This review describes the basics of pharmacokinetic and pharmacodynamic drug interactions and methodological points of particular interest when designing drug interaction studies. It also provides an ...overview of the available literature concerning interactions, with emphasis on graphic representation of interactions using isoboles and response surface models. It gives examples on how to transform this knowledge into clinically and educationally applicable (bedside) tools.
Background
Surgery for catecholamine‐producing tumours can be complicated by intraoperative and postoperative haemodynamic instability. Several perioperative management strategies have emerged but ...none has been evaluated in randomized trials. To assess this issue, contemporary perioperative management and outcome data from 21 centres were collected.
Methods
Twenty‐one centres contributed outcome data from patients who had surgery for phaeochromocytoma and paraganglioma between 2000 and 2017. The data included the number of patients with and without α‐receptor blockade, surgical and anaesthetic techniques, complications and perioperative mortality.
Results
Across all centres, data were reported on 1860 patients with phaeochromocytoma or paraganglioma, of whom 343 underwent surgery without α‐receptor blockade. The majority of operations (78·9 per cent) were performed using minimally invasive techniques, including 16·1 per cent adrenal cortex‐sparing procedures. The cardiovascular complication rate was 5·0 per cent overall: 5·9 per cent (90 of 1517) in patients with preoperative α‐receptor blockade and 0·9 per cent (3 of 343) among patients without α‐receptor blockade. The mortality rate was 0·5 per cent overall (9 of 1860): 0·5 per cent (8 of 517) in pretreated and 0·3 per cent (1 of 343) in non‐pretreated patients.
Conclusion
There is substantial variability in the perioperative management of catecholamine‐producing tumours, yet the overall complication rate is low. Further studies are needed to better define the optimal management approach, and reappraisal of international perioperative guidelines appears desirable.
Antecedentes
La cirugía de los tumores productores de catecolaminas puede complicarse por la inestabilidad hemodinámica intraoperatoria y postoperatoria. Se han propuesto distintas estrategias de manejo perioperatorio, pero ninguna ha sido evaluada en ensayos aleatorizados. Para evaluar este tema, se han recogido los datos de los resultados y del manejo perioperatorio contemporáneo de 21 centros.
Métodos
Veintiún centros aportaron datos de los resultados de los pacientes operados por feocromocitoma y paraganglioma entre 2000‐2017. Los datos incluyeron el número de pacientes con y sin bloqueo del receptor α, las técnicas quirúrgicas y anestésicas, las complicaciones y la mortalidad perioperatoria.
Resultados
Los centros en su conjunto aportaron datos de 1.860 pacientes con feocromocitoma y paraganglioma, de los cuales 343 pacientes fueron intervenidos sin bloqueo del receptor α. La gran mayoría (79%) de las cirugías se realizaron utilizando técnicas mínimamente invasivas, incluido un 17% de procedimientos con preservación de la corteza suprarrenal. La tasa de complicaciones cardiovasculares fue de 5,0% en total; 5,9% (90/1517) en pacientes con bloqueo preoperatorio de los receptores α y 0,9% (3/343) en pacientes no pretratados. La mortalidad global fue del 0,5% (9/1860); 0,5% (8/1517) en pacientes pretratados y 0,3% (1/343) en pacientes no tratados previamente.
Conclusión
Existe una variabilidad sustancial en el manejo perioperatorio de los tumores productores de catecolaminas, aunque la tasa global de complicaciones es baja. Este estudio brinda la oportunidad para efectuar comparaciones sistemáticas entre estrategias de prácticas terapéuticas variables. Se necesitan más estudios para definir mejor el enfoque de manejo óptimo y parece conveniente volver a evaluar las guías internacionales perioperatorias.
Morbidity and mortality rates are difficult to determine in rare diseases like phaeochromocytoma. To date there has been no randomized study of the perioperative management of these patients. Therefore, an international and interdisciplinary effort was made to provide a broad overview of the current management of phaeochromocytoma.
Adverse effects frequent with preoperative blocking
Summary
The dye indocyanine green is familiar to anaesthetists, and has been studied for more than half a century for cardiovascular and hepatic function monitoring. It is still, however, not yet in ...routine clinical use in anaesthesia and critical care, at least in Europe. This review is intended to provide a critical analysis of the available evidence concerning the indications for clinical measurement of indocyanine green elimination as a diagnostic and prognostic tool in two areas: its role in peri‐operative liver function monitoring during major hepatic resection and liver transplantation; and its role in critically ill patients on the intensive care unit, where it is used for prediction of mortality, and for assessment of the severity of acute liver failure or that of intra‐abdominal hypertension. Although numerous studies have demonstrated that indocyanine green elimination measurements in these patient populations can provide diagnostic or prognostic information to the clinician, ‘hard’ evidence – i.e. high‐quality prospective randomised controlled trials – is lacking, and therefore it is not yet time to give a green light for use of indocyanine green in routine clinical practice.
Abstract
Context
Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL).
...Objective
To determine which type of α-adrenergic receptor blocker provides the best efficacy.
Design
Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898)
Setting
Multicenter study including 9 centers in The Netherlands.
Patients
134 patients with nonmetastatic PPGL.
