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Anesthetic Pharmacology: Research Report

First Human Study of the Investigational Sedative and Anesthetic Drug AZD3043

A Dose-Escalation Trial to Assess the Safety, Pharmacokinetics, and Efficacy of a 30-Minute Infusion in Healthy Male Volunteers

Kalman, Sigridur MD, PhD*; Koch, Pauline MD*; Ahlén, Kjell MD; Kanes, Stephen J. MD, PhD; Barassin, Stéphane PhD; Björnsson, Marcus A. MSc Pharm, PhD§; Norberg, Åke MD, PhD*

Author Information
doi: 10.1213/ANE.0000000000000831

Current short-acting IV sedative/hypnotic drugs are limited by ventilatory and circulatory depression,1–3 pain on injection,4,5 and accumulation on prolonged infusion,6,7 which impede the rate and quality of recovery. Rapid recovery is increasingly important in medical practice, particularly for outpatient and procedural sedation. One approach to achieve rapid recovery is to use metabolically fragile drugs, so-called soft drugs, that after administration are very quickly transformed into inactive metabolites.8 Such a drug with rapid onset and offset together with a wide therapeutic window between the desired anesthetic effects and the unwanted side effects could be a valuable addition to the sedative/hypnotic armamentarium.

AZD3043, originally called THRX-918661, is an investigational anesthetic drug belonging to the phenylpropionate eugenol class of compounds. AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A (GABAA) receptor that is extensively and rapidly metabolized to an inactive carboxylate metabolite (THRX-108893) through hydrolysis by esterases, including butyrylcholinesterases, present in blood and liver.9 Preclinical results in rats and minipigs indicate that AZD3043 has the potential as a short-acting drug for anesthesia and sedation with rapid, predictable, and complete recovery characteristics and a favorable safety and tolerability profile.9

We report the results of the first human study of AZD3043 in healthy male volunteers. The primary objective was to evaluate the safety and tolerability of AZD3043 after IV infusion of ascending doses and to estimate the maximal tolerated dose. Secondary objectives included characterization of the pharmacokinetics of AZD3043 and its main metabolite, THRX-108893, and assessment of sedation/anesthesia.

METHODS

This phase 1, open-label, single-center study (clinicaltrials.gov identifier NCT00918515) was performed in accordance with the Declaration of Helsinki and Good Clinical Practice. The study protocol and consent forms were approved by the Regional Independent Ethics Committee in Stockholm and by the Swedish Medical Products Agency. All subjects gave written informed consent.

Subjects

Healthy male volunteers aged between 18 and 45 years were eligible to enter this study. Health was assessed on the basis of medical history and physical examination, including 12-lead electrocardiogram (ECG), vital signs, blood and urinary laboratory assessments as well as a preanesthesia assessment of risk of airway compromise and contraindications for the study procedures, including Mallampati score, neck circumference, and the Allen test. A resting heart rate within 55 to 85 bpm and normal phenotype for butyrylcholinesterase (pseudocholinesterase) were required. The 55-bpm lower limit for heart rate was set as a precaution in case AZD3043 was found to induce bradycardia, as reported with other anesthetics.10

Treatment

AZD3043 was administered by IV infusion over 30 minutes as an emulsion containing 60 mg/mL AZD3043 formulated with Lipoid MCT® (Ludwigshafen, Germany), lecithin, and glycerol. An arterial catheter was inserted in the radial artery of the nondominant hand. Venous catheters were placed in the cubital veins bilaterally, one for drug infusion in the same arm as the arterial line and one in the contralateral arm for blood sampling. Six subjects were scheduled to receive AZD3043 in each dose group. After each dose assessment, the Safety Review Committee evaluated all available safety, tolerability, pharmacokinetic, and pharmacodynamic data of AZD3043 and THRX-108893 and decided the next dose (increased or decreased dose, repeated dose, or termination of the study). The maximum allowed dose increase was 3-fold for the first dose escalation (dose group 2) and 2-fold for the subsequent dose escalations. Each subject participated in 1 dose assessment only. The starting dose of 1 mg/kg/h (30-minute infusion) was selected to provide exposure below the predicted sedative and anesthetic range, based on preclinical data, and reflected a safety factor of 150 based on preclinical toxicology. The predefined exposure limit was venous Cmax 100 μM or area under the curve 2000 μmol/L•h that approximately equals 660 mg/L•h (sum of AZD3043 and main metabolite), extrapolated from the preclinical no observed adverse effects level of 315 mg/kg observed in a minipig 14-day toxicology study (unpublished data, Huntingdon Life Sciences Ltd., Alconbury, Huntingdon, Cambridgeshire, UK).

