Pulsatile Mode Research Articles

Pulsatile control of rotary blood pumps: Does the modulation waveform matter?

Mechanical support of a failing heart is typically performed with rotary blood pumps running at constant speed, which results in a limited control on cardiac workload and nonpulsatile hemodynamics. A potential solution to overcome these limitations is to modulate the pump speed to create pulses. This study aims at developing a pulsatile control algorithm for rotary pumps, while investigating its effect on left ventricle unloading and the hemodynamics. The CentriMag (Levitronix GmbH, Zürich, Switzerland) rotary blood pump was implanted in 5 sheep and cannulated from the ventricular apex to the descending aorta. A modified controller was connected to the pump yielding direct speed control via analog voltage. Pump speed modulation patterns, including sine, saw tooth, triangle, and square waveforms with 2 different phase shifts, were synchronized with heartbeat. Various hemodynamic parameters, such as left ventricular pressure and volume, coronary flow, and arterial pressure, were analyzed to examine the influence of pump support. The pump speed modulation significantly affected left ventricular pressure and volume and arterial pressure, whereas coronary flow was not influenced by pump support mode. Stroke work in the pulsatile modes varied from 69% to 91% of baseline value and from 74% to 96% of constant speed value. Consequently, cardiac workload can be adjusted to provide relaxation, which may lead to myocardial recovery. A synchronized pulsing rotary blood pump offers a simple and powerful control modality for heart unloading. This technique provides pulsatile hemodynamics, which is more physiologic than continuous blood flow and may be useful for perfusion of the other organs.

Introduction to special topic—estrogenic control of hypothalamic GnRH neurons

In female mammals, sexual maturation is initiated by a change in the release pattern of pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and a consequential increase in the secretion of ovarian sex-steroids, estradiol and progesterone. Orchestrating these endocrine changes is a diffuse population of hypothalamic neurons that produce the neuropeptide, gonadotropin-releasing hormone (GnRH). Although the development and functional integration of GnRH neurons with the rest of the central nervous system is still poorly understood, recent progress has been made on several fronts. For example, there is now evidence that some mammalian species express more than one molecular form of GnRH (GnRH-I and GnRH-II), and that the two corresponding GnRH neuronal sub-populations may play different roles in the regulation of reproductive function and behavior. Moreover, through the use of transgenic animal models, neuronal fiber tracing, gene expression profiling, and electrophysiologcal recordings, new insights have been gained into the mechanisms that regulate GnRH release. This volume brings together 10 articles that reflect current thinking about the role of GnRH in mediating estrogenic feedback to the neuroendocrine reproductive axis. The main focus is on the negative and positive actions that estrogens exert within the hypothalamus of mammals, especially around the time of the preovulatory LH surge. However, the articles also present findings from other vertebrate classes, and so provide an intersting comparative perspective. Taken together, the knowledge presented in this volume represents a foundation upon which to develop more effective therapies for pubertal disorders, infertility, and menopause. The first article (Sower and Baron, 2011) demonstrates the expression of estrogen receptors within the lamprey hypothalamus, suggesting potential feedback interactions between esatradiol and GnRH neurons. Phylogenetically, lampreys are positioned as basal vertebrates, and like many other non-mammalian vertebrates they express multiple forms of GnRH. Consequently, studies in lampreys provide us with important insights into the molecular evolution of estrogenic-GnRH interactions. A cluster of three articles then focus on hypothalamic neuropeptides that exert a major influences on the secretion of GnRH, and which are thought to mediate the feedback effects of sex-steroids on the reproductive axis. For example, studies in rodents have clearly shown the importance of kisspeptin to both pulsatile and surge modes of GnRH release (Navarro, 2012), while human studies have observed sexual dimorphism in kisspeptin neurons during aging (Hrabovszky et al., 2011). Again, an interesting evolutionary perspective is provided by comparing the steroid sensitivity of kisspeptin neurons in various non-mammalian vertebrates (Kanda and Oka, 2012). Although the exact mechanism by which estrogens interact with the reproductive neuroendocrine axis is unclear, our general understanding of this issue is neatly summarized by a series of three reviews (Micevych and Sinchak, 2011; Kenealy and Terasawa, 2012; Radovick et al., 2012). Of particular interest is the finding that sex-steroids exert their feedback not only through classic estrogen receptors located in the nucleus, but also more rapidly through receptors located in the cell membrane. Various physiological functions show adaptations for life in an environment that undergoes marked changes across the 24-h day. For example, in many mammals the timing of the preovulatory LH surge occurs at a very specific time of day. Two articles discuss the interactions between the circadian timing system and estrogen-sensitive neural circuits that regulate GnRH secretion and the preovulatory surge (Sun et al., 2012; Williams and Kriegsfeld, 2012). Finally, a novel hypothesis is proposed to explain the conundrum of how estrogens appear to exert both negative and positive feedback actions on the reproductive axis (Urbanski, 2012). Data is presented from non-human primate studies to suggest that negative and positive estrogen feedback are two completely separate mechanisms, which are mediated, respectively, by two distinct GnRH neuronal populations. This hypothesis challenges the common assumption that has dominated the field for the past four decades, namely that individual GnRH neurons are relatively homogenous and can mediate both negative and positive estrogen feedback.

