Perioperative use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors for diabetes mellitus.

Type 2 diabetes mellitus is an increasingly common long-term condition, and suboptimal perioperative glycaemic control can lead to postoperative harms. The advent of new antidiabetic drugs, in particular glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors, has enabled perioperative continuation of these medicines, thus avoiding the harms of variable rate i.v. insulin infusions whilst providing glycaemic control. There are differences between medicines regulatory agencies and organisations on how these classes that are most often used to treat diabetes mellitus, (but also in the case of SGLT2 inhibitors chronic kidney disease and heart failure in those without diabetes) should be managed in the perioperative period. In this commentary, we argue that GLP-1 receptor agonists should continue during the perioperative period and that SGLT2 inhibitors should only be omitted the day prior to a planned procedure . The reasons for the differing advice advocated between regulatory agencies and what anaesthetic practitioners should do in the face of continuing uncertainty are discussed.

Managing hyperglycaemia during antenatal steroid administration, labour and birth in pregnant women with diabetes - an updated guideline from the Joint British Diabetes Society for Inpatient Care.

This article summarises the Joint British Diabetes Societies for Inpatient Care guidelines on the management of glycaemia in pregnant women with diabetes on obstetric wards and delivery units, Joint British Diabetes Societies (JBDS) for Inpatient Care Group, ABCD (Diabetes Care) Ltd. The updated guideline offers two approaches - the traditional approach with tight glycaemic targets (4.0-7.0 mmol/L) and an updated pragmatic approach (5.0-8.0 mmol/L) to reduce the risk of maternal hypoglycaemia whilst maintaining safe glycaemia. This is particularly relevant for women with type 1 diabetes who are increasingly using Continuous Glucose Monitoring (CGM) and Continuous Subcutaneous Insulin Infusion (CSII) during pregnancy. All women with diabetes should have a documented delivery plan agreed during antenatal clinic appointments. Hyperglycaemia following steroid administration can be managed either by increasing basal and prandial insulin doses, typically by 50% to 80%, or by adding a variable rate of intravenous insulin infusion (VRIII). Glucose levels, either capillary blood glucose or CGM glucose levels, should be measured at least hourly from the onset of established labour, artificial rupture of membranes or admission for elective caesarean section. If intrapartum glucose levels are higher than 7.0 or 8.0 mmol/L on two consecutive occasions, VRIII is recommended. Hourly capillary blood glucose rather than CGM glucose measurements should be used to adjust VRIII. The recommended substrate fluid to be administered alongside a VRIII is 0.9% sodium chloride solution with 5% glucose and 0.15% potassium chloride (KCl) (20 mmol/L) or 0.3% KCl (40 mmol/L) at 50 ml/hr. Both the VRIII and CSII rates should be reduced by at least 50% after delivery.

No place for routine use of modified-release opioids in postoperative pain management.

Modified-release opioid tablets were introduced into surgical practice in the belief that they provided superior pain relief and reduced nursing workload, and they rapidly became embedded into many perioperative pathways. Although national and international guidelines for the management of postoperative pain now advise against the use of modified-release opioids, they continue to be prescribed in many centres. Recognition that modified-release opioids show lack of benefit and increased risk of harm compared with immediate-release opioids in the acute, postoperative setting has become clear. Their slow onset and offset make rapid and safe titration of these opioids impossible, including down-titration as the patient recovers; pain relief may be less effective; they have been associated with an increased incidence of opioid-related adverse drug events, increased length of hospital stay, and higher readmission rates; and they lead to higher rates of opioid-induced ventilatory impairment and persistent postoperative opioid use. Evidence indicates that modified-release opioids should not be used routinely in the postoperative period.

Misappropriation of the 1986 WHO analgesic ladder: the pitfalls of labelling opioids as weak or strong.

Opioids have a vital role in alleviating pain from cancer and surgery. Despite good intentions, it is now recognised that the original WHO Cancer Pain Relief guidance from 1986, in which opioids were classified as either weak or strong, has been both inadvertently and purposefully misused, thereby contributing to harm from opioid use and misuse. However, the recommendation in the 2018 update of the WHO analgesic ladder that a combination of a high-potency opioid with simple analgesics is better than alternative analgesics for the maintenance of pain relief is also applicable to patients who require short-term opioids. Furthermore, because potential harm through opioid use and misuse is intrinsic to all opioids, whether weak or strong, we argue that the arbitrary classification of opioids either as weak or strong should be discontinued, as this description is not helpful to either prescribers or consumers.

