One Small Step for a Patient, One Giant Leap for Orthostatic Hypotension.

A 52-year-old man with ischemic cardiomyopathy presented with progressive, severe orthostatic hypotension refractory to medical therapy. Standard abdominal and leg compression devices were used without success. A novel, inflatable abdominal compression device was created that alleviated the patient's symptoms and maintained his blood pressure.

A Portable Negative Pressure Isolation System as a Solution to Minimize Exposure of Health Care Providers to Infectious Pathogens.

The COVID-19 pandemic has resulted in the exposure of many surgeons and healthcare providers (HCPs) to disease given high patient loads and limited availability of negative pressure rooms. For these reasons we pursued the development of a portable patient isolation system (COVIAGE™ by iSolace, Inc.) that can be used to contain patients with respiratory illness and minimize the exposure of HCPs. COVIAGE™ is comprised of a reusable aluminum frame, a disposable thermoplastic polyurethane tent and a HEPA filtration/ventilation system (HVAC) utilizing two inline filters. The efficacy of filtration was tested by comparing particulate concentration inside and outside of the device by an independent third party. Additionally, physician, nursing, and respiratory tasks were performed initially on simulated patients and then on intubated patients in the ICU. The system attained a verified filtration efficiency greater than 99.999% for an average 0.3-µm size particulates. Simulation testing revealed that most common physician, nursing, and respiratory tasks could be completed in the device, including endotracheal intubation. Emergency removal of the device can be accomplished in 8.8 ± 2.8 seconds. The reusable aluminum frame allows for simple attachment to the bed, and adaptability to different types and sizes of beds/stretchers. An emergency use authorization was granted by the FDA. The device created results in a portable negative pressure isolation system that can be placed over the patient's bed to contain aerosols during high aerosol generating procedures, transportation of patients or for total patient care in environments where negative pressure rooms are not available.

Helmet Modification to PPE With 3D Printing During the COVID-19 Pandemic at Duke University Medical Center: A Novel Technique.

Care for patients during COVID-19 poses challenges that require the protection of staff with recommendations that health care workers wear at minimum, an N95 mask or equivalent while performing an aerosol-generating procedure with a face shield. The United States faces shortages of personal protective equipment (PPE), and surgeons who use loupes and headlights have difficulty using these in conjunction with face shields. Most arthroplasty surgeons use surgical helmet systems, but in the current pandemic, many hospitals have delayed elective arthroplasty surgeries and the helmet systems are going unused. As a result, the authors have begun retrofitting these arthroplasty helmets to serve as PPE. The purpose of this article is to outline the conception, design, donning technique, and safety testing of these arthroplasty helmets being repurposed as PPE.

Pediatric medical device development by surgeons via capstone engineering design programs.

BACKGROUND: There is a need for pediatric medical devices that accommodate the unique physiology and anatomy of pediatric patients that is increasingly receiving more attention. However, there is limited literature on the programs within children's hospitals and academia that can support pediatric device development. We describe our experience with pediatric device design utilizing collaborations between a children's hospital and two engineering schools. METHODS: Utilizing the academic year as a timeline, unmet pediatric device needs were identified by surgical faculty and matched with an engineering mentor and a team of students within the Capstone Engineering Design programs at two universities. The final prototypes were showcased at the end of the academic year and if appropriate, provisional patent applications were filed. RESULTS: All twelve teams successfully developed device prototypes, and five teams obtained provisional patents. The prototypes that obtained provisional patents included a non-operative ureteral stent removal system, an evacuation device for small kidney stone fragments, a mechanical leech, an anchoring system of the chorio-amniotic membranes during fetal surgery, and a fetal oxygenation monitor during fetoscopic procedures. CONCLUSIONS: Capstone Engineering Design programs in partnership with surgical faculty at children's hospitals can play an effective role in the prototype development of novel pediatric medical devices. LEVELS OF EVIDENCE: N/A - No clinical subjects or human testing was performed.

Cardiac responses to the intrapericardial delivery of metoprolol: targeted delivery compared to intravenous administration.

Anti-arrhythmic drugs have narrow therapeutic ranges and typically can engender harmful side effects. The intrapericardial (IP) delivery of anti-arrhythmic agents proposes to achieve higher myocardial levels while minimizing plasma concentrations, thus diminishing systemic side effects. Furthermore, IP delivery enables concentrations at the target site to be more precisely controlled. Our study objective was to compare the relative cardiac effects of intrapericardial administration of metoprolol to standard intravenous (IV) delivery in a swine surgical model. In order to answer the question of how IP metoprolol affects sinus tachycardia, atrial electrophysiology, and pharmacokinetics compared with IV delivery, a medial sternotomy was performed on 21 swine that were divided into three groups: (1) After inducing sinus tachycardia, metoprolol boluses were delivered IP (n = 4) or IV (n = 4); (2) metoprolol was administered either IP (n = 3) or IV (n = 3) with saline controls (n = 3), and electrophysiologic data were collected; (3) metoprolol levels were tracked both in the blood (IV, n = 2) and pericardial (IP, n = 2) fluid. After either IP or IV delivery of metoprolol, heart rates were lowered significantly to 70% and 73% of control rate, respectively. The therapeutic effect of IV-administered metoprolol was considerably reduced after 1 h but was sustained longer in the IP group. Additionally, ventricular contractility and mean arterial pressure parameters were significantly lower in IV-treated animals but were nearly unaffected in IP-treated animals. With IP administration, the elimination half-life of metoprolol in pericardial fluid was 14.4 min with negligible accumulations in the plasma, whereas with IV delivery, the elimination half-life in plasma was 11.1 min with negligible amounts found in the pericardial fluid. The targeted intrapericardial delivery of metoprolol effectively lowers heart rates for sustained periods of time, with minimal effect on either ventricular contractility or mean arterial pressure. We did not observe dramatic changes in induced atrial fibrillation times or refractory periods using this model.

