Risk factors for anesthetic-related complications in pediatric patients with a newly diagnosed mediastinal mass.

BACKGROUND: Pediatric patients with a mediastinal mass can experience severe complications while undergoing anesthesia. Nearly, all published reviews involve either patients with an anterior mediastinal mass or patients with an oncologic disease. AIM: The identification of risk factors for anesthetic-related complications in pediatric patients with any type of mediastinal mass. METHODS: From January 1, 2008 to December 31, 2019, patients with a newly diagnosed mediastinal mass that underwent anesthesia were retrospectively identified. Each patient's medical record was reviewed for presenting symptoms, preprocedure imaging results, the type of anesthetic delivered, and the occurrence of any anesthetic-related complications. A complication was defined as severe hypoxia, severe hypotension, or loss of endtidal carbon dioxide. RESULTS: Eighty-six patients presented with a new mediastinal mass. Six of these patients (7%) had a complication. Complications were no more likely in patients with orthopnea than in patients without orthopnea (P = 1.00; relative risk (RR) = 0.95; 95% CI (0.1, 7.5). Complication rates in patients with anterior, middle, and posterior mediastinal masses were similar, as were complication rates in patients with large, medium, and small masses. Six of the 41 patients (15%) who had tracheal compression had a complication, while none of the 45 patients (0%) who did not have tracheal compression had a complication (p = .0096). Six of the 48 patients (13%) that were intubated had a complication, while none of the 38 patients (0%) who were not intubated had a complication (p = .032). Five of 36 patients (14%) who had mainstem bronchus compression had a complication, while one of 50 patients (2%) who did not have mainstem bronchus compression had a complication (p = .078; RR = 6.9l; 95% CI (0.8, 56.9)). CONCLUSIONS: Anesthetic-related complications were associated with airway compression and endotracheal intubation. The absence of preprocedure orthopnea did not ensure that the anesthetic would be uncomplicated. Complications occurred in similar frequencies in patients with a mediastinal mass of any location or size.

Extubation during pediatric extracorporeal membrane oxygenation: a single-center experience.

OBJECTIVES: Describe aspects of one center's experience extubating infants and children during extracorporeal membrane oxygenation. DESIGN: Retrospective review of medical records. SETTING: Seventy-one-bed critical care service (PICU and cardiovascular ICU) in a large urban tertiary children's hospital. PATIENTS: Pediatric and neonatal patients supported on extracorporeal membrane oxygenation between 1996 and 2013 who were either not intubated or extubated greater than 24 hours during their extracorporeal membrane oxygenation course. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sixteen of 511 patients on extracorporeal membrane oxygenation were extubated for at least 24 hours during their extracorporeal membrane oxygenation courses. Fourteen had respiratory failure and two had cardiac disease. Five patients died while on extracorporeal membrane oxygenation, but the cause of death was not related to complications associated with extubation. Extubated patients were supported a median of 19.7 days on extracorporeal membrane oxygenation, with a median extubation latency (time between cannulation and first extubation) of 6.2 days and a median extubation duration of 5.5 days. Mean time extubated was 43% of the total time on extracorporeal membrane oxygenation. Two patients were reintubated briefly or had a laryngeal mask airway placed for decannulation (n = 1). The remaining patients were extubated within 5 days of decannulation, weeks afterward (n = 2), transferred to outside facilities (n = 2), or died during extracorporeal membrane oxygenation support (n = 5). We also observed no complications directly attributable to extubation and spontaneous reaeration of consolidated lungs in acute respiratory distress syndrome in extubated patients on extracorporeal membrane oxygenation. CONCLUSION: Extubation and discontinuation of mechanical ventilation appear feasible in patients requiring long-term extracorporeal membrane oxygenation. Emergency procedure planning may need to be modified in extubated patients on extracorporeal membrane oxygenation.

Management of difficult airway patients and the use of a difficult airway registry at a tertiary care pediatric hospital.