Results of Animal Experiments With the Fourth Model of the Undulation Pump Total Artificial Heart

Animal experiments using a total artificial heart in a goat are not easy to perform. The fourth model of the undulation pump total artificial heart (UPTAH4), which was designed to perform a long-term physiological experiment including pulsatile and nonpulsatile TAH operations with a conductance- and arterial pressure-based control method named 1/R control, was implanted in 31 goats weighing 38.5 to 60.4 kg (average of 46.8 kg). The 1/R control is a physiological flow control method of TAH developed with a conductance (1/R: reciprocal of a resistance) parallel circuit model. The survival periods were from 0.1 to 153 days (average of 14.5 days). The causes of termination were postoperative bleeding in eight goats, respiratory failure in five goats, device failure in 14 goats, dissected aneurysm in two goats, and thrombus in one goat. The thrombus case was the longest surviving goat. The respiratory failure tended to occur when the extracorporeal circulation time was prolonged. Autotransfusion was effective for the prolongation of survival time. The left-right balance control and the suction control were performed successfully in all goats. The 1/R control was performed for a long time in five goats that survived for more than 1 month. With three goats that survived for 48, 52, and 53 days mainly with the pulsatile mode, the 1/R control was stable. With a goat that survived for 73 days, the nonpulsatile mode with the 1/R control could be tested for 3 weeks. With the longest surviving goat that was maintained mainly with the pulsatile mode, the 1/R control was unstable, possibly due to the mismatching of the response time of the control system between the computer and the body. However, liver and kidney functions were almost normal, and the total protein level recovered. Further study to stabilize the 1/R control in the UPTAH is necessary.

Clinical Effectiveness of Centrifugal Pump to Produce Pulsatile Flow During Cardiopulmonary Bypass in Patients Undergoing Cardiac Surgery

Although the centrifugal pump has been widely used as a nonpulsatile pump for cardiopulmonary bypass (CPB), little is known about its performance as a pulsatile pump for CPB, especially on its efficacy in producing hemodynamic energy and its clinical effectiveness. We performed a study to evaluate whether the Rotaflow centrifugal pump produces effective pulsatile flow during CPB and whether the pulsatile flow in this setting is clinically effective in adult patients undergoing cardiac surgery. Thirty-two patients undergoing CPB for elective coronary artery bypass grafting were randomly allocated to a pulsatile perfusion group (n = 16) or a nonpulsatile perfusion group (n = 16). All patients were perfused with the Rotaflow centrifugal pump. In the pulsatile group, the centrifugal pump was adjusted to the pulsatile mode (60 cycles/min) during aortic cross-clamping, whereas in the nonpulsatile group, the pump was kept in its nonpulsatile mode during the same period of time. Compared with the nonpulsatile group, the pulsatile group had a higher pulse pressure (P <0.01) and a fraction higher energy equivalent pressure (EEP, P = 0.058). The net gain of pulsatile flow, represented by the surplus hemodynamic energy (SHE), was found much higher in the CPB circuit than in patients (P <0.01). Clinically, there was no difference between the pulsatile and nonpulsatile groups with regard to postoperative acute kidney injury, endothelial activation, or inflammatory response. Postoperative organ function and the duration of hospital stay were similar in the two patient groups. In conclusion, pulsatile CPB with the Rotaflow centrifugal pump is associated with a small gain of EEP and SHE, which does not seem to be clinically effective in adult cardiac surgical patients.

