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Frontiers in Endocrinology 2023Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of... (Review)
Review
AIMS/HYPOTHESIS
Glucagon-like peptide 1 (GLP-1) agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors are novel drugs which have recently seen rapid uptake in the treatment of type 2 diabetes and obesity. The paucity of data regarding their safety during pregnancy and lactation causes a dilemma for the physician. The aim of the present study was to systematically review all available data on the offspring effects of GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation.
METHODS
We systematically searched PubMed, clinicaltrials.gov, FDA and EMA product information on GLP-1 agonists and SGLT2 inhibitors in pregnancy and lactation from inception up to 19 April 2022 without language restrictions. We approached both the Netherlands Pharmacovigilance Centre Lareb on January 17 2023 and the Teratology Information Service (TIS) of Switzerland on February 6 2023. Eligible studies investigating the safety (including congenital anomalies, fetal growth, perinatal demise) in animals or humans, or reporting the degree of transfer of these drugs to the fetus, breast milk or breastfed neonate. Two reviewers independently assessed and selected studies for inclusion and subsequently resolved discrepancies by discussion.
RESULTS
We included 39 records (n=9 theoretical; based on drug properties, n=7 human; n=23 animal, including 76 human offspring, and an unknown number of animal offspring as these numbers could not be retrieved from the FDA and EMA product information). In animal studies, GLP1-agonists were associated with reduced fetal weight and/or growth, delayed ossification and skeletal variants, usually associated with a reduction in maternal weight gain and decreased food consumption. Exendin-4 (GLP1-agonist) was not transported across the maternal-fetal placental interface. In human studies, exenatide (GLP1-agonist) showed a fetal-to-maternal peptide concentration ratio of ≤ 0.017 in ex vivo human placental perfusion in a single placenta. Liraglutide (GLP1-agonist) showed no significant maternal to fetal transfer at least 3.5 hours after maternal exposure in a human study with one subject. In animal studies, GLP-1 agonists were excreted in breast milk; human data on excretion were not available. In animal studies, SGLT2 inhibitors were generally safe during the first trimester but exposure during postnatal day 21 to 90 in juvenile rats, a period coinciding with the late second and third trimester of human renal development, caused dilatation of the renal pelvis and tubules. Human data consisted of a pharmaceutical database of inadvertent pregnancies during SGLT2 inhibitor use, which found an increase in miscarriages and congenital malformations. In animal studies SGLT2 inhibitors were excreted in breast milk and affected neonatal growth, but human data are not available.
CONCLUSION/INTERPRETATION
We found evidence for adverse offspring effects of GLP-1 agonists and SGLT2 inhibitors also in human studies. Our findings broadly support the advice to discontinue GLP-1 agonists and SGLT2 inhibitors during pregnancy and lactation, and also support the ongoing registration of pregnancy outcomes in pharmacological databases since the amount of available data is scarce and mostly limited to animal studies.
REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=219877.
Topics: Female; Humans; Pregnancy; Rats; Animals; Sodium-Glucose Transporter 2 Inhibitors; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Breast Feeding; Placenta; Exenatide; Liraglutide; Lactation
PubMed: 37881498
DOI: 10.3389/fendo.2023.1215356 -
Critical Care (London, England) Sep 2023Cardiac surgery-associated acute kidney injury (CSA-AKI) is frequent. While two network meta-analyses assessed the impact of pharmacological interventions to prevent... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cardiac surgery-associated acute kidney injury (CSA-AKI) is frequent. While two network meta-analyses assessed the impact of pharmacological interventions to prevent CSA-AKI, none focused on non-pharmacological interventions. We aim to assess the effectiveness of non-pharmacological interventions to reduce the incidence of CSA-AKI.
METHODS
We searched PubMed, Embase, Central and clinical trial registries from January 1, 2004 (first consensus definition of AKI) to July 1, 2023. Additionally, we conducted manual screening of abstracts of major anesthesia and intensive care conferences over the last 5 years and reference lists of relevant studies. We selected all randomized controlled trials (RCTs) assessing a non-pharmacological intervention to reduce the incidence of CSA-AKI, without language restriction. We excluded RCTs of heart transplantation or involving a pediatric population. The primary outcome variable was CSA-AKI. Two reviewers independently identified trials, extracted data and assessed risk of bias. Random-effects meta-analyses were conducted to calculate risk ratios (RRs) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence.
