Inhaled nitric oxide as temporary respiratory stabilization in patients with COVID-19 related respiratory failure (INOCOV): Study protocol for a randomized controlled trial

Background In March 2020, WHO announced the COVID-19 a pandemic and a major global public health emergency. Mortality from COVID-19 is rapidly increasing globally, with acute respiratory failure as the predominant cause of death. Many patients experience severe hypoxia and life-threatening respiratory failure often requiring mechanical ventilation. To increase safety margins during emergency anaesthesia and rapid sequence intubation (RSI), patients are preoxygenated with a closed facemask with high-flow oxygen and positive end-expiratory pressure (PEEP). Due to the high shunt fraction of deoxygenated blood through the lungs frequently described in COVID-19 however, these measures may be insufficient to avoid harmful hypoxemia. Preoxygenation with inhaled nitric oxide (iNO) potentially reduces the shunt fraction and may thus allow for the necessary margins of safety during RSI. Methods and design The INOCOV protocol describes a phase II pharmacological trial of inhaled nitric oxide (iNO) as an adjunct to standard of care with medical oxygen in initial airway and ventilation management of patients with known or suspected COVID-19 in acute respiratory failure. The trial is parallel two-arm, randomized, controlled, blinded trial. The primary outcome measure is the change in oxygen saturation (SpO2), and the null hypothesis is that there is no difference in the change in SpO2 following initiation of iNO.publishedVersio

Characteristics of Opioid Overdoses and Intranasal Pharmacology of Naloxone

Sammendrag Opioider, morfinlignende stoffer, fører til overdoser og dødsfall. I Norge dør rundt 250 mennesker hvert år. Disse dødsfallene kan i prinsippet forebygges. Det er økende fokus på skadereduserende tiltak, for eksempel sprøyterom og væresteder. Opioidforgiftning behandles med motgiften nalokson som har vært på markedet som injeksjon i over femti år. Verdens Helseorganisasjon anbefaler at alle som kan bli vitne til en opioidoverdose skal ha tilgang til nalokson, og flere harjobbet for at nalokson skal bli tilgjengelig som nesespray, ikke bare i sprøyteform. Slik nesespray er brukt som førstehjelp i flere år. Sprayene har vært provisoriske løsninger uten godkjenning fra myndighetene og grunnleggende kunnskap om deres farmakologiske egenskaper har manglet. Denne ph.d. oppgaven tar sikte på å øke vitenskapelig forståelse av både forhold rundt opioidoverdoser og av farmakologiske egenskaper ved nalokson gitt intranasalt. Vi har analysert kliniske data og oppfølgingen etter behandling i 1054 tilfeller av overdoser i Oslo Sentrum 2014-15. Vi har gjennomført to farmakokinetiske og farmakodynamiske studier (n= 12ogn= 22). I disse har friske frivillige deltagere fått nalokson intranasalt, intramuskulært og intravenøst. I ett studie fikk de bare nalokson, i den andre også opioidet remifentanil for å kunne måle virkningen av nalokson. Ved avansert modellering av resultatene beregnet vi en nasal dose som skulle være sammenlignbar med en effektiv sprøytedose. Fra de 1054 overdosene fant vi at medianalderen for overdose var 35år,og 79% er menn. Pasienter på Sprøyterommet og i private hjem var sykere enn de som ble behandlet på offentlige steder. Studiene i friske frivillige viste at intranasalt nalokson har enbiotilgjenglighet sammenlignet med sprøyte på 0,50, men som økte til 0,75 ved samtidig bruk av et opioid. Måling av pupillstørrelse, men ikke smerteterskel, egnet seg til å vurdere virkningen av nalokson i friske frivillige . Etter beregning og utprøving fant vi at intranasal 1,4 mg nalokson må ansees som like god behandling som intramuskulært 0,8 mg. Vår nesespray på 1,4 mg er nå godkjent for bruk i 12 land i Europa

The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers

Purpose Remifentanil has been shown to increase the bioavailability of nasally administered naloxone. The aim of this study was to explore the nature of this observation. Methods We analysed samples from three pharmacokinetic studies to determine the serum concentrations of naloxone3-glucuronide (N3G), the main metabolite of naloxone, with or without exposure to remifentanil. To enable direct comparison of the three studies, the data are presented as metabolic ratios (ratio of metabolite to mother substance, N3G/naloxone) and dose-corrected values of the area under the curve and maximum concentration (Cmax). Results. Under remifentanil exposure, the time to maximum concentration (Tmax) for N3G was signifcantly higher for intranasal administration of 71 min compared to intramuscular administration of 40 min. The dose-corrected Cmax of N3G after intranasal administration of naloxone under remifentanil exposure was signifcantly lower (4.5 ng/mL) than in subjects not exposed to remifentanil (7.8–8.4 ng/mL). The metabolic ratios after intranasal administration rose quickly after 30–90 min and were 2–3 times higher at 360 min compared to intravenous and intramuscular administration. Remifentanil exposure resulted in a much slower increase of the N3G/naloxone ratio after intranasal administration compared to intranasal administration with the absence of remifentanil. After remifentanil infusion was discontinued, this efect gradually diminished. From 240 min there was no signifcant diference between the ratios observed after intranasal naloxone administration. Conclusion. Remifentanil increases the bioavailability of naloxone after nasal administration by reducing the pre-systemic metabolism of the swallowed part of the nasal dose

