Altered pharmacological effects of adrenergic agonists during hypothermia

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver applies to the data made available in this article, unless otherwise stated. This article is also available via DOI:10.1186/s13049-016-0339-8Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiac dysfunction, calling for immediate pharmacologic intervention. Studies show that although cardiac pharmacologic support is applied when rewarming these patients, a lack of updated treatment recommendations exist. Mainly due to lack of clinical and experimental data, neither of the international guidelines includes information about pharmacologic cardiac support at temperatures below 30 °C. However, core temperature of accidental hypothermia patients is often reduced below 30 °C. Few human studies exploring effects of adrenergic drugs during hypothermia have been published, and therefore prevailing information is collected from pre-clinical studies. The most prominent finding in these studies is an apparent depressive effect of adrenaline on cardiac function when used in doses which elevate cardiac output during normothermia. Also noradrenaline and isoprenaline largely lacked positive cardiac effects during hypothermia, while dopamine is a more promising drug for supporting cardiac function during rewarming. Data and information from these studies are in support of the prevailing notion; not to use adrenergic drugs at core temperatures below 30 °

Molecular modeling study of the testosterone metabolizing enzyme UDP-glucuronosyltransferase 2B17

The dominant sex hormone testosterone is mainly metabolized by liver enzymes belonging to the uridine-diphospho (UDP) glucuronosyltransferase (UGT) family. These enzymes are the main phase II enzymes, and they have an important role in the detoxification of endogenous and exogenous compounds in humans. The aim of the present study was to improve the understanding of the binding properties of UGT2B17. A homology modelling procedure was used to generate models of the UGT2B17 enzyme based on templates with known crystal structures. Molecular docking of inhibitors was performed to gain further insights in the interactions between ligand and binding site, and to determine which of the models had the best accuracy. ROC curves were made to evaluate the ability of the models to differentiate between binders (inhibitors) and non-binders (decoys). When comparing the four models, which were based on four different crystal structures, the model based on the 4AMG crystal structure was the most accurate in distinguishing between true binders and non-binders. Investigating pharmacological UGT2B17 inhibition may provide novel treatment for patients with low testosterone levels. Such treatment may elevate endogenous testosterone levels and provide a more predictable increase in serum concentrations rather than un-physiological elevation of serum levels through direct treatment with testosterone, and this could be favorable both for giving a predictable treatment regime with reduced chances of serious adverse effects. The present study may serve as a tool in the search for novel drugs aiming for increasing testosterone levels

A novel ECG-biomarker for cardiac arrest during hypothermia

Background: Treatment of arrhythmias evoked by accidental or therapeutic hypothermia and rewarming remains challenging. We aim to find an ECG-biomarker that can predict ventricular arrhythmias at temperatures occurring in therapeutic and accidental hypothermia. Main body: Evaluation of ECG-data from accidental and therapeutic hypothermia patients and experimental data on ECG and ventricular fibrillation (VF) threshold in hypothermic New Zealand White Rabbits. VF threshold was measured in rabbit hearts cooled to moderate (31 °C) and severe (17 °C) hypothermia. QRS-interval divided by corrected QT-interval (QTc) was calculated at same temperatures. Clinical QRS/QTc data were obtained after a systematic literature review. Rabbit QRS/QTc values correlated with risk for VF (correlation coefficient: 0.97). Human QRS/QTc values from hypothermic patients, showed similar correlation with risk for ventricular fibrillation in the experimental data (correlation coefficient: 1.00). Conclusions: These calculations indicate that QRS/QTc has potential as novel biomarker for predicting risk of hypothermia-induced cardiac arrest. Our findings apply both to victims of accidental hypothermia and to patients undergoing therapeutic hypothermia during surgery or after e.g. cardiac arrest

How should tranexamic acid be administered in haemorrhagic shock? - continuous serum concentration measurements in a swine model

Background: Tranexamic acid (TXA) reduces mortality in trauma patients. Intramuscular (IM) administration could be advantageous in low-resource and military settings. Achieving the same serum concentration as intravenous (IV) administration is important to achieve equal mortality reduction. Therefore, we aimed to investigate whether dividing an IM dose of TXA between two injection sites and whether an increase in dose would lead to serum concentrations comparable to those achieved by IV administration. Methods: Norwegian landrace pigs (n = 29) from a course in hemostatic emergency surgery were given TXA 1 h after start of surgery. Blood samples were drawn at 0, 5, 10, 15, 20, 25, 35, 45, 60, and 85 min. The samples were centrifuged and serum TXA concentrations quantified with liquid chromatography-tandem mass spectrometry. The use of two injection sites was compared with distributing the dose on one injection site, and a dose of 15 mg/kg was compared with a dose of 30 mg/kg. All IM groups were compared with IV administration. Results: The groups were in a similar degree of shock. Increasing the IM dose from the standard of 15 mg/kg to 30 mg/kg resulted in significantly higher serum concentrations of TXA, comparable to those achieved by IV administration. Distributing the IM dose on two injection sites did not affect drug uptake, as shown by equal serum concentrations. Conclusions: For IM administration of TXA, 30 mg/kg should be the standard dose. With a short delay, IM administration will provide equal serum concentrations as IV administration, above what is considered necessary to inhibit fibrinolysis

