Historical overview of (non-opioid) reversal agents of opioid-induced respiratory depression (OIRD): Lessons from the past and new developments

The development of respiratory stimulants and opioid antagonists to treat opioid induced respiratory depression remains one of the biggest challenges in respiratory research. A variety of substances with stimulatory effects on respiration have been shown to be of little use in clinical practice, either because of narrow margins of safety or due to serious side effects. With the introduction of naloxone a safe treatment for OIRD came within reach, although it reverses all opioid effects, thereby also affecting analgesia. This makes naloxone a very useful drug to treat life-threatening OIRD, but not efficacious for prevention of OIRD. Recent studies have shown that the development of ampakines and potassium-channel blockers such as GAL021 make prevention of OIRD without incidence of serious side effects possible. In the forthcoming years these respiratory stimulants might become a valuable addition to the anesthesiologists’ armamentarium. The development of respiratory stimulants and opioid antagonists to treat opioid induced respiratory depression remains one of the biggest challenges in respiratory research. A variety of substances with stimulatory effects on respiration have been shown to be of little use in clinical practice, either because of narrow margins of safety or due to serious side effects. With the introduction of naloxone a safe treatment for OIRD came within reach, although it reverses all opioid effects, thereby also affecting analgesia. This makes naloxone a very useful drug to treat life-threatening OIRD, but not efficacious for prevention of OIRD. Recent studies have shown that the development of ampakines and potassium-channel blockers such as GAL021 make prevention of OIRD without incidence of serious side effects possible. In the forthcoming years these respiratory stimulants might become a valuable addition to the anesthesiologists’ armamentarium.Perioperative Medicine: Efficacy, Safety and Outcom

Opioid-induced respiratory depression: reversal by non-opioid drugs

The human body is critically dependent on the ventilatory control system for adequate uptake of oxygen and removal of carbon dioxide (CO2). Potent opioid analgesics, through their actions on μ-opioid receptor (MOR) expressed on respiratory neurons in the brainstem, depress ventilation. Opioid-induced respiratory depression (OIRD) is potentially life threatening and the cause of substantial morbidity and mortality. One possible way of prevention of OIRD is by adding a respiratory stimulant to the opioid treatment, which through activation of non-opioidergic pathways will excite breathing and consequently will offset OIRD and should not affect analgesia. Various new respiratory stimulants are currently under investigation including (a) potassium channel blockers acting at the carotid bodies, and (b) ampakines and (c) serotonin receptor agonists acting within the brainstem. (a) GAL-021 targets BKCa-channels. Initial animal and human experimental evidence indicates that this potassium channel blocker is a potent respiratory stimulant that reverses OIRD without affecting antinociception. GAL021 is safe and better tolerated than the older K(+)-channel blocker doxapram and more efficacious in its effect on respiration. (b) Ampakines modulate glutamatergicrespiratory neurons in brainstem respiratory centers. Various ampakines have been studied showing their ability to increase respiratory drive during OIRD by increasing respiratory rate. Currently, CX717 is the most promising ampakine for use in humans as it is safe and does not affect opioid analgesia. (c) While animal studies show that serotonin receptor agonists increase respiratory drive via activation of serotonin receptors in brainstem respiratory centers, human studies are without success. Further clinical studies are required to improve our care of patients that are treated with potent opioid analgesics. The use of non-opioid adjuvants may reduce the probability of OIRD but does never relieve us of our duty to continuously monitor these patients, irrespective whether they are treated in-house or in an ambulatory setting.Perioperative Medicine: Efficacy, Safety and Outcom