BACKGROUND: Appropriate recognition and management of the pediatric difficult airway is essential. Two patient deaths in a 2-year period involving children with a known difficult airway led to the formation of the institution's multidisciplinary Difficult Airway Committee. METHODS: Patients with a suspected difficult airway or a known difficult airway are entered into a registry of difficult airway patients. A note describing the airway and any experiences at airway manipulation is entered as part of a difficult airway note in the patient's electronic medical record as soon as the patient is recognized as having a difficult airway. A call system has been developed to mobilize expert emergency airway assistance for these patients. Multiple additional methods are employed to ensure that all hospital personnel are aware that these patients are difficult to intubate. RESULTS: Since inception almost 6 years ago, 164 patients (mean age 9.2 years) have been enrolled in the difficult airway registry. Eighty-seven patients (53%) had one of 28 identified syndromes or diagnoses. The most common reasons for airway obstruction were mandibular hypoplasia/micrognathia, decreased neck extension, and limited temporomandibular joint mobility. One hundred sixty-one patients (98%) in the registry were predicted by history or physical to have a difficult airway. The mortality of registry patients was 9.8% (n = 16) and was most commonly due to co-existing diseases. During the time period reviewed, there was one in-hospital death of a known difficult airway patient, in which expert airway assistance was not obtained in a timely fashion. CONCLUSION: The institution's difficult airway registry identifies patients with a suspected or known difficult airway. The presence of a difficult airway in children can usually be predicted based on history and physical examination by anesthesiologists and otolaryngologists. Providers without advanced airway skills, however, may not appreciate that an airway is difficult to intubate until multiple attempts have failed. Both redundant notification methods and a call system optimize medical care of these fragile patients.

Phase-shift perfluorocarbon agents enhance high intensity focused ultrasound thermal delivery with reduced near-field heating.

Ultrasound contrast agents are known to enhance high intensity focused ultrasound (HIFU) ablation, but these perfluorocarbon microbubbles are limited to the vasculature, have a short half-life in vivo, and may result in unintended heating away from the target site. Herein, a nano-sized (100-300 nm), dual perfluorocarbon (decafluorobutane/dodecafluoropentane) droplet that is stable, is sufficiently small to extravasate, and is convertible to micron-sized bubbles upon acoustic activation was investigated. Microbubbles and nanodroplets were incorporated into tissue-mimicking acrylamide-albumin phantoms. Microbubbles or nanodroplets at 0.1 × 10(6) per cm(3) resulted in mean lesion volumes of 80.4 ± 33.1 mm(3) and 52.8 ± 14.2 mm(3) (mean ± s.e.), respectively, after 20 s of continuous 1 MHz HIFU at a peak negative pressure of 4 MPa, compared to a lesion volume of 1.0 ± 0.8 mm(3) in agent-free control phantoms. Magnetic resonance thermometry mapping during HIFU confirmed undesired surface heating in phantoms containing microbubbles, whereas heating occurred at the acoustic focus of phantoms containing the nanodroplets. Maximal change in temperature at the target site was enhanced by 16.9% and 37.0% by microbubbles and nanodroplets, respectively. This perfluorocarbon nanodroplet has the potential to reduce the time to ablate tumors by one-third during focused ultrasound surgery while also safely enhancing thermal deposition at the target site.

Bradycardic Arrest in a Child with Complex Congenital Heart Disease Due to Sugammadex Administration.

The neuromuscular blocking drugs rocuronium and vecuronium are often used during general anesthesia. These drugs temporarily paralyze the patient and thus both facilitate placement of an endotracheal tube and prevent any patient movement during surgery. Reversal of neuromuscular blockade is necessary at the end of surgery to avoid postoperative weakness and adverse respiratory events in the recovery room. Neostigmine, the traditional reversal agent, may not completely restore muscle strength. Sugammadex is a reversal agent that is more effective and quicker acting than neostigmine. In adults, sugammadex administration has rarely been associated with bradycardia and cardiac arrest. In healthy children, the bradycardia that occurs after sugammadex administration is benign and does not require intervention. There is 1 case report of a 10- to 15-second bradycardic arrest after sugammadex administration to a 10-year-old child with heart disease. The present case report describes an 8-month-old child with complex congenital heart disease who experienced a 10-minute bradycardic arrest after the administration of sugammadex. Pediatric anesthesiologists should be aware that sugammadex administration to children with heart disease may cause hemodynamically significant bradycardia.

