Chronic stimulation desensitizes ß2-adrenergic receptor responses in natural killer cells.

Adrenergic receptors (ARs) are preferentially expressed by innate lymphocytes such as natural killer (NK) cells. Here, we study the effect of epinephrine-mediated stimulation of the ß2-adrenergic receptor (ß2AR) on the function of human NK cells. Epinephrine stimulation inhibited early NK cell signaling events and blocked the function of the integrin LFA-1. This reduced the adhesion of NK cells to ICAM-1, explaining how NK cells are mobilized into the peripheral blood upon epinephrine release during acute stress or exercise. Additionally, epinephrine stimulation transiently reduced NK cell degranulation, serial killing, and cytokine production and affected metabolic changes upon NK cell activation via the cAMP-protein kinase A (PKA) pathway. Repeated exposure to ß2AR agonists resulted in the desensitization of the ß2AR via a PKA feedback loop-initiated G-protein switch. Therefore, acute epinephrine stimulation of chronically ß2AR stimulated NK cells no longer resulted in inhibited signaling and reduced LFA-1 activity. Sustained stimulation by long-acting ß2-agonists (LABA) not only inhibited NK cell functions but also resulted in desensitization of the ß2AR. However, peripheral NK cells from LABA-treated asthma patients still reacted unchanged to epinephrine stimulation, demonstrating that local LABA administration does not result in detectable systemic effects on NK cells.

Abnormal expression of natural mating behaviour of captive adult giant pandas is related to physiological stress.

During ex situ conservation, the adaptability of giant pandas to environmental changes is greatly challenged. The issue of natural reproduction in captive giant pandas remains unresolved both domestically and internationally. It hypothesized that the restricted natural reproductive capacity may be linked to abnormal mating behavior expression due to physiological stress resulting from incompatible pairings in confined environments. To test this hypothesis, we utilized ultra-high performance liquid chromatographytandem quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) to analyse urine metabolites in captive adult giant pandas during their breeding period. Simultaneously, enzyme-linked immunosorbent assay was employed to measure the levels of cortisol and epinephrine in urine, providing insight into the psychological state of captive giant pandas during mate selection by examining all metabolites and related biochemical pathways. This comprehensive approach aims to fully elucidate the physiological mechanisms underlying the decline in natural reproductive capacity. The metabolomics findings indicate that the aberrant expression of natural mating behaviour in captive adult male and female giant pandas may be associated with dysfunction in amino acid metabolic pathways. The activation of these metabolic pathways is linked to psychological stress, such as the tryptophan metabolic pathway and GABAergic synapse pathway. The results of physiological indicators indicate a significant correlation between the expression of natural mating behaviour in captive adult pandas and the hormone urine cortisol, which is associated with physiological stress. These findings indicate that the atypical manifestation of natural mating behaviour in captive adult giant pandas may be associated with physiological stress induced by incompatible pairings within confined environments.

Local Adverse Events Associated with Peripheral Vasoactive Infusion in Children: A Systematic Review with Meta-analysis.

Prior meta-analysis suggested a low incidence of local adverse events after infusion of vasoactive agents via a peripheral venous catheter in children. However, the number of included patients was relatively low, and the vasoactive agents used were mostly dopamine. We performed an updated systematic review with meta-analysis using databases of MEDLINE (via PubMed) and Cochrane Central Register of Controlled Trials to explore the safety of infusing vasoactive agents, including epinephrine and norepinephrine, through peripheral venous catheters or intraosseous access in critically ill children. The primary outcome was the occurrence of local adverse events associated with peripheral vasoactive infusion, such as extravasation or infiltration. Twelve observational studies and 1 randomized controlled trial were finally included. The pooled incidence rates of local adverse events associated with infusion of vasoactive agents through peripheral venous catheters or intraosseous access, peripheral venous catheters only, and intraosseous access only were 2.1% (95% confidence interval [CI]: 0.8%-3.9%), 2.3% (95% CI: 1.0%-4.0%), and 1.1% (95% CI: 0.0%-9.8%), respectively. Based on the findings of this meta-analysis, the incidence rate of local adverse events associated with peripheral vasoactive infusion appears to be low. Peripheral infusion of vasoactive agents, including epinephrine and norepinephrine, can be considered when necessary.

Pre-hospital 'dirty adrenaline': A descriptive case series of patients receiving peripheral dilute adrenaline infusions in Central Australian remote nurse-led clinics prior to aeromedical retrieval.