Pharmacodynamics and arteriovenous difference of intravenous naloxone in healthy volunteers exposed to remifentanil

Purpose Pharmacodynamic studies of naloxone require opioid agonism. Steady state condition may be achieved by remifentanil TCI (target controlled infusion). Opioid agonism can be measured by pupillometry. It is not known whether there are arteriovenous concentration differences for naloxone. The aim was thus to further develop a model for studying pharmacokinetic/pharmacodynamic aspects of naloxone and to explore whether a significant arteriovenous concentration difference for naloxone in humans was present. Methods Relevant authorities approved this study. Healthy volunteers (n = 12) were given 1.0 mg intravenous (IV) naloxone after steady state opioid agonism was obtained by TCI of remifentanil (1.3 ng/ml). Opioid effect was measured by pupillometry. Arterial and venous samples were collected simultaneously before and for 2 h after naloxone administration for quantification of naloxone and remifentanil. Results Arterial remifentanil was in steady state at 12 min. One milligram IV naloxone reversed the effect of remifentanil to 93% of pre-opioid pupil-size within 4 min. The estimated duration of antagonism was 118 min. At that time, the concentration of naloxone was 0.51 ng/ml. The time course of arterial and venous serum concentrations for naloxone was similar, although arterial AUC (area under the curve) was slightly lower (94%) than the venous AUC (p = 0.03). There were no serious adverse events. Conclusion Onset of reversal by IV naloxone was rapid and lasted 118 min. The minimum effective concentration was 0.5 ng/ml. Using TCI remifentanil to obtain a steady-state opioid agonism may be a useful tool to compare new naloxone products

Pharmacokinetics of a new, nasal formulation of naloxone

Purpose Nasal naloxone is wanted for bystander administration in opioid overdose and as a needle-free alternative for emergency medical personnel. Epidemiologic studies have indicated a therapeutic effect of bystander administration of low-concentration/high-volume formulations. The objective for this study was to describe the nasal pharmacokinetics of a new high-concentration/low-volume nasal formulation of naloxone. Methods This was an open, randomized triple crossover trial in healthy, human volunteers (n = 12) where two doses of nasal naloxone (0.8 and 1.6 mg) and one intravenous dose (1.0 mg) were compared. Fifteen serum samples were collected before and until 6 h after naloxone administration. Quantification of naloxone was performed by a validated liquid chromatography-tandem mass spectrometry method. Results Bioavailability was 0.54 (0.45–0.63) for the 0.8 mg and 0.52 (0.37–0.67) for the 1.6 mg nasal naloxone formulation. Maximum concentration levels (Cmax) were 1.45 ng/ml (1.07–1.84) for 0.8 mg and 2.57 ng/ml (1.49–3.66) for the 1.6 mg. Time to maximum concentrations (Tmax) were reached at 17.9 min (11.4–24.5) and 18.6 min (14.4–22.9) for the 0.8 mg and the 1.6 mg doses, respectively. Conclusion This nasal naloxone formulation had a rapid, systemic uptake and higher bioavailability than naloxone formulations not designed for IN use. This indicates that an optimized high-concentration/low-volume nasal spray formulation may deliver a therapeutic dose. The 1.6 mg nasal dose provided serum concentrations that surpassed those of 1.0 mg IV after 15–20 min and stayed above for the rest of the study period

Pharmacokinetics of a novel, approved, 1.4-mg intranasal naloxone formulation for reversal of opioid overdose—a randomized controlled trial

