New Approaches in Intravenous Anesthesia and Anesthetics

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Anesthesiology".

Deadline for manuscript submissions: closed (31 May 2021) | Viewed by 47716

Special Issue Editor


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Guest Editor
Harvard Medical School, Boston Children’s Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, 300 Longwood Ave., Boston, MA 02115, USA
Interests: anesthesia and safety outside the operating room; dental sedation; sedation; target-controlled infusion (TCI)
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Special Issue Information

Dear Colleagues,

The area of intravenous anesthesia is evolving and developing as new sedatives and anesthetics are being introduced, pharmacology and pharmacokinetic studies progress, and the desire to reduce exposure to inhalational/volatile anesthetics strengthens. This Special Issue will be a comprehensive aggregation of contributions from international leaders in the area of intravenous anesthesia and safety. New and developing intravenous anesthetics, pharmacology and pharmacokinetic modeling, safety, target-controlled infusion, strategies in managing the obese, and new considerations for sedation in the critically ill are some of the topics that will be explored. In summary, this Special Issue will be an enduring contribution to the field of intravenous anesthesia and sedation and will provide a valuable resource for multispecialty providers worldwide.

Dr. Keira P. Mason
Guest Editor

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Keywords

  • sedation
  • safety
  • intravenous
  • target controlled infusions

Published Papers (13 papers)