OBJECTIVES: 'Dirty adrenaline' is the informal term used for a rapidly made peripheral dilute adrenaline infusion in the emergency treatment of shock, most commonly 1 mg adrenaline in 1 L 0.9% NaCl. It has long been part of the remote clinician's arsenal despite no supporting scientific literature. Remote clinics in Central Australia can be hours away from critical care support. The region's high prevalence of renal and cardiac disease means that access to early vasopressors and inotropes is a necessity for treating shock. To tackle this, remote clinicians often use 'dirty adrenaline'. We present a review of 'dirty adrenaline' use in this region. METHODS: Central Australian Retrieval Service's database was screened to identify cases in which a peripheral dilute adrenaline infusion was administered in a remote clinic prior to patient aeromedical retrieval. A retrospective chart review collected: patient demographics; clinical characteristics; infusion details; adverse events; hospital lengths of stay; and mortality outcomes. RESULTS: Fifty-seven cases were identified. Median patient age was 50 (range: 2-96). Septic shock was the most common clinical indication (40/57). Median infusion duration was 155 min. Median systolic BP from commencement until retrieval increased from 75.5 to 91 mmHg. Survival to hospital discharge was 86% (49/57). No significant adverse events associated with 'dirty adrenaline' were recorded. CONCLUSION: 'Dirty adrenaline' is safe to administer and appears to considerably improve survival when used to treat fluid-resistant shock in remote nurse-led clinics guided by an off-site critical care physician.

To the ER? Can Patients Treat Their Anaphylaxis at Home?

PURPOSE OF REVIEW: To discuss if all patients who use self-injectable epinephrine outside the hospital setting require immediate emergency care. RECENT FINDINGS: Prior to 2023, anaphylaxis management guidance universally recommended that patients who use self-injectable epinephrine outside of the hospital or clinic setting immediately activate emergency medical services and seek further care. Additional food-induced anaphylaxis management recommendations specified that all patients always carry 2 auto-injector devices and give a second dose of epinephrine if there was not immediate response within 5 min of injection. Patients presenting for emergency care after epinephrine are often observed for up to 4-6 h afterwards, even when completely asymptomatic. These management steps have lacked evidence for improving outcomes, and universal implementation of these approaches is not cost-effective as guidance for food allergic patients. Epinephrine pharmacokinetics and pharmacodynamics suggest that peak physiologic response is more likely to occur closer to 15 min than before 5 min, that few patients require a second dose of epinephrine as most stabilize within 15 min of use, that 60 min of observation after a patient stabilizes after epinephrine use may be adequate as patients infrequently have further sequelae, and that not everyone needs to carry 2 epinephrine auto-injectors on their person at all times. The most recent anaphylaxis practice parameter promotes a contextualized approach to these management questions, outlining the option for watchful waiting to gauge response to epinephrine before seeking emergency care, which has been proven as a more cost-effective management strategy. The recent updated anaphylaxis care guidelines support the evolution of anaphylaxis care, in that universal, immediate activation of emergency services is not required for using self-injectable epinephrine outside the hospital setting.

Epinephrine autoinjectors for individuals with food allergy: Who, how many, and when to use.

Background: Anaphylaxis is a serious allergic reaction that is effectively treated with epinephrine. Epinephrine autoinjectors are devices that contain fixed doses of medication that can be carried by patients at risk for anaphylaxis so that ready access to first line medication is available outside the medical setting. Methods: This review will discuss recent studies evaluating patient characteristics to consider when prescribing epinephrine autoinjectors. Results: Decisions regarding who should be prescribed epinephrine autoinjectors will depend on the type of allergy, as well as co-morbidities and other risk factors that can increase a patient's risk for poor outcomes. Conclusion: Shared decision-making is essential when developing guidance regarding post-epinephrine management. Regular education during routine follow-up visits can reinforce knowledge and skills for managing food allergy reactions.

Fish and shellfish allergy: Presentation and management differences in the UK and US-analysis of 945 patients.