Electrophysiological mechanisms of the anti-arrhythmic effects of omega-3 fatty acids.

Heart rhythm disorders, or arrhythmias, are a leading cause of morbidity and mortality worldwide. Omega-3 polyunsaturated fatty acids (ω3PUFAs), commonly found in fish oils and plant seeds, have recently emerged as potential anti-arrhythmic agents. The purpose of this review is to summarize the electrophysiological basis of the anti-arrhythmic properties of ω3PUFAs from clinical, animal, and cellular research. Evidence of the anti-arrhythmic effects of ω3PUFAs originated from epidemiological studies that correlated a low incidence of sudden cardiac death with high dietary ω3PUFA intake. Subsequently, multiple clinical trials have confirmed the therapeutic effects of ω3PUFAs in preventing sudden cardiac death and multiple other arrhythmia-related disorders. This has led basic scientists to investigate the effects of ω3PUFAs on several ion channels including sodium, potassium, and calcium channels, as well as Na/Ca exchangers. Therefore, ω3PUFAs may hold promise as safe and effective anti-arrhythmic agents. Nevertheless, further research is needed in areas such as: (1) identifying which form(s) of ω3PUFAs (i.e., phospholipid, triglyceride, or free) is (are) responsible for anti-arrhythmic actions; and (2) developing reproducible methods for delivery so that the appropriate form and concentration may be present at the target site to prevent and treat arrhythmias.

Hysteresis in human HCN4 channels: a crucial feature potentially affecting sinoatrial node pacemaking.

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate and regulate cardiac rhythm and rate. It has been suggested that, unlike the HCN1 and HCN2 channels, the slower HCN4 channel may not exhibit voltage-dependent hysteresis. We studied the electrophysiological properties of human HCN4 (hHCN4) channels and its modulation by cAMP to determine whether hHCN4 exhibits hysteresis, by using single-cell patch-clamp in HEK293 cells stably transfected with hHCN4. Quantitative real-time RT-PCR was also used to determine levels of expression of HCNs in human cardiac tissue. Voltage-clamp analysis revealed that hHCN4 current (I(h)) activation shifted in the depolarizing direction with more hyperpolarized holding potentials. Triangular ramp and action potential clamp protocols also revealed hHCN4 hysteresis. cAMP enhanced I(h) and shifted activation in the depolarizing direction, thus modifying the intrinsic hHCN4 hysteresis behavior. Quantitative PCR analysis of human sinoatrial node (SAN) tissue showed that HCN4 accounts for 75% of the HCNs in human SAN while HCN1 (21%), HCN2 (3%), and HCN3 (0.7%) constitute the remainder. Our data suggest that HCN4 is the predominant HCN subtype in the human SAN and that I(h) exhibits voltage-dependent hysteresis behavior that can be modified by cAMP. Therefore, hHCN4 hysteresis potentially plays a crucial role in human SAN pacemaking activity.

Over-pressure suppresses ultrasonic-induced drug uptake.

Ultrasound (US) is used to enhance and target delivery of drugs and genes to cancer tissues. The present study further examines the role of acoustic cavitation in US-induced permeabilization of cell membranes and subsequent drug or gene uptake by the cell. Rat colon cancer cells were exposed to ultrasound at various static pressures to examine the hypothesis that oscillating bubbles, also known as cavitating bubbles, permeabilize cells. Increasing pressure suppresses bubble cavitation activity; thus, if applied pressure were to reduce drug uptake, cell permeabilization would be strongly linked to bubble cavitation activity. Cells were exposed to 476 kHz pulsed ultrasound at average intensities of 2.75 W/cm(2) and 5.5 W/cm(2) at various pressures and times in an isothermal chamber. Cell fractions with reversible membrane damage (calcein uptake) and irreversible damage (propidium iodide uptake) were analyzed by flow cytometry. Pressurization to 3 atm nearly eliminated the biological effect of US in promoting calcein uptake. Data also showed a linear increase in membrane permeability with respect to insonation time and intensity. This research shows that US-mediated cell membrane permeability is likely linked to cavitation bubble activity.