Intervention
Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized.
Main Outcome Measures
Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP <60 mmHg) expressed as a percentage of total surgical procedure time. Secondary efficacy endpoint was the value on a hemodynamic instability score.
Results
Median cumulative time outside blood pressure targets was 11.1% (interquartile range IQR: 4.3–20.6 in the phenoxybenzamine group compared to 12.2% (5.3–20.2) in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8–58.0) and 50.0 (35.3–63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days.
Conclusions
The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.
Dynamic preload variables to predict fluid responsiveness are based either on the arterial pressure waveform (APW) or on the plethysmographic waveform (PW). We compared the ability of APW-based ...variations in stroke volume (SVV) and pulse pressure (PPV) and of PW-based plethysmographic variability index (PVI) to predict fluid responsiveness and to track fluid changes in patients undergoing major hepatic resection. Furthermore, we assessed whether the PPV/SVV ratio, as a measure of dynamic arterial elastance (Eadyn), could predict a reduction in norepinephrine requirement after fluid administration.
Thirty patients received i.v. fluid (15 ml kg−1 in 30 min) after hepatic resection and were considered responders when stroke volume index (SVI) increased ≥20% after fluid administration. SVV and SVI were measured by the FloTrac-Vigileo® device, and PVI was measured by the Masimo Radical 7 pulse co-oximeter®.
The areas under a receiver operating characteristic curve for SVV, PPV, and PVI were 0.81, 0.77, and 0.78, respectively. In responders, all dynamic variables, except PVI, decreased after fluid administration. Eadyn predicted a reduced norepinephrine requirement (AUC = 0.81).
In patients undergoing major hepatic resection, both APW- and PW-based dynamic preload variables predict fluid responsiveness (preload) to a similar extent. Most variables (except PVI) also tracked fluid changes. Eadyn, as a measure of arterial elastance (afterload), might be helpful to distinguish the origin of hypotension.
ClinicalTrials.gov, NCT01060683.
The Masimo Radical 7 (Masimo Corp., Irvine, CA, USA) pulse co-oximeter® calculates haemoglobin concentration (SpHb) non-invasively using transcutaneous spectrophotometry. We compared SpHb with ...invasive satellite-lab haemoglobin monitoring (Hbsatlab) during major hepatic resections both under steady-state conditions and in a dynamic phase with fluid administration of crystalloid and colloid solutions.
Thirty patients undergoing major hepatic resection were included and randomized to receive a fluid bolus of 15 ml kg−1 colloid (n=15) or crystalloid (n=15) solution over 30 min. SpHb was continuously measured on the index finger, and venous blood samples were analysed in both the steady-state phase (from induction until completion of parenchymal transection) and the dynamic phase (during fluid bolus).
Correlation was significant between SpHb and Hbsatlab (R2=0.50, n=543). The modified Bland–Altman analysis for repeated measurements showed a bias (precision) of −0.27 (1.06) and −0.02 (1.07) g dl−1 for the steady-state and dynamic phases, respectively. SpHb accuracy increased when Hbsatlab was <10 g dl−1, with a bias (precision) of 0.41 (0.47) vs −0.26 (1.12) g dl−1 for values >10 g dl−1, but accuracy decreased after colloid administration (R2=0.25).
SpHb correlated moderately with Hbsatlab with a slight underestimation in both phases in patients undergoing major hepatic resection. Accuracy increased for lower Hbsatlab values but decreased in the presence of colloid solution. Further improvements are necessary to improve device accuracy under these conditions, so that SpHb might become a sensitive screening device for clinically significant anaemia.
To facilitate various transitions of medical residents, healthcare team members and departments may employ various organizational socialization strategies, including formal and informal onboarding ...methods. However, residents' preferences for these organizational socialization strategies to ease their transition can vary. This study identifies patterns (viewpoints) in these preferences.
Using Q-methodology, we asked a purposeful sample of early-career residents to rank a set of statements into a quasi-normal distributed grid. Statements were based on previous qualitative interviews and organizational socialization theory. Participants responded to the question, 'What are your preferences regarding strategies other health care professionals, departments, or hospitals should use to optimize your next transition?' Participants then explained their sorting choices in a post-sort questionnaire. We identified different viewpoints based on by-person (inverted) factor analysis and Varimax rotation. We interpreted the viewpoints using distinguishing and consensus statements, enriched by residents' comments.
Fifty-one residents ranked 42 statements, among whom 36 residents displayed four distinct viewpoints: Dependent residents (n = 10) favored a task-oriented approach, clear guidance, and formal colleague relationships; Social Capitalizing residents (n = 9) preferred structure in the onboarding period and informal workplace social interactions; Autonomous residents (n = 12) prioritized a loosely structured onboarding period, independence, responsibility, and informal social interactions; and Development-oriented residents (n = 5) desired a balanced onboarding period that allowed independence, exploration, and development.
This identification of four viewpoints highlights the inadequacy of one-size-fits-all approaches to resident transition. Healthcare professionals and departments should tailor their socialization strategies to residents' preferences for support, structure, and formal/informal social interaction.
