Effects of hand catalepsy on subjective trance perception and relative parasympathetic tone in healthy volunteers during pleasant hypnotic session: a randomized controlled study.

This study was designed to evaluate the effects on hand catalepsy on parasympathetic tone assessed using Analgesia/Nociception Index (ANI) and on subjective rating of absorption, dissociation, and time perception among healthy volunteers. This was a randomized controlled trial including participants to a medical hypnosis congress in France. Ninety volunteers were randomized in two arms, all receiving a fifteen-minute positive hypnotic trance, with or without hand catalepsy. The relative parasympathetic tone assessed by ANI (Analgesia/Nociception Index), heart rate and respiratory rate were recorded at different times of the study protocol. The actual duration of the hypnotic session, calculated from eye closing to eye opening, was also recorded. At the end of the hypnotic trance, participants subjectively rated their level of absorption and dissociation on a 0-10 scale. They were also asked to estimate the duration of the hypnotic session from eye closing to eye opening. In total, ninety subjects were included in the study. One subject was excluded because of deviation in the protocol standard, leaving eighty-nine subjects for analysis. Subject characteristics were similar between groups. There was a statistically different increase in ANI and decrease in both heart rate and respiratory rate over time with no difference with or without hand catalepsy. There was no statistically significant difference in absorption and dissociation subjective scales between groups. The median [Q1-Q3] actual duration of hypnotic sessions was similar between the catalepsy and the control groups (9 [8-10] min vs. 8 [7-10] min, respectively). However, subjects in the catalepsy group estimated a longer duration of the hypnotic session (12 [10-15] min) than in the control group (10 [5-10] min) with a mean ± SD overestimation of 3 ± 4 min (p < 0.001). Parasympathetic comfort increased during the hypnotic trance with no difference between groups. However, adding hand catalepsy to a pleasant hypnotic trance did not appear to increase feelings of absorption or dissociation but created time distortion on the longer side that could be useful in some clinical settings. Nevertheless, further study is still needed to determine more precisely the physiological and psychological effects on hand catalepsy during the hypnotic trance.

Relationship between ANI and qNOX and between MAC and qCON during outpatient laparoscopic cholecystectomy using remifentanil and desflurane without muscle relaxants: a prospective observational preliminary study.

This study was designed to investigate qCON and qNOX variations during outpatient laparoscopic cholecystectomy using remifentanil and desflurane without muscle relaxants and compare these indices with ANI and MAC. Adult patients undergoing outpatient laparoscopic cholecystectomy were included in this prospective observational study. Maintenance of anesthesia was performed using remifentanil targeted to ANI 50-80 and desflurane targeted to MAC 0.8-1.2 without muscle relaxants. The ANI, qCON and qNOX and desflurane MAC values were collected at different time-points and analyzed using repeated measures ANOVA. The relationship between ANI and qNOX and between qCON and MAC were analyzed by linear regression. The ANI was comprised between 50 and 80 during maintenance of anesthesia. Higher values of qNOX and qCON were observed at induction and extubation than during all other time-points where they were comprised between 40 and 60. A poor but significant negative linear relationship (r2 = 0.07, p < 0.001) was observed between ANI and qNOX. There also was a negative linear relationship between qCON and MAC (r2 = 0.48, p < 0.001) and between qNOX and remifentanil infusion rate (r2 = 0.13, p < 0.001). The linear mixed-effect regression correlation (r2) was 0.65 for ANI-qNOX and 0.96 for qCON-MAC. The qCON and qNOX monitoring seems informative during general anesthesia using desflurane and remifentanil without muscle relaxants in patients undergoing ambulatory laparoscopic cholecystectomy. While qCON correlated with MAC, the correlation of overall qCON and ANI was poor but significant. Additionally, the qNOX weakly correlated with the remifentanil infusion rate. This observational study suggests that the proposed ranges of 40-60 for both indexes may correspond to adequate levels of hypnosis and analgesia during general anesthesia, although this should be confirmed by further research.

ANI and BIS variations in supine and prone position during closed-tracheal suction in sedated and myorelaxed ICU patients with severe COVID-19: A retrospective study.

