Family members' experiences of COVID-19 visiting restrictions in the intensive care unit-A qualitative study.

OBJECTIVE: To describe how family members of critically ill patients experienced the COVID-19 visiting restrictions in Sweden. BACKGROUND: In Sweden, the response to COVID-19 was less invasive than in many other countries. However, some visiting restrictions were introduced for intensive care units, with local variations. Although there is a growing body of literature regarding healthcare professionals' and family caregivers' perspectives on visiting restriction policies, there may be inter-country differences, which remain to be elucidated. DESIGN: This study has a qualitative descriptive design. Focus group interviews with 14 family members of patients treated for severe COVID-19 infection were conducted. The interviews took place via digital meetings during the months after the patients' hospital discharge. Qualitative content analysis was used to interpret the interview transcripts. Reporting of the study followed the COREQ checklist. RESULTS: Two categories-dealing with uncertainty and being involved at a distance-described family members' experiences of coping with visiting restrictions during the COVID-19 pandemic. These restrictions were found to reduce family members' ability to cope with the situation. Communication via telephone or video calls to maintain contact was appreciated but could not replace the importance of personal contact. CONCLUSIONS: Family members perceived that the visiting restriction routines in place during the COVID-19 pandemic negatively influenced their ability to cope with the situation and to achieve realistic expectations of the patients' needs when they returned home. RELEVANCE TO CLINICAL PRACTICE: This study suggests that, during the COVID-19 pandemic, the visiting restrictions were experienced negatively by family members and specific family-centred care guidelines need to be developed for use during crises, including the possibility of regular family visits to the ICU. PATIENT AND PUBLIC CONTRIBUTION: None in the conceptualisation or design of the study.

Voluntary apnea evokes diving responses in obstructive sleep apnea patients.

PURPOSE: Two potentially protective responses to apnea were studied in obstructive sleep apnea (OSA) patients; the diving response and the increase in Hb concentration [Hb] via spleen contraction. METHODS: Eight OSA patients and ten healthy controls performed apneas in air (A) and apneas with facial immersion in 15 °C water (FIA) after inspiration and without prior hyperventilation. In each condition, subjects performed three apneas of maximal voluntary duration spaced by 2 min of rest. Cardiorespiratory parameters were measured non-invasively, and venous blood samples for [Hb] analysis were drawn before and after apneas. RESULT: Mean (SD) apnea durations were similar between groups (NS). In controls, the heart rate (HR) reduction was 10 ± 10 % at apnea and 19 ± 10 % in FIA (P < 0.05). In OSA patients, however, the fall in HR was the same in both conditions, 13 ± 10 and 14 ± 8 % for A and FIA, respectively (NS). In controls, the [Hb] increase was the same in A and FIA (2.2 ± 2.9 and 2.1 ± 2.2 %), while in OSA the [Hb] increase was greater during FIA compared to A (3.3 ± 2.2 and 1.4 ± 0.9 %; P < 0.05). CONCLUSION: Apnea induces a diving response and [Hb] increase in both groups. OSA patients did not show the typical training effect of the diving response seen in apnea divers despite their frequent nocturnal apneas. However, they also deviated from normal controls in response pattern; face immersion enhanced the cardiovascular diving response in controls but not in OSA, while the hematological response was enhanced by face immersion only in OSA patients.

Comparison of the QT interval response during sinus and paced rhythm in conscious and anesthetized beagle dogs.

INTRODUCTION: The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different pharmacological and pharmacokinetic profiles. METHOD: Dofetilide and moxifloxacin were tested in all models, whereas cisapride and terfenadine were tested in the conscious telemetered and paced models. All substances were given as two consecutive 1.5-h intravenous infusions (infusions 1 and 2). The individual concentration-time courses of dofetilide, moxifloxacin, and cisapride were linked to the drug-induced effects on the QT interval and described with a pharmacokinetic-pharmacodynamic model to obtain an estimate of the unbound plasma concentrations at steady state that give a 10- and 20-ms drug-induced QT interval prolongation (CE10ms and CE20ms). RESULTS: In the conscious telemetered, conscious paced, and anesthetized dog models, the mean CE10ms values were 1.4, 4.0, and 2.5 nM for dofetilide and 1300, 1800, and 12,200 nM for moxifloxacin. For cisapride, the CE10ms values were 8.0 and 4.4 nM in the conscious telemetered and conscious paced dog models. The drug-induced QT interval prolongation during the last 30 min of infusions 1 and 2 was comparable in the conscious models, but smaller in the anesthetized dog model. Terfenadine displayed a marked delay in onset of response, which could only be detected by the extended ECG recording. DISCUSSION: All dog models investigated detected QT interval prolongation after administration of the investigated test substances with similar sensitivity, except for a lower sensitivity in the anesthetized dogs following moxifloxacin administration. The conscious telemetered dog model was favorable, mainly due to the extended continuous ECG recording, which facilitated detection and quantification of delayed temporal differences between systemic exposure and drug-induced QT interval prolongation.