RESULTS
We included 86 trials (25,855 patients) evaluating 10 non-pharmacological interventions to reduce the incidence of CSA-AKI. No intervention had high-quality evidence to reduce CSA-AKI. Two interventions were associated with a significant reduction in CSA-AKI incidence, with moderate quality of evidence: goal-directed perfusion (RR, 0.55 [95% CI 0.40-0.76], I = 0%; P = 0.44) and remote ischemic preconditioning (RR, 0.86 [0.78-0.95]; I = 23%; P = 0.07). Pulsatile flow during cardiopulmonary bypass was associated with a significant reduction in CSA-AKI incidence but with very low quality of evidence (RR = 0.69 [0.48; 0.99]; I = 53%; P < 0.01). We found high quality of evidence for lack of effect of restrictive transfusion strategy (RR, 1.02 [95% CI 0.92; 1.12; P = 0.67; I = 3%) and tight glycemic control (RR, 0.86 [95% CI 0.55; 1.35]; P = 0.25; I = 26%).
CONCLUSIONS
Two non-pharmacological interventions are likely to reduce CSA-AKI incidence, with moderate quality of evidence: goal-directed perfusion and remote ischemic preconditioning.
Topics: Child; Humans; Cardiac Surgical Procedures; Acute Kidney Injury; Anesthesia; Anesthesiology; Cardiopulmonary Bypass
PubMed: 37700297
DOI: 10.1186/s13054-023-04640-1 -
The Cochrane Database of Systematic... Sep 2023Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The... (Review)
Review
BACKGROUND
Liver transplantation is the only chance of cure for people with end-stage liver disease and some people with advanced liver cancers or acute liver failure. The increasing prevalence of these conditions drives demand and necessitates the increasing use of donated livers which have traditionally been considered suboptimal. Several novel machine perfusion preservation technologies have been developed, which attempt to ameliorate some of the deleterious effects of ischaemia reperfusion injury. Machine perfusion technology aims to improve organ quality, thereby improving outcomes in recipients of suboptimal livers when compared to traditional static cold storage (SCS; ice box).
OBJECTIVES
To evaluate the effects of different methods of machine perfusion (including hypothermic oxygenated machine perfusion (HOPE), normothermic machine perfusion (NMP), controlled oxygenated rewarming, and normothermic regional perfusion) versus each other or versus static cold storage (SCS) in people undergoing liver transplantation.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search date was 10 January 2023.
SELECTION CRITERIA
We included randomised clinical trials which compared different methods of machine perfusion, either with each other or with SCS. Studies comparing HOPE via both hepatic artery and portal vein, or via portal vein only, were grouped. The protocol detailed that we also planned to include quasi-randomised studies to assess treatment harms.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were 1. overall participant survival, 2. quality of life, and 3. serious adverse events. Secondary outcomes were 4. graft survival, 5. ischaemic biliary complications, 6. primary non-function of the graft, 7. early allograft function, 8. non-serious adverse events, 9. transplant utilisation, and 10. transaminase release during the first week post-transplant. We assessed bias using Cochrane's RoB 2 tool and used GRADE to assess certainty of evidence.
MAIN RESULTS
We included seven randomised trials (1024 transplant recipients from 1301 randomised/included livers). All trials were parallel two-group trials; four compared HOPE versus SCS, and three compared NMP versus SCS. No trials used normothermic regional perfusion. When compared with SCS, it was uncertain whether overall participant survival was improved with either HOPE (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.42 to 1.98; P = 0.81, I = 0%; 4 trials, 482 recipients; low-certainty evidence due to imprecision because of low number of events) or NMP (HR 1.08, 95% CI 0.31 to 3.80; P = 0.90; 1 trial, 222 recipients; very low-certainty evidence due to imprecision and risk of bias). No trials reported quality of life. When compared with SCS alone, HOPE was associated with improvement in the following clinically relevant outcomes: graft survival (HR 0.45, 95% CI 0.23 to 0.87; P = 0.02, I = 0%; 4 trials, 482 recipients; high-certainty evidence), serious adverse events in extended criteria DBD liver transplants (OR 0.45, 95% CI 0.22 to 0.91; P = 0.03, I = 0%; 2 trials, 156 participants; moderate-certainty evidence) and clinically significant ischaemic cholangiopathy in recipients of DCD livers (OR 0.31, 95% CI 0.11 to 0.92; P = 0.03; 1 trial, 156 recipients; high-certainty evidence). In contrast, NMP was not associated with improvement in any of these clinically relevant outcomes. NMP was associated with improved utilisation compared with SCS (one trial found a 50% lower rate of organ discard; P = 0.008), but the reasons underlying this effect are unknown. We identified 11 ongoing studies investigating machine perfusion technologies.