The purpose of this study was to assess Analgesia/Nociception Index (ANI) and bispectral index (BIS) variations in supine and prone position during closed-tracheal suction in intensive care unit (ICU) patients with severe COVID-19 pneumonia requiring myorelaxation and prone positioning. We retrospectively reviewed the data of 15 patients hospitalized in ICU for severe COVID-19 pneumonia requiring sedation, myorelaxation and prone positioning. The BIS, instant ANI (ANIi), mean ANI (ANIm), heart rate (HR), systolic blood pressure (SBP) and SpO2 were retrieved in supine and prone position 1 min before tracheal suction then every minute from the beginning of tracheal suction during 4 min and compared using ANOVA for repeated measures (p < 0.05 considered as statistically significant). Both ANIm and ANIi decreased significantly during tracheal suction with no difference between positions, whereas BIS showed no significant variation within time and between groups. The median [Q1-Q3] ANIm value decreased from 87 [68-98] to 79 [63-09] in supine position and from 79 [63-95] to 78 [66-98] in prone position 2 min after the beginning of tracheal suction. The median [Q1-Q3] ANIi value decreased earlier 1 min after the beginning of tracheal suction from 84 [69-98] to 73 [60-90] in supine position and from 84 [60-99] to 71 [51-88] in prone position. Both HR, SBP and SpO2 varied modestly but significantly during tracheal suction with no difference between positions. Monitoring ANI, but not BIS, may be of interest to detect noxious stimuli such as tracheal suction in ICU myorelaxed patients with severe COVID-19 pneumonia requiring prone positioning.

Prospective pilot study for evaluation of high-flow oxygen therapy in dyspnoeic dogs: the HOT-DOG study.

OBJECTIVES: To describe the use, effectiveness and tolerance of high-flow oxygen therapy in dyspnoeic dogs. MATERIALS AND METHODS: Prospectively, dogs in acute respiratory distress admitted to an intensive care unit between January and May 2018 that failed to respond to nasal oxygen therapy and medical stabilisation after 30 minutes were transitioned to high-flow oxygen therapy. High-flow oxygen therapy, delivered an inspired oxygen fraction of 100% using an air/oxygen blender, active humidifier, single warmed tube and specific nasal cannula. Respiratory rate, pulse oximetry (SpO2 ), heart rate and a tolerance score were assessed every 15 minutes from T0 (under nasal oxygen) to 1 hour (T60 ), and PaO2 and PaCO2 at T0 and T60 . Complications were recorded for each dog. RESULTS: Eleven dogs were included. At T60 , PaO2 , flow rate and SpO2 were significantly greater than at T0 (171 ± 123 versus 73 ± 24 mmHg; P=0.015; 18 ±12 L/minute versus 3.2 ± 2.0 L/minute, P<0.01; 97.7 ±2.3% versus 91.6 ±7.2%, P=0.03, respectively). There was no significant difference in PaCO2 , respiratory rate or heart rate between T0 and T60 . Tolerance was excellent, and there were no complications. CLINICAL SIGNIFICANCE: High-flow oxygen therapy improves markers of oxygenation in dyspnoeic dogs and is an effective means to deliver oxygen with comfort and minimal complications.

[Evaluation of spinal anesthesia in urological outpatient surgery, comparison between two local anesthetics (Chloroprocaine/Bupivacaine)]. / Évaluation de la rachianesthésie en chirurgie ambulatoire urologique, comparaison entre deux anesthésiques locaux (Chloroprocaïne/Bupivacaïne).

INTRODUCTION: Spinal anesthesia in outpatient urology is controversial (longer hospital stay, risk of urinary retention). The main goal was to evaluate outpatient spinal anesthesia and to compare 2 local anesthetics secondarily. MATERIAL: Monocentric retrospective study including all patients undergoing surgery in urological ambulatory surgery under spinal anesthesia between December 2011 and May 2015, split into two groups according to the local anesthetic used: bupivacaine (BP) and chloroprocaine (CP). Quantitative variables were compared by Student's t-test, qualitative variables by χ2 test. RESULTS: Seventy-one (95%) out of the 75 patients included have been discharged the same day. Discharge was impossible in these cases: patient alone at home (1), bladder clot (1), JJ intolerance (1), delayed micturition (1). The mean duration of the procedure was 27±19min, the SSPI's was 55±31min, the stay's was 360±91min. A total of 45 patients (60%) received BP and 30 (40%) received CP. The mean residence time in SSPI was significantly reduced in the CP group (47±24min vs. 61±34min, P=0.04). One patient experienced urination delay in the BP group with no significant difference. No significant difference for the other criteria studied despite the mean age, which is higher in the CP group (P=0.02). CONCLUSION: Spinal anesthesia is adapted to ambulatory urology, and does not increase the risk of urinary retention, especially with CP that would decrease the length of stay in SSPI compared to BP. LEVEL OF EVIDENCE: 4.