Utility of unidimensional and functional pain assessment tools in adult postoperative patients: a systematic review.

BACKGROUND: We aimed to appraise the evidence relating to the measurement properties of unidimensional tools to quantify pain after surgery. Furthermore, we wished to identify the tools used to assess interference of pain with functional recovery. METHODS: Four electronic sources (MEDLINE, Embase, CINAHL, PsycINFO) were searched in August 2020. Two reviewers independently screened articles and assessed risk of bias using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. RESULTS: Thirty-one studies with a total of 12 498 participants were included. Most of the studies failed to meet the methodological quality standards required by COSMIN. Studies of unidimensional assessment tools were underpinned by low-quality evidence for reliability (five studies), and responsiveness (seven studies). Convergent validity was the most studied property (13 studies) with moderate to high correlation ranging from 0.5 to 0.9 between unidimensional tools. Interpretability results were available only for the visual analogue scale (seven studies) and numerical rating scale (four studies). Studies on functional assessment tools were scarce; only one study included an 'Objective Pain Score,' a tool assessing pain interference with respiratory function, and it had low-quality for convergent validity. CONCLUSIONS: This systematic review challenges the validity and reliability of unidimensional tools in adult patients after surgery. We found no evidence that any one unidimensional tool has superior measurement properties in assessing postoperative pain. In addition, because promoting function is a crucial perioperative goal, psychometric validation studies of functional pain assessment tools are needed to improve pain assessment and management. CLINICAL TRIAL REGISTRATION: PROSPERO CRD42020213495.

System-level policies on appropriate opioid use, a multi-stakeholder consensus.

BACKGROUND: This consensus statement was developed because there are concerns about the appropriate use of opioids for acute pain management, with opposing views in the literature. Consensus statement on policies for system-level interventions may help inform organisations such as management structures, government agencies and funding bodies. METHODS: We conducted a multi-stakeholder survey using a modified Delphi methodology focusing on policies, at the system level, rather than at the prescriber or patient level. We aimed to provide consensus statements for current developments and priorities for future developments. RESULTS: Twenty-five experts from a variety of fields with experience in acute pain management were invited to join a review panel, of whom 23 completed a modified Delphi survey of policies designed to improve the safety and quality of opioids prescribing for acute pain in the secondary care setting. Strong agreement, defined as consistent among> 75% of panellists, was observed for ten statements. CONCLUSIONS: Using a modified Delphi study, we found agreement among a multidisciplinary panel, including patient representation, on prioritisation of policies for system-level interventions, to improve governance, pain management, patient/consumers care, safety and engagement.

Surgery and opioids: evidence-based expert consensus guidelines on the perioperative use of opioids in the United Kingdom.

There are significant concerns regarding prescription and misuse of prescription opioids in the perioperative period. The Faculty of Pain Medicine at the Royal College of Anaesthetists have produced this evidence-based expert consensus guideline on surgery and opioids along with the Royal College of Surgery, Royal College of Psychiatry, Royal College of Nursing, and the British Pain Society. This expert consensus practice advisory reproduces the Faculty of Pain Medicine guidance. Perioperative stewardship of opioids starts with judicious opioid prescribing in primary and secondary care. Before surgery, it is important to assess risk factors for continued opioid use after surgery and identify those with chronic pain before surgery, some of whom may be taking opioids. A multidisciplinary perioperative care plan that includes a prehabilitation strategy and intraoperative and postoperative care needs to be formulated. This may need the input of a pain specialist. Emphasis is placed on optimum management of pain pre-, intra-, and postoperatively. The use of immediate-release opioids is preferred in the immediate postoperative period. Attention to ensuring a smooth care transition and communication from secondary to primary care for those taking opioids is highlighted. For opioid-naive patients (patients not taking opioids before surgery), no more than 7 days of opioid prescription is recommended. Persistent use of opioid needs a medical evaluation and exclusion of chronic post-surgical pain. The lack of grading of the evidence of each individual recommendation remains a major weakness of this guidance; however, evidence supporting each recommendation has been rigorously reviewed by experts in perioperative pain management.

Knockout of a difficult-to-remove CHO host cell protein, lipoprotein lipase, for improved polysorbate stability in monoclonal antibody formulations.