Pericardial delivery of omega-3 fatty acid: a novel approach to reducing myocardial infarct sizes and arrhythmias.

Basic and clinical evidence suggests that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) decrease fatal arrhythmias and infarct sizes. This study investigated if pericardial delivery of n-3 PUFAs would protect the myocardium from ischemic damages and arrhythmias. Acute myocardial infarctions were induced in 23 pigs with either 45 min balloon inflations or clamp occlusions of the left anterior descending coronary arteries and 180 min reperfusion. Docosahexaenoic acid (C22:6n-3, DHA, 45 mg), one of the main n-3 PUFAs in fish oil, was infused within the pericardial space only during the 40-min stabilizing phase, 45 min ischemia and initial 5 min reperfusion. Hemodynamics and cardiac functions were very similar between the DHA-treated and control groups. However, DHA therapy significantly reduced infarct sizes from 56.8 +/- 4.9% for controls (n = 12) to 28.8 +/- 7.9% (P < 0.01) for DHA-treated animals (n = 11). Compared with controls, DHA-treated animals significantly decreased heart rates and reduced ventricular arrhythmia scores during ischemia. Furthermore, three (25%) control animals experienced eight episodes of ventricular fibrillation (VF), and two died subsequent to unsuccessful defibrillation. In contrast, only 1 (9%) of 11 DHA-treated pigs elicited one episode of VF that was successfully converted via defibrillation to normal rhythm; thus, mortality was reduced from 17% in the controls to 0% in the DHA-treated animals. These data demonstrate that pericardial infusion of n-3 PUFA DHA can significantly reduce both malignant arrhythmias and infarct sizes in a porcine infarct model. Pericardial administration of n-3 PUFAs could represent a novel approach to treating or preventing myocardial infarctions.

The role of cavitation in liposome formation.

Liposome size is a vital parameter of many quantitative biophysical studies. Sonication, or exposure to ultrasound, is used widely to manufacture artificial liposomes, yet little is known about the mechanism by which liposomes are affected by ultrasound. Cavitation, or the oscillation of small gas bubbles in a pressure-varying field, has been shown to be responsible for many biophysical effects of ultrasound on cells. In this study, we correlate the presence and type of cavitation with a decrease in liposome size. Aqueous lipid suspensions surrounding a hydrophone were exposed to various intensities of ultrasound and hydrostatic pressures before measuring their size distribution with dynamic light scattering. As expected, increasing ultrasound intensity at atmospheric pressure decreased the average liposome diameter. The presence of collapse cavitation was manifested in the acoustic spectrum at high ultrasonic intensities. Increasing hydrostatic pressure was shown to inhibit the presence of collapse cavitation. Collapse cavitation, however, did not correlate with decreases in liposome size, as changes in size still occurred when collapse cavitation was inhibited either by lowering ultrasound intensity or by increasing static pressure. We propose a mechanism whereby stable cavitation, another type of cavitation present in sound fields, causes fluid shearing of liposomes and reduction of liposome size. A mathematical model was developed based on the Rayleigh-Plesset equation of bubble dynamics and principles of acoustic microstreaming to estimate the shear field magnitude around an oscillating bubble. This model predicts the ultrasound intensities and pressures needed to create shear fields sufficient to cause liposome size change, and correlates well with our experimental data.

Reducing liposome size with ultrasound: bimodal size distributions.

Sonication is a simple method for reducing the size of liposomes. We report the size distributions of liposomes as a function of sonication time using three different techniques. Liposomes, mildly sonicated for just 30 sec, had bimodal distributions when surface-weighted with modes at about 140 and 750 nm. With extended sonication, the size distribution remains bimodal but the average diameter of each population decreases and the smaller population becomes more numerous. Independent measurements of liposome size using Dynamic Light Scattering (DLS), transmission electron microscopy (TEM), and the nystatin/ergosterol fusion assay all gave consistent results. The bimodal distribution (even when number-weighted) differs from the Weibull distribution commonly observed for liposomes sonicated at high powers over long periods of time and suggests that a different mechanism may be involved in mild sonication. The observations are consistent with the following mechanism for decreasing liposome size. During ultrasonic irradiation, cavitation, caused by oscillating microbubbles, produces shear fields. Large liposomes that enter these fields form long tube-like appendages that can pinch-off into smaller liposomes. This proposed mechanism is consistent with colloidal theory and the observed behavior of liposomes in shear fields.

The role of cavitation in acoustically activated drug delivery.

Pluronic P105 micelles are potential candidates as chemotherapy drug delivery vehicles using ultrasonic stimulation as a release trigger. Acoustic power has been previously shown to release two anthracycline agents from these polymeric carriers. In this study, an ultrasonic exposure chamber with fluorescence detection was used to examine the mechanism of doxorubicin release from P105 micelles. Acoustic spectra were collected and analyzed, at the same spatial position as fluorescence data, to probe the role of cavitation in drug release. Our study showed a strong correlation between percent drug release and subharmonic acoustic emissions, and we attribute the drug release to collapse cavitation that perturbs the structure of the micelle and releases drug.