Hypovolaemia is generally believed to induce centralization of blood volume. Therefore, we evaluated whether induced hypo- and hypervolaemia result in changes in central blood volumes (pulmonary ...blood volume (PBV), intrathoracic blood volume (ITBV)) and we explored the effects on the distribution between these central blood volumes and circulating blood volume (Vd circ).
Six anaesthetized, spontaneously breathing Foxhound dogs underwent random blood volume alterations in steps of 150 ml (mild) to 450 ml (moderate), either by haemorrhage, retransfusion of blood, or colloid infusion. PBV, ITBV and Vd circ were measured using (transpulmonary) dye dilution. The PBV/Vd circ ratio and the ITBV/Vd circ ratio were used as an assessment of blood volume distribution.
68 blood volume alterations resulted in changes in Vdcirc ranging from −33 to +31%. PBV and ITBV decreased during mild and moderate haemorrhage, while during retransfusion, PBV and ITBV increased during moderate hypervolaemia only. The PBV/Vd circ ratio remained constant during all stages of hypo- and hypervolaemia (mean values between 0.20–0.22). This was also true for the ITBV/Vd circ ratio, which remained between 0.31 and 0.32, except for moderate hypervolaemia, where it increased slightly to 0.33 (0.02), P<0.05.
Mild to moderate blood volume alterations result in changes of Vd circ, PBV and ITBV. The ratio between the central blood volumes and Vd circ generally remained unaltered. Therefore, it could be suggested that in anaesthetized spontaneously breathing dogs, the cardiovascular system maintains the distribution of blood between central and circulating blood volume.
: Educational activities for students are typically arranged without consideration of their preferences or peak performance hours. Students might prefer to study at different times based on their ...chronotype, aiming to optimize their performance. While face-to-face activities during the academic schedule do not offer flexibility and cannot reflect students' natural learning rhythm, asynchronous e-learning facilitates studying at one's preferred time. Given their ubiquitous accessibility, students can use e-learning resources according to their individual needs and preferences. E-learning usage data hence serves as a valuable proxy for certain study behaviors, presenting research opportunities to explore students' study patterns. This retrospective study aims to investigate when and for how long undergraduate students used medical e-learning modules.
: We performed a cross-sectional analysis of e-learning usage at one medical faculty in the Netherlands. We used data from 562 undergraduate multimedia e-learning modules for pre-clinical students, covering various medical topics over a span of two academic years (2018/19 and 2019/20). We employed educational data mining approaches to process the data and subsequently identified patterns in access times and durations.
: We obtained data from 70,805 e-learning sessions with 116,569 module visits and 1,495,342 page views. On average, students used e-learning for 16.8 min daily and stopped using a module after 10.2 min, but access patterns varied widely. E-learning was used seven days a week with an hourly access pattern during business hours on weekdays. Across all other times, there was a smooth increase or decrease in e-learning usage. During the week, more students started e-learning sessions in the morning (34.5% vs. 19.1%) while fewer students started in the afternoon (42.6% vs. 50.8%) and the evening (19.4% vs. 27.0%). We identified 'early bird' and 'night owl' user groups that show distinct study patterns.
: This retrospective educational data mining study reveals new insights into the study patterns of a complete student cohort during and outside lecture hours. These findings underline the value of 24/7 accessible study material. In addition, our findings may serve as a guide for researchers and educationalists seeking to develop more individualized educational programs.
BACKGROUNDThere is no consensus on how to define haemodynamic instability during general anaesthesia. Patients are often classified as stable or unstable based solely on blood pressure thresholds, ...disregarding the degree of instability. Vasoactive agents and volume therapy can directly influence classification but are usually not considered.
OBJECTIVETo develop and validate a scoring tool to quantify the overall degree of haemodynamic instability.
DESIGNRetrospective observational study.
SETTINGUniversity hospital.
PATIENTSThe development cohort consisted of 50 patients undergoing high-risk surgery with a control group of 50 undergoing video-assisted thoracoscopic surgery. In the validation cohort, there were 153 high-risk surgery patients and 78 controls.
INTERVENTIONNone.
MAIN OUTCOME MEASURESThe haemodynamic instability score (HI-score) was calculated as a weighted continuous measure ranging from 0 to 160 points, intended to reflect deviations of blood pressure and heart rate from predefined thresholds, and infusion rates of vasoactive agents and fluids. Thresholds were first determined in a development cohort and subsequently tested in a validation cohort. Results are presented as median interquartile range.
RESULTSIn the validation cohort the HI-score was 59 37 to 96 in the high-risk surgery group compared with 44 24 to 58 in the control group (P < 0.001). The score of the haemodynamic domain did not differ (P = 0.69) between groups10 8 to 16 vs. 10 8 to 16. However, scores for volume therapy and vasoactive medication were significantly higher in the high-risk surgery group compared with the control group14 6 to 30 vs. 6 2 to 18, P = 0.003 and 35 15 to 75 vs. 15 5 to 35, P < 0.001, respectively.
CONCLUSIONWe developed the HI-score and demonstrated that it can appropriately quantify the degree of intra-operative haemodynamic instability. The HI-score provides a clinical tool which, after further external validation, may have future applications in both patient management and clinical research.
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