The study consisted of 3 visits: a screening visit followed within 30 days by a 2-day residential treatment visit followed within 5 to 10 days by a follow-up visit including laboratory testing. For the treatment visit, subjects arrived in the evening of day 1 and fasted overnight and during the infusion/anesthesia. Subjects were discharged the day after the infusion.

Assessments

Adverse events (AEs) were recorded according to MedDRA Preferred Term version 13.0 for the period from start of infusion to the follow-up visit. Heart rate, systolic and diastolic blood pressure, and mean arterial blood pressure were measured noninvasively and monitored continuously during infusion using a Dräger Delta anesthesia monitor (Lübeck, Germany). A 3-lead real-time ECG was monitored from ≥5 minutes before the infusion until 2 hours after infusion, and 12-lead digital ECGs were recorded from 20 minutes before infusion to 5 minutes after infusion (55-minute recording) with subsequent 5-minute recordings at 25, 70, 130, and 205 minutes after infusion. The interval between the Q and T wave on the ECG (QT interval) was corrected for heart rate using the Fridericia formula (QTcF).11 Blood and urine samples for laboratory assessments were taken at baseline (day 1), the day after treatment (day 2), and at the follow-up visit. AZD3043 and its major metabolite, THRX-108893, were stabilized by using EDTA/sodium fluoride–coated tubes (Teklab, Durham, UK). Laboratory assessments comprise plasma albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, total calcium, creatinine, glucose, potassium, sodium, C-reactive protein, lactate dehydrogenase, creatine kinase, urea, uric acid, chloride, triglycerides, high-density lipoprotein, low-density lipoprotein, cholesterol, cystatin C, serum total thyroxine, thyroid-stimulating hormone, blood standard bicarbonate, hemoglobin, leukocytes, absolute leukocyte differential count, platelet count, hematocrit, erythrocyte-mean corpuscular volume, activated partial thromboplastin time; urine glucose, erythrocytes, protein, and pH.

Ventilation pattern and rate, peripheral arterial oxygen saturation measured by pulse oximeter, and end-tidal carbon dioxide concentration measured in nasal and oral exhalation were assessed continuously throughout infusion until the subject had recovered sufficiently to respond, at least lethargically, to their name spoken in a normal tone. Samples for arterial blood gas and pH assessment were taken immediately before infusion and at 10, 30, 35, and 150 minutes after the start of infusion. Apnea was defined as a pause of breath of >30 seconds or leading to peripheral arterial oxygen saturation ≤93%.

Depth of sedation/anesthesia was assessed using a Modified Observers Assessment of Alertness/Sedation score (MOAA/S; modified from Chernik et al.12; Table 1). In addition, bispectral index score (BIS) was measured continuously using an integrated Aspect A-2000 BIS® monitor. Onset and offset of sedation/anesthesia were assessed by clinical signs and by the recovery of orientation to person, time, place, and situation as well as by recovery of proprioception on ability to stand and walk according to a nonvalidated pragmatic scale used in our department (Table 1). MOAA/S and oral command tests were performed immediately before the infusion, every 10 minutes during infusion, at the end of infusion, and at 5, 10, 15, 20, 25, 30, 45, 60, 120, 180, and 240 minutes thereafter until a MOAA/S score ≥4 was obtained. Time to loss of handgrip (syringe drop) was measured, and eyelash reflex was checked every minute. Orientation and proprioception were assessed 30 minutes before the start of infusion and at 30, 45, 60, 120, 180, and 240 minutes after infusion, provided MOAA/S had reached ≥4, until scores returned to baseline.

Table 1
Table 1:
Assessment Scales

This was a dose-ranging study in which every subject in each dose panel received the same dose, and there was no blinding of doses or observations. Nevertheless, we endeavored to make systematic observations on the characteristics of anesthesia using the scoring system depicted in Table 2, which was developed for this study and has not been validated.

