Low-frequency ventilation during cardiopulmonary bypass for lung protection: A randomized controlled trial.

OBJECTIVE: Pulmonary dysfunction is a common complication in patients undergoing heart surgery. Current clinical practice does not include any specific strategy for lung protection. To compare the anti-inflammatory effects of low-frequency ventilation (LFV), as measured by nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) p65 pathway activation, for the entire cardiopulmonary bypass (CPB) vs both lungs left collapsed in patients undergoing coronary artery bypass grafting (CABG). METHODS: Two groups parallel randomized controlled trial. The primary outcome was inflammation measured by NF-κB p65 activation in pre- and post-CPB lung biopsies. Secondary outcomes were additional inflammatory markers in both biopsy tissue and blood. RESULTS: Thirty-seven patients were randomly allocated to LFV (18) and to both lungs left collapsed (19). The mean concentration of NF-κB p65 in the biopsies before chest closure (adjusted for pre-CPB concentration) was higher in the LFV group compared to both lungs left collapsed group but this was not significant (0.102, 95% confidence interval, -0.022 to 0.226, P = 0.104). There were no significant differences between groups in the other inflammatory markers measured in tissue and blood. CONCLUSIONS: In patients undergoing elective CABG, the use of LFV during CPB when compared to both lungs left collapsed does not seem to reduce inflammation in lung biopsies and blood.

Evaluation of a computer program for non-invasive determination of pulmonary shunt and ventilation-perfusion mismatch.

We describe a three-compartment model (shunt and two perfused compartments) to analyse the relationship between inspired oxygen (FIO2) and arterial oxygen saturation (SaO2) in terms of pulmonary shunt and ventilation-perfusion ratio (VA/Q). The program was tested using 24 exact datasets, each with six pairs of FIO2 and SaO2 data points with known VA/Q and shunt, generated by a complex calculator of gas exchange. Additional datasets were created by adding noise and rounding the exact sets, and by reducing the number of data points per dataset. The importance of the oxyhaemoglobin dissociation curve and the arterio-venous difference in oxygen content (avDO2) were also tested. Analysis using the three compartment model was more accurate than the two compartment model and less affected by data degradation. The absolute error in shunt estimation was never more than 2.2 % for the exact and rounded datasets, but the error in VA/Q estimation was -29 to 19 % of the true value (10th-90th centiles). The characteristics of the well-ventilated compartment were not determined accurately. At extremes of cardiac output, an assumed value of avDO2 resulted in significant errors. It is probably advantageous to correct for foetal haemoglobin in neonatal datasets. Analysis of FIO2 versus SaO2 datasets using a three compartment model provides accurate estimates of shunt and VA/Q when arterio-venous difference in oxygen content is known. The estimates may have value as objective measures of gas exchange, and as a visual guide for oxygen therapy.

Unstable SpO2 in preterm infants: The key role of reduced ventilation to perfusion ratio.

Introduction: Instability of peripheral oxyhemoglobin saturation (SpO2) in preterm infants is correlated with late disability and is poorly understood. We hypothesised that a reduced ventilation to perfusion ratio (VA/Q) is the key predisposing factor for SpO2 instability. Methods: We first used a mathematical model to compare the effects of reduced VA/Q or shunt on SaO2 stability (SaO2 and SpO2 are used for model and clinical studies respectively). Stability was inferred from the slope of the SaO2 vs. inspired oxygen pressure (P IO2) curve as it intersects the 21 kPa P IO2 line (breathing air). Then, in a tertiary neonatal intensive care unit, paired hourly readings of SpO2 and P IO2 were recorded over a 24 h period in week old extremely preterm infants. We noted SpO2 variability and used an algorithm to derive VA/Q and shunt from the paired SpO2 and P IO2 measurements. Results: Our model predicted that when VA/Q < 0.4, a 1% change in P IO2 results in >8% fluctuation in SaO2 at 21 kPa P IO2. In contrast, when a 20% intrapulmonary shunt was included in the model, a 1% change in P IO2 results in <1% fluctuation in the SaO2. Moreover, further reducing the VA/Q from 0.4 to 0.3 at 21 kPa P IO2 resulted in a 24% fall in SaO2. All 31 preterm infants [mean gestation (±standard deviation) 26.2 (±1) week] had VA/Q < 0.74 (normal >0.85) but only two infants had increased shunt at 1.1 (±0.5) weeks' postnatal age. Median (IQR) SpO2 fluctuation was 8 (7)%. The greatest SpO2 fluctuations were seen in infants with VA/Q < 0.52 (n = 10): SpO2 fluctuations ranged from 11%-17% at a constant P IO2 when VA/Q < 0.52. Two infants had reduced VA/Q and increased shunt (21% and 27%) which resolved into low VA/Q after 3-6 h. Discussion: Routine monitoring of P IO2 and SpO2 can be used to derive a hitherto elusive measure of VA/Q. Predisposition to SpO2 instability results from reduced VA/Q rather than increased intrapulmonary shunt in preterm infants with cardiorespiratory disease. SpO2 instability can be prevented by a small increase in P IO2.