Microfluidic generation of acoustically active nanodroplets.

A microfluidic approach for the generation of perfluorocarbon nanodroplets as the primary emulsion with diameters as small as 300-400 nm is described. The system uses a pressure-controlled delivery of all reagents and increased viscosity in the continuous phase to drive the device into an advanced tip-streaming regime, which results in generation of droplets in the sub-micrometer range. Such nanodroplets may be appropriate for emerging biomedical applications.

The use of extracorporeal life support in adolescent amlodipine overdose.

Calcium channel blocker (CCB) toxicity is associated with refractory hypotension and can be fatal. A 13 year old young woman presented to the emergency department(ED) six hours after an intentional overdose of amlodipine, barbiturates, and alcohol. She remained extremely hypotensive despite the administration of normal saline and calcium chloride and despite infusions of norepinephrine, epinephrine, insulin, and dextrose. Due to increasing evidence of end organ dysfunction, Extracorporeal Life Support (ECLS) was initiated 9 hours after presentation to the ED. The patient's blood pressure and end organ function immediately improved after cannulation. She was successfully decannulated after 57 hours of ECLS and was neurologically intact. Patients with calcium channel blocker overdose who are resistant to medical interventions may respond favorably to early ECLS.

Formulation and acoustic studies of a new phase-shift agent for diagnostic and therapeutic ultrasound.

Recent efforts in the area of acoustic droplet vaporization with the objective of designing extravascular ultrasound contrast agents has led to the development of stabilized, lipid-encapsulated nanodroplets of the highly volatile compound decafluorobutane (DFB). We developed two methods of generating DFB droplets, the first of which involves condensing DFB gas (boiling point from -1.1 to -2 °C) followed by extrusion with a lipid formulation in HEPES buffer. Acoustic droplet vaporization of micrometer-sized lipid-coated droplets at diagnostic ultrasound frequencies and mechanical indices were confirmed optically. In our second formulation methodology, we demonstrate the formulation of submicrometer-sized lipid-coated nanodroplets based upon condensation of preformed microbubbles containing DFB. The droplets are routinely in the 200-300 nm range and yield microbubbles on the order of 1-5 µm once vaporized, consistent with ideal gas law expansion predictions. The simple and effective nature of this methodology allows for the development of a variety of different formulations that can be used for imaging, drug and gene delivery, and therapy. This study is the first to our knowledge to demonstrate both a method of generating ADV agents by microbubble condensation and formulation of primarily submicrometer droplets of decafluorobutane that remain stable at physiological temperatures. Finally, activation of DFB nanodroplets is demonstrated using pressures within the FDA guidelines for diagnostic imaging, which may minimize the potential for bioeffects in humans. This methodology offers a new means of developing extravascular contrast agents for diagnostic and therapeutic applications.

A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions.