Electrocardiogram‐Synchronized Rotational Speed Change Mode in Rotary Pumps Could Improve Pulsatility

Continuous-flow left ventricular assist devices (LVADs) have greatly improved the prognosis of patients with end-stage heart failure, even if continuous flow is different from physiological flow in that it has less pulsatility. A novel pump controller of continuous-flow LVADs has been developed, which can change its rotational speed (RS) in synchronization with the native cardiac cycle, and we speculated that pulsatile mode, which increases RS just in the systolic phase, can create more pulsatility than the current system with constant RS does. The purpose of the present study is to evaluate the effect of this pulsatile mode of continuous-flow LVADs on pulsatility in in vivo settings. Experiments were performed on eight adult goats (61.7 ± 7.5 kg). A centrifugal pump, EVAHEART (Sun Medical Technology Research Corporation, Nagano, Japan), was installed by the apex drainage and the descending aortic perfusion. A pacing lead for the detection of ventricular electrocardiogram was sutured on the anterior wall of the right ventricle. In the present study, we compared pulse pressure or other parameters in the following three conditions, including Circuit-Clamp (i.e., no pump support), Continuous mode (constant RS), and Pulsatile mode (increase RS in systole). Assist rate was calculated by dividing pump flow (PF) by the sum of PF and ascending aortic flow (AoF). In continuous and pulsatile modes, these assist rates were adjusted around 80-90%. The following three parameters were used to evaluate pulsatility, including pulse pressure, dp/dt of aortic pressure (AoP), and energy equivalent pulse pressure (EEP = (∫PF*AoP dt)/(∫PF dt), mm Hg). The percent difference between EEP and mean AoP is used as an indicator of pulsatility, and normally it is around 10% of mean AoP in physiological pulse. Both pulse pressure and mean dp/dt max were decreased in continuous mode compared with clamp condition, while those were regained by pulsatile mode nearly to clamp condition (pulse pressure, clamp/continuous/pulsatile, 25.0 ± 7.6/11.7 ± 6.4/22.6 ± 9.8 mm Hg, mean dp/dt max, 481.9 ± 207.6/75.6 ± 36.2/351.1 ± 137.8 mm Hg/s, respectively). In clamp condition, %EEP was 10% higher than mean AoP (P = 0.0078), while in continuous mode, %EEP was nearly equivalent to mean AoP (N.S.). In pulsatile mode, %EEP was 9% higher than mean AoP (P = 0.038). Our newly developed pulsatile mode of continuous-flow LVADs can produce pulsatility comparable to physiological pulsatile flow. Further investigation on the effect of this novel drive mode on organ perfusion is currently ongoing.

Clinical Effectiveness of Centrifugal Pump to Produce Pulsatile Flow During Cardiopulmonary Bypass in Patients Undergoing Cardiac Surgery

Although the centrifugal pump has been widely used as a nonpulsatile pump for cardiopulmonary bypass (CPB), little is known about its performance as a pulsatile pump for CPB, especially on its efficacy in producing hemodynamic energy and its clinical effectiveness. We performed a study to evaluate whether the Rotaflow centrifugal pump produces effective pulsatile flow during CPB and whether the pulsatile flow in this setting is clinically effective in adult patients undergoing cardiac surgery. Thirty-two patients undergoing CPB for elective coronary artery bypass grafting were randomly allocated to a pulsatile perfusion group (n = 16) or a nonpulsatile perfusion group (n = 16). All patients were perfused with the Rotaflow centrifugal pump. In the pulsatile group, the centrifugal pump was adjusted to the pulsatile mode (60 cycles/min) during aortic cross-clamping, whereas in the nonpulsatile group, the pump was kept in its nonpulsatile mode during the same period of time. Compared with the nonpulsatile group, the pulsatile group had a higher pulse pressure (P < 0.01) and a fraction higher energy equivalent pressure (EEP, P = 0.058). The net gain of pulsatile flow, represented by the surplus hemodynamic energy (SHE), was found much higher in the CPB circuit than in patients (P < 0.01). Clinically, there was no difference between the pulsatile and nonpulsatile groups with regard to postoperative acute kidney injury, endothelial activation, or inflammatory response. Postoperative organ function and the duration of hospital stay were similar in the two patient groups. In conclusion, pulsatile CPB with the Rotaflow centrifugal pump is associated with a small gain of EEP and SHE, which does not seem to be clinically effective in adult cardiac surgical patients.

