Pharmacologic methods to minimise coughing during extubation in the era of COVID-19.

BACKGROUND/AIM: Given the current severe acute respiratory syndrome coronavirus 2 pandemic, coughing at the time of extubation is at risk of creating aerosolisation. This may place health care workers at risk of nosocomial infection during the perioperative period. This study aims to summarise the current pharmacologic methods to minimise cough at the time of extubation, and to determine whether some strategies could be more beneficial than others. METHODS: This is a summary of systematic reviews. A comprehensive search through MEDLINE was performed. Thirty-three publications were screened for eligibility. Only the manuscripts discussing pharmacologic methods to minimise coughing on extubation were included in this review. FINDINGS: Many pharmacological agents have been proposed to decrease the incidence of cough at the time of extubation. Of these, intravenous administration of dexmedetomidine (relative risk 0.4; 95% CI: 0.4-0.5) or remifentanil (RR 0.4; 95% CI: 0.4-0.5) seems to have the largest effect to reduce cough on extubation. CONCLUSION: The available data in the current literature is sparse. Yet, dexmedetomidine and remifentanil seem to be the most efficient agents to decrease the incidence of emergence coughing.

Functional capacity of prediabetic patients: effect of multimodal prehabilitation in patients undergoing colorectal cancer resection.

BACKGROUND: Prehabilitation is the process of increasing functional capacity (FC) before surgery. Poor glycemic control is associated with worse outcomes in patients undergoing surgery. Therefore, prediabetic patients could particularly benefit from prehabilitation. METHODS: This is a pooled analysis of individual patient data from three multimodal prehabilitation trials in colorectal cancer surgery. Following a baseline assessment using the 6-minute walking test (6MWT), subjects were randomized to multimodal prehabilitation or to a control group. Participants were reassessed 24 h before surgery and 4 weeks after surgery. Prediabetes (PreDM) was defined as HbA1c 5.7%-6.4%. Multivariable logistic regression was used to adjust for potentially confounding variables. RESULTS: Participation in a prehabilitation program was the most important predictive factor of clinical improvement in FC prior to surgery (Adjusted OR 2.42, 95% CI 1.18, 4.94); prediabetes was not a statistically significant predictor of improvement in FC after adjustments for covariates. Prehabilitation attenuated the loss of FC in unadjusted analyses after surgery in prediabetic patients (PreDM Control: median change -6 m [IQR -50-20] vs PreDM Prehab: median change +25 m [IQR -20-53], p = 0.045). Adjusted analyses also suggested the protective effect against loss of FC after surgery was stronger in prediabetic patients (PreDM Prehab vs PreDM Control: OR 5.5, 95% CI: 1.2-25.8; Normo Prehab vs Normo Control: OR 1.5, 95% CI: 0.53-4.52). CONCLUSIONS: Multimodal prehabilitation favored clinical recovery of FC after surgery in CRC patients, especially prediabetic patients.

Prehabilitation: metabolic considerations.

PURPOSE OF REVIEW: The major components of ERAS attenuate the inflammatory response and modulate metabolism in direction of sparing body protein and preserving function. However, these perioperative interventions might have limited effectiveness on postoperative outcomes if preoperative risk factors are not addressed and optimized. RECENT FINDINGS: The preoperative metabolic perturbations characterized by insulin resistance and sarcopenia might predispose patients to a higher degree of postoperative catabolism. High-risk populations for such metabolic disturbances include elderly and frail patients, and patients with metabolic syndrome. Research on the effect of prehabilitation on perioperative metabolism is limited, but recent findings suggest that interventions designed to improve insulin sensitivity prior to surgery might represent a promising therapeutic target to minimize surgical complications. SUMMARY: The present paper will discuss the metabolic implications of modulating preoperative risk factors with elements of multimodal prehabilitation, such as exercise training and nutrition.

Intravenous catheters induce a local inflammatory response.