Table 2
Table 2:
Quality of Anesthesia in Spontaneously Breathing Patients Given AZD3043 in Doses Resulting in General Anesthesia

Arterial and venous blood samples for pharmacokinetic assessments were taken predose and at 2, 5, 15, 29, 31, 32, 35, 37, 40, 45, 60, 75, 90, and 150 minutes after the start of the 30-minute infusion with additional venous blood samples at 4.5, 8, and 24 hours after the start of infusion. Each sample was 3 mL, and approximately 100 mL of blood was taken in total. Urine samples were collected over 0 to 6, 6 to 12, and 12 to 24 hours after the start of infusion. Plasma samples were collected in the presence of stabilizers to avoid esterase-induced plasma hydrolysis of AZD3043. Total AZD3043 and THRX-108893 plasma and urine concentrations were determined by Huntingdon Life Sciences Ltd, Huntingdon, UK, using a validated high-throughput liquid chromatography–mass spectrometry method with an API 3000 (Applied Biosystems/MDS SCIEX, Concord, Ontario, Canada) using TurboionSpray ionization in the positive ion mode with multiple reaction monitoring. For human plasma, the method was validated over the concentration range 0.01 to 20 μg/mL for AZD3043 and THRX-108893. The limit of quantification was 0.01 μg/mL for both AZD3043 and THRX-108893. The overall mean precision (coefficient of variation [%CV]) and accuracy (%Bias) for the QC samples at 3 concentrations in plasma were 8.4% and ±4.6% for AZD3043 and 6.5% and ±3.1% for THRX-108893.

Statistics

The sample size was based on experience with other compounds to obtain adequate safety, tolerability, and pharmacokinetic data to achieve the objectives of the study while exposing as few subjects as possible to study medication and procedures. Data were summarized using descriptive statistics. Between-subject variability is expressed as ± SD or as CV%, being the ratio of the SD to the mean, expressed as a percentage.

RESULTS

One hundred twenty-six healthy male volunteers were screened at a single study site, of whom 53 passed screening and received AZD3043. The first subject enrolled June 8, 2009, and the last subject completed August 21, 2009. Demographic characteristics were similar between dose groups. The overall mean age was 27 years (range 18–42 years), and all subjects were white. The first dose group (infusion rate 1 mg/kg/h) comprises only 5 subjects owing to an unexpectedly high screening failure rate because of a resting heart rate <55 bpm. Recruitment was increased for subsequent cohorts. Dose escalation proceeded without interruption with infusion rates of 3, 6, 12, 18, 27, 36, 54, and 81 mg/kg/h. At the highest dose rate, 2 subjects had Cmax >35 μg/mL (>100 μM) in venous plasma, indicating that the predefined exposure limit had been reached. The sum of drug and metabolite geometric mean area under the curve in arterial plasma did not reach >20% of the predefined area under the curve limit (Supplemental Digital Content, http://links.lww.com/AA/B151). A nontolerated dose was not identified, and the maximal tolerated dose was not established.

Safety and Tolerability

Sixteen subjects (30%) experienced at least 1 AE. There were no discontinuations because of AEs. AEs occurring in >1 subject were headache (n = 4), erythema (n = 3), chest discomfort (n = 2), nausea (n = 2), and dyspnea (n = 2). The frequency and character of AEs did not change with increasing dose. Three subjects (1 in each of the 12-, 27-, and 81-mg/kg/h groups) experienced erythema after the start of the infusion, of which 2 also experienced dyspnea and chest pressure (12- and 27-mg/kg/h infusion rate). No changes were observed in these 3 subjects’ study measures of ECG, vital signs, or laboratory values, no rhonchi was heard, and the infusion was continued while the symptoms disappeared and the subjects fell asleep. Supplementary tryptase tests performed in 1 subject (immediately and after 2 hours) were both negative. Two subjects (27- and 54-mg/kg/h group) experienced nausea after the end of infusion, one of whom (in the 54-mg/kg/h group) experienced intermittent nausea and vomiting of moderate intensity during the entire 12-hour postdose period. There were no spontaneous reports of pain on injection and no significant changes in clinical chemistry variables.