Carbon dioxide tolerability and toxicity in rat and man: a translational study

Background: Due the increasing need for storage of carbon dioxide (CO2) more individuals are prone to be exposed to high concentrations of CO2 accidentally released into atmosphere, with deleterious consequences. Methods: We tested the effect of increasing CO2 concentrations in humans (6–12%) and rats (10–50%) at varying inhalation times (10–60 min). In humans, a continuous positive airway pressure helmet was used to deliver the gas mixture to the participants. Unrestrained rats were exposed to CO2 in a transparent chamber. In both species regular arterial blood gas samples were obtained. After the studies, the lungs of the animals were examined for macroscopic and microscopic abnormalities. Results: In humans, CO2 concentrations of 9% inhaled for >10 min, and higher concentrations inhaled for </p

The impact of climate change on the critical weather conditions at Schiphol airport (Impact)

Schiphol is van groot belang voor de economische positie van Nederland. De luchthaven is erg gevoelig voor kritieke weersomstandigheden zoals mist, intensieve neerslag en hevige wind. Als gevolg van klimaatverandering verwachten we dat ook de variabiliteit van het weer op de luchthaven en de frequentie en intensiteit van kritieke weersomstandigheden zullen veranderen, maar een precieze kwantificering daarvan ontbreekt. De belangrijkste doelstelling van dit project is daarom het verstrekken en demonstreren van het volgende generatie weer‐ en klimaatmodel HARMONIE. Dit is een nieuw model dat beter geschikt lijkt om het effect van klimaatverandering op lokale kritieke weersomstandigheden op de luchthaven te kwantificeren en te begrijpen. Bovendien zal kennis uit dit project worden gebruikt om de kwaliteit van onze huidige en toekomstige weersvoorspellingen te verbeteren. In dit project wordt het potentieel van het HARMONIE model, om meer gedetailleerdere en nauwkeurigere weersvoorspellingen voor luchthaven Schiphol te leveren dan ons huidige operationele weermodel HIRLAM, nagegaan in het huidige klimaat

Impact of COVID-19 pandemic on diagnostic pathology in the Netherlands

Background The COVID-19 pandemic has a huge impact on healthcare provided. The nationwide pathology registry of the Netherlands, PALGA, offers an outstanding opportunity to measure this impact for diseases in which pathology examinations are involved. Methods Pathology specimen numbers in 2020 were compared with specimen numbers in 2019 for 5 periods of 4 weeks, representing two lockdowns and the periods in between, taking into account localization, procedure and benign versus malignant diagnosis. Results The largest decrease was seen during the first lockdown (spring 2020), when numbers of pathology reports declined up to 88% and almost all specimen types were affected. Afterwards each specimen type showed its own dynamics with a decrease during the second lockdown for some, while for others numbers remained relatively low during the whole year. Generally, for most tissue types resections, cytology and malignant diagnoses showed less decrease than biopsies and benign diagnoses. A significant but small catch-up (up to 17%) was seen for benign cervical cytology, benign resections of the lower gastro-intestinal tract, malignant skin resections and gallbladder resections. Conclusion The COVID-19 pandemic has had a significant effect on pathology diagnostics in 2020. This effect was most pronounced during the first lockdown, diverse for different anatomical sites and for cytology compared with histology. The data presented here can help to assess the consequences on (public) health and provide a starting point in the discussion on how to make the best choices in times of scarce healthcare resources, considering the impact of both benign and malignant disease on quality of life.Clinical epidemiolog

The impact of deep versus standard neuromuscular block on intraoperative safety during laparoscopic surgery: an international multicenter randomized controlled double-blind strategy trial - EURO-RELAX TRIAL