Encoding and Decoding Mechanisms of Pulsatile Hormone Secretion

Ultradian pulsatile hormone secretion underlies the activity of most neuroendocrine systems, including the hypothalamic-pituitary adrenal (HPA) and gonadal (HPG) axes, and this pulsatile mode of signalling permits the encoding of information through both amplitude and frequency modulation. In the HPA axis, glucocorticoid pulse amplitude increases in anticipation of waking, and, in the HPG axis, changing gonadotrophin-releasing hormone pulse frequency is the primary means by which the body alters its reproductive status during development (i.e. puberty). The prevalence of hormone pulsatility raises two crucial questions: how are ultradian pulses encoded (or generated) by these systems, and how are these pulses decoded (or interpreted) at their target sites? We have looked at mechanisms within the HPA axis responsible for encoding the pulsatile mode of glucocorticoid signalling that we observe in vivo. We review evidence regarding the 'hypothalamic pulse generator' hypothesis, and describe an alternative model for pulse generation, which involves steroid feedback-dependent endogenous rhythmic activity throughout the HPA axis. We consider the decoding of hormone pulsatility by taking the HPG axis as a model system and focussing on molecular mechanisms of frequency decoding by pituitary gonadotrophs.

Perfusion Enhances Solute Transfer into the Shell of Hollow Fiber Membrane Bioreactors for Bone Tissue Engineering

Preparation of tissue engineered (TE) 3D constructs to repair large bone defects is limited by the difficult supply of nutrients and oxygen to cells in the innermost regions of constructs cultured in bioreactors. Poor oxygenation negatively affects cell viability and function. Bioreactor design optimization may help relieve these limitations. Bioreactors in which cells are cultured outside bundles of hollow fiber membranes (HFMBs) are structurally similar to natural bone. HFMB operation in pure diffusion has been reported to suffice for fibroblasts, but is deemed insufficient for bone cells. In this paper, the effect of perfusion flows in the cell compartment on solute transfer was investigated in HFMBs differing in design and operating conditions. HFMBs were designed and operated using values of non-dimensional groups that ensured solutes transfer towards the cell compartment mainly by diffusion; in the presence of low to high Starling flows; in the presence of pulsatile radial flows obtained by periodically stopping the solution flow leaving the bioreactor using a pinch valve. Distribution of matter in cell-free HFMBs was evaluated with tracer experiments in an optimized apparatus. Effectiveness of solute transfer to cell compartment was assessed based on the bioreactor response in terms of the shell volume actively involved in mass transfer (V(MTA)) according to transport models developed specifically for the purpose. V(MTA) increased with increasing Starling flows. In the pulsatile radial flow mode, tracer concentration in the shell increased 3 times faster than at high Starling flows. This suggests that controlled perfusion flows in HFMBs might enable the engineering of large TE bone constructs.

Comparison of Pumps and Oxygenators With Pulsatile and Nonpulsatile Modes in an Infant Cardiopulmonary Bypass Model

As the evidence mounts in favor of pulsatile perfusion during CPB, it is necessary to investigate the effect of circuit components on the quality of pulsatility delivered throughout the circuit. We compared two bloodpumps, the Jostra HL-20 heart-lung machine and the MEDOS DELTASTREAM DP1 Bloodpump, and two oxygenators, the Capiox Baby RX05 and the MEDOS HILITE 800LT, in terms of mean arterial pressure, energy equivalent pressure, surplus hemodynamic energy, total hemodynamic energy, and pressure drop over the oxygenators using a blood analog. The pumps and oxygenators were combined in unique circuits and tested in nonpulsatile and pulsatile modes, at two flow rates (500 and 800 mL/min), and three rotational speed differentials when using the MEDOS DELTASTREAM DP1 Bloodpump for 144 trials in total. The Jostra Roller pump produced some pulsatility in nonpulsatile mode and better pulsatility in pulsatile mode than the MEDOS DP1 Bloodpump at a rotational speed differential of 2500 rpm, but not at 3500 or 4500 rpm. The MEDOS DP1 Bloodpump produced almost no pulsatility in nonpulsatile mode. Pressure drops over the Capiox Baby RX05 were markedly higher, at 92.5 +/- 0.4 mm Hg with the MEDOS DP1 Bloodpump at 800 mL/min and 4500 rpm in pulsatile mode, than those of the MEDOS HILITE 800LT oxygenator, which was 67.0 +/- 0.1 mm Hg at the same settings. These results suggest that careful selection of each circuit component, based on the individual clinical case and component specifics, are necessary to achieve the best quality of pulsatility.