An apparently dose-dependent increase in heart rate was observed at infusion rates of 18 mg/kg/h and above (Fig. 1A). Increases in heart rate began shortly after the start of the infusion and returned to near baseline approximately 15 minutes after the end of infusion. The maximal mean group heart rate was 136 bpm (SD 12, range 119–151) at 30 minutes (end of infusion) in the 81-mg/kg/h infusion rate group. A number of moderate QTcF shortenings were observed in the high-dose groups, which appeared to be related to the increased heart rate. No individual QTcF shortening >40 milliseconds or prolongation >30 milliseconds was observed. There were no clinically relevant treatment-related changes or trends in systolic, diastolic, or mean arterial blood pressure (Fig. 1B).

Figure 1
Figure 1:
Vital signs: (A) heart rate and (B) mean arterial blood pressure. Group mean values are presented.
Figure 2
Figure 2:
Mean PCO2 in arterial blood for each dose study group.

There were no persistent changes in respiratory rate, and peripheral arterial oxygen saturation did not decrease <94% in any subject. Three episodes of apnea were recorded (1 each in the 3-, 12-, and 27-mg/kg/h infusion rate groups; duration 30, 33, and 42 seconds). Two subjects required airway support, both in the 81-mg/kg/h group. No subject required assisted ventilation. A dose-dependent increase in mean PCO2 in arterial blood was observed over time during the infusion. All dose groups up to infusion rate 27 mg/kg/h reached their observed maximum at the 31-minute measurement with only the 27-mg/kg/h group mean above the normal range, 45.5 ± 4.2 mm Hg (Fig. 2). The 36-, 54-, and 81-mg/kg/h infusion rate groups reached 45.3 ± 2.2, 49.2 ± 5.1, and 51.7 ± 2.1 mm Hg, respectively, as their observed maximum at 36 minutes after start of infusion (Fig. 2). Likewise, there was a trend for increased end-tidal carbon dioxide concentration in the 36-, 54-, and 81-mg/kg/h infusion rate groups. Blood pH remained stable in all subjects. Variation in laboratory assessment variables between baseline and postdose samples did not exhibit any dose-dependency or trend for AZD3043 treatment effect.

Pharmacokinetics

Figure 3
Figure 3:
Mean ± SD plasma concentration of AZD3043 and its carboxylated metabolite THRX-108893 at representative infusion rate of 12 mg/kg/h. The molecular weights of AZD3043 and THRX-108893 are 351.4 and 309.4 g/mol, respectively. Because the terminal half-life of the inactive metabolite THRX-108893 is more than twice that of AZD3043, it will dominate the AUC related to limit of exposure. AUC = area under the curve.

Figure 3 shows the mean plasma concentration–time profile observed in a single-dose group (12 mg/kg/h), which is representative of the profile observed in each dose group. Pharmacokinetic data for all individuals and groups are provided in the accompanying manuscript.13 Steady state was not reached during 30 minutes of infusion. AZD3043 was mainly excreted in urine as THRX-108893; the maximal individual fraction of AZD3043 excreted unchanged in urine was 0.0175%.

Pharmacodynamics and Efficacy

Incidence and depth of sedation/anesthesia corresponded with dose. As judged by the investigator, 24 subjects were anesthetized, including all subjects who received infusion rates of 36 mg/kg/h and greater (Table 3). The slowest applied infusion rate at which MOAA/S <4 was observed was 12 mg/kg/h (Fig. 4A). Likewise, 12 mg/kg/h was the slowest infusion rate associated with a mean BIS of <80 (Fig. 4B). The variability (CV%, 100 × SD/mean) of mean BIS ranged from 4% to 84% with the greatest variability in the highest dose group toward the end of infusion at 28 minutes. On the basis of clinical signs, onset of anesthesia ranged from approximately 4 minutes in the highest dose group to 29 minutes in the single subject who achieved anesthesia (loss of eyelash reflex) in the 12-mg/kg/h group (Fig. 5, A–C). Recovery from sedation/anesthesia was smooth, and time to recovery increased with increasing dose (Fig. 5, D and E). Likewise, the time to achieve all 3 correct answers in the orientation assessment increased with dose, ranging from 5 minutes in a subject in the 12-mg/kg/h group to 120 minutes in a subject in the 81-mg/kg/h group. All subjects recovered proprioception by the first assessment at 30 minutes after the end of infusion, except for 1 subject in each of the 54- and 81-mg/kg/h infusion rate groups, who recovered proprioception by the subsequent assessment, 45 minutes after the end of infusion.