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13 pages, 1644 KiB  
Article
Amnesia after Midazolam and Ketamine Sedation in Children: A Secondary Analysis of a Randomized Controlled Trial
by Karolline A. Viana, Mônica M. Moterane, Steven M. Green, Keira P. Mason and Luciane R. Costa
J. Clin. Med. 2021, 10(22), 5430; https://doi.org/10.3390/jcm10225430 - 20 Nov 2021
Cited by 1 | Viewed by 1965
Abstract
The incidence of peri-procedural amnesia following procedural sedation in children is unclear and difficult to determine. This study aimed to apply quantitative and qualitative approaches to better understand amnesia following dental sedation of children. After Institutional Review Board Approval, children scheduled for sedation [...] Read more.
The incidence of peri-procedural amnesia following procedural sedation in children is unclear and difficult to determine. This study aimed to apply quantitative and qualitative approaches to better understand amnesia following dental sedation of children. After Institutional Review Board Approval, children scheduled for sedation for dental procedures with oral midazolam (OM), oral midazolam and ketamine (OMK), or intranasal midazolam and ketamine (IMK) were recruited for examination of peri-procedural amnesia. Amnesia during the dental session was assessed using a three-stage method, using identification of pictures and an animal toy. On the day following the sedation, primary caregivers answered two questions about their children’s memory. One week later, the children received a semi-structured interview. Behavior and level of sedation during the dental session were recorded. Quantitative data were analyzed using descriptive statistics and comparison tests. Qualitative data were analyzed using content analysis. Triangulation was used. Thirty-five children (age: 36 to 76 months) participated in the quantitative analysis. Most children showed amnesia for the dental procedure (82.9%, n = 29/35) and remembered receiving the sedation (82.1%, n = 23/28 for oral administration; 59.3%, n = 16/27 for intranasal administration). The occurrence of amnesia for the dental procedure was slightly higher in the oral midazolam group compared with the other groups (44.8%, n = 13/29 for OM, 13.8%, n = 4/29 for OMK, and 41.4%, n = 12/29 for IMK). Twenty-eight children participated in the qualitative approach. The major theme identified was that some children could remember their procedures in detail. We conclude that peri-procedural amnesia of the dental procedure was common following sedation. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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11 pages, 1797 KiB  
Article
Administration of Low-Dose Dexmedetomidine Did Not Affect Acute Inflammatory Response after Cytoreductive Surgery Combined with Hyperthermic Intraperitoneal Chemotherapy: A Double-Blind Randomized Controlled Trial
by Jiae Moon, Young Chul Yoo, Myoung Hwa Kim, Soyoung Jeon, Hye Ji Joo, Duk-Hee Chun and Na Young Kim
J. Clin. Med. 2021, 10(14), 3145; https://doi.org/10.3390/jcm10143145 - 16 Jul 2021
Cited by 3 | Viewed by 1907
Abstract
During cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), attenuation of inflammatory responses that increase susceptibility to postoperative complications, morbidity, and mortality is important. We aimed to evaluate whether intraoperative dexmedetomidine infusion impacted inflammatory response in patients undergoing CRS with HIPEC. Fifty-six patients [...] Read more.
During cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC), attenuation of inflammatory responses that increase susceptibility to postoperative complications, morbidity, and mortality is important. We aimed to evaluate whether intraoperative dexmedetomidine infusion impacted inflammatory response in patients undergoing CRS with HIPEC. Fifty-six patients scheduled for CRS with HIPEC were randomly assigned to the control (n = 28) and dexmedetomidine (n = 28) groups. The primary endpoint was the effect of dexmedetomidine on the interleukin-6 (IL-6) level measured at pre-operation (Pre-OP), before HIPEC initiation (Pre-HIPEC), immediately after HIPEC; after the end of the operation; and on postoperative day (POD) 1. In both groups, the IL-6 levels from Pre-HIPEC until POD 1 and the C-reactive protein (CRP) levels on PODs 1, 2, and 3 were significantly higher than the Pre-OP values (all Bonferroni corrected, p < 0.001). However, total differences in IL-6 and CRP levels, based on the mean area under the curve, were not detected between the two groups. The continuous intraoperative infusion of dexmedetomidine (0.4 μg/kg/h) in patients undergoing CRS with HIPEC did not significantly lower the inflammatory indices. Further dose investigative studies are needed to find the dexmedetomidine dose that provides anti-inflammatory and sympatholytic effects during HIPEC. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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11 pages, 444 KiB  
Article
Intranasal Dexmedetomidine Compared to a Combination of Intranasal Dexmedetomidine with Ketamine for Sedation of Children Requiring Dental Treatment: A Randomized Clinical Trial
by Joji Sado-Filho, Patrícia Corrêa-Faria, Karolline A. Viana, Fausto M. Mendes, Keira P. Mason, Luciane R. Costa and Paulo S. Costa
J. Clin. Med. 2021, 10(13), 2840; https://doi.org/10.3390/jcm10132840 - 27 Jun 2021
Cited by 6 | Viewed by 2723
Abstract
Outpatient pediatric sedation is challenging. This study aimed to test intranasal dexmedetomidine efficacy as a single drug or combined with ketamine (DK) to sedate children undergoing dental treatment. Children < 7 years were randomized into dexmedetomidine 2 mcg/kg and ketamine 1 mg/kg (DK) [...] Read more.