Pro-arrhythmic effect of escitalopram and citalopram at serum concentrations commonly observed in older patients – a study based on a cohort of 19,742 patients

Background - For a decade, patients have been advised against using high citalopram- and escitalopram-doses due to risk for ventricular arrhythmia and cardiac arrest. Still, these drugs are widely used to treat depression and anxiety especially in older patients. It is unclear why they are cardiotoxic and at what serum concentrations patients are at risk for arrhythmias. Thus, how many patients that are at risk for iatrogenic cardiac arrest is unknown. Methods - We studied the arrhythmogenic effects of citalopram, escitalopram and their metabolites on human cardiomyocytes. Concentrations showing pro-arrhythmic activity were compared with observed drug and metabolite serum concentrations in a cohort of 19,742 patients (age 12–105 years) using escitalopram or citalopram in Norway (2010–2019). As arrhythmia-risk is related to maximum serum concentration, this was simulated for different age-groups from the escitalopram patient material. Findings - Therapeutic concentrations of both citalopram and escitalopram but not their metabolites showed pro-arrhythmic changes in the human cardiac action potential. Due to age-dependent reduction of drug clearance, the proportion of patients above threshold for arrhythmia-risk increased with age. 20% of patients >65 years were predicted to reach potentially pro-arrhythmic concentrations, following intake of 10 mg escitalopram. Interpretation - All patients that are using escitalopram or citalopram and have genetic disposition for acquired long-QT syndrome, are >65 years, are using additional pro-arrhythmic drugs or have predisposition for arrhythmias, should be monitored with therapeutic drug monitoring (TDM) to avoid exposure to potentially cardiotoxic concentrations. Serum concentrations should be kept below 100 nM, to reduce arrhythmia-risk

Genotyping av pasienter behandlet med selektive serotoninreopptakshemmere

BAKGRUNN - Selektive serotoninreopptakshemmere (SSRI) brukes av over 180 000 mennesker i Norge. Enzymene CYP2D6 og CYP2C19 er sentrale i metabolismen av SSRI-antidepressiver. Serotonintransportøren kodet av SLC6A4 kan ha betydning for effekten av medikamentene. MATERIALE OG METODE - Alle pasienter som hadde blitt genotypet for CYP2D6, CYP2C19 og SLC6A4 ved Senter for psykofarmakologi i 2020, uavhengig av indikasjon, ble inkludert. Hos de pasientene der data var tilgjengelige, ble CYP2C19-genotype koblet til serumkonsentrasjonsmåling av escitalopram, som er det mest brukte SSRI-preparatet. RESULTATER - 432 av 3 492 pasienter (12,4 %) hadde en kombinasjon av genotyper av CYP2D6, CYP2C19 og SLC6A4 som anses å gi mest gunstig metabolisme og effekt av SSRI-antidepressiver. Pasienter med manglende CYP2C19-metabolisme hadde mer enn halvert dosebehov for å oppnå samme konsentrasjon av escitalopram som pasienter med normal metabolisme. FORTOLKNING - Våre funn viser lav forekomst av den gunstigste genotypekombinasjonen for respons av SSRI-preparater. Genotypekombinasjoner bidrar sannsynligvis til den store individuelle variasjonen i effekt av disse medikamentene og til at behandlingen ikke gir ønsket utfall hos mange pasienter

Pharmacodynamic properties for inhibition of cAMP- and cGMP elimination by pentoxifylline remain unaltered in vitro during hypothermia