AUTHORS' CONCLUSIONS
In situations where the decision has been made to transplant a liver donated after circulatory death or donated following brain death, end-ischaemic HOPE will provide superior clinically relevant outcomes compared with SCS alone. Specifically, graft survival is improved (high-certainty evidence), serious adverse events are reduced (moderate-certainty evidence), and in donors after circulatory death, clinically relevant ischaemic biliary complications are reduced (high-certainty evidence). There is no good evidence that NMP has the same benefits over SCS in terms of these clinically relevant outcomes. NMP does appear to improve utilisation of grafts that would otherwise be discarded with SCS; however, the reasons for this, and whether this effect is specific to NMP, is not clear. Further studies into NMP viability criteria and utilisation, as well as head-to-head trials with other perfusion technologies are needed. In the setting of donation following circulatory death transplantation, further trials are needed to assess the effect of these ex situ machine perfusion methods against, or in combination with, normothermic regional perfusion.
Topics: Humans; Liver Transplantation; Quality of Life; Perfusion; End Stage Liver Disease
PubMed: 37698189
DOI: 10.1002/14651858.CD014685.pub2 -
The Journal of Surgical Research Dec 2023Heart transplantation is the treatment of choice for end-stage heart failure. There is a mismatch between the number of donor hearts available and the number of patients... (Review)
Review
INTRODUCTION
Heart transplantation is the treatment of choice for end-stage heart failure. There is a mismatch between the number of donor hearts available and the number of patients awaiting transplantation. Expanding the donor pool is critically important. The use of hearts donated following circulatory death is one approach to increasing the number of available donor hearts.
MATERIALS AND METHODS
A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines utilizing Pubmed/MEDLINE and Embase. Articles including adult human studies and preclinical animal studies of heart transplantation following donation after circulatory death were included. Studies of pediatric populations or including organs other than heart were excluded.
RESULTS
Clinical experience and preclinical studies are reviewed. Clinical experience with direct procurement, normothermic regional perfusion, and machine perfusion are included. Preclinical studies addressing organ function assessment and enhancement of performance of marginal organs through preischemic, procurement, preservation, and reperfusion maneuvers are included. Articles addressing the ethical considerations of thoracic transplantation following circulatory death are also reviewed.
CONCLUSIONS
Heart transplantation utilizing organs procured following circulatory death is a promising method to increase the donor pool and offer life-saving transplantation to patients on the waitlist living with end-stage heart failure. There is robust ongoing preclinical and clinical research to optimize this technique and improve organ yield. There are also ongoing ethical considerations that must be addressed by consensus before wide adoption of this approach.
PubMed: 37657140
DOI: 10.1016/j.jss.2023.07.050 -
Hepatology (Baltimore, Md.) Sep 2023Acute cellular rejection (ACR) is a frequent complication after liver transplantation. By reducing ischemia and graft damage, dynamic preservation techniques may... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Acute cellular rejection (ACR) is a frequent complication after liver transplantation. By reducing ischemia and graft damage, dynamic preservation techniques may diminish ACR. We performed a systematic review to assess the effect of currently tested organ perfusion (OP) approaches versus static cold storage (SCS) on post-transplant ACR-rates.
APPROACH AND RESULTS
A systematic search of Medline, Embase, Cochrane Library, and Web of Science was conducted. Studies reporting ACR-rates between OP and SCS and comprising at least 10 liver transplants performed with either hypothermic oxygenated perfusion (HOPE), normothermic machine perfusion, or normothermic regional perfusion were included. Studies with mixed perfusion approaches were excluded. Eight studies were identified (226 patients in OP and 330 in SCS). Six studies were on HOPE, one on normothermic machine perfusion, and one on normothermic regional perfusion. At meta-analysis, OP was associated with a reduction in ACR compared with SCS [OR: 0.55 (95% CI, 0.33-0.91), p =0.02]. This effect remained significant when considering HOPE alone [OR: 0.54 (95% CI, 0.29-1), p =0.05], in a subgroup analysis of studies including only grafts from donation after cardiac death [OR: 0.43 (0.20-0.91) p =0.03], and in HOPE studies with only donation after cardiac death grafts [OR: 0.37 (0.14-1), p =0.05].