Background: Seafood allergy (SA), including allergy to shellfish (crustacean and mollusks) and fish, is among the 4 most common food allergies causing anaphylaxis, but there are limited data showing SA clinical management in different countries. Objective: We sought to characterize a large cohort of patients with fish and shellfish allergy and to facilitate standardization of future care for this increasingly common allergic disease. Methods: We performed a retrospective, observational, noninterventional study from 945 patients from 2015 to 2019 in 7 hospitals in the United States and the United Kingdom to evaluate SA. A chi-square test was used to detect differences in family history, medical history, and current symptoms between patients in 2 countries. Results: Underdiagnosed anaphylaxis in patients with SA was associated with underuse of epinephrine (adrenaline) autoinjectors in both countries. Oral food challenge was used only when skin or serologic test results were negative. Asthma and allergic rhinitis were more common in the US patients with SA, but eczema was more common in UK patients with SA (P < .001). Respiratory, gastrointestinal, and neurological symptoms were higher in UK patients with SA than in US patients with SA (P < .001). Conclusions: In international multicenter cohorts of patients with fish and shellfish allergy, there are opportunities for improvement in management. Physician identification of anaphylaxis, use of diagnostic oral food challenges, and anaphylaxis treatment with epinephrine are areas with significant knowledge gaps in need of improvement in the United Kingdom and the United States. There is an opportunity for the development of unified, standardized diagnostic protocols for SA with distribution for allergists and trainees.

Rhodium-Catalyzed Asymmetric Transfer Hydrogenation of Aryl Ketones Involving Free Phenolic Hydroxyl Group(s).

A straightforward asymmetric transfer hydrogenation for accessing enantiomerically enriched secondary benzyl alcohols involving free phenolic hydroxyl group(s) under mild conditions was developed. Various of optical pure aryl alcohols with a remarkable functional group compatibility were achieved with 78%-97% yields, 84%->99% ee's and up to 10 000 TON. This rhodium-catalyzed reaction could be performed in a gram-scale without loss of the efficiency. Furthermore, the synthetic utility has also been demonstrated in the asymmetric synthesis of (S)-adrenaline and (S)-phenylephrine.

Changes in epinephrine dispensings and allergy hospitalisations in Sweden in the years following the removal of autoinjector co-payments.

Introduction: To understand any possible healthcare system benefits and changes of behavior for the patients with the change in prescription co-payment in Sweden we aimed to provide an update on the trends of EAI dispensings and hospitalizations for the Swedish paediatric population (ages 0-19 years), from 2018 to 2022, including by sex and geographic region. Methods: Using publically-available, population-level aggregate data from Sweden's National Board of Health and Welfare, we extracted information on annual epinephrine (ATC C01CA24) dispensings per 1,000 inhabitants from 2018 to 2023, overall, as well as stratified by sex, age groups and geographic region; and on inpatient stays 2018-2022 (ICD-10 code T78), anaphylaxis and other allergic reactions, per 100,000 individuals. We compared these estimates to those for adults ages 18 + years, for whom prescription co-payments remained in place. Results: EAI dispensings remained stable for children and adults across the study period, with the exception of statistically significant decreases amongst dispensings for children across all ages in 2021 (6.65/1,000) and 2022 (7.37/1,000), compared to 2018 (8.63/1,000) (each year p = 0.03 compared to 2018 dispensings). National EAI dispensings did not statistically significantly differ from 2018 (8.63/1,000) to 2023 (6.70/1,000) amongst children. EAI dispensings for children ages 5 + years consistently exceed dispensings for adults per 1,000 inhabitants; only children aged 0-4 years had proportionately fewer dispensings. Children ages 0-4 years tended to be hospitalised more often than older children, albeit these differences were not statistically significant (all p > 0.97). Conclusion: Subsequent to the removal of out-of-pocket costs for EAI, dispensings did not increase for children, although more EAI were dispensed to children from age 5 years, compared to younger children. Allergy-related hospitalisations were highest amongst children ages 0-4, lower amongst children ages 5-14 years, and again higher amongst those ages 15-19 years.

Topical larynx lidocaine Spraying reduces cardiovascular stress response caused by suspension laryngoscopic surgery.