OBJECTIVES: To compare the efficacy of a low-dose methadone tapering schedule to a high-dose methadone tapering schedule in pediatric intensive care unit patients exposed to infusions of fentanyl, with or without infusions of midazolam, for ≥ 5 days. DESIGN: Prospective, double-blind, randomized trial. SETTING: Pediatric intensive care unit in a tertiary care children's hospital. PATIENTS: Seventy-eight patients, 74 of whom had been receiving infusions of both fentanyl and midazolam, were randomized. Forty-one patients were randomized to the low-dose methadone group and 37 were randomized to the high-dose methadone group. Sixty patients successfully completed the trial, 34 were in the low-dose methadone group, and 26 were in the high-dose methadone group. INTERVENTIONS: Patients were randomized to receive methadone either at a starting dose of 0.1 mg/kg/dose (low-dose methadone group) or at a starting dose based on both the patient's weight and the most recent fentanyl infusion rate (high-dose methadone group). In each group, methadone was administered every 6 hrs for the first 24 hrs and then every 12 hrs for the second 24 hrs. The methadone was then decreased to once daily and tapered off over the next 10 days. Patients were monitored for withdrawal symptoms using the Modified Narcotic Withdrawal Score. MEASUREMENTS AND MAIN RESULTS: The percentage of patients who successfully completed the 10-day methadone taper was the same in the low-dose methadone group as in the high-dose methadone group (56% vs. 62%; p = .79). Patients that failed to complete the assigned methadone taper had a greater total fentanyl dose and longer pediatric intensive care unit length of stay compared to patients who completed the assigned methadone taper. CONCLUSIONS: Patients who received infusions of fentanyl for at least 5 days were just as likely to complete a low-dose methadone taper as a high-dose methadone taper. Because of the risks of both withdrawal and oversedation with any fixed methadone schedule, the methadone dose must be adjusted according to each patient's response.

Synthesis and Characterization of Multi-Modal Phase-Change Porphyrin Droplets.

Phase-change droplets are a class of ultrasound contrast agents that can convert into echogenic microbubbles in situ with the application of sufficient acoustic energy. Droplets are smaller and more stable than their microbubble counterparts. However, traditional ultrasound contrast agents are not trackable beyond acoustic feedback measurements, which makes quantifying contrast agent bio-distribution or accumulation ex vivo difficult. Researchers may have to rely on fluorescent or optically absorbent companion diagnostic particles to infer bio-distribution. The purpose of this protocol is to detail steps for creating multi-modal phase-change porphyrin droplets using a condensation method. Porphyrins are fluorescent molecules with distinct absorbance bands that can be conjugated onto lipids and incorporated into droplets to extend droplet versatility, enabling more robust bio-distribution while retaining acoustic properties. Seven formulations with varying porphyrin-lipid and base lipid contents were made to investigate microbubble and droplet size distributions. Characterizations suited to porphyrin-containing structures are also described in the protocol to demonstrate their analytic versatility in-solution. Sizing showed that the post-condensed mean diameters were 1.72 to 2.38 times smaller than precursor populations. Absorbance characterization showed intact assemblies had a Q-band peak of 700 nm while disrupted samples had an absorbance peak at 671 nm. Fluorescence characterization showed intact 30% porphyrin-lipid assemblies were fluorescently quenched (>97%), with fluorescence recovery achieved upon disruption. Acoustic vaporization showed that porphyrin droplets were non-echogenic at lower pressures and could be converted into echogenic microbubbles with sufficient pressures. These characterizations show the potential for porphyrin droplets to eliminate the need for absorbance or fluorescence-based companion diagnostic strategies to quantify ultrasound contrast agent bio-distribution for delivery or therapeutic applications in vivo or ex vivo.

Cavitation Therapy Monitoring of Commercial Microbubbles With a Clinical Scanner.

The ability to monitor cavitation activity during ultrasound and microbubble-mediated procedures is of high clinical value. However, there has been little reported literature comparing the cavitation characteristics of different clinical microbubbles, nor have current clinical scanners been used to perform passive cavitation detection in real time. The goal of this work was to investigate and characterize standard microbubble formulations (Optison, Sonovue, Sonazoid, and a custom microbubble made with similar components as Definity) with a custom passive cavitation detector (two confocal single-element focused transducers) and with a Philips EPIQ scanner with a C5-1 curvilinear probe passively listening. We evaluated three different methods for investigating cavitation thresholds, two from previously reported work and one developed in this work. For all three techniques, it was observed that the inertial cavitation thresholds were between 0.1 and 0.3 MPa for all agents when detected with both systems. Notably, we found that most microbubble formulations in bulk solution behaved generally similarly, with some differences. We show that these characteristics and thresholds are maintained when using a diagnostic ultrasound system for detecting cavitation activity. We believe that a systematic evaluation of the frequency response of the cavitation activity of different microbubbles in order to inform real-time therapy monitoring using a clinical ultrasound device could make an immediate clinical impact.