CONCLUSIONS
Dynamic OP techniques are associated with a reduction in ACR after liver transplantation compared with SCS. PROSPERO registration: CRD42022348356.
Topics: Humans; Liver Transplantation; Organ Preservation; Perfusion; Graft Rejection; Death; Liver; Graft Survival
PubMed: 36988381
DOI: 10.1097/HEP.0000000000000363 -
Ultrasound in Medicine & Biology Sep 2023The aim of the work described here was to provide an evidence-based evaluation of contrast-enhanced ultrasonography (CEUS) in acute kidney injury (AKI) and assess... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
The aim of the work described here was to provide an evidence-based evaluation of contrast-enhanced ultrasonography (CEUS) in acute kidney injury (AKI) and assess variations in renal microperfusion with CEUS quantitative parameters in patients at a high risk of developing AKI.
METHODS
A meta-analysis and systematic review were conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the Embase, MEDLINE, Web of Science and the Cochrane Library databases were used to search the relevant articles systematically (2000-2022). Studies using CEUS to assess renal cortical microcirculation in AKI were included.
RESULTS
Six prospective studies (374 patients) were included. The overall quality of included studies was moderate to high. CEUS measures, maximum intensity (standard mean difference [SMD]: -1.37, 95% confidence interval [CI]: -1.64 to -1.09) and wash-in rate (SMD: -0.77, 95% CI: -1.09 to -0.45) were lower in the AKI+ group than in the AKI- group, and mean transit time (SMD: 0.76, 95% CI: 0.11-1.40) and time to peak (SMD: 1.63, 95% CI: 0.99-2.27) were higher in the AKI+ group. Moreover, maximum intensity and wash-in rate values changed before creatinine changed in the AKI+ group.
CONCLUSION
Patients with AKI had reduced microcirculatory perfusion, prolonged perfusion time and a reduced rising slope in the renal cortex, which occurred before serum creatinine changes. And they could be measured using CEUS, indicating that CEUS could help in the diagnosis of AKI.
Topics: Humans; Prospective Studies; Microcirculation; Acute Kidney Injury; Kidney; Ultrasonography; Contrast Media
PubMed: 37391293
DOI: 10.1016/j.ultrasmedbio.2023.06.002 -
Fluids and Barriers of the CNS Dec 2023The neurovascular unit (NVU) is a complex structure that facilitates nutrient delivery and metabolic waste clearance, forms the blood-brain barrier (BBB), and supports... (Review)
Review
The neurovascular unit (NVU) is a complex structure that facilitates nutrient delivery and metabolic waste clearance, forms the blood-brain barrier (BBB), and supports fluid homeostasis in the brain. The integrity of NVU subcomponents can be measured in vivo using magnetic resonance imaging (MRI), including quantification of enlarged perivascular spaces (ePVS), BBB permeability, cerebral perfusion and extracellular free water. The breakdown of NVU subparts is individually associated with aging, pathology, and cognition. However, how these subcomponents interact as a system, and how interdependencies are impacted by pathology remains unclear. This systematic scoping review identified 26 studies that investigated the inter-relationships between multiple subcomponents of the NVU in nonclinical and neurodegenerative populations using MRI. A further 112 studies investigated associations between the NVU and white matter hyperintensities (WMH). We identify two putative clusters of NVU interdependencies: a 'vascular' cluster comprising BBB permeability, perfusion and basal ganglia ePVS; and a 'fluid' cluster comprising ePVS, free water and WMH. Emerging evidence suggests that subcomponent coupling within these clusters may be differentially related to aging, neurovascular injury or neurodegenerative pathology.
Topics: Magnetic Resonance Imaging; Brain; Blood-Brain Barrier; Water
PubMed: 38129925
DOI: 10.1186/s12987-023-00499-0 -
Brain and Behavior Nov 2023Obstructive sleep apnea (OSA) is a common sleep disorder that causes intermittent hypoxia and sleep fragmentation, leading to attention impairment and other cognitive... (Review)
Review
BACKGROUND AND OBJECTIVE
Obstructive sleep apnea (OSA) is a common sleep disorder that causes intermittent hypoxia and sleep fragmentation, leading to attention impairment and other cognitive deficits. Magnetic resonance imaging (MRI) is a powerful modality that can reveal the structural and functional brain alterations associated with attention impairment in OSA patients. The objective of this systematic review is to identify and synthesize the evidence on MRI biomarkers and neuropsychological assessments of attention deficits in OSA patients.