Comparison of piperacillin exposure in the lungs of critically ill patients and healthy volunteers.

Background: Severe infections of the respiratory tracts of critically ill patients are common and associated with excess morbidity and mortality. Piperacillin is commonly used to treat pulmonary infections in critically ill patients. Adequate antibiotic concentration in the epithelial lining fluid (ELF) of the lung is essential for successful treatment of pulmonary infection. Objectives: To compare piperacillin pharmacokinetics/pharmacodynamics in the serum and ELF of healthy volunteers and critically ill patients. Methods: Piperacillin concentrations in the serum and ELF of healthy volunteers and critically ill patients were compared using population methodologies. Results: Median piperacillin exposure was significantly higher in the serum and the ELF of critically ill patients compared with healthy volunteers. The IQR for serum piperacillin exposure in critically ill patients was six times greater than for healthy volunteers. The IQR for piperacillin exposure in the ELF of critically ill patients was four times greater than for healthy volunteers. The median pulmonary piperacillin penetration ratio was 0.31 in healthy volunteers and 0.54 in critically ill patients. Conclusions: Greater variability in serum and ELF piperacillin concentrations is observed in critically ill patients compared with healthy adult subjects and must be considered in the development of dosage regimens. Pulmonary penetration of antimicrobial agents should be studied in critically ill patients, as well as healthy volunteers, during drug development to ensure appropriate dosing of patients with pneumonia.

Effects of hypnosis on the relative parasympathetic tone assessed by ANI (Analgesia/Nociception Index) in healthy volunteers: a prospective observational study.

Hypnosis has shown an effect on the regulation of the autonomic nervous system by increasing parasympathetic activity. The Analgesia/Nociception Index (ANI) is derived from heart rate variability and represents the relative parasympathetic tone. We investigated the effects of hypnosis on ANI in healthy volunteers. Participants to the 2016 International Hypnosis congress, Saint Malo, France were recruited in this prospective observational study. After comfortable positioning of the subject in the sitting position (T0), the hypnotic trance was induced (T1) then conducted with suggestions of comfort (T2) before return to normal consciousness (T3). The ANI, heart rate (HR) and respiratory rate (RR) were recorded at the different time-points. Forty subjects were enrolled (31 women, 9 men). The mean ± SD ANI at T2 (84 ± 12) was significantly greater than at T0 (60 ± 10), T1 (62 ± 9) and T3 (59 ± 11). The median [25th-75th percentile] ANI values at T2 were significantly greater in women (90 [83-95]) than in men (74 [68-83]). There were no significant variations of HR during time. The median [25th-75th percentile] RR at T1 (16 [14-18] breaths/min) and T2 (14 [12-16] breaths/min) were significantly smaller than at T0 (18 [16-20] breaths/min) and T3 (18 [16-20] breaths/min). This study shows that hypnosis induces an increase in the relative parasympathetic tone assessed by ANI in healthy volunteers, with greater ANI values observed in women. These results suggest that ANI monitoring may provide an objective tool for the measurement of the intensity of the hypnotic process, although this should be confirmed by further studies.

Prevalence and factors predictive of full stomach in elective and emergency surgical patients: a prospective cohort study.

Background: This prospective observational study sought to assess the rate of full and empty stomach in elective and emergency patients and to determine the factors associated with full stomach. Methods: Non-premedicated patients were consecutively included between May 2014 and October 2014. Ultrasound examination of the gastric antrum was performed by an operator blinded to the history of the patient. It included measurement of the antral cross-sectional area, performed in the supine position with the head of the bed elevated to 45°, and qualitative assessment of the gastric antrum, performed in both semirecumbent and right lateral decubitus positions. Full stomach was defined by the appearance of any gastric content in both positions (Grade 2). Empty stomach was defined either by empty antrum in both positions (Grade 0) or by empty antrum in the semirecumbent position only (Grade 1) with measured antral area <340 mm2. The combination of Grade 1 and antral area >340 mm2 defined intermediate stomach. Logistic regression analyses were performed for the identification of factors associated with full stomach. Results: Four hundred and forty patients were analysed. The prevalence of full stomach was 5% (95% confidence interval: 2­9) in elective patients and 56% (95% confidence interval: 50­62) in emergency patients (P<0.0001). Obesity, diabetes mellitus, emergency surgery, and preoperative consumption of opiates were independent factors predictive of full stomach. Conclusions: The results suggest that preoperative ultrasound assessment of gastric content should be performed in all emergency patients, and in elective patients with identified predictive factors for full stomach.