Outpatient pediatric sedation is challenging. This study aimed to test intranasal dexmedetomidine efficacy as a single drug or combined with ketamine (DK) to sedate children undergoing dental treatment. Children < 7 years were randomized into dexmedetomidine 2 mcg/kg and ketamine 1 mg/kg (DK) or dexmedetomidine 2.5 mcg/kg (D) groups. Videos from the dental sedation allowed the systematic assessment of children’s behavior (primary outcome) according to the Ohio State University Behavioral Rating Scale (OSUBRS). Secondary outcomes were parental and dentist satisfaction, adverse events, and recovery time. The data were analyzed descriptively and through regression models. Participants were 88 children (44 per group; 50 boys). The duration of quiet behavior (OSUBRS) was higher than 50% (DK mean 58.4 [standard deviation 38.1]; D 55.2 [39.1]; p = 0.225). Parents (DK 78.0 [32.2]; D 72.7 [35.1]; p = 0.203) and dentists (KD 62.7 [41.0]; D 62.8 [40.1]; p = 0.339) were overall satisfied. Adverse events occurred in 16 cases (DK n = 10, 62.5%; D n= 6, 37.5%; p = 0.104) and were minor. The median recovery time in the DK group was 1.3 times greater than in group D (p < 0.05). Intranasal sedation with dexmedetomidine alone is equally efficacious and satisfactory for pediatric sedation with fewer adverse events and faster recovery than the DK combination. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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14 pages, 1969 KiB  
Article
Effects on the Upper Airway Morphology with Intravenous Addition of Ketamine after Dexmedetomidine Administration in Normal Children
by Goutham Mylavarapu, Robert J. Fleck, Michale S. Ok, Lili Ding, Ali Kandil, Raouf S. Amin, Bobby Das and Mohamed Mahmoud
J. Clin. Med. 2020, 9(11), 3723; https://doi.org/10.3390/jcm9113723 - 20 Nov 2020
Cited by 4 | Viewed by 1754
Abstract
General anesthesia decreases the tone of upper airway muscles in a dose-dependent fashion, potentially narrowing the pharyngeal airway. We examined the effects of adding ketamine on the airway configuration after dexmedetomidine administration in spontaneously breathing children with normal airways. 25 children presenting for [...] Read more.
General anesthesia decreases the tone of upper airway muscles in a dose-dependent fashion, potentially narrowing the pharyngeal airway. We examined the effects of adding ketamine on the airway configuration after dexmedetomidine administration in spontaneously breathing children with normal airways. 25 children presenting for Magnetic Resonance Imaging (MRI) of the brain/spine under general anesthesia were prospectively recruited in the study. Patients were anesthetized with dexmedetomidine bolus (2 mcg over 10 min) followed by dexmedetomidine infusion (2 mcg·kg1·h) and ketamine and permitted to breathe spontaneously via the native airway. MR-CINE images of the upper airway were obtained with dexmedetomidine infusion alone (baseline) and 5, 10, and 15 min after administering ketamine bolus (2 mg·kg1) in two anatomical axial planes at the nasopharynx and the retroglossal upper airway. Airway lumen is segmented with a semi-automatic image processing approach using a region-growing algorithm. Outcome measures of cross-sectional area, transverse and anterior-posterior diameters of the airway in axial planes at the level of the epiglottis in the retroglossal airway, and in the superior nasopharynx were evaluated for changes in airway size with sedation. Airway dimensions corresponding to the maximum, mean, and minimum sizes during a respiratory cycle were obtained to compare the temporal changes in the airway size. The dose-response of adding ketamine to dexmedetomidine alone condition on airway dimensions were examined using mixed-effects of covariance models. 22/25 patients based on inclusion/exclusion criteria were included in the final analysis. The changes in airway measures with the addition of ketamine, when compared to the baseline of dexmedetomidine alone, were statistically insignificant. The modest changes in airway dimensions are clinically less impactful and within the accuracy of the semi-automatic airway segmentation approach. The effect sizes were small for most airway measures. The duration of ketamine seems to not affect the airway size. In conclusion, adding ketamine to dexmedetomidine did not significantly reduce upper airway configuration when compared to dexmedetomidine alone. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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13 pages, 1382 KiB  
Article
A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults
by James D. Morse, L. Ignacio Cortinez and Brian J. Anderson
J. Clin. Med. 2020, 9(11), 3480; https://doi.org/10.3390/jcm9113480 - 28 Oct 2020
Cited by 22 | Viewed by 3072
Abstract
A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1–152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter [...] Read more.
A universal pharmacokinetic model was developed from pooled paediatric and adult data (40.6 postmenstrual weeks, 70.8 years, 3.1–152 kg). A three-compartment pharmacokinetic model with first-order elimination was superior to a two-compartment model to describe these pooled dexmedetomidine data. Population parameter estimates (population parameter variability%) were clearance (CL) 0.9 L/min/70 kg (36); intercompartmental clearances (Q2) 1.68 L/min/70 kg (63); Q3 0.62 L/min/70 kg (90); volume of distribution in the central compartment (V1) 25.2 L/70 kg (103.9); rapidly equilibrating peripheral compartment (V2) 34.4 L/70 kg (41.8); slow equilibrating peripheral compartment (V3) 65.4 L/70 kg (62). Obesity was best described by fat-free mass for clearances and normal fat mass for volumes with a factor for fat mass (FfatV) of 0.293. Models describing dexmedetomidine pharmacokinetics in adults can be applied to children by accounting for size (allometry) and age (maturation). This universal dexmedetomidine model is applicable to a broad range of ages and weights: neonates through to obese adults. Lean body weight is a better size descriptor for dexmedetomidine clearance than total body weight. This parameter set could be programmed into target-controlled infusion pumps for use in a broad population. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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Review