AIM: Chronic inflammation has been associated to the development of cardiometabolic dysfunctions. The use of an intravenous (IV) catheter is highly recommended for physiology testing. Yet, the presence of an IV catheter triggers local inflammation that does not reflect systemic inflammatory status. The aim of this study was to assess the effect of an IV catheter on serum concentrations of IL-6, IL-8 and hsCRP in a fasting state and after a high-fat meal known to trigger low-grade inflammation. METHODS: Twenty-two healthy subjects (7 men, 15 women) were included in this study. The trial included 2 visits. After an overnight fast, a venous catheter was inserted into an antecubital vein. A first blood sample was collected through this catheter at T = 0 min. On each visit, participants were requested either to drink only water for the whole duration of the test (WO test), or to consume a high-fat meal (HFM). Blood samples were collected through the catheter at T60, T120, T180 and T300 min. Additional venous punctures were performed on the contralateral arm at T180 and T300 min. Serum inflammatory mediators were measured at each time point of both interventions. RESULTS: When serum was collected by venous punctures, IL-6 concentrations remained unchanged during both WO and HFM tests (Ptime = 0.15 and Ptime = 0.23, respectively), whereas the concentrations increased progressively over time when serum was collected through the catheter (Ptime < 0.001). The high-fat meal had no additional effect on IL-6 levels (Pmeal = 0.27) neither in serum collected by venous puncture nor in serum collected through the catheter. Serum IL-8 and hsCRP concentrations did not vary over time, and were influenced neither by the meal type nor by the blood collection method. CONCLUSION: The insertion of an indwelling catheter is associated with a local inflammatory response possibly mediated by IL-6 but not IL-8. This inflammatory response was not enhanced by a pro-inflammatory high-fat meal.

Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics.

BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that interacts with the low-density lipoprotein (LDL) receptor at the surface of hepatocytes to regulate circulating LDL cholesterol levels. High circulating PCSK9 levels have been associated with elevated LDL cholesterol. Recently, the Food and Drug Administration of the United States approved new LDL cholesterol-lowering drugs that specifically target the inhibition of PCSK9. Similar to most human proteins, PCSK9 exists in multiple forms as it is the target of posttranslational modifications (PTMs) such as proteolytic cleavage, phosphorylation, and others, which can affect its biological activity. However, commercially available assays, such as enzyme-linked immunosorbent assays, do not discriminate between these forms. OBJECTIVE: To investigate, in 2 patient cohorts, the relationships between circulating levels of multiple forms of PCSK9 and cardiometabolic interventions or treatments known to reduce LDL cholesterol levels. METHODS: PCSK9 forms were measured in plasma: (1) in 20 patients before and 6 months after bariatric surgery and (2) in 132 patients before and 12 months after daily statin treatment. A series of specific peptides used as surrogates for various PCSK9 forms were quantified by a novel semiautomated proteomic assay termed protein affinity capture coupled to quantitative mass spectrometry. RESULTS: Bariatric surgery resulted in a decrease in the plasma level of PCSK9 prodomain (P < .05), but did not result in a significant change in other measured PCSK9 forms. Statin treatment resulted in an increase in all measured plasma PCSK9 peptides (P < .001), but a 25% decrease in the phosphorylated state of PCSK9 at S688 (P < .05). CONCLUSIONS: These unexpected findings indicate that measuring the circulating levels of the various domains and PTMs of PCSK9 provides more in depth information than total PCSK9 and that the prodomain and the phosphorylated state of S688 may represent novel biomarkers to explore in cardiometabolic diseases and response to treatment. In addition, our data generated new hypotheses on the function of PCSK9 PTMs in health and disease.

Relative contribution of muscle and liver insulin resistance to dysglycemia in postmenopausal overweight and obese women: A MONET group study.

OBJECTIVES: The relative contribution of muscle and liver insulin resistance (IR) in the development of dysglycemia and metabolic abnormalities is difficult to establish. The present study aimed to investigate the relative contribution of muscle IR vs. liver IR to dysglycemia in non-diabetic overweight or obese postmenopausal women and to determine differences in body composition and cardiometabolic indicators associated with hepatic or muscle IR. MATERIAL AND METHODS: Secondary analysis of 156 non-diabetic overweight or obese postmenopausal women. Glucose tolerance was measured using an oral glucose tolerance test. Whole-body insulin sensitivity (IS) was determined as glucose disposal rate during a euglycemic-hyperinsulinemic clamp. Muscle and liver IR have been calculated using Abdul-Ghani et al. OGTT-derived formulas. Participant's body compositions as well as cardiometabolic risk indicators were also determined. RESULTS: Overall, 57 (36.5%) of patients had dysglycemia, among them 25 (16.0%); 21 (13.5%); 11 (7.1%) had impaired fasting glycemia, impaired glucose tolerance and combined glucose intolerance respectively. Fifty-three (34.0%) participants were classified as combined IS while on the opposite 51 participants (32.7%) were classified as combined IR and 26 (16.7%) participants had either muscle IR or liver IR. For similar body mass index and total fat mass, participants with liver IR were more likely to have lower whole-body IS, dysglycemia and higher visceral fat, liver fat index, triglycerides and alanine aminotransferase than participants with muscle IR. CONCLUSION: In the present study, the presence of liver IR is associated with a higher prevalence of dysglycemia, ectopic fat accumulation and metabolic abnormalities than muscle IR.