Background: Muscle relaxants are routinely used during anesthesia to facilitate endotracheal intubation and to optimize surgical conditions. However, controversy remains about the required depth of neuromuscular block (NMB) needed for optimal surgical working conditions and how this relates to other outcomes. For instance, a deep neuromuscular block yields superior surgical working conditions compared to a standard NMB in laparoscopic surgery, however, a robust association to other (safety) outcomes has not yet been established.Methods: Trial design: an international multicenter randomized controlled double-blind strategy trial. Trial population: 922 patients planned for elective, laparoscopic or robotic, abdominal surgery. Intervention: Patients will be randomized to a deep NMB (post-tetanic count 1-2 twitches) or standard care (single-dose muscle relaxant administration at induction and repeated only if warranted by surgical team). Main trial endpoints: Primary endpoint is the difference in incidence of intraoperative adverse events during laparoscopic surgery graded according to ClassIntra (R) classification (i.e., ClassIntra (R) grade >= 2) between both groups. Secondary endpoints include the surgical working conditions, 30-day postoperative complications, and patients' quality of recovery.Discussion: This trial was designed to analyze the effect of deep neuromuscular block compared to standard neuromuscular block on intra- and postoperative adverse events in patients undergoing laparoscopic surgery.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Evaluating operational AVHRR sea surface temperature data at the coastline using surfers

Sea surface temperature (SST) is an essential climate variable that can be measured routinely from Earth Observation (EO) with high temporal and spatial coverage. To evaluate its suitability for an application, it is critical to know the accuracy and precision (performance) of the EO SST data. This requires comparisons with co-located and concomitant in situ data. Owing to a relatively large network of in situ platforms there is a good understanding of the performance of EO SST data in the open ocean. However, at the coastline this performance is not well known, impeded by a lack of in situ data. Here, we used in situ SST measurements collected by a group of surfers over a three year period in the coastal waters of the UK and Ireland, to improve our understanding of the performance of EO SST data at the coastline. At two beaches near the city of Plymouth, UK, the in situ SST measurements collected by the surfers were compared with in situ SST collected from two autonomous buoys located ∼7 km and ∼33 km from the coastline, and showed good agreement, with discrepancies consistent with the spatial separation of the sites. The in situ SST measurements collected by the surfers around the coastline, and those collected offshore by the two autonomous buoys, were used to evaluate the performance of operational Advanced Very High Resolution Radiometer (AVHRR) EO SST data. Results indicate: (i) a significant reduction in the performance of AVHRR at retrieving SST at the coastline, with root mean square errors in the range of 1.0 to 2.0 °C depending on the temporal difference between match-ups, significantly higher than those at the two offshore stations (0.4 to 0.6 °C); (ii) a systematic negative bias in the AVHRR retrievals of approximately 1 °C at the coastline, not observed at the two offshore stations; and (iii) an increase in the root mean square error at the coastline when the temporal difference between match-ups exceeded three hours. Harnessing new solutions to improve in situ sampling coverage at the coastline, such as tagging surfers with sensors, can improve our understanding of the performance of EO SST data in coastal regions, helping inform users interested in EO SST products for coastal applications. Yet, validating EO SST products using in situ SST data at the coastline is challenged by difficulties reconciling the two measurements, which are provided at different spatial scales in a dynamic and complex environment

Opioid-induced respiratory depression: implications & prevention

The goal of this thesis was to study the ability to reverse opioid-induced respiratory depression with respiratory stimulants and to study drugs that might prevent opioid-induced respiratory depression. The benefit-harm composite of opioids is discussed, followed by a recapitulation of the possible treatments of opioid-induced respiratory depression. Based on the data presented in this thesis, the following can be concluded: 1) Doxapram reduces alfentanil-induced antinociception due to an increase in alfentanil distribution and elimination. 2) GAL021, a novel calcium-activated potassium channel blocker, produces an increase in tidal volume and respiratory rate during opioid-induced respiratory depression without affecting the analgesic effect 3) GAL021 efficacy reduces at low ventilation levels and demonstrates ceiling in its efficacy to reverse opioid-induced respiratory depression 4) The utility function of alfentanil is further developed to assess specific conditions in terms of wanted and unwanted effects. The utility function may be used to compare the respiratory effects of analgesics and might allow for comparison between different opioid treatments 5) RM101 causes respiratory depression in all subjects with a rapid effect on ventilation and a slower effect on CO2 sensitivity. </div