METHODS
We searched the Scopus and PubMed databases for studies that used MRI to measure biomarkers related to attention alteration in OSA patients and reported qualitative and quantitative data on the association between MRI biomarkers and attention outcomes. We also included studies that found an association between neuropsychological assessments and MRI findings in OSA patients with attention deficits.
RESULTS
We included 19 studies that met our inclusion criteria and extracted the relevant data from each study. We categorized the studies into three groups based on the MRI modality and the cognitive domain they used: structural and diffusion tensor imaging MRI findings, functional, perfusion, and metabolic MRI findings, and neuropsychological assessment findings.
CONCLUSIONS
We found that OSA is associated with structural, functional, and metabolic brain alterations in multiple regions and networks that are involved in attention processing. Treatment with continuous positive airway pressure can partially reverse some of the brain changes and improve cognitive function in some domains and in some studies. This review suggests that MRI techniques and neuropsychological assessments can be useful tools for monitoring the progression and response to treatment of OSA patients.
Topics: Humans; Diffusion Tensor Imaging; Sleep Apnea, Obstructive; Brain; Magnetic Resonance Imaging; Biomarkers; Neuropsychological Tests
PubMed: 37743582
DOI: 10.1002/brb3.3262 -
Obesity Surgery Nov 2023Indocyanine green (ICG) is a fluorescent dye that can be used intraoperatively to assess tissue perfusion, as well as perform leak testing. This study aims to summarize... (Review)
Review
Indocyanine green (ICG) is a fluorescent dye that can be used intraoperatively to assess tissue perfusion, as well as perform leak testing. This study aims to summarize published manuscripts on outcomes of ICG use and reduction of complications compared to traditional leak test and tissue perfusion evaluation. A PubMed search using "ICG and bariatric surgery," "ICG and gastric sleeve," "ICG and gastric bypass," and "ICG and revisional bariatric surgery" was performed. The proportion of patients who underwent an intraoperative decision change due to ICG was 3.8% (95% CI: 2.0 to 7.2%). ICG fluorescent imaging in bariatric surgery is a valuable tool, and further studies are needed to confirm its utility for routine use in both standard or complex cases (PROSPERO #418126).
Topics: Humans; Indocyanine Green; Anastomotic Leak; Anastomosis, Surgical; Obesity, Morbid; Coloring Agents; Gastric Bypass
PubMed: 37713041
DOI: 10.1007/s11695-023-06801-1 -
The British Journal of Surgery Aug 2023Anastomotic leak is one of the most feared complications of colorectal surgery, and probably linked to poor blood supply to the anastomotic site. Several technologies... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Anastomotic leak is one of the most feared complications of colorectal surgery, and probably linked to poor blood supply to the anastomotic site. Several technologies have been described for intraoperative assessment of bowel perfusion. This systematic review and meta-analysis aimed to evaluate the most frequently used bowel perfusion assessment modalities in elective colorectal procedures, and to assess their associated risk of anastomotic leak. Technologies included indocyanine green fluorescence angiography, diffuse reflectance spectroscopy, laser speckle contrast imaging, and hyperspectral imaging.
METHODS
The review was preregistered with PROSPERO (CRD42021297299). A comprehensive literature search was performed using Embase, MEDLINE, Cochrane Library, Scopus, and Web of Science. The final search was undertaken on 29 July 2022. Data were extracted by two reviewers and the MINORS criteria were applied to assess the risk of bias.
RESULTS
Some 66 eligible studies involving 11 560 participants were included. Indocyanine green fluorescence angiography was most used with 10 789 participants, followed by diffuse reflectance spectroscopy with 321, hyperspectral imaging with 265, and laser speckle contrast imaging with 185. In the meta-analysis, the total pooled effect of an intervention on anastomotic leak was 0.05 (95 per cent c.i. 0.04 to 0.07) in comparison with 0.10 (0.08 to 0.12) without. Use of indocyanine green fluorescence angiography, hyperspectral imaging, or laser speckle contrast imaging was associated with a significant reduction in anastomotic leak.
CONCLUSION
Bowel perfusion assessment reduced the incidence of anastomotic leak, with intraoperative indocyanine green fluorescence angiography, hyperspectral imaging, and laser speckle contrast imaging all demonstrating comparable results.
Topics: Humans; Anastomotic Leak; Indocyanine Green; Anastomosis, Surgical; Digestive System Surgical Procedures; Perfusion
PubMed: 37253021
DOI: 10.1093/bjs/znad154