OBJECTIVE: This study aimed to investigate the potential reduction of cardiovascular stress response caused by suspension laryngoscopic surgery through the application of lidocaine spray on the larynx and trachea. METHODS: A total of 68 patients scheduled for elective suspension laryngoscopic surgery were randomly assigned to either the lidocaine group (Group L, n = 34) or the control group (Group C, n = 33). In Group L, patients received a sprayed lidocaine dose of 2 mg/kg on the larynx and trachea after anesthesia induction, prior to intubation. In Group C, equal volumes of saline solution were administered. MAP and HR were recorded at various time points: before anesthesia (T0), 1-minute after intubation (T1), 1 and 3 min after suspension laryngoscopy (T2 and T3), at the end of the operation (T4), and at 1, 5, and 30 min after extubation (T5, T6, and T7). Arterial blood glucose, epinephrine, and norepinephrine levels were measured at T0, T2, T5, and T7. The occurrence of severe cough and sore throat at T6 and T7 after extubation was compared between the two groups. RESULTS: At T0 and T1, there were no statistically significant differences in mean arterial pressures, heart rate, and blood catecholamine levels between the two groups. However, from T2 to T7, the blood pressure and heart rate in Group L were lower compared to Group C, with significant differences observed at T2‒T6 (p < 0.05). Group L also showed less elevation in blood glucose at T2, T5, and T7 (p < 0.05). The changes in epinephrine and norepinephrine levels between the two groups were statistically significant at T2 and T5 (p < 0.05). CONCLUSIONS: Administering lidocaine spray on the larynx and trachea during intubation for suspension laryngoscopic surgery can effectively alleviate the stress response. LEVEL 1 EVIDENCE: Patients in this study are randomly assigned to the treatment or control group and are followed prospectively.

Association of stress hormones and the risk of cardiovascular diseases systematic review and meta-analysis.

Background: The roles of endogenous stress hormones (norepinephrine, epinephrine, and cortisol) in cardiovascular diseases have been discussed. However, the higher versus lower level of stress hormones in relation to cardiovascular risks remained uncertain. Methods: We searched databases from their inception to 31, March 2023. We conducted a meta-analysis to estimate the effect of higher to lower level of stress hormones with random effect model. Subgroup and meta-regression analysis were done to clarify the heterogeneity. Results: In total, 33 studies involving 43641 participants were included. With regard to cardiovascular disease risks, a higher risk for individuals with higher level of all stress hormones (risk ratio (RR), 1.63; 95 % Confidence intervals (CIs): 1.36, 1.97) was noted compared with lower level of all stress hormones. The meta-regression showed that as the follow-up year increased per year, the impact of higher level of all stress hormones on the risk of cardiovascular disease declined significantly (RR, -0.09; 95 % CIs: 0.15, -0.03, p = 0.006). A significantly higher risk of cardiovascular diseases for individuals with higher level of norepinephrine (RR, 1.68; 95 % CIs: 1.37, 2.06), with higher level of epinephrine (RR, 1.58; 95 % CIs: 1.10, 2.26), and with higher level of cortisol (RR, 1.60; 95 % CIs: 1.04, 2.26) were noted compared with a lower level of each stress hormone. Conclusion: Higher levels of stress hormones were significantly associated with higher risks of cardiovascular diseases compared with lower levels of stress hormones.

Epinephrine, Pregabalin, and Crizotinib as Three Medicines with Polish Implications over Three Last Centuries and in View of Three Different Drug Discovery Approaches.

The discovery of epinephrine (adrenaline) and its subsequent implications in medicine owes significant contributions to Cybulski across different centuries, who, in 1894, was pivotal in identifying the adrenal medulla's role in blood pressure regulation and naming the active substance "nadnerczyna", known today as adrenaline. His work demonstrated the adrenal glands' critical function in the body's regulatory mechanisms beyond the nervous system. Cybulski's groundbreaking research laid foundational knowledge for future endocrinological studies and pharmaceutical advancements. In the late 20th century, Andruszkiewicz collaborated with Silverman at Northwestern University to develop pregabalin, the active ingredient in Lyrica. Their innovative synthesis of gamma-aminobutyric acid derivatives led to a significant advancement in treating epilepsy, neuropathic pain, and fibromyalgia. Andruszkiewicz's expertise in organic chemistry and enzymology was crucial in this collaborative effort, resulting in the successful development and commercialization of Lyrica. Additionally, Mroczkowski's leadership at Pfizer contributed to the development of crizotinib, a notable anaplastic lymphoma kinase and proto-oncogene 1 tyrosine-protein kinase inhibitor used to treat specific types of non-small cell lung cancer. Her work exemplifies the continuing influence of Polish researchers in pioneering drug discovery and advancing therapeutic treatments over the past three centuries. These contributions highlight Poland's significant role in global pharmaceutical innovations and medical research.