Augmentation of Tissue Perfusion with Contrast Ultrasound: Influence of Three-Dimensional Beam Geometry and Conducted Vasodilation.

BACKGROUND: Cavitation of microbubble contrast agents with ultrasound produces shear-mediated vasodilation and an increase in tissue perfusion. We investigated the influence of the size of the cavitation volume by comparing flow augmentation produced by two-dimensional (2D) versus three-dimensional (3D) therapeutic ultrasound. We also hypothesized that cavitation could augment flow beyond the ultrasound field through release of vasodilators that are carried downstream. METHODS: In 11 rhesus macaques, cavitation of intravenously administered lipid-shelled microbubbles was performed in the proximal forearm flexor muscles unilaterally for 10 min. Ultrasound cavitation (1.3 MHz, 1.5 MPa peak negative pressure) was performed with 2D or 3D transmission with beam elevations of 5 and 25 mm, respectively, and pulsing intervals (PIs) sufficient to allow complete postdestruction refill (5 and 12 sec for 2D and 3D, respectively). Contrast ultrasound perfusion imaging was performed before and after cavitation, using multiplane assessment within and beyond the cavitation field in 1.5-cm increments. Cavitation in the hindlimb of mice using 2D ultrasound at a PI of 1 or 5 sec was performed to examine microvascular flow changes from cavitation in only arteries versus the microcirculation. RESULTS: In primates, the degree of muscle flow augmentation in the center of the cavitation field was similar for 2D and 3D conditions (five- to sixfold increase for both, P < .01 vs baseline). The spatial extent of flow augmentation was only modestly greater for 3D cavitation because of an increase in perfusion with 2D transmission that was detected outside of the cavitation field. In mice, cavitation in the microvascular compartment (PI 5 sec) produced the greatest degree of flow augmentation, yet cavitation in the arterial compartment (PI 1 sec) still produced a three- to fourfold increase in flow (P < .001 vs control). The mechanism for flow augmentation beyond the cavitation zone was investigated by in vitro studies that demonstrated cavitation-related release of vasodilators, including adenosine triphosphate and nitric oxide, from erythrocytes and endothelial cells. CONCLUSIONS: Compared with 2D transmission, 3D cavitation of microbubbles generates a similar degree of muscle flow augmentation, possibly because of a trade-off between volume of cavitation and PI, and only modestly increases the spatial extent of flow augmentation because of the ability of cavitation to produce conducted effects beyond the ultrasound field.

Treatment of Limb Ischemia with Conducted Effects of Catheter-Based Endovascular Ultrasound.

Ultrasound (US) is known to stimulate endogenous shear-dependent pathways, and can lower microvascular resistance through mediators that are conducted downstream from US exposure. We hypothesized that endovascular US, already in use for thrombolysis in humans, can improve tissue perfusion in the setting of acute limb ischemia through downstream-conducted effects. Models of severe peripheral arterial disease were developed in mice and in rhesus macaques. An endovascular US catheter (2.3 MHz, 0.5-1.1 MPa) was used to expose the limb adductor in mice for 10 min or the femoral artery distal to stenosis in macaques for 15 min. Quantitative contrast-enhanced ultrasound perfusion imaging was performed to assess flow augmentation in the adductor muscle of mice and the calf muscle of macaques. Microvascular blood flow in the ischemic limb relative to the contralateral control limb was reduced to 22 ± 8% in mice and 36 ± 20% in macaques. US produced immediate 2.3- and 3-fold increases (p < 0.05) in the murine and macaque ischemic limbs, respectively. In macaques, perfusion in the ischemic limb was increased to a normal level. We conclude that non-cavitating US produced by endovascular catheters that are used to enhance thrombolysis in humans can reduce vascular resistance and increase limb perfusion in the setting of acute ischemia.

Withdrawal from multiple sedative agent therapy in an infant: is dexmedetomidine the cause or the cure?