The use of ultrasound in France: a point of view from experienced regional anesthesiologists.

A cross-sectional survey study on French practice in ultrasound-guided regional anesthesia was carried out. A questionnaire (demographic data, assessment of the likely benefits of ultrasonography, and its use in daily practice: blocks and hygiene) was emailed to all members of the French-speaking association of anesthesiologists involved in regional anesthesia. The questionnaire was filled out and returned by 634 experienced anesthesiologists. An ultrasound machine was available in 94% of cases. Ultrasound-guided regional anesthesia has become the gold standard technique for three-quarters of responders. Axillary, interscalene, popliteal sciatic and femoral nerve blocks were performed by more than 90% of responders, most frequently under ultrasound supervision. Conversely, ultrasound guidance was rarely used for spinal or deep nerve blocks. A specific sterile sheath was used in only 43% of cases. The present study confirms that ultrasound guidance has gained in popularity for many superficial, but not deep, regional anesthesia procedures in France.

Prediction of hemodynamic reactivity using dynamic variations of Analgesia/Nociception Index (∆ANI).

The Analgesia/Nociception Index (ANI), a 0-100 non-invasive index calculated from heart rate variability, reflects the analgesia/nociception balance during general anesthesia. We hypothesized that dynamic variations of ANI (∆ANI) would provide better performance than static values to predict hemodynamic reactivity during desflurane/remifentanil general anesthesia. One hundred and twenty-eight patients undergoing ear-nose-throat or lower limb orthopedic surgery were analyzed in this prospective observational study. The ANI, heart rate and systolic blood pressure were recorded before induction, at skin incision, during procedure and at emergence from general anesthesia. Changes in these variables were recorded after 1 min for ANI (ANI1min) and 5 min for heart rate and systolic blood pressure. The dynamic variation of ANI at the different time points was defined as: ∆ANI = (ANI1min - ANI)/([ANI + ANI1min]/2). Receiver-operating characteristic (ROC) curves were built to evaluate the performance of ANI, ANI1 min and ∆ANI to predict hemodynamic reactivity (increase by more than 20 % in heart rate and/or systolic blood pressure within 5 min). For the prediction of hemodynamic reactivity, better performance was observed with ∆ANI (area under ROC curve (AUC ROC) = 0.90) in comparison to ANI (ROC AUC = 0.50) and ANI1min (ROC AUC = 0.77). A ∆ANI threshold of -19 % predicts hemodynamic reactivity with 85 % [95 % CI 77-91] sensitivity and 85 % [95 % CI 81-89] specificity. Dynamic variations of ANI provide better performance than static values to predict hemodynamic reactivity during desflurane/remifentanil general anesthesia. These findings may be of interest for the individual adaptation of remifentanil doses guided by ∆ANI during general anesthesia, although this remains to be demonstrated.

Effect of acute cigarette smoking on gastric contents in regular smoker volunteers. A prospective randomized cross-over study.

BACKGROUND: The authors sought to assess the effect of acute smoking on gastric contents in regular smoker volunteers. The primary endpoint was the variation in antral area during the 120-min study period after cigarette smoking. METHODS: Regular smoker volunteers were included in this prospective randomized single blind cross-over study. Volunteers attended two separate study sessions: Control and Smoking sessions. The study started with an initial ultrasound measurement of the antral area, immediately followed by a 30-min periods of waiting (Control session) or of two-cigarettes smoking (Smoking session). Ultrasound measurements of the antral area were then performed 30, 60, 90 and 120 min after the initial ultrasonography, allowing for the calculations of the variation rates in antral area during the periods 0-30, 0-60, 0-90 and 0-120 min in both sessions. RESULTS: The variation in antral area during the period 0-120 min was equivalent in both sessions, as the difference in the variation rates between both sessions was -1.2%, with 90% confidence interval of the difference including 0 and lying entirely within the range of equivalence of -10% to 10%. No equivalence was found for the periods 0-30, 0-60 and 0-90 min, because of a non-significant decrease in antral area in the Smoking sessions during these periods. CONCLUSIONS: Preoperative acute smoking did not affect the variation in the gastric volume in regular smoker volunteers during the study period. These results allow for the suggestion that acute preoperative smoking does not probably change the risk of pulmonary aspiration of gastric contents in healthy regular smokers. CLINICAL TRIAL REGISTRATION: NCT 02080598.