Intramuscular versus intravenous epinephrine administration in a pediatric porcine model of cardiopulmonary resuscitation.

Background: American Heart Association Pediatric Life Support guidelines recommend epinephrine administration via intravenous (IV) or intraosseous (IO) route, with endotracheal (ET) administration admissible in the absence of IV/IO access. Establishing IV/IO/ET access can take several minutes and may require proficient skills and/or specific equipment, which may not be readily available in all situations. Alternatively, intramuscular (IM) epinephrine could be administered immediately. At present, there is limited data on the use of IM epinephrine in pediatric resuscitation. Aim: To compare IM with IV epinephrine in a pediatric porcine model of asphyxia-induced cardiac arrest. We hypothesized that in a pediatric animal model of cardiac arrest, IM epinephrine would result in a similar time to achieve return of spontaneous circulation (ROSC) to IV epinephrine. Methods: Twenty pediatric piglets (5-10 days old) were anesthetized and asphyxiated by clamping the endotracheal tube. Piglets were randomized to IM or IV epinephrine with bradycardic or asystolic cardiac arrest (n = 5/group) and were resuscitated. Time to ROSC was recorded; blood plasma was collected throughout resuscitation for measurement of epinephrine concentration; heart rate, arterial blood pressure, carotid blood flow, cardiac function, and cerebral oxygenation were continuously recorded throughout the experiment. Results: Time to ROSC and the number of piglets that achieved ROSC were comparable between IM and IV epinephrine groups with either bradycardic or asystolic cardiac arrest. Conclusions: In a pediatric piglet model of bradycardic and asystolic cardiac arrest, administration of IM epinephrine resulted in similar resuscitative outcomes to IV epinephrine. Although immediate IM epinephrine injection may provide a first-line treatment option until subsequent IV/IO access is established, large, randomized trials are needed to confirm our finding before it can be used during pediatric resuscitation.

Adult Laryngotracheobronchitis in the Setting of a COVID-19 Infection.

We describe a case of adult croup in an 18-year-old female caused by the SARS-CoV-2 virus. Her complaints started as lower respiratory tract symptoms that evolved into stridor, barking cough, and dyspnea. The patient was diagnosed with SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR) testing from a nasopharyngeal swab. The patient received multiple doses of nebulized racemic epinephrine with minimal improvement, and later the patient required mechanical ventilation. Intravenous remdesivir was administered for five days. Multiple doses of dexamethasone were required throughout the course of the illness. Croup in adults secondary to COVID-19 infections appears to be severe and might be poorly responsive to standard treatment protocols.

Beta vulgaris Betalains Mitigate Parasitemia and Brain Oxidative Stress Induced by Plasmodium berghei in Mice.

Although many drugs have been discovered to treat malaria infection, many of them face resistance from the host's body with long-term use. Therefore, this study aimed to evaluate the activity of betalains (from Beta vulgaris) and chloroquine (a reference drug) against brain oxidative stress induced by Plasmodium berghei in male mice. Two protocols were applied in this study: the therapeutic and prophylactic protocols. The results of the therapeutic protocol revealed a significant decrease in the level of parasitemia caused by P. berghei. Additionally, the histopathological changes in various brain regions were markedly improved after treatment with betalains. Regarding the prophylactic protocol, betalains were able to protect the brain tissues from oxidative stress, inflammation, and disrupted neurotransmitters expected to occur as a result of infection by P. berghei. This was demonstrated by modulating the activities of brain antioxidants (SOD and GSH), inflammatory cytokines (IL-6, IL-10, IL-12, TNF-α, and INF-γ), and neurotransmitters (serotonin, epinephrine, and norepinephrine). This study has proven that using betalains as a treatment or as a preventive has a vital and effective role in confronting the brain histopathological, oxidative stress, and inflammatory changes induced by P. berghei infection.

A Buffered Local Anesthetic Without Epinephrine: Development, Characterization, and In Vivo Efficacy and Toxicity Analysis.

