The HEV Ventilator: at the interface between particle physics and biomedical engineering.

A high-quality, low-cost ventilator, dubbed HEV, has been developed by the particle physics community working together with biomedical engineers and physicians around the world. The HEV design is suitable for use both in and out of hospital intensive care units, provides a variety of modes and is capable of supporting spontaneous breathing and supplying oxygen-enriched air. An external air supply can be combined with the unit for use in situations where compressed air is not readily available. HEV supports remote training and post market surveillance via a Web interface and data logging to complement standard touch screen operation, making it suitable for a wide range of geographical deployment. The HEV design places emphasis on the ventilation performance, especially the quality and accuracy of the pressure curves, reactivity of the trigger, measurement of delivered volume and control of oxygen mixing, delivering a global performance which will be applicable to ventilator needs beyond the COVID-19 pandemic. This article describes the conceptual design and presents the prototype units together with a performance evaluation.

Who Gets the Last Bed? A Discrete-Choice Experiment Examining General Population Preferences for Intensive Care Bed Prioritization in a Pandemic.

OBJECTIVE: To explore the key patient attributes important to members of the Australian general population when prioritizing patients for the final intensive care unit (ICU) bed in a pandemic over-capacity scenario. METHODS: A discrete-choice experiment administered online asked respondents (N = 306) to imagine the COVID-19 caseload had surged and that they were lay members of a panel tasked to allocate the final ICU bed. They had to decide which patient was more deserving for each of 14 patient pairs. Patients were characterized by 5 attributes: age, occupation, caregiver status, health prior to being infected, and prognosis. Respondents were randomly allocated to one of 7 sets of 14 pairs. Multinomial, mixed logit, and latent class models were used to model the observed choice behavior. RESULTS: A latent class model with 3 classes was found to be the most informative. Two classes valued active decision making and were slightly more likely to choose patients with caregiving responsibilities over those without. One of these classes valued prognosis most strongly, with a decreasing probability of bed allocation for those 65 y and older. The other valued both prognosis and age highly, with decreasing probability of bed allocation for those 45 y and older and a slight preference in favor of frontline health care workers. The third class preferred more random decision-making strategies. CONCLUSIONS: For two-thirds of those sampled, prognosis, age, and caregiving responsibilities were the important features when making allocation decisions, although the emphasis varies. The remainder appeared to choose randomly.

Evaluating the influence of data collector training for predictive risk of death models: an observational study.

BACKGROUND: Severity-of-illness scoring systems are widely used for quality assurance and research. Although validated by trained data collectors, there is little data on the accuracy of real-world data collection practices. OBJECTIVE: To evaluate the influence of formal data collection training on the accuracy of scoring system data in intensive care units (ICUs). STUDY DESIGN AND METHODS: Quality assurance audit conducted using survey methodology principles. Between June and December 2018, an electronic document with details of three fictitious ICU patients was emailed to staff from 19 Australian ICUs who voluntarily submitted data on a web-based data entry form. Their entries were used to generate severity-of-illness scores and risks of death (RoDs) for four scoring systems. The primary outcome was the variation of severity-of-illness scores and RoDs from a reference standard. RESULTS: 50/83 staff (60.3%) submitted data. Using Bayesian multilevel analysis, severity-of-illness scores and RoDs were found to be significantly higher for untrained staff. The mean (95% high-density interval) overestimation in RoD due to training effect for patients 1, 2 and 3, respectively, were 0.24 (0.16, 0.31), 0.19 (0.09, 0.29) and 0.24 (0.1, 0.38) respectively (Bayesian factor >300, decisive evidence). Both groups (trained and untrained) had wide coefficients of variation up to 38.1%, indicating wide variability. Untrained staff made more errors in interpreting scoring system definitions. INTERPRETATION: In a fictitious patient dataset, data collection staff without formal training significantly overestimated the severity-of-illness scores and RoDs compared with trained staff. Both groups exhibited wide variability. Strategies to improve practice may include providing adequate training for all data collection staff, refresher training for previously trained staff and auditing the raw data submitted by individual ICUs. The results of this simulated study need revalidation on real patients.

Impact of Critical Care Point-of-Care Ultrasound Short-Courses on Trainee Competence.