A novel approach to data processing of the QT interval response in the conscious telemetered beagle dog.

INTRODUCTION: Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model. METHODS: The test substances cisapride, dofetilide, haloperidol, and terfenadine and corresponding vehicles were given to male and female beagle dogs during two consecutive 90-min intravenous infusions. Cardiovascular parameters were recorded for 24 h and exposure to the drugs was measured. The delayed response in the QT interval after an abrupt change in heart rate was investigated. Eight mathematical models to describe the QT interval-heart rate relationship were compared and different sets of covariates were used to quantify the drug-induced effect on the QT interval. RESULTS: After an abrupt decrease in heart rate, a 75% adaptation of the QT interval was reached after 54+/-9 s. A linear model was preferred to correct the drug-induced effect on the QT interval for heart rate, vehicle effect, serial correlation, plasma concentration and time of day. All test substances significantly prolonged the QT interval. DISCUSSION: To optimize the processing of QT interval data, the delay in QT interval response after an abrupt change in heart rate should be considered. The QT interval-heart rate relationship and vehicle response were individual-specific and corrections were therefore made individually. When estimating the drug-induced effect on the QT interval it is considered advantageous to use plasma concentration as a covariate, as well as adjusting for vehicle effect and serial correlation in measurements. The conscious dog model detected significant increases in the QT interval for all test substances investigated.

Pharmacokinetic-pharmacodynamic modeling of drug-induced effect on the QT interval in conscious telemetered dogs.

INTRODUCTION: To assure drug safety, the investigation of the relationship between plasma concentration and drug-induced prolongation of the QT interval of the ECG is a challenge in drug discovery. For this purpose, dofetilide was utilized to demonstrate the benefits of characterizing the complete time course of concentrations and effect in conscious beagle dogs in the assessment of drug safety. METHOD: On two separate occasions, four male and two female beagle dogs were given vehicle or the test substance, dofetilide (0.25 mumol/kg), over a 3-h intravenous infusion. Cardiovascular parameters, including QT intervals, were recorded for 24-h using radiotelemetry. The QT interval was corrected individually for heart rate, vehicle treatment, and serial correlation (QT(c)). Exposure (plasma concentration) to dofetilide was measured and described by a two-compartment model. The individual concentration-time course of dofetilide was linked to the QT(c) interval via an effect compartment and a pharmacodynamic E(max) model, to account for the observed hysteresis. RESULTS: Dofetilide induced a concentration-dependent increase in the QT(c) interval, with an EC(50) of 9 nM (3-30 nM, 95% C.I.) and an E(max) of 59+/-9 ms. A hysteresis loop was observed by plotting plasma concentrations vs. QT interval in time order, indicating a delay in onset of effect. It was found to have an equilibrium half-life of 11+/-8 min. Based on the parameters potency and E(max), a representation was made of the drug-induced changes to the QT interval. DISCUSSION: An effect compartment model was found to accurately mimic the QT interval prolongation following administration of the test substance, dofetilide. The assessment of the individual concentration-effect relationship and confounding factors such as hysteresis might provide a better prediction of the safety profiles of new drug candidates.

Modeling drug- and system-related changes in body temperature: application to clomethiazole-induced hypothermia, long-lasting tolerance development, and circadian rhythm in rats.