OBJECTIVE: To report withdrawal symptoms experienced by an infant following the prolonged use of dexmedetomidine. DESIGN: Case report. SETTING: Pediatric intensive care unit at a freestanding tertiary care children's hospital. PATIENTS: One pediatric patient with respiratory failure following pertussis infection that required prolonged intubation and sedation. The patient required dexmedetomidine to maintain optimal sedation before ventilator weaning. Subsequent to receiving dexmedetomidine the patient developed withdrawal symptoms. CONCLUSION: In patients who fail to achieve adequate sedation with the use of traditional medications, dexmedetomidine is an adequate alternative. However, abrupt discontinuation of dexmedetomidine may result in withdrawal symptoms that may be avoided with a dexmedetomidine taper.

Imaging Methods for Ultrasound Contrast Agents.

Microbubble contrast agents were introduced more than 25 years ago with the objective of enhancing blood echoes and enabling diagnostic ultrasound to image the microcirculation. Cardiology and oncology waited anxiously for the fulfillment of that objective with one clinical application each: myocardial perfusion, tumor perfusion and angiogenesis imaging. What was necessary though at first was the scientific understanding of microbubble behavior in vivo and the development of imaging technology to deliver the original objective. And indeed, for more than 25 years bubble science and imaging technology have evolved methodically to deliver contrast-enhanced ultrasound. Realization of the basic bubbles properties, non-linear response and ultrasound-induced destruction, has led to a plethora of methods; algorithms and techniques for contrast-enhanced ultrasound (CEUS) and imaging modes such as harmonic imaging, harmonic power Doppler, pulse inversion, amplitude modulation, maximum intensity projection and many others were invented, developed and validated. Today, CEUS is used everywhere in the world with clinical indications both in cardiology and in radiology, and it continues to mature and evolve and has become a basic clinical tool that transforms diagnostic ultrasound into a functional imaging modality. In this review article, we present and explain in detail bubble imaging methods and associated artifacts, perfusion quantification approaches, and implementation considerations and regulatory aspects.

Augmentation of Tissue Perfusion in Patients With Peripheral Artery Disease Using Microbubble Cavitation.

OBJECTIVES: The authors investigated ideal acoustic conditions on a clinical scanner custom-programmed for ultrasound (US) cavitation-mediated flow augmentation in preclinical models. We then applied these conditions in a first-in-human study to test the hypothesis that contrast US can increase limb perfusion in normal subjects and patients with peripheral artery disease (PAD). BACKGROUND: US-induced cavitation of microbubble contrast agents augments tissue perfusion by convective shear and secondary purinergic signaling that mediates release of endogenous vasodilators. METHODS: In mice, unilateral exposure of the proximal hindlimb to therapeutic US (1.3 MHz, mechanical index 1.3) was performed for 10 min after intravenous injection of lipid microbubbles. US varied according to line density (17, 37, 65 lines) and pulse duration. Microvascular perfusion was evaluated by US perfusion imaging, and in vivo adenosine triphosphate (ATP) release was assessed using in vivo optical imaging. Optimal parameters were then used in healthy volunteers and patients with PAD where calf US alone or in combination with intravenous microbubble contrast infusion was performed for 10 min. RESULTS: In mice, flow was augmented in the US-exposed limb for all acoustic conditions. Only at the lowest line density was there a stepwise increase in perfusion for longer (40-cycle) versus shorter (5-cycle) pulse duration. For higher line densities, blood flow consistently increased by 3-fold to 4-fold in the US-exposed limb irrespective of pulse duration. High line density and long pulse duration resulted in the greatest release of ATP in the cavitation zone. Application of these optimized conditions in humans together with intravenous contrast increased calf muscle blood flow by >2-fold in both healthy subjects and patients with PAD, whereas US alone had no effect. CONCLUSIONS: US of microbubbles when using optimized acoustic environments can increase perfusion in limb skeletal muscle, raising the possibility of a therapy for patients with PAD. (Augmentation of Limb Perfusion With Contrast Ultrasound; NCT03195556).

Investigating the Accumulation of Submicron Phase-Change Droplets in Tumors.