Fabrication and performance of a 40-MHz linear array based on a 1-3 composite with geometric elevation focusing.

The fabrication and performance of a 256-element high-frequency (40-MHz) linear array is described. The array was fabricated using a high-frequency 1-3 PZT-polymer composite material developed in our laboratory. The spacing of the pillars in the composite was chosen to match the 40-microm center-to-center element spacing of the array electrodes. The element electrodes were created using photolithography, and connections to the electrodes were made using ultrasonic wire bonding. The array was focused in the elevation direction by geometrically shaping the composite material using a cylindrical die with a 6-mm radius of curvature. The resulting transducer produced pulses with a -6 dB two-way bandwidth of 50% and a peak-to-peak pressure of 503 kPa when excited with a +/-30 V monocycle pulse. The measured one-way (-6 dB) directivity for a single array element was 24 degrees and the -3 dB one-way elevation beamwidth was measured to be 130 microm. The radiation pattern for a focused 64-element subaperture was measured by mechanically translating the aperture above a needle hydrophone. A -3 dB one-way beamwidth of 97 microm was found at a depth of 6 mm. The one-way radiation pattern decreased smoothly to less than -30 dB at a lateral distance of 640 microm.

Fabrication of PZT sol gel composite ultrasonic transducers using batch fabrication micromolding.

A new micromolding technique for fabricating high-frequency (>20 MHz) ultrasound transducers has been developed. The technique combines sol gel processing with an epoxy-based, photo-resist Su-8 micromold to form miniature PZT structures. An advantage of this technique as compared to more traditional lithographic galvanforming and abforming (LIGA) processing is that the intermediate step of producing a nickel-plated mold is avoided. Instead, the PZT is formed directly using a photo-resist. The resulting structures can be fabricated with aspect ratios up to 3:1 and thicknesses up to 50 micro. We have successfully fabricated 50-micro-thick linear array elements with 23-micro-wide elements separated by 15 kerfs. A 50-micro thick, 2.5-mm diameter, five-element annular array structure with 20-micro kerfs also has been fabricated. The micromolded PZT composite has a density of 5.7-5.8 micro 0.4 g/cm3 and a thickness coupling coefficient as high as 0.32.

Investigation of cross talk in Kerfless annular arrays for high-frequency imaging.

The effect of electromechanical cross talk in high-frequency (> 30 MHz) kerfless annular arrays is investigated. Finite-element model predictions of the radiation patterns from arrays are compared to predictions from an ideal model without cross talk and with experimental measurements. High cross talk in the array causes element broadening and an increase in the amplitude of secondary lobes in the radiation pattern. However, an increase in the pulse ring-down time was not found. This can be attributed to the absence of lateral modes in the kerfless substrate. The level of the pedestal secondary lobes in the two-way radiation pattern increases linearly with the element path difference. The element broadening increases the effective element path difference, which increases the pedestal level for a kerfless annular array above the level for an ideal array. The broadening limits how close to an array one can image compared to the ideal case by reducing the contrast available in the image at small f-numbers. When the element broadening is taken into account by widening the electrode dimensions, the ideal radiation pattern agrees well with the finite-element model and experimental radiation patterns.

A digital beamformer for high-frequency annular arrays.