Glucose Fluctuations are Not Modulated by the Proportion of Calories from Macronutrients or Spontaneous Total Energy Expenditure in Adults with Cystic Fibrosis.

OBJECTIVES: To determine the modifiable factors affecting glucose variability in people with cystic fibrosis (CF). CF-related diabetes (CFRD) is the most common complication of CF, and its presence increases morbidity and mortality in patients. Patients with CF (with and without CFRD) have potentially harmful glucose fluctuations and glucose excursions when compared to healthy adults. Carbohydrate intake and exercise have been shown to affect glycemia. Therefore, our hypothesis was that the proportion of energy from carbohydrates and total energy expenditure (TEE) would influence glucose fluctuations in adults with CF. METHODS: A cross-sectional study involved 36 patients with CF, in whom continuous glucose monitoring systems were installed. Glucose fluctuations were then quantified using 3 indexes: mean amplitude of glucose excursions, standard deviation and coefficient of variation. Patients filled out a 3-day food diary to quantify energy intake and the proportions of calories from carbohydrates, fats and proteins, and they wore Sensewear Armbands to estimate spontaneous TEE and footsteps walked. Glucose tolerance status was determined using oral glucose tolerance tests. RESULTS: Patients with CF with normal and impaired glucose tolerance had fewer glucose fluctuations than patients with CFRD (p<0.05). However, linear regression models used to determine whether nutrition or energy expenditure affects glucose fluctuations demonstrated that energy, the proportion of carbohydrates, of fat and of protein, TEE or the number of footsteps walked did not affect glucose fluctuation indexes (p>0.05). CONCLUSIONS: TEE and the proportion of energy from carbohydrates did not affect glucose fluctuations in adults with CF.

A semi-automated mass spectrometric immunoassay coupled to selected reaction monitoring (MSIA-SRM) reveals novel relationships between circulating PCSK9 and metabolic phenotypes in patient cohorts.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of circulating low density lipoprotein cholesterol (LDL-C) levels. Besides its full-length mature form, multiple variants of PCSK9 have been reported such as forms that are truncated, mutated and/or with posttranslational modifications (PTMs). Previous studies have demonstrated that most of these variants affect PCSK9's function and thereby LDL-C levels. Commercial ELISA kits are available for quantification of PCSK9, but do not allow discrimination between the various forms and PTMs of the protein. To address this issue and given the complexity and wide dynamic range of the plasma proteome, we have developed a mass spectrometric immunoassay coupled to selected reaction monitoring (MSIA-SRM) for the multiplexed quantification of several forms of circulating PCSK9 in human plasma. Our MSIA-SRM assay quantifies peptides spanning the various protein domains and the S688 phosphorylation site. The assay was applied in two distinct cohorts of obese patients and healthy pregnant women stratified by their circulating LDL-C levels. Seven PCSK9 peptides were monitored in plasma samples: one in the prodomain prior to the autocleavage site at Q152, one in the catalytic domain prior to the furin cleavage site at R218, two in the catalytic domain following R218, one in the cysteine and histidine rich domain (CHRD) and the C-terminal peptide phosphorylated at S688 and unmodified. The latter was not detectable in sufficient amounts to be quantified in human plasma. All peptides were measured with high reproducibility and with LLOQ and LOD below the clinical range. The abundance of 5 of the 6 detectable PCSK9 peptides was higher in obese patients stratified with high circulating LDL-C levels as compared to those with low LDL-C (p < 0.05). The same 5 peptides showed good and statistically significant correlations with LDL-C levels (0.55 < r < 0.65; 0.0002 ⩽ p ⩽ 0.002), but not the S688 phosphorylated peptide. However, this phosphopeptide was significantly correlated with insulin resistance (r = 0.48; p = 0.04). In the pregnant women cohort, none of the peptides were associated to LDL-C levels. However, the 6 detectable PCSK9 peptides, but not PCSK9 measured by ELISA, were significantly correlated with serum triglyceride levels in this cohort. Our results also suggest that PCSK9 circulates with S688 phosphorylated at high stoichiometry. In summary, we have developed and applied a robust and sensitive MSIA-SRM assay for the absolute quantification of all PCSK9 domains and a PTM in human plasma. This assay revealed novel relationships between PCSK9 and metabolic phenotypes, as compared to classical ELISA assays.