The aim of the present investigation was to develop a pharmacokinetic-pharmacodynamic model for the characterization of clomethiazole (CMZ)-induced hypothermia and the rapid development of long-lasting tolerance in rats while taking into account circadian rhythm in baseline and the influence of handling. CMZ-induced hypothermia and tolerance was measured using body temperature telemetry in male Sprague-Dawley rats, which were given s.c. bolus injections of 0, 15, 150, 300, and 600 micromol kg(-1) and 24-h s.c. continuous infusions of 0, 20, and 40 micromol kg(-1) h(-1) using osmotic pumps. The duration of tolerance was studied by repeated injections of 300 micromol kg(-1) at 3- to 32-day intervals. Plasma exposure to CMZ was obtained in satellite groups of catheterized rats. Fitted population concentration-time profiles served as input for the pharmacodynamic analysis. The asymmetric circadian rhythm in baseline body temperature was successfully described by a novel negative feedback model incorporating external light-dark conditions. An empirical function characterized the transient increase in temperature upon handling of the animal. A feedback model for temperature regulation and tolerance development allowed estimation of CMZ potency at 30 +/- 1 microM. The delay in onset of tolerance was estimated via a series of four transit compartments at 7.6 +/- 2 h. The long-lasting tolerance was assumed to be caused by inactivation of a mediator with an estimated turnover time of 46 +/- 3 days. This multicomponent turnover model was able to quantify the CMZ-induced hypothermia, circadian rhythm in baseline, and rapid onset of a long-lasting tolerance to CMZ in rats.

A pharmacodynamic turnover model capturing asymmetric circadian baselines of body temperature, heart rate and blood pressure in rats: challenges in terms of tolerance and animal-handling effects.

This study presents development and behaviour of a feedback turnover model that mimics asymmetric circadian oscillations of body temperature, blood pressure and heart rate in rats. The study also includes an application to drug-induced hypothermia, tolerance and handling effects. Data were collected inn normotensive Sprague-Dawley rats, housed at 25 degrees C with a 12:12 hr light dark cycle (light on at 06:00 am) and with free access of food and water. The model consisted of two intertwined parallel compartments which captured a free-running rhythm with a period close to but not exactly 24 hrs. The free-running rhythm was synchronised to exactly 24 hrs by the environmental timekeeper (12:12 hr light on/off cycle) in experimental settings. The baseline model was fitted to a standardised 24-hr period derived from mean data of six animals over a period of nine consecutive days. The first-order rate constants related to the turnover of the baseline temperature, alpha and beta, were 0.026 min(-1) (+/-5%) and 0.0037 min(-1) (+/-3%). The alpha and beta parameters are approximately 2/transition time between day and night and 2/night time, respectively. The day:night timekeeper g(t), reference point T(ref) and amplitude were 0.053(+/-2%), 37.3(+/-0.02%) and 3.3% (+/-2%), respectively. Simulations with the baseline model revealed stable oscillations (free-running rhythm) in the absence of the timekeeper. This temperature-time profile was then symmetric and had a smaller amplitude, with a slightly shorter period and less pronounced temperature shift as compared to the profile in the presence of an external Timekeeper. Fitting the model to 96 hr mean profiles of blood pressure and heart rate from 10 control animals demonstrated the usefulness of the model. Simulations of the integrated temperature model succeeded in mimicking other modes of administration such as oral dosing.

Rapid and long-lasting tolerance to clomethiazole-induced hypothermia in the rat.

Mechanism, onset and duration of tolerance development to clomethiazole-induced hypothermia were investigated in rats using telemetry. The hypothermic effect of clomethiazole was completely abolished for 10 days after an s.c. injection of 300 micromol/kg and the effect returned to approximately 50% in 32 days. The gamma-aminobutyric acidA (GABA(A)) receptor agonist muscimol induced hypothermia at 88 micromol/kg without any (cross-) tolerance. GABA(A) receptor antagonists, bicuculline (5.4 micromol/kg) and picrotoxin (3.3 micromol/kg), did not inhibit clomethiazole-induced hypothermia nor the tolerance. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine, counteracted clomethiazole-induced hypothermia at 3 micromol/kg but not the tolerance. Tolerance to the 5-hydroxytryptamine(1A) (5-HT(1A)) receptor agonist R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (R-8-OH-DPAT)-induced hypothermia was blocked by dizocilpine and clomethiazole but not vice versa. No pharmacokinetic interaction was observed. In conclusion, long-lasting tolerance to clomethiazole-induced hypothermia does not involve GABA(A) or 5-HT(1A) receptor functions. Glutamate via NMDA receptors may be involved in the hypothermic response but not in the tolerance.