassica juncea L.

A novel DREB (dehydration responsive element binding protein) gene, designated BjDREB1B, was isolated from Brassica juncea L. BjDREB1B contains a conserved EREBP/AP2 domain and was classified into the A-1 subgroup of the DREB subfamily based on phylogenetic tree analysis. RT-PCR showed that BjDREB1B was induced by abiotic stresses and exogenous phytohormones, such as drought, salt, low temperature, heavy metals, abscisic acid, and salicylic acid. Gel shift assay revealed that BjDREB1B specifically bound to the DRE element in vitro. Yeast one-hybrid assay showed that full-length BjDREB1B or its C-terminal region functioned effectively as a trans-activator. Furthermore, overexpression of BjDREB1B in tobacco up-regulated the expression of NtERD10B, and BjDREB1B transgenic plants accumulated higher levels of proline than control plants under normal and saline conditions, together showing that BjDREB1B plays important roles in improving plant tolerance to drought and salinity.

BjDHNs confer heavy-metal tolerance in plants.

Dehydrin gene transcript could be induced by heavy metals, and some dehydrins possess the ability to bind metals. However, the correlation between dehydrins and heavy-metal stress is unknown. In order to elucidate the contribution of dehydrins to heavy-metal stress tolerance in plants, we cloned two SK(2)-type dehydrin genes from heavy-metal hyperaccumulator Brassica juncea, and investigated their Cd/Zn tolerance in transgenic plants. Semi-quantitative RT-PCR analysis revealed that BjDHN2/BjDHN3 expressed in the leaves, stems and roots at a low level and were up-regulated by heavy metals. Antisense BjDHN3 Brassica juncea plants showed more electrolyte leakage and higher malondialdehyde production than the control plants when exposed to heavy metals, and the total amount of metals accumulated in the whole plant was reduced. Transgenic tobacco plants overexpressing BjDHN2/BjDHN3 showed lower electrolyte leakage and malondialdehyde production than the control plants when exposed to Cd/Zn. These results indicated that BjDHN2/BjDHN3 enhanced the tolerance for heavy metals by reducing lipid peroxidation and maintaining membrane stability in the plants.

The bean PvSR2 gene produces two transcripts by alternative promoter usage.

The bean (Phaseolus vulgaris) stress-related gene number 2 (PvSR2) is heavy metal-inducible. Here, the intron of PvSR2 (I-PvSR) within the coding sequence was isolated and characterized. I-PvSR exhibited a weak and constitutive promoter activity and enhanced the PvSR2 promoter activity in transiently transformed tobacco protoplasts. The transcription start site of I-PvSR promoter was mapped 72 bp upstream of the 3'-splice site. The shorter PvSR2 transcript (768nt) in bean is generated from this intronic promoter and lacks the last 56 bases of 3'-end sequence of longer PvSR2 transcript (829nt) by utilizing an alternative polyadenylation site. Quantitative competitive PCR analysis further revealed that two transcripts were differently accumulated in response to Hg(2+)-exposure and the longer transcript was more abundant than the shorter one. These results demonstrate an additional non-metal inducible transcription of PvSR2 via alternative intronic promoter usage and provide new insights into expression mechanism of metal inducible gene.