Lidocaine hydrochloride (HCl) 2% with 1:100,000 epinephrine (LW/E) is widely used to prevent pain during dental procedures and has been associated with injection sting, jittering effects, slow onset, and a bitter aftertaste. Since LW/E's introduction in 1948, no significant modifications have been proposed. This study aims to design and characterize an improved dental lidocaine HCl injectable formulation without epinephrine (LW/O/E) via buffers, sweeteners, and amino acids. LW/O/E injections were prepared with pH and osmolality values of 6.5-7.0 and 590-610 mOsm/kg. Using the electronic tongue (ETongue), the LW/O/E injectable formulations were characterized for viscosity, injectability, and taste analysis. The results were compared with the LW/E control. In vivo efficacy and anesthetic duration of the samples were measured through radiant heat tail-flick latency (RHTFL) and hot plate (HP) tests and local toxicity was assessed after a single intra-oral injection in Sprague Dawley rats (SDR). The viscosity and injectability values of the LW/O/E samples were found to be comparable to the LW/E injection. ETongue taste analysis showed an improvement in bitterness reduction of the LW/O/E samples compared to the LW/E formulation. Toxicity studies of samples in SDR showed minor and transient signs of erythema/eschar and edema. Anesthetic duration via RHTFL and HP paw withdrawal latency time in SDR were found to be comparable for the LW/O/E Sample 3A and the LW/E injection (p < 0.05). In conclusion, the buffered, higher osmolality and reduced bitterness developed LW/O/E formulation (Sample 3A) could be considered a promising alternative to the LW/E formulation for dental use.

Comparison of Systemic Exposure Between Epinephrine Delivered via Metered-Dose Inhalation and Intramuscular Injection.

Background: Primatene® MIST, an epinephrine metered-dose inhaler (MDI), has long been questioned by some medical professionals for asthma treatment despite having been approved by the Food and Drug Administration. One of the primary reasons for their concerns stemmed from potential cardiovascular complications following epinephrine administration. However, the majority of documented cardiovascular complications seemed to occur following the injection route of the epinephrine. The aim of this study was to evaluate the systemic exposure of epinephrine delivered through different administration routes and to understand its relationship with cardiovascular effects. Since albuterol inhalers are commonly recommended for asthma, albuterol was also studied as a comparator drug. Method: A randomized, evaluator-blinded, three-arm crossover study was conducted in 28 healthy adult subjects to compare the profiles of systemic exposure for epinephrine delivered by MDI versus epinephrine intramuscular (IM) injection and albuterol MDI. Serially sampled plasma epinephrine and albuterol levels were measured and compared between treatment groups. Safety was assessed by adverse events, serial vital signs, electrocardiograms (ECGs), and clinical laboratory tests obtained at each crossover dosing visit. Results: Systemic exogenous drug exposure for inhaled epinephrine MDI (39 pg/mL × hour) was ∼9 times lower than that of epinephrine IM (435 pg/mL × hour) and 122 times lower than that of albuterol MDI (3453 pg/mL × hour) after dose normalization. The Cmax in epinephrine MDI (345 pg/mL) was approximately half of that of epinephrine IM (816 pg/mL) and that of albuterol MDI (681 pg/mL). Plasma drug concentrations for epinephrine MDI dropped rapidly to baseline (∼0.6 hour), while epinephrine IM took ∼8 hours, and albuterol MDI required more than 24 hours. Epinephrine MDI and albuterol MDI resulted in minimal, clinically insignificant changes in vital signs and ECGs, whereas epinephrine IM led to mild transient increases in systolic blood pressure, heart rate, and corrected QT interval. Conclusion: Epinephrine MDI (Primatene MIST) had ∼9 times lower systemic drug exposure (SDE) than that of epinephrine IM and ∼122 times lower than that of albuterol MDI. The lower SDE of inhaled epinephrine also correlated with reassuring safety findings, with no significant cardiovascular adverse effects found, compared with transient effects seen after IM epinephrine. Clinical trial registration number: NCT04207840.

The effects of bolus compared to continuous administration of adrenaline on cerebral oxygenation during experimental cardiopulmonary resuscitation.