OBJECTIVES: Competence in point-of-care ultrasound is recommended/mandated by several critical care specialties. Although doctors commonly attend point-of-care ultrasound short-courses for introductory training, there is little follow-up data on whether they eventually attain competence. This study was done to determine the impact of point-of-care ultrasound short-courses on point-of-care ultrasound competence. DESIGN: Web-based survey. SETTING: Follow-up after point-of-care ultrasound short-courses in the Asia-Pacific region. SUBJECTS: Doctors who attended a point-of-care ultrasound short-course between December 2015 and February 2018. INTERVENTIONS: Each subject was emailed a questionnaire on or after 6 months following their short-course. They were asked if they had performed at least 30 structured point-of-care ultrasound scans and/or reached point-of-care ultrasound competence and their perceived reasons/challenges/barriers. They were also asked if they used point-of-care ultrasound as a clinical diagnostic aid. MEASUREMENTS AND MAIN RESULTS: The response rate was 74.9% (182/243). Among the 182 respondents, only 12 (6.6%) had attained competence in their chosen point-of-care ultrasound modality, attributing their success to self-motivation and time management. For the remaining doctors who did not attain competence (170/182, 93.4%), the common reasons were lack of time, change of priorities, and less commonly, difficulties in accessing an ultrasound machine/supervisor. Common suggestions to improve short-courses included requests for scanning practice on acutely ill ICU patients and prior information on the challenges regarding point-of-care ultrasound competence. Suggestions to improve competence pathways included regular supervision and protected learning time. All 12 credentialled doctors regularly used point-of-care ultrasound as a clinical diagnostic aid. Of the 170 noncredentialled doctors, 123 (72.4%) reported performing unsupervised point-of-care ultrasound for clinical management, either sporadically (42/170, 24.7%) or regularly (81/170, 47.7%). CONCLUSIONS: In this survey of doctors attending point-of-care ultrasound short-courses in Australasia, the majority of doctors did not attain competence. However, the practice of unsupervised point-of-care ultrasound use by noncredentialled doctors was common. Further research into effective strategies to improve point-of-care ultrasound competence is required.

Estimation of cardiac output and systemic vascular resistance using a multivariate regression model with features selected from the finger photoplethysmogram and routine cardiovascular measurements.

BACKGROUND: Cardiac output (CO) and systemic vascular resistance (SVR) are two important parameters of the cardiovascular system. The ability to measure these parameters continuously and noninvasively may assist in diagnosing and monitoring patients with suspected cardiovascular diseases, or other critical illnesses. In this study, a method is proposed to estimate both the CO and SVR of a heterogeneous cohort of intensive care unit patients (N=48). METHODS: Spectral and morphological features were extracted from the finger photoplethysmogram, and added to heart rate and mean arterial pressure as input features to a multivariate regression model to estimate CO and SVR. A stepwise feature search algorithm was employed to select statistically significant features. Leave-one-out cross validation was used to assess the generalized model performance. The degree of agreement between the estimation method and the gold standard was assessed using Bland-Altman analysis. RESULTS: The Bland-Altman bias ±precision (1.96 times standard deviation) for CO was -0.01 ±2.70 L min-1 when only photoplethysmogram (PPG) features were used, and for SVR was -0.87 ±412 dyn.s.cm-5 when only one PPG variability feature was used. CONCLUSIONS: These promising results indicate the feasibility of using the method described as a non-invasive preliminary diagnostic tool in supervised or unsupervised clinical settings.

Pro/con debate: Is etomidate safe in hemodynamically unstable critically ill patients?

Etomidate is an induction agent known for its smooth intubating conditions and cardiovascular stability. Studies, however, have shown that a single dose of etomidate can result in a prolonged adrenal insufficiency. The impact of this in patients with sepsis has been a matter for debate. This review presents a pro/con case for using etomidate in hemodynamically unstable critically ill patients and provides guidance for alternative induction techniques and when the use of etomidate might be justified despite these concerns.

Multivariate classification of systemic vascular resistance using photoplethysmography.