Submicron phase-change droplets are an emerging class of ultrasound contrast agent. Compared with microbubbles, their relatively small size and increased stability offer the potential to passively extravasate and accumulate in solid tumors through the enhanced permeability and retention effect. Under exposure to sufficiently powerful ultrasound, these droplets can convert into in situ gas microbubbles and thus be used as an extravascular-specific contrast agent. However, in vivo imaging methods to detect extravasated droplets have yet to be established. Here, we develop an ultrasound imaging pulse sequence within diagnostic safety limits to selectively detect droplet extravasation in tumors. Tumor-bearing mice were injected with submicron perfluorobutane droplets and interrogated with our imaging-vaporization-imaging sequence. By use of a pulse subtraction method, median droplet extravasation signal relative to the total signal within the tumor was estimated to be Etumor=37±5% compared with the kidney Ekidney=-2±8% (p < 0.001). This work contributes toward the advancement of volatile phase-shift droplets as a next-generation ultrasound agent for imaging and therapy.

3-D Perfusion Imaging Using Principal Curvature Detection Rendering.

Three-dimensional contrast-enhanced ultrasound (CEUS) imaging presents a clear advantage over its 2-D counterpart in detecting and characterizing suspicious lesions as it properly surveys the inherent heterogeneity of tumors. However, 3-D CEUS is also slow compared to 2-D CEUS and tends to undersample the microbubble wash-in. This makes it difficult to resolve the feeding vessels, an important oncogenic marker, from the background perfusion cloud. Contrast-enhanced Doppler is helpful in isolating this conduit flow, but requires too many pulses in conventional line-by-line beamforming design. Recent breakthroughs in plane-wave imaging have greatly accelerated the volumetric imaging frame rate, but volumetric Doppler angiography still remains challenging when considering real-time limitations on the Doppler ensemble length. In this work, we demonstrate the feasibility of volumetric CEUS angiography subjected to real-time imaging constraints. Namely, we show how principal curvature detection can significantly improve 3-D rendering of relatively noisy ultrasound angiograms without degrading the spatial resolution while subjected to a reasonable Doppler ensemble size. Singular value decomposition is also shown to be capable of identifying the quasi-stationary capillary perfusion.

The Role of Microbubble Echo Phase Lag in Multipulse Contrast-Enhanced Ultrasound Imaging.

In this paper, we assess the importance of microbubble shell composition for contrast-enhanced imaging sequences commonly used on clinical scanners. While the gas core dynamics are primarily responsible for the nonlinear harmonic response of microbubbles at diagnostic pressures, it is now understood that the shell rheology plays a dominant role in the nonlinear response of microbubbles subjected to low acoustic pressures. Of particular interest here, acoustic pressures of tens of kilopascal can cause a reversible phase transition of the phospholipid coatings from a stiff elastic organized state to a less stiff disorganized buckled state. Such a transition from elastic to buckled shell induces a steep variation of the shell elasticity, which alters the microbubble acoustic scattering properties. We demonstrate in this paper that this mechanism plays a dominant role in contrast pulse sequences that modulate the amplitude of the insonifying pulse pressure. The contrast-to-tissue ratio (CTR) for amplitude modulation (AM), pulse inversion (PI), and amplitude modulation pulse inversion (AMPI) is measured in vitro for Definity, Sonazoid, both lipid-encapsulted microbubbles, and the albumin-coated Optison. It is found that pulse sequences using AM significantly enhanced the nonlinear response of all studied microbubbles compared to PI (up to 15 dB more) when low insonation pressures under 200 kPa were used. Further investigation reveals that the origin of the hyperechoicity is a small phase lag occurring between the echoes from the full-and half-amplitude driving pulses, and that the effect could be attributed to the shell softening dynamics of lipid and albumin coatings. We assess that this additional phase in microbubble ultrasound scattering can have a dominant role in the CTR achieved in contrast sequences using AM. We also show that the pressure dependent phase lag is a specific marker for microbubbles with no equivalent in tissue, which can be used to segment microbubbles from the tissue harmonics and significantly increase the CTR.