Background and aims Intranasal (i.n.) naloxone is an established treatment for opioid overdose. Anyone likely to witness an overdose should have access to the antidote. We aimed to determine whether an i.n. formulation delivering 1.4 mg naloxone hydrochloride would achieve systemic exposure comparable to that of 0.8 mg intramuscular (i.m.) naloxone. Design Open, randomized four‐way cross‐over trial. Setting Clinical Trials Units in St Olav's Hospital, Trondheim and Rikshospitalet, Oslo, Norway. Participants Twenty‐two healthy human volunteers, 10 women, median age = 25.8 years. Intervention and comparator One and two doses of i.n. 1.4 mg naloxone compared with i.m. 0.8 mg and intravenous (i.v.) 0.4 mg naloxone. Measurements Quantification of plasma naloxone was performed by liquid chromatography tandem mass spectrometry. Pharmacokinetic non‐compartment analyses were used for the main analyses. A non‐parametric pharmacokinetic population model was developed for Monte Carlo simulations of different dosing scenarios. Findings Area under the curve from administration to last measured concentration (AUC0‐last) for i.n. 1.4 mg and i.m. 0.8 mg were 2.62 ± 0.94 and 3.09 ± 0.64 h × ng/ml, respectively (P = 0.33). Maximum concentration (Cmax) was 2.36 ± 0.68 ng/ml for i.n. 1.4 mg and 3.73 ± 3.34 for i.m. 0.8 mg (P = 0.72). Two i.n. doses showed dose linearity and achieved a Cmax of 4.18 ± 1.53 ng/ml. Tmax was reached after 20.2 ± 9.4 minutes for i.n. 1.4 mg and 13.6 ± 15.4 minutes for i.m. 0.8 mg (P = 0.098). The absolute bioavailability for i.n. 1.4 mg was 0.49 (±0.24), while the relative i.n./i.m. bioavailability was 0.52 (±0.25). Conclusion Intranasal 1.4 mg naloxone provides adequate systemic concentrations to treat opioid overdose compared with intramuscular 0.8 mg, without statistical difference on maximum plasma concentration, time to maximum plasma concentration or area under the curve. Simulations support its appropriateness both as peer administered antidote and for titration of treatment by professionals

Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers

Purpose This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg. Methods Two-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured. Results The relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02–p < 0.001). Heat pain threshold showed no statistical difference. Conclusions A target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose

Ambulance-attended opioid overdoses: An examination into overdose locations and the role of a safe injection facility

Background: Although the United States and numerous other countries are amidst an opioid overdose crisis, access to safe injection facilities remains limited. Methods: We used prospective data from ambulance journals in Oslo, Norway, to describe the patterns, severity, and outcomes of opioid overdoses and compared these characteristics among various overdose locations. We also examined what role a safe injection facility may have had on these overdoses. Results: Based on 48,825 ambulance calls, 1054 were for opioid overdoses from 465 individuals during 2014 and 2015. The rate of calls for overdoses was 1 out of 48 of the total ambulance calls. Males made up the majority of the sample (n = 368, 79%), and the median age was 35 (range: 18–96). Overdoses occurred in public locations (n = 530, 50.3%), the safe injection facility (n = 353, 33.5%), in private homes (n = 83, 7.9%), and other locations (n = 88, 8.3%). Patients from the safe injection facility and private homes had similarly severe initial clinical symptoms (Glasgow Coma Scale median =3 and respiratory frequency median =4 breaths per minute) when compared with other locations, yet the majority from the safe injection facility did not require further ambulance transport to the hospital (n = 302, 85.6%). Those overdosed in public locations (odds ratio [OR] = 1.66, 95% confidence interval [CI] = 1.17–2.35), and when the safe injection facility was closed (OR =1.4, 95% CI =1.04–1.89), were more likely to receive transport for further treatment. Conclusions: Our findings suggest that the opening hours at the safe injection facility and the overdose location may impact the likelihood of ambulance transport for further treatment

REBOARREST, resuscitative endovascular balloon occlusion of the aorta in non-traumatic out-of-hospital cardiac arrest: a study protocol for a randomised, parallel group, clinical multicentre trial

Background Survival after out-of-hospital cardiac arrest (OHCA) is poor and dependent on high-quality cardiopulmonary resuscitation. Resuscitative endovascular balloon occlusion of the aorta (REBOA) may be advantageous in non-traumatic OHCA due to the potential benefit of redistributing the cardiac output to organs proximal to the aortic occlusion. This theory is supported by data from both preclinical studies and human case reports. Methods This multicentre trial will enrol 200 adult patients, who will be randomised in a 1:1 ratio to either a control group that receives advanced cardiovascular life support (ACLS) or an intervention group that receives ACLS and REBOA. The primary endpoint will be the proportion of patients who achieve return of spontaneous circulation with a duration of at least 20 min. The secondary objectives of this trial are to measure the proportion of patients surviving to 30 days with good neurological status, to describe the haemodynamic physiology of aortic occlusion during ACLS, and to document adverse events. Discussion Results from this study will assess the efficacy and safety of REBOA as an adjunctive treatment for non-traumatic OHCA. This novel use of REBOA may contribute to improve treatment for this patient cohort.publishedVersio