Digital transmit and receive beamformers for a 45-MHz, 7-element annular array are described. The transmit beamformer produces 0- to 80-Vpp monocycle pulses with a timing error of less than +/-125 ps. Up to four adjustable transmit focal zones can be selected. The dynamic receive beamformer uses a variable frequency sampling technique in which the frequency of analog-to-digital conversion on each channel is adjusted as the signals are received. The variable frequency clock signals required to trigger analog-to-digital conversion are obtained using a pair of high-frequency field-programmable gate arrays and a precision quartz oscillator. The gate arrays are also used to sum the digitized signals. A maximum receive beamformer timing error of less than +/-900 ps was obtained on each channel. The performance of the combined transmit and receive beamformer was tested by imaging wire phantoms. Images of CD-1 mice were also generated. The system produced images with a dynamic range of 60 dB.

Predicting the behaviour of G-RAM networks.

A Generalising Random Access Memory (G-RAM) neuron is distinguished from conventional neuron models by the fact that its tolerance to departures in similarity from its training pattern is variable. Details of this are given in this paper as it affects the behaviour a class of digital probabilistic neural networks which have been achieving attention in the neural networks literature for some years now. Such systems are also called n-tuple systems, weightless systems or p-RAM systems. After reviewing the literature on such networks, a novel simple combinatoric analysis of the most likely behaviour of recursive GRAM networks is described. The best network performance, measured by a key parameter called 'radius of retrievability' (first defined by Wong and Sherrington [J. Phys. A 22 (1989) 2233] as the error in the input that still allows evolution of the dynamic network to the correct attractor state), is obtained with a training set composed of random data patterns. Increasing the size of the training set reduces this radius of retrievability in a predictable manner. Changing the nature of the training set to non-random patterns also reduces the radius of retrievability to an extent that we show can be estimated from a measure of the diversity of the elements of the training set (we refer to this as the 'mean intra-set Hamming distance of the training set'). As mentioned earlier the feature of G-RAMs (indicated by the G) is that there exists a generalization parameter which determines how far a neuron input vector can stray from a training input for the neuron to respond in the trained way. It is shown that when this generalization parameter is reduced, then the radius of retrievability is also reduced but it is then stable in the face of an increase in size, or change in nature, of the training set. This is a novel prediction of the behaviour of systems and of the robustness of such behaviour in the face of varying the size and correlation properties of the training set.

Design and fabrication of annular arrays for high-frequency ultrasound.

The design, fabrication, and performance of miniature high-frequency annular arrays are described. A 50-MHz, 2-mm-diameter, 7-element, equal-area annular array was fabricated and tested. The array elements were defined using photolithography and the electrical contacts were made using ultrasonic wire bonding. The resulting transducer produced pulses with a -6 dB bandwidth of 52% and an insertion loss of -16 dB. A radiation pattern was collected by scanning the transducer array above the tip of a glass fiber. A -6 dB two-way beam width of 75 microns was found at f/2. The radiation pattern decreased smoothly to less than -60 dB at a distance of 550 microns.

Unit-delay focusing architecture and integrated-circuit implementation for high-frequency ultrasound.

High-frequency ultrasound (above 10 MHz) has been used successfully in many medical applications, including eye, skin, gastrointestinal, intravascular, and Doppler flow imaging. Most of these applications use single-element transducers, thereby imposing a tradeoff between resolution and depth of field. Fabrication difficulties and the need for high-speed electronic beamformers have prevented widespread use of arrays at high frequencies. In this paper, a unit-delay focusing architecture suitable for use with high-frequency ultrasound annular arrays is described. It uses a collection of identical, active delay cells that may be simultaneously varied to accomplish focusing. Results are presented for an analog integrated circuit intended for use with a five-element, 50-MHz planar annular array. Focusing is possible over an axial range for which the ratio of maximum to minimum f-number is 2.1. Unit-delay architectures also are described for curved annular arrays and linear arrays.

High-frequency annular array fabrication using a flex circuit matching layer.