Systemic vascular resistance (SVR) classification is useful for the diagnosis and prognosis of critical pathophysiological conditions, with the ability to identify patients with abnormally high or low SVR of immense clinical value. In this study, a supervised classifier, based on Bayes' rule, is employed to classify a heterogeneous group of intensive care unit patients (N = 48) as being below (SVR < 900 dyn s cm(-5)), within (900 ⩽ SVR ⩽ 1200 dyn s cm(-5)) or above (SVR > 1200 dyn s cm(-5)) the clinically accepted range for normal SVR. Features derived from the finger photoplethysmogram (PPG) waveform and other routine cardiovascular measurements (heart rate and mean arterial pressure) were used as inputs to the classifier. In the construction of the classifier model, two techniques were used to approximate the class conditional probability densities--a single Gaussian distribution model (also known as discriminant analysis) and a non-parametric model using the Parzen window kernel density estimation method. An exhaustive feature search was performed to select a feature subset that maximized the performance indicator, Cohen's kappa coefficient (κ). The Gaussian model with multiple features achieved the best overall kappa coefficient (κ = 0.57), although the results from the non-parametric model were comparable (κ = 0.51). The optimum subset in the Gaussian model consisted of PPG waveform variability features, including the low-frequency to high-frequency ratio (LF/HF) and the normalized mid-frequency power (MF(NU)), in addition to the PPG pulse wave features, such as pulse width, peak-to-notch time, reflection index, and notch time ratio. The classifier performed particularly well in discriminating low SVR, with a sensitivity of 85%, specificity of 86%, positive predictive value of 88% and a negative predictive value of 82%. The results highlight the feasibility of deploying a multivariate statistical approach of SVR classification in the clinical setting, simply using a non-invasive and easy-to-measure PPG waveform signal.

Fingertip photoplethysmographic waveform variability and systemic vascular resistance in intensive care unit patients.

Low frequency variability in the fingertip photoplethysmogram (PPG) waveform has been utilized for inferring sympathetic vascular control, but its relationship with a quantitative measure of vascular tone has not been established. In this study, we examined the association between fingertip PPG waveform variability (PPGV) and systemic vascular resistance (SVR) obtained from thermodilution cardiac output (CO) and intra-arterial pressure measurements in 48 post cardiac surgery intensive care unit patients. Among the hemodynamic measurements, both CO (P < 0.05) and SVR (P < 0.0001) had statistically significant relationships with the normalized low frequency power (LF(nu)) of PPGV. The LF(nu) of baseline PPGV had moderate but significant positive correlation with SVR (r = 0.54, P < 0.0001), and a value below 52.5 nu was able to identify SVR < 900 dyn s cm⁻5 with sensitivity of 59% and specificity of 95%. The results have provided quantitative evidence to confirm the link between fingertip PPGV and sympathetic vascular control. Suppression of LF vasomotor waves leading to dominance of respiration-related HF fluctuations in the fingertip circulation was a specific (though not sensitive) marker of systemic vasodilatation, which could be potentially utilized for the assessment of critical care patients.

Helium-oxygen reduces the production of carbon dioxide during weaning from mechanical ventilation.

BACKGROUND: Prolonged weaning from mechanical ventilation has a major impact on ICU bed occupancy and patient outcome, and has significant cost implications.There is evidence in patients around the period of extubation that helium-oxygen leads to a reduction in the work of breathing. Therefore breathing helium-oxygen during weaning may be a useful adjunct to facilitate weaning. We hypothesised that breathing helium-oxygen would reduce carbon dioxide production during the weaning phase of mechanical ventilation. MATERIALS/PATIENTS AND METHODS: We performed a prospective randomised controlled single blinded cross-over trial on 19 adult intensive care patients without significant airways disease who fulfilled criteria for weaning with CPAP. Patients were randomised to helium-oxygen and air-oxygen delivered during a 2 hour period of CPAP ventilation. Carbon dioxide production (VCO2) was measured using a near patient main stream infrared carbon dioxide sensor and fixed orifice pneumotachograph. RESULTS: Compared to air-oxygen, helium-oxygen significantly decreased VCO2 production at the end of the 2 hour period of CPAP ventilation; there was a mean difference in CO2 production of 48.9 ml/min (95% CI 18.7-79.2 p = 0.003) between the groups. There were no significant differences in other respiratory and haemodynamic parameters. CONCLUSION: This study shows that breathing a helium-oxygen mixture during weaning reduces carbon dioxide production. This physiological study supports the need for a clinical trial of helium-oxygen mixture during the weaning phase of mechanical ventilation with duration of weaning as the primary outcome. TRIAL REGISTRATION: ISRCTN56470948.

Paracetamol induced skin blood flow and blood pressure changes in febrile intensive care patients: An observational study.