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12 pages, 748 KiB  
Review
Applications and Limitations of Neuro-Monitoring in Paediatric Anaesthesia and Intravenous Anaesthesia: A Narrative Review
by Chiara Grasso, Vanessa Marchesini and Nicola Disma
J. Clin. Med. 2021, 10(12), 2639; https://doi.org/10.3390/jcm10122639 - 15 Jun 2021
Cited by 9 | Viewed by 3782
Abstract
Safe management of anaesthesia in children has been one of the top areas of research over the last decade. After the large volume of articles which focused on the putative neurotoxic effect of anaesthetic agents on the developing brain, the attention and research [...] Read more.
Safe management of anaesthesia in children has been one of the top areas of research over the last decade. After the large volume of articles which focused on the putative neurotoxic effect of anaesthetic agents on the developing brain, the attention and research efforts shifted toward prevention and treatment of critical events and the importance of peri-anaesthetic haemodynamic stability to prevent negative neurological outcomes. Safetots.org is an international initiative aiming at raising the attention on the relevance of a high-quality anaesthesia in children undergoing surgical and non-surgical procedures to guarantee a favourable outcome. Children might experience hemodynamic instability for many reasons, and how the range of normality within brain autoregulation is maintained is still unknown. Neuro-monitoring can guide anaesthesia providers in delivering optimal anaesthetic drugs dosages and also correcting underling conditions that can negatively affect the neurological outcome. In particular, it is referred to EEG-based monitoring and monitoring for brain oxygenation. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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11 pages, 1244 KiB  
Review
Why do We Use the Concepts of Adult Anesthesia Pharmacology in Developing Brains? Will It Have an Impact on Outcomes? Challenges in Neuromonitoring and Pharmacology in Pediatric Anesthesia
by Pablo O. Sepúlveda, Valeria Epulef and Gustavo Campos
J. Clin. Med. 2021, 10(10), 2175; https://doi.org/10.3390/jcm10102175 - 18 May 2021
Cited by 2 | Viewed by 2591
Abstract
Background: Pediatric sedation and anesthesia techniques have plenty of difficulties and challenges. Data on the pharmacologic, electroencephalographic, and neurologic response to anesthesia at different brain development times are only partially known. New data in neuroscience, pharmacology, and intraoperative neuromonitoring will impact changing concepts [...] Read more.
Background: Pediatric sedation and anesthesia techniques have plenty of difficulties and challenges. Data on the pharmacologic, electroencephalographic, and neurologic response to anesthesia at different brain development times are only partially known. New data in neuroscience, pharmacology, and intraoperative neuromonitoring will impact changing concepts and clinical practice. In this article, we develop a conversation to guide the debate and search for a view more attuned to the updated knowledge in neurodevelopment, electroencephalography, and clinical pharmacology for the anesthesiologic practice in the pediatric population. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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26 pages, 631 KiB  
Review
Current State of Analgesia and Sedation in the Pediatric Intensive Care Unit
by Chinyere Egbuta and Keira P. Mason
J. Clin. Med. 2021, 10(9), 1847; https://doi.org/10.3390/jcm10091847 - 23 Apr 2021
Cited by 23 | Viewed by 11057
Abstract
Critically ill pediatric patients often require complex medical procedures as well as invasive testing and monitoring which tend to be painful and anxiety-provoking, necessitating the provision of analgesia and sedation to reduce stress response. Achieving the optimal combination of adequate analgesia and appropriate [...] Read more.