While the majority of host cell protein (HCP) impurities are effectively removed in typical downstream purification processes, a small population of HCPs are particularly challenging. Previous studies have identified HCPs that are challenging for a variety of reasons. Lipoprotein lipase (LPL)-a Chinese hamster ovary (CHO) HCP that functions to hydrolyze esters in triglycerides-was one of ten HCPs identified in previous studies as being susceptible to retention in downstream processing. LPL may degrade polysorbate 80 (PS-80) and polysorbate 20 (PS-20) in final product formulations due to the structural similarity between polysorbates and triglycerides. In this work, recombinant LPL was found to have enzymatic activity against PS-80 and PS-20 in a range of solution conditions that are typical of mAb formulations. LPL knockout CHO cells were created with CRISPR and TALEN technologies and resulting cell culture harvest fluid demonstrated significantly reduced polysorbate degradation without significant impact on cell viability when compared to wild-type samples. Biotechnol. Bioeng. 2017;114: 1006-1015. © 2016 Wiley Periodicals, Inc.

Host cell protein impurities in chromatographic polishing steps for monoclonal antibody purification.

Downstream purification of monoclonal antibodies (mAbs) is normally performed using a platform process that is empirically tuned to optimize impurity removal for each new product. A more fundamental understanding of impurities and the product itself would provide insights into the rational design of efficient downstream processes. This work examines the chromatographic properties of Chinese hamster ovary host cell protein (HCP) impurities in non-affinity chromatographic resins commonly used in polishing steps for monoclonal antibody purification: ion-exchange, hydrophobic interaction, and multimodal. Using proteomic analysis, the specific HCP impurities that elute close to mAb products are identified for these resins at typical downstream processing conditions. Additionally, the interactions of HCP impurities with mAb products are profiled to determine the total extent of product association and the specific HCP species that form associative complexes under conditions encountered in polishing columns. Product association and co-elution were both identified as viable mechanisms of HCP retention for the non-affinity resins tested here. A relatively large sub-population of HCP impurities was found to co-elute or associate with mAbs in each polishing column, but only a small population of HCPs-including lipoprotein lipase, chrondroitin sulfate proteoglycan 4, nidogen-1, and SPARC-were identified as difficult to remove across an entire downstream mAb process. Biotechnol. Bioeng. 2016;113: 1260-1272. © 2015 Wiley Periodicals, Inc.

The impact of glycaemic variability on the surgical patient.

PURPOSE OF REVIEW: Diabetes is the most prevalent long-term metabolic condition and its incidence continues to increase unabated. Patients with diabetes are overrepresented in the surgical population. It has been well recognized that poor perioperative diabetes control is associated with poor surgical outcomes. The outcomes are worst for those people who were not recognized as having hyperglycaemia. RECENT FINDINGS: Recent work has shown that preoperative recognition of diabetes and good communication between the clinical teams at all stages of the patient pathway help to minimize the potential for errors, and improve glycaemic control. The stages of the patient journey start in primary care and end when the patient goes home. The early involvement of the diabetes specialist team is important if the glycated haemoglobin is more than 8.5%, and advice sought if the preoperative assessment team is not familiar with the drug regimens. To date the glycaemic targets for the perioperative period have remained uncertain, but recently a consensus is being reached to ensure glucose levels remain between 108 and180 mg/dl (6.0 and 10.0 mmol/l). There have been a number of ways to achieve these - primarily by manipulating the patients' usual diabetes medications, to also allow day of surgery admission. SUMMARY: glycaemic control remains an important consideration in the surgical patient.

Identification and characterization of host cell protein product-associated impurities in monoclonal antibody bioprocessing.

Downstream processing of monoclonal antibodies (mAbs) has evolved to allow the specific process for a new product to be developed largely by empirical specialization of a platform process that enables removal of impurities of different kinds. A more complete characterization of impurities and the product itself would provide insights into the rational design of efficient downstream processes. This work identifies and characterizes host cell protein (HCP) product-associated impurities, that is, HCP species carried through the downstream processes via direct interactions with the mAb. Interactions between HCPs and mAbs are characterized using cross-interaction chromatography under solution conditions typical of those used in downstream processing. The interacting species are then identified by two-dimensional gel electrophoresis and mass spectrometry. This methodology has been applied to identify product-associated impurities in one particular purification step, namely protein A affinity chromatography, for four therapeutic mAbs as well as the Fab and Fc domains of one of these mAbs. The results show both the differences in HCP-mAb interactions among different mAbs, and the relative importance of product association compared to co-elution in protein A affinity chromatography.