Table 3
Table 3:
Number of Subjects Sedated/Anesthetized
Figure 4
Figure 4:
Depth of sedation and anesthesia over time. A, Number of subjects with MOAA/S ≥4, and (B) mean BIS for each dose study group at the given time points. MOAA/S = Modified Observers Assessment of Alertness/Sedation; BIS = bispectral index score.
Figure 5
Figure 5:
Clinical signs indicating onset and recovery from anesthesia. Time to onset: (A) loss of handgrip, (B) loss of eyelash reflex, and (C) response to oral command. Time to recovery: (D) spontaneous eye opening and (E) return of response to oral command. Although anesthetized, one subject in the 36-mg/kg/h infusion rate group had no onset/offset data owing to technical problems with assessment and was not included in the analysis. There were 6 subjects in all groups except the 6-mg/kg/h infusion rate group, which had 5 subjects, none of whom lost spontaneous eye opening or response to oral command.

The investigator’s assessment of anesthesia, according to the predefined categories in Table 2, indicated that spontaneous movements and increases in heart rate of >40% from baseline were encountered in the majority of subjects in the higher dose groups (Table 2). The involuntary movements ranged from minor twitches in lower dose groups to slow but strong internal rotation of the limbs accompanied by an increase in muscle tone in the higher dose groups. These movements began shortly after the start of infusion and ceased shortly after the end of infusion. One subject in the 36-mg/kg/h group exhibited profound restlessness, laughter, and strong verbal expressions for 7 minutes starting 10 minutes after the end of administration (MOAA/S = 3) and reported hyperacusis.

DISCUSSION

In this first human study, a 30-minute IV infusion of AZD3043 was well tolerated up to the highest dose of 81 mg/kg/h. A nontolerated dose was not identified, and dose escalation stopped at the 81-mg/kg/h level because the predefined maximal exposure was reached. Systemic exposure of AZD3043 was measured by sampling blood in commercially available EDTA/sodium fluoride-coated tubes to prevent the hydrolysis of AZD3043 into its inactive metabolite. Generally, the effects of AZD3043 were as expected for a GABAA receptor agonist with rapid onset of effect leading to sedation at lower doses and anesthesia at higher doses. In addition, as predicted from preclinical data,9 recovery from AZD3043 anesthesia was swift. The ability of nearly all subjects to stand and walk at the first proprioception test, 30 minutes after the end of infusion, illustrates the rapid recovery associated with AZD3043. These results show that the desired characteristics of rapid recovery seem to have translated successfully from preclinical development into the clinical setting and support continued investigation of AZD3043 as a potential new drug for anesthesia and sedation.

AZD3043 was not associated with the respiratory and circulatory depression reported with the currently used drugs midazolam and propofol,1–3 and there were no spontaneous reports of pain on injection, a recognized adverse effect of propofol.4 However, AZD3043 was associated with increased heart rate, which appeared to be dose-related. The mechanism for this effect is unknown. Arterial blood pressure was mainly unchanged with no trend toward decreases or increases throughout the dose range tested (Fig. 1B). The observations of erythema, dyspnea, and chest pressure need a formal evaluation in future studies.

The majority of subjects treated with the higher doses of AZD3043 exhibited involuntary movements, and in some cases, these movements were extensive. Involuntary movements are common during anesthesia with a range of anesthetic drugs, including etomidate,14 methohexital,15 steroid anesthetics,16,17 and propofol.18 Although the mechanisms of these effects have not been established, several hypotheses have been proposed around the ability of GABAergic inhibition to sensitize the cortex to enter oscillatory excitation states in response to small initial stimuli.19 Further study is required in the mechanisms and clinical significance of increased heart rate and involuntary movements associated with AZD3043.