Background - Rewarming from hypothermia is associated with severe complications, one of which is hypothermia-induced cardiac dysfunction. This condition is characterized by decreased cardiac output accompanied by increased total peripheral resistance. This contributes to mortality rate approaching 40%. Despite this, no pharmacological interventions are recommended for these patients below 30 °C. Raising the intracellular levels of cAMP and/or cGMP, through PDE3- and PDE5-inhibitors respectively, have showed the ability to alleviate hypothermia-induced cardiac dysfunction in vivo. Drugs that raise levels of both cAMP and cGMP could therefore prove beneficial in patients suffering from hypothermia-induced cardiac dysfunction. Methods - The unselective PDE-inhibitor pentoxifylline was investigated to determine its ability to reach the intracellular space, inhibit PDE3 and PDE5 and inhibit cellular efflux of cAMP and cGMP at temperatures 37, 34, 30, 28, 24 and 20 °C. Recombinant human PDE-enzymes and human erythrocytes were used in the experiments. IC50-values were calculated at all temperatures to determine temperature-dependent changes. Results - At 20 °C, the IC50-value for PDE5-mediated enzymatic breakdown of cGMP was significantly increased compared to normothermia (IC50: 39.4 µM ± 10.9 µM vs. 7.70 µM ± 0.265 µM, p-value = 0.011). No other significant changes in IC50-values were observed during hypothermia. Conclusions - This study shows that pentoxifylline has minimal temperature-dependent pharmacodynamic changes, and that it can inhibit elimination of both cAMP and cGMP at low temperatures. This can potentially be effective treatment of hypothermia-induced cardiac dysfunction

Cardiovascular Effects of Epinephrine During Experimental Hypothermia (32°C) With Spontaneous Circulation in an Intact Porcine Model

Aims: Rewarming from accidental hypothermia and therapeutic temperature management could be complicated by cardiac dysfunction. Although pharmacologic support is often applied when rewarming these patients, updated treatment recommendations are lacking. There is an underlying deficiency of clinical and experimental data to support such interventions and this prevents the development of clinical guidelines. Accordingly, we explored the clinical effects of epinephrine during hypothermic conditions. Materials and methods: Anesthetized pigs were immersion cooled to 32°C. Predetermined variables were compared at temperature/time-point baseline, after receiving 30 ng/kg/min and 90 ng/kg/min epinephrine infusions: (1) before and during hypothermia at 32°C, and after rewarming to 38°C (n = 7) and (2) a time-matched (5 h) normothermic control group (n = 5). Results: At 32°C, both stroke volume and cardiac output were elevated after 30 ng/kg/min administration, while systemic vascular resistance was reduced after 90 ng/kg/min. Epinephrine infusion did not alter blood flow in observed organs, except small intestine flow, and global O2 extraction rate was significantly reduced in response to 90 ng/kg/min infusion. Electrocardiographic measurements were unaffected by epinephrine infusion. Conclusion: Administration of both 30 ng/kg/min and 90 ng/kg/min at 32°C had a positive inotropic effect and reduced afterload. We found no evidence of increased pro-arrhythmic activity after epinephrine infusion in hypothermic pigs. Our experiment therefore suggests that β₁-receptor stimulation with epinephrine could be a favorable strategy for providing cardiovascular support in hypothermic patients, at core temperatures >32°C

Proarrhythmic changes in human cardiomyocytes during hypothermia by milrinone and isoprenaline, but not levosimendan: an experimental in vitro study

BackgroundAccidental hypothermia, recognized by core temperature below 35 °C, is a lethal condition with a mortality rate up to 25%. Hypothermia-induced cardiac dysfunction causing increased total peripheral resistance and reduced cardiac output contributes to the high mortality rate in this patient group. Recent studies, in vivo and in vitro, have suggested levosimendan, milrinone and isoprenaline as inotropic treatment strategies in this patient group. However, these drugs may pose increased risk of ventricular arrhythmias during hypothermia. Our aim was therefore to describe the effects of levosimendan, milrinone and isoprenaline on the action potential in human cardiomyocytes during hypothermia.MethodsUsing an experimental in vitro-design, levosimendan, milrinone and isoprenaline were incubated with iCell2 hiPSC-derived cardiomyocytes and cellular action potential waveforms and contraction were recorded from monolayers of cultured cells. Experiments were conducted at temperatures from 37 °C down to 26 °C. One-way repeated measures ANOVA was performed to evaluate differences from baseline recordings and one-way ANOVA was performed to evaluate differences between drugs, untreated control and between drug concentrations at the specific temperatures.ResultsMilrinone and isoprenaline both significantly increases action potential triangulation during hypothermia, and thereby the risk of ventricular arrhythmias. Levosimendan, however, does not increase triangulation and the contractile properties also remain preserved during hypothermia down to 26 °C.ConclusionsLevosimendan remains a promising candidate drug for inotropic treatment of hypothermic patients as it possesses ability to treat hypothermia-induced cardiac dysfunction and no increased risk of ventricular arrhythmias is detected. Milrinone and isoprenaline, on the other hand, appears more dangerous in the hypothermic setting