Physiological Signal Processing for Individualized Anti-nociception Management During General Anesthesia: a Review.

OBJECTIVE: The aim of this paper is to review existing technologies for the nociception / anti-nociception balance evaluation during surgery under general anesthesia. METHODS: General anesthesia combines the use of analgesic, hypnotic and muscle-relaxant drugs in order to obtain a correct level of patient non-responsiveness during surgery. During the last decade, great efforts have been deployed in order to find adequate ways to measure how anesthetic drugs affect a patient's response to surgical nociception. Nowadays, though some monitoring devices allow obtaining information about hypnosis and muscle relaxation, no gold standard exists for the nociception / anti-nociception balance evaluation. Articles from the PubMed literature search engine were reviewed. As this paper focused on surgery under general anesthesia, articles about nociception monitoring on conscious patients, in post-anesthesia care unit or in intensive care unit were not considered. RESULTS: In this article, we present a review of existing technologies for the nociception / anti-nociception balance evaluation, which is based in all cases on the analysis of the autonomous nervous system activity. Presented systems, based on sensors and physiological signals processing algorithms, allow studying the patients' reaction regarding anesthesia and surgery. CONCLUSION: Some technological solutions for nociception / antinociception balance monitoring were described. Though presented devices could constitute efficient solutions for individualized anti-nociception management during general anesthesia, this review of current literature emphasizes the fact that the choice to use one or the other mainly relies on the clinical context and the general purpose of the monitoring.

[Assessment of anesthesiologist intervention during cataract surgery under topical anesthesia]. / Évaluation du recours à l'anesthésiste-réanimateur lors de la chirurgie de la cataracte réalisée sous anesthésie topique.

OBJECTIVES: The current demographic situation in France regarding anesthesiologists calls for a reconsideration of anesthesia management for patients undergoing cataract surgery under topical anesthesia. This prospective observational study aimed to assess the requirement for anesthesiologist intervention during cataract surgery performed under topical anesthesia. PATIENTS AND METHODS: Patients operated between November 2, 2011 and July 31, 2012 were included after indication of topical anesthesia for phacoemulsification proposed by the surgeon and confirmed by the anesthesiologist. Each patient was premedicated. All patients were monitored and supervised during the surgery by a nurse anesthesiologist. An anesthesiologist could be called at any time at the request of the surgeon or nurse anesthesiologist. For each patient, medical histories were recorded as well as the event "anesthesiologist called", along with the reason and the treatment performed. RESULTS: Five hundred and seventy-five phacoemulsifications were performed in 486 patients. The event "anesthesiologist called" was recorded 20 times: 18 times for hypertension, once for anxiety and once for non-emergent conversion to general anesthesia after a surgical complication. Each episode of hypertension was successfully treated by following the nicardipine protocol. Preoperatively uncontrolled hypertension was the only significant predictive risk factor for anesthesiologist requirement. CONCLUSIONS: These results question the usefulness of preoperative anesthesia consultation for all patients who underwent phacoemulsification under topical anesthesia, since this consultation does not lead to an anesthesiologist service. Intraoperative medical complications may be treated according to medical protocols developed jointly by surgeons and anesthesiologists. This practice may free up anesthesiologists' time, without compromising patient safety.

Ultrasound-guided intermediate cervical plexus block for carotid endarterectomy using a new anterior approach: a two-centre prospective observational study.