OBJECTIVE: To determine the relationship between paracetamol administration and skin blood flow (skBF) and blood pressure (BP) in critically ill patients treated for fever. DESIGN: Prospective, observational study. SETTING: Intensive care units of university teaching hospital. PATIENTS: 29 adults (17 males and 12 females), aged 58±15 years treated with enteral or intravenous paracetamol for fever. APACHE II score was 17.2±8.3 and admission classifications were 41% medical (n=12), 31% surgical (n=9), and 28% neurological intervention (n=8). Thirty healthy afebrile volunteers were also studied after ingesting 1g paracetamol. MEASUREMENTS AND MAIN RESULTS: Temperature, BP and skBF (laser Doppler flowmetry perfusion units) were recorded 15 min prior to administration of paracetamol, at administration (T0) and then for every 15 min for 60 min. Cutaneous vascular conductance (CVC=skBF/mean arterial pressure) was calculated. Thirty data sets were recorded from 29 patients. Temperature at T0 was 38.7±0.6°C. BP decreased over the study period whilst skBF and CVC increased (repeated measured ANOVA, p<.05). Systolic BP decreased significantly (p<.01) at all post-administration times and was 90±13% of T0 at 60 min. CVC was 128±48% of T0 at 60 min. Systolic BP fell by a clinically significant amount (≥15%) in 17 patients (59%) and hypotension was treated during 33% (n=10) of the observation periods. BP and skBF did not change significantly in afebrile volunteers. CONCLUSIONS: Paracetamol induced increases in skBF consistent with its antipyretic action and may be associated with significant falls in BP in the critically ill.

Assessment of the clinical utility of an ultrasonic monitor of cardiac output (the USCOM) and agreement with thermodilution measurement.

OBJECTIVE: To assess the clinical utility of an ultrasonic monitor of cardiac output (USCOM), its reliability in tracking cardiac output (CO) changes and agreement with thermodilution (TD) measurements of CO. DESIGN: Prospective comparison study. SETTING AND PARTICIPANTS: 55 adults undergoing thermodilution (TD) CO monitoring in a cardiothoracic or general intensive care unit between December 2006 and December 2007. MAIN OUTCOME MEASURES: USCOM and TD measurements of CO on two occasions in each patient were compared by Bland-Altman analysis for bias and limit of agreement. A mean percentage error <30% was considered acceptable. Per cent change in cardiac index (CI) was determined by each method. Doppler profiles obtained by the USCOM were assessed against an ideal standard ("acceptable"). RESULTS: 55 patients had measurements on 110 occasions, but Doppler waveforms were not obtained on 18 of these (16%), leaving 39 patients with paired comparisons for analysis (including 27 men; mean age, 64.7 [SD, 14.5] years). Mean TD CI was 3.4 +/-1.0L/min/m(2) (range, 2.0-6.0L/min/m(2)). The bias was 0.6L/min/m(2) (95% confidence limits [CLs], 0.4-0.8 L/min/m(2)), and the mean percentage error was 56% (95% CLs, 45%-65%). Twenty-two Doppler profiles (28%) were classed as acceptable; the mean percentage error for these was 62% (95% CLs, 38%-65%). On 15/19 occasions (74%) where TD CI changed > 15%, USCOM CI also changed >15%, but three of these changes (16%) were in the opposite direction. USCOM CI changed >15% on 9/20 occasions (45%) when TD CI did not. CONCLUSIONS: Poor agreement with TD and a substantial rate of failure to obtain an USCOM measurement suggest that this device is unsuitable as a monitoring tool in intensive care.

Absorption rate limit considerations for oral phosphate prodrugs.

PURPOSE: To evaluate the potential of phosphate ester prodrugs to significantly improve the absorptive flux of poorly soluble parent drugs. METHODS: Absorptive transport studies of parent drugs and their prodrugs were carried out in Caco-2 cells. Prodrugs of parent drugs with variable aqueous solubilities were tested: Hydrocortisone-phosphate/Hydrocortisone, Fosphenytoin/phenytoin, TAT-59/DP-TAT-59, and Entacapone phosphate/Entacapone. Additional absorption studies were carried out in rats. RESULTS: Absorptive fluxes of DP-TAT-59 and phenytoin increased 9.8 or 3.3-fold after dosing TAT-59 and 500 microM fosphenytoin, respectively. Hydrocortisone's flux did not increase with hydrocortisone-phosphate at 100 microM. Permeability of the highly lipophilic and protein bound compound, DP-TAT-59, was significantly increased with serosal albumin. No permeability increase was observed for the other drugs with albumin. Entacapone phosphate failed to improve the flux of entacapone compared to an entacapone solution, but the prodrug solution did yield higher entacapone plasma levels in rats when compared with an entacapone suspension. CONCLUSION: Ideal phosphate prodrug candidates are characterized by high permeability and low solubility (BCS Class II drugs). For low dose BCS Class II drug candidates, however, no biopharmaceutical advantage may be gained. Phosphate prodrugs of parent drugs with limited permeability may fail. When screening highly lipophilic parent drugs transport studies should be done with albumin.