The infusion regimen used in this study was designed primarily to assess safety rather than efficacy and did not closely model clinical practice. As a result, robust efficacy comparisons with other anesthetics are not possible because there are no comparable settings of 30- minute steady infusion into healthy volunteers. A blinded design with a placebo control arm was considered unsuitable because of the expected pharmacodynamic effects of AZD3043 and the escalating dose panel design. In addition, the vehicle itself could not be used as a control because AZD3043 contributes to the physical characteristics of the formulation and is essential to form the emulsion. Replacing AZD3043 with another constituent might alter pharmacodynamic properties and/or reveal the identity of the treatment.

One limitation of the study is that although BIS is well established for GABA-acting drugs,20,21 and the BIS results in this study followed MOAA/S closely, BIS is not validated for monitoring depth of anesthesia with AZD3043. Moreover, in addition to using the MOAA/S and BIS, we used clinical signs to measure the onset/offset of sedation/anesthesia. The time point of transition from sedation to anesthesia was measured as loss of eyelash reflex and as loss of handgrip of a filled 20-mL syringe. These 2 tests have not been validated for that purpose. The disappearance of eyelash reflex is used in everyday anesthetic practice to evaluate whether the patient is anesthetized during induction and is regarded as a trustworthy clinical sign that anesthesia has been established. Loss of handgrip is not used clinically and was not a useful tool because the syringe remained in the hand in some subjects although deep anesthesia had been established. The recovery was described by MOAA/S,12 a clinical scale used to evaluate the ability to stand and walk after day surgery, and by recovery of orientation to person, time, place, and situation. The clinical scales are pragmatic and not validated for this setting. Nevertheless, the scales give useful information in everyday practice, and in this study, they provide a clinically recognized estimate of recovery of proprioception and orientation. The problem with many clinical measures used is that they actually stimulate the person and so affect what they are used to measure, that is, time to anesthesia and recovery. Another limitation of the study is that we do not have access to the report that validates the sample transfer, storage, and drug concentration determination protocols used for the pharmacokinetic measures.

There was an unexpectedly high screening failure rate in the study, which was primarily because of the large proportion of volunteers with resting heart rate of <55 beats per minute. This exclusion criterion was set as a precaution in case AZD3043 induced bradycardia and had the result of excluding the more athletic volunteers. In retrospect, this precaution turned out to be unnecessary.

In conclusion, the results of this first human trial indicate that AZD3043 shows the potential to be a useful new drug for sedation and anesthesia. Further clinical trials are warranted.

DISCLOSURES

Name: Sigridur Kalman, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Sigridur Kalman has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Sigridur Kalman received an honorarium from AstraZeneca 3 years ago for participating in an advisory board on AZD3043.

Name: Pauline Koch, MD.

Contribution: This author helped conduct the study, analyze the data, and write the manuscript.

Attestation: Pauline Koch approved the final manuscript.

Conflicts of Interest: Pauline Koch has equity interest in AstraZeneca.

Name: Kjell Ahlén, MD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Kjell Ahlén approved the final manuscript.

Conflicts of Interest: Kjell Ahlén is employed by AstraZeneca and has equity interest in AstraZeneca.

Name: Stephen J. Kanes, MD, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Stephen J. Kanes approved the final manuscript and is the author responsible for archiving the study files.

Conflicts of Interest: Stephen J. Kanes is employed by AstraZeneca and has equity interest in AstraZeneca.

Name: Stéphane Barassin, PhD.

Contribution: This author helped design the study and write the manuscript.

Attestation: Stéphane Barassin approved the final manuscript.

Conflicts of Interest: Stéphane Barassin is employed by AstraZeneca and has equity interest in AstraZeneca.

Name: Marcus A. Björnsson, MSc Pharm, PhD.

Contribution: This author helped design the study, analyze the data, and write the manuscript.

Attestation: Marcus A. Björnsson approved the final manuscript.

Conflicts of Interest: Marcus A. Björnsson is employed by AstraZeneca and has equity interest in AstraZeneca.

Name: Åke Norberg, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Åke Norberg has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Åke Norberg received an honorarium from AstraZeneca 3 years ago for participating in an advisory board on AZD3043.

This manuscript was handled by: Steven L. Shafer, MD.

ACKNOWLEDGMENTS

We thank anesthetist nurses Ann-Marie Olsson, CRNA, and Marion Cornelius, CRNA, for excellent nursing skill and Matt Lewis, PhD, of Lucid Medical Writing for medical writing assistance funded by AstraZeneca.

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