The aim of this prospective, double-centre, observational study performed in 116 patients was to describe a new anterior approach of ultrasound-guided intermediate cervical plexus block for carotid endarterectomy. The median (IQR [range]) volume of ropivacaine 0.5% administered was 30 (25-30 [20-45]) ml. Supplemental local anaesthesia (infiltration and topical) was needed in 66 (57%) patients. Overall, 41 (35%) patients needed additional sedation (18 midazolam; 23 remifentanil). There was no intra-operative complication or systemic toxicity of ropivacaine. One regional anaesthesia procedure was converted to general anaesthesia because of patient agitation. Adverse effects were of short duration and did not affect surgery. Satisfaction scores were high for 92 (79%) patients (63 satisfied; 29 very satisfied) and 104 (90%) surgeons (51 satisfied; 53 very satisfied). This study shows that the ultrasound-guided intermediate cervical plexus block using an anterior approach is feasible and provides similar results to other regional techniques during carotid endarterectomy.

Prediction of hemodynamic reactivity during total intravenous anesthesia for suspension laryngoscopy using Analgesia/Nociception Index (ANI): a prospective observational study.

BACKGROUND: The Analgesia/Nociception Index (ANI), a 0-100 non-invasive index calculated from heart rate variability, reflects the analgesia/nociception balance during general anesthesia. The principal objective of this study was to evaluate the performance of ANI to predict hemodynamic reactivity during suspension laryngoscopy. The secondary objectives were to investigate the performances of ANI and bispectral index (BIS) to assess sedation and of BIS to predict hemodynamic reactivity during the procedure. METHODS: Fifty patients undergoing suspension laryngoscopy with total intravenous anesthesia using propofol and remifentanil were analysed in this prospective observational study. The ANI, BIS and Observer's Assessment of Alertness/Sedation (OAA/S) scale were measured at predefined time-points during the procedure. Receiver-operating characteristic (ROC) curves were built to evaluate the performance of ANI and BIS to predict hemodynamic reactivity (increase by more than 20% of heart rate and/or systolic blood pressure within 5 min) and assess sedation (OAA/S ≤ 2) during the procedure. RESULTS: For the prediction of hemodynamic reactivity, better performance was observed with ANI in comparison to BIS (ROC curve AUC [95% CI] = 0.88 [0.83-0.92] vs. 0.73 [0.66-0.79], P < 0.05). The sensitivity and specificity of ANI ≤ 55 to predict hemodynamic reactivity within 5 min were 88% and 83%, respectively. For the assessment of sedation, a better performance was observed with BIS in comparison to ANI (ROC curve AUC [95% CI] = 0.91 [0.86-0.94] vs. 0.68 [0.61-0.74], respectively, P < 0.05). CONCLUSION: ANI exhibits good performance for the prediction of hemodynamic reactivity and BIS exhibits good performance for the assessment of sedation during suspension laryngoscopy with propofol/remifentanil total intravenous anesthesia.

Individualization of piperacillin dosing for critically ill patients: dosing software to optimize antimicrobial therapy.

Piperacillin-tazobactam is frequently used for empirical and targeted therapy of infections in critically ill patients. Considerable pharmacokinetic (PK) variability is observed in critically ill patients. By estimating an individual's PK, dosage optimization Bayesian estimation techniques can be used to calculate the appropriate piperacillin regimen to achieve desired drug exposure targets. The aim of this study was to establish a population PK model for piperacillin in critically ill patients and then analyze the performance of the model in the dose optimization software program BestDose. Linear, with estimated creatinine clearance and weight as covariates, Michaelis-Menten (MM) and parallel linear/MM structural models were fitted to the data from 146 critically ill patients with nosocomial infection. Piperacillin concentrations measured in the first dosing interval, from each of 8 additional individuals, combined with the population model were embedded into the dose optimization software. The impact of the number of observations was assessed. Precision was assessed by (i) the predicted piperacillin dosage and by (ii) linear regression of the observed-versus-predicted piperacillin concentrations from the second 24 h of treatment. We found that a linear clearance model with creatinine clearance and weight as covariates for drug clearance and volume of distribution, respectively, best described the observed data. When there were at least two observed piperacillin concentrations, the dose optimization software predicted a mean piperacillin dosage of 4.02 g in the 8 patients administered piperacillin doses of 4.00 g. Linear regression of the observed-versus-predicted piperacillin concentrations for 8 individuals after 24 h of piperacillin dosing demonstrated an r(2) of >0.89. In conclusion, for most critically ill patients, individualized piperacillin regimens delivering a target serum piperacillin concentration is achievable. Further validation of the dosage optimization software in a clinical trial is required.