Fabricating arrays for high-frequency image applications such as ophthalmic imaging, intravascular imaging, and small animal imaging is challenging. For example, an array for intravascular imaging must be small enough to fit within the lumen of a catheter and inexpensive enough to be discarded after a single use. This article presents a new method for fabricating high-frequency annular arrays that is simple and inexpensive. The annular array elements are defined by the electrode pattern on a back surface of a polyimide quarter-wavelength matching layer that is glued to the front face of a ceramic transducer substrate (PZT5H). Electrical losses associated with bonding the matching layer to the transducer substrate are reduced by fabricating a second set of electrodes on the transducer substrate and then bonding the substrates using an anisotropic conductive epoxy. The feasibility of this technique was established by fabricating a seven-element, 20-MHz, 5-mm diameter annular array. The prototype array produced a pulse with a -6-dB factional bandwidth of 50%, an insertion loss of 22 dB, and secondary lobes in the radiation pattern at f/2 that decreased to -65 dB with respect to the main lobe with a peak amplitude of -53 dB.

Real-time volume imaging using a crossed electrode array.

This paper describes a unique crossed electrode array for real-time volume ultrasound imaging. By placing orthogonal linear array electrode patterns on the opposite sides of a hemispherically shaped composite transducer substrate, a 2-D array can be fabricated using a small fraction of the elements required for a traditional 2-D array. The performance of the array is investigated using a computer simulation of the radiation pattern. We show that by using a 288-element crossed electrode pattern it is possible to collect large field of view volume images (60 degrees x 60 degrees sector) at real-time frame rates (>20 volume images/s), with image contrast and resolution comparable to what can be obtained using a conventional 128-element linear phased array.

High-frequency ex vivo ultrasound imaging of the auditory system.

A 50MHz array-based imaging system was used to obtain high-resolution images of the ear and auditory system. This previously described custom built imaging system (Brown et al. 2004a, 2004b; Brown and Lockwood 2005) is capable of 50 microm axial resolution, and lateral resolution varying from 80 microm to 130 microm over a 5.12 mm scan depth. The imaging system is based on a 2mm diameter, seven-element equal-area annular array, and a digital beamformer that uses high-speed field programmable gate arrays (FPGAs). The images produced by this system have shown far superior depth of field compared with commercially available single-element systems. Ex vivo, three-dimensional (3-D) images were obtained of human cadaveric tissues including the ossicles (stapes, incus, malleus) and the tympanic membrane. In addition, two-dimensional (2-D) images were obtained of an intact cochlea by imaging through the round window membrane. The basilar membrane inside the cochlea could clearly be visualized. These images demonstrate that high-frequency ultrasound imaging of the middle and inner ear can provide valuable diagnostic information using minimally invasive techniques that could potentially be implemented in vivo.

Feasibility and safety of delivering xenon to patients undergoing coronary artery bypass graft surgery while on cardiopulmonary bypass: phase I study.

BACKGROUND: Postoperative neurocognitive deficit is prevalent after cardiac surgery. Xenon may prevent or ameliorate acute neuronal injury, but it also may aggravate injury during cardiac surgery by increasing bubble embolism. Before embarking on a randomized clinical trial to test the safety and efficacy of xenon for postoperative neurocognitive deficit, we undertook a phase I study to investigate the safety of administering xenon to patients undergoing coronary artery bypass grafting while on cardiopulmonary bypass and to assess the practicability of our xenon delivery system. METHODS: Sixteen patients scheduled for coronary artery bypass grafting surgery with hypothermic cardiopulmonary bypass gave their informed consent to participate in an open-label dose-escalation study (0, 20, 35, 50% xenon in oxygen and air). Xenon was delivered throughout surgery using both a standard anesthetic breathing circuit and the oxygenator. Gaseous and blood xenon partial pressures were measured five times before, during, and after cardiopulmonary bypass. Middle cerebral artery Doppler was used to assess embolic load, and major organ system function was assessed before and after surgery. RESULTS: Middle cerebral artery Doppler showed no evidence of increased emboli with xenon. Patients receiving xenon had no major organ dysfunction: Troponin I and S100beta levels tended to be lower in patients receiving xenon. Up to 25 l xenon was used per patient. Xenon partial pressure in the blood tracked the delivered concentration throughout. CONCLUSIONS: Xenon was safely and efficiently delivered to coronary artery bypass grafting patients while on cardiopulmonary bypass. Prevention of nervous system injury by xenon should be tested in a large placebo-controlled, randomized clinical trial.