Chemical stabilities and biological activities of thalidomide and its N-alkyl analogs.

UNLABELLED: PURPOSE. To determine whether the N-alkyl analogs of the thalidomide are active and stable, their stabilities in buffer and their abilities to inhibit tumor necrosis factor alpha (TNF-alpha) in vitro in human peripheral blood mononuclear cell cultures were investigated. METHODS: TNF-alpha concentrations were determined with the aid of ELISA kits. Chemical stabilities of the compounds were determined in three phosphate buffer solutions (pH 6, 6.4, and 7.4) at 25 and 32 degrees C by high-pressure liquid chromatography, and half-lives were calculated. RESULTS: The addition of N-alkyl groups to the glutarimide ring of the thalidomide molecule had little effect on the ability such compounds have to inhibit TNF-alpha production. There was no statistical difference between the activity of thalidomide and its N-alkyl analogs at a 95% confidence level. Like thalidomide, the N-alkyl analogs in this series inhibit an average of 60% of the TNF-alpha synthesis in lipopolysaccharide-stimulated peripheral blood mononuclear cell cultures. Thalidomide and its N-alkyl analogs are hydrolyzed at very similar rates, with half-lives ranging from 25 to 35 h at 32 degrees C at pH 6.4 and an average rate constant of 2.35 x 10(-2)/h. CONCLUSION: Alkylating thalidomide had little effect on its ability to inhibit the production of TNF-alpha in these cell cultures. All of the compounds tested seem to have some, perhaps comparable, therapeutic potential.

Percutaneous delivery of thalidomide and its N-alkyl analogs.

PURPOSE: The purpose of this study was to determine the permeation parameters of thalidomide and three of its N-alkyl analogs and to establish a correlation between the physicochemical properties of these compounds and their percutaneous rates of absorption. METHODS: In vitro permeation studies were performed from buffer, n-alkanols and various mixed components using vertical Franz diffusion cells fitted with human epidermal membranes. RESULTS: Measured steady-state fluxes indicate that N-methyl thalidomide is a far better penetrant of human skin than the "parent molecule". However, fluxes through skin drop off markedly from that of the methylated compound when the chain length is extended to propyl and pentyl. However, they remain well above the flux of thalidomide, which is less than 0.025 microg/cm2/h. CONCLUSIONS: The best skin permeant of this series was the N-methyl analog, which also exhibited the highest water (buffer) solubility compared to thalidomide, and the N-propyl and N-pentyl analogs. The N-propyl and N-pentyl analogs were more lipid soluble and exhibited higher partition coefficient values than the N-methyl analog. From all the permeability data using buffer, a series of n-alkanols and various combinations of solvents and enhancers as vehicles, the more water-soluble compound and not the more lipid soluble one was the best skin permeant.

Physicochemical characterization and solubility analysis of thalidomide and its N-alkyl analogs.

PURPOSE: The present study was primarily aimed at exploring the feasibility of improving percutaneous delivery via chemical manipulation of the thalidomide molecule to form analogs with improved physicochemical properties. N-Alkyl analogs were synthesized with the belief that these would be suitably hydrophobic and far less crystalline than the reference compound. This article presents their physicochemical properties. METHODS: Thalidomide and three of its N-alkyl analogs were synthesized. Identification and levels of purity (>96%) were assured through element analysis, fast atom-bombardment mass spectrometry, nuclear magnetic resonance spectroscopy, and high-performance liquid chromatography. N-Octanol/water partition coefficients were determined at pH 6.4. Solubilities in water and a series of n-alkanols were obtained. Best-fit solubility parameters were determined from the solubilities of the respective compounds in London solvents and were also calculated from respective hexane solubilities. melting points and heats of fusion. RESULTS: Methylation of the thalidomide molecule at its acidic nitrogen led to an aqueous solubility about 6-fold higher than thalidomide but, because the alkyl chain length was further extended from methyl to pentyl. aqueous solubilities decreased essentially exponentially. The destabilization of the crystalline structure with increasing alkyl chain length led to an increased solubility in nonpolar media. The log partition coefficient increased linearly with increasing alkyl chain length and the solubility parameters declined systematically through this series. By adding a methyl group to the thalidomide structure, the melting point dropped by more than 100 degrees C. Adding to the alkyl chain length led to further, more modest decreases. Heats of fusion decreased dramatically upon thalidomide's alkylation as well. CONCLUSION: Alkylation of the thalidomide molecule resulted in compounds with physicochemical properties that appear to be markedly better suited for percutaneous delivery.