Background: Bolus administration of adrenaline during cardiopulmonary resuscitation (CPR) results in only short-term increases in systemic and cerebral perfusion pressure (CePP) with unclear effects on cerebral oxygenation. The aim of this study was to investigate the effects of bolus compared to continuous adrenaline administration on cerebral oxygenation in a porcine CPR model. Methods: After five minutes of cardiac arrest, mechanical CPR was performed for 15 min. Adrenaline (45 µg/kg) was administered either as a bolus every five minutes or continuously over the same period via an infusion pump. Main outcome parameter was brain tissue oxygen tension (PbtO2), secondary outcome parameters included mean arterial pressure (MAP), intracranial pressure (ICP), CePP and cerebral regional oxygen saturation (rSO2) as well as arterial and cerebral venous blood gases. Results: During CPR, mean MAP (45 ± 8 mmHg vs. 38 ± 8 mmHg; p = 0.0827), mean ICP (27 ± 7 mmHg vs. 20 ± 7 mmHg; p = 0.0653) and mean CePP (18 ± 8 mmHg vs. 18 ± 8 mmHg; p = 0.9008) were similar in the bolus and the continuous adrenaline group. Also, rSO2 (both 24 ± 6 mmHg; p = 0.9903) and cerebral venous oxygen saturation (18 ± 12% versus 27.5 ± 12%; p = 0.1596) did not differ. In contrast, relative PbtO2 reached higher values in the continuous group after five minutes of CPR and remained significantly higher than in the bolus group until the end of resuscitation. Conclusion: Continuous administration of adrenaline improved brain tissue oxygen tension compared with bolus administration during prolonged CPR.

Optimal weight-based epinephrine dosing for patients with a low likelihood of survival following out-of-hospital cardiac arrest.

INTRODUCTION: Cardiac arrest patients presenting with non-shockable rhythms have a low probability of survival, and epinephrine is one of the few pharmaceutical options for this group. The recommended 1.0 mg adult dose is extrapolated from early animal studies and lacks adjustment for patient weight. Although several prior studies have investigated "low-" and "high-" dose epinephrine, none have identified a benefit to either strategy. AIMS: To identify an optimal weight-based epinephrine dose for return-of-spontaneous-circulation (ROSC) after a single bolus among patients with low likelihood of survival. METHODS: Included were adult patients who experienced a witnessed, non-traumatic out-of-hospital cardiac arrest prior to EMS arrival. Patients with shockable presenting rhythms or receiving bystander CPR were excluded. The AUROC was used to assess the predictive value of epinephrine dose (mg/kg) for ROSC following a single bolus. From the ROC curve, the optimal threshold dosage (OTD) was determined using the Youden Index. A logistic regression model calculated the adjusted odds ratio of OTD on ROSC. RESULTS: A total of 2,463 patients met inclusion criteria, of which 190 (7.7%) attained ROSC after the first epinephrine administration. The dosage AUROC for ROSC was 0.603 (p < 0.01). As calculated by the Youden index, the OTD was 0.013 mg/kg. Patients receiving ≥ OTD were more likely to attain ROSC after a single epinephrine bolus (OR = 2.25,p < 0.001). CONCLUSIONS: Among patients with a low likelihood of survival, the optimal dose of epinephrine for attaining ROSC with a single bolus of epinephrine was 0.013 mg/kg. These findings should inspire further investigation into optimal dosing strategies for epinephrine.

Design and Optimization of Molecularly Imprinted Polymer Targeting Epinephrine Molecule: A Theoretical Approach.

Molecularly imprinted polymers (MIPs) are a growing highlight in polymer chemistry. They are chemically and thermally stable, may be used in a variety of environments, and fulfill a wide range of applications. Computer-aided studies of MIPs often involve the use of computational techniques to design, analyze, and optimize the production of MIPs. Limited information is available on the computational study of interactions between the epinephrine (EPI) MIP and its target molecule. A rational design for EPI-MIP preparation was performed in this study. First, density functional theory (DFT) and molecular dynamic (MD) simulation were used for the screening of functional monomers suitable for the design of MIPs of EPI in the presence of a crosslinker and a solvent environment. Among the tested functional monomers, acrylic acid (AA) was the most appropriate monomer for EPI-MIP formulation. The trends observed for five out of six DFT functionals assessed confirmed AA as the suitable monomer. The theoretical optimal molar ratio was 1:4 EPI:AA in the presence of ethylene glycol dimethacrylate (EGDMA) and acetonitrile. The effect of temperature was analyzed at this ratio of EPI:AA on mean square displacement, X-ray diffraction, density distribution, specific volume, radius of gyration, and equilibrium energies. The stability observed for all these parameters is much better, ranging from 338 to 353 K. This temperature may determine the processing and operating temperature range of EPI-MIP development using AA as a functional monomer. For cost-effectiveness and to reduce time used to prepare MIPs in the laboratory, these results could serve as a useful template for designing and developing EPI-MIPs.