Critically ill pediatric patients often require complex medical procedures as well as invasive testing and monitoring which tend to be painful and anxiety-provoking, necessitating the provision of analgesia and sedation to reduce stress response. Achieving the optimal combination of adequate analgesia and appropriate sedation can be quite challenging in a patient population with a wide spectrum of ages, sizes, and developmental stages. The added complexities of critical illness in the pediatric population such as evolving pathophysiology, impaired organ function, as well as altered pharmacodynamics and pharmacokinetics must be considered. Undersedation leaves patients at risk of physical and psychological stress which may have significant long term consequences. Oversedation, on the other hand, leaves the patient at risk of needing prolonged respiratory, specifically mechanical ventilator, support, prolonged ICU stay and hospital admission, and higher risk of untoward effects of analgosedative agents. Both undersedation and oversedation put critically ill pediatric patients at high risk of developing PICU-acquired complications (PACs) like delirium, withdrawal syndrome, neuromuscular atrophy and weakness, post-traumatic stress disorder, and poor rehabilitation. Optimal analgesia and sedation is dependent on continuous patient assessment with appropriately validated tools that help guide the titration of analgosedative agents to effect. Bundled interventions that emphasize minimizing benzodiazepines, screening for delirium frequently, avoiding physical and chemical restraints thereby allowing for greater mobility, and promoting adequate and proper sleep will disrupt the PICU culture of immobility and reduce the incidence of PACs. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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7 pages, 217 KiB  
Review
Emerging Approaches in Intravenous Moderate and Deep Sedation
by Basavana Goudra and Keira P. Mason
J. Clin. Med. 2021, 10(8), 1735; https://doi.org/10.3390/jcm10081735 - 16 Apr 2021
Cited by 8 | Viewed by 2712
Abstract
Successful pharmacological innovations that have made a difference in daily practice are rare in the world of anesthesia and sedation. After many years of research, it seems that we finally have two new drug innovations that are likely to change the paradigm of [...] Read more.
Successful pharmacological innovations that have made a difference in daily practice are rare in the world of anesthesia and sedation. After many years of research, it seems that we finally have two new drug innovations that are likely to change the paradigm of moderate and deep sedation. These are oliceridine and remimazolam. Both have been in development for over a decade. Oliceridine was synthesized in a lab as an entirely new molecule. It is a biased μ- receptor agonist that acts preferentially on the G-protein pathway (which is responsible for analgesia). At least in lower doses, it has minimal effect on the beta-arrestin pathway, which is responsible for unwanted effects of μ-opioid receptor activation such as respiratory depression and gastrointestinal dysfunction. Like any other μ- receptor agonist, it produces appropriate dose-dependent analgesia. Remimazolam is structurally similar to midazolam; however, it has an additional ester linkage that delivers the kinetics of remifentanil. As a result, while pharmacodynamically identical to midazolam, remimazolam is metabolized by ester hydrolysis and subsequently its elimination is rapid and predictable. The present review discusses the two drugs in detail with a particular emphasis on their potential role in moderate and deep sedation. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
10 pages, 474 KiB  
Review
In the Arms of Morpheus without Morphia; Mitigating the United States Opioid Epidemic by Decreasing the Surgical Use of Opioids
by Karen Boretsky and Keira Mason
J. Clin. Med. 2021, 10(7), 1472; https://doi.org/10.3390/jcm10071472 - 2 Apr 2021
Cited by 12 | Viewed by 2958
Abstract
The opioid epidemic is a major public health issue in the United States. Exposure of opioid naïve-patients to opioids in the perioperative period is a well-documented source of continued use with one in 20 opioid-naïve surgical patients continuing to use opioids beyond 90 [...] Read more.
The opioid epidemic is a major public health issue in the United States. Exposure of opioid naïve-patients to opioids in the perioperative period is a well-documented source of continued use with one in 20 opioid-naïve surgical patients continuing to use opioids beyond 90 days. There is no association with magnitude of surgery, major versus minor, and the strongest predictor of continued use is surgical exposure. Causal factors include over reliance on opioids for intraoperative and postoperative analgesia and excessive ambulatory opioid prescribing. Opioid-induced hyperalgesia can paradoxically result from intraoperative (anesthesia controlled) opioid administration. Increasing size of initial prescription is a strong predictor of continued use necessitating procedure specific supplies limited to under 3-days. Alternative multimodal pain management (non-opioid medications and regional anesthesia) that limit opioid use must be a high priority with opioids reserved for severe breakthrough pain. Barriers to implementation of opioid-sparing pathways include reluctance to adopt protocols and apprehension about opioid elimination. Considering the number of surgeries performed annually in the United States, perioperative physicians must aggressively address modifiable factors in surgical patients. Patient care pathways need to be constructed collaboratively by surgeons and anesthesiologists with continuing feedback to optimize patient outcomes including iatrogenic opioid dependence. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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22 pages, 900 KiB  
Review
Inhaled Anesthetics: Environmental Role, Occupational Risk, and Clinical Use
by Mariana Gaya da Costa, Alain F. Kalmar and Michel M. R. F. Struys
J. Clin. Med. 2021, 10(6), 1306; https://doi.org/10.3390/jcm10061306 - 22 Mar 2021
Cited by 40 | Viewed by 8273
Abstract
Inhaled anesthetics have been in clinical use for over 150 years and are still commonly used in daily practice. The initial view of inhaled anesthetics as indispensable for general anesthesia has evolved during the years and, currently, its general use has even been [...] Read more.
Inhaled anesthetics have been in clinical use for over 150 years and are still commonly used in daily practice. The initial view of inhaled anesthetics as indispensable for general anesthesia has evolved during the years and, currently, its general use has even been questioned. Beyond the traditional risks inherent to any drug in use, inhaled anesthetics are exceptionally strong greenhouse gases (GHG) and may pose considerable occupational risks. This emphasizes the importance of evaluating and considering its use in clinical practices. Despite the overwhelming scientific evidence of worsening climate changes, control measures are very slowly implemented. Therefore, it is the responsibility of all society sectors, including the health sector to maximally decrease GHG emissions where possible. Within the field of anesthesia, the potential to reduce GHG emissions can be briefly summarized as follows: Stop or avoid the use of nitrous oxide (N2O) and desflurane, consider the use of total intravenous or local-regional anesthesia, invest in the development of new technologies to minimize volatile anesthetics consumption, scavenging systems, and destruction of waste gas. The improved and sustained awareness of the medical community regarding the climate impact of inhaled anesthetics is mandatory to bring change in the current practice. Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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Other

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4 pages, 568 KiB  
Reply
Estimation of the Loading Dose for Target-Controlled Infusion of Dexmedetomidine. Reply to Eleveld et al. Comment on “Morse et al. A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults. J. Clin. Med. 2020, 9, 3480”
by James D. Morse, L. Ignacio Cortinez and Brian J. Anderson
J. Clin. Med. 2021, 10(14), 3004; https://doi.org/10.3390/jcm10143004 - 6 Jul 2021
Cited by 4 | Viewed by 1727
Abstract
The parameters for a three-compartment model described by Morse and colleagues [...] Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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3 pages, 478 KiB  
Comment
Comment on Morse et al. A Universal Pharmacokinetic Model for Dexmedetomidine in Children and Adults. J. Clin. Med. 2020, 9, 3480
by Douglas J. Eleveld, Pieter J. Colin, Laura N. Hannivoort, Anthony R. Absalom and Michel M. R. F. Struys
J. Clin. Med. 2021, 10(14), 3003; https://doi.org/10.3390/jcm10143003 - 6 Jul 2021
Cited by 1 | Viewed by 1874
Abstract
We read with interest the recently published manuscript [...] Full article
(This article belongs to the Special Issue New Approaches in Intravenous Anesthesia and Anesthetics)
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