Initiation of gonadotropin responsiveness in hypothalamic hypogonadism: comparison of pulsatile and continuous nocturnal subcutaneous administration of LH-RH.

An enhanced secretion of LH and FSH was observed in two patients with hypothalamic hypogonadism following treatment with nocturnal s.c. administration of LH-RH. Using portable infusion pumps two forms of therapy were used for 9 nights with a two months interval in between: A) continuous nocturnal s.c. LH-RH; B) pulsatile nocturnal s.c. LH-RH with administration of a bolus dose at 90 min intervals. Both therapeutical regimens induced a rise in the 8:00 h concentrations of LH. The secretory response of LH during an infusion of LH-RH (200 micrograms i.v.; t = 4 hours) was increased after both forms of therapy, whereas FSH secretion was enhanced only after the pulsatile mode of LH-RH application.

Impact of the Postpump Resistance on Pressure-Flow Waveform and Hemodynamic Energy Level in a Neonatal Pulsatile Centrifugal Pump

This study tested the impact of different postpump resistances on pulsatile pressure-flow waveforms and hemodynamic energy output in a mock extracorporeal system. The circuit was primed with a 40% glycerin-water mixture, and a PediVAS centrifugal pump was used. The pre- and postpump pressures and flow rates were monitored via a data acquisition system. The postpump resistance was adjusted using a Hoffman clamp at the outlet of the pump. Five different postpump resistances and rotational speeds were tested with nonpulsatile (NP: 5000 RPM) and pulsatile (P: 4000 RPM) modes. No backflow was found when using pulsatile flow. With isoresistance, increased arterial resistances decreased pump flow rates (NP: from 1,912 ml/min to 373 ml/min; P: from 1,485 ml/min to 288 ml/min), increased postpump pressures (NP: from 333 mm Hg to 402 mm Hg; P: from 223 mm Hg to 274 mm Hg), and increased hemodynamic energy output with pulsatile mode. Pump flow rate correlated linearly with rotational speed (RPMs) of the pump, whereas postpump pressures and hemodynamic energy outputs showed curvilinear relationships with RPMs. The maximal pump flow rate also increased from 618 ml/min to 4,293 ml/min with pulsatile mode and from 581 ml/min to 5,665 ml/min with nonpulsatile mode. Results showed that higher postpump resistance reduced the pump flow range, and increased postpump pressure and surplus hemodynamic energy output with pulsatile mode. Higher rotational speeds also generated higher pump flow rates, postpump pressures, and increased pulsatility.

Multiscale modelling of endocrine systems: new insight on the gonadotrope axis

In vertebrates, the gonadotrope axis is made up of the hypothalamus, belonging to the central nervous system, the pituitary gland and the gonads. These organs communicate with one another within entangled endocrine loops. From a dynamical viewpoint, the gonadotrope axis exhibits remarkable features, such as the pulsatile mode of secretion of the master reproductive hormone GnRH (gonadotropin releasing hormone) and the permanent renewal of the gonadic tissues related to the maturation of the germ cell lines. We will present a multilevel and multiscale modelling approach of the gonadotrope axis focusing on the ovulation process. On the gonadic level, we address the question of the selection of ovarian follicles within the framework of controlled conservation laws. We have to deal with a 2D EDP with integro-differential expressions in the velocity and source terms. On the hypothalamic level, we design a model of GnRH secretion within the framework of weakly coupled nonlinear oscillators. The model outputs reproduce the transition from the pulsatile to the surge pattern and the changes in pulse frequency. To explain the behaviour of the model and meet qualitative and quantitative endocrinological specifications, we explore the whole sequence of bifurcations occurring within the model.

Effects of Continuous Versus Intermittent Exercise, Obesity, and Gender on Growth Hormone Secretion

Obesity attenuates spontaneous GH secretion and the GH response to exercise. Obese individuals often have low fitness levels, limiting their ability to complete a typical 30-min bout of continuous exercise. An alternative regimen in obese subjects may be shorter bouts of exercise interspersed throughout the day. The objective of the study was to examine whether intermittent and continuous exercise interventions evoke similar patterns of 24-h GH secretion and whether responses are attenuated in obese subjects or affected by gender. This was a repeated-measures design in which each subject served as their own control. This study was conducted at the University of Virginia General Clinical Research Center. Subjects were healthy nonobese (n = 15) and obese (n = 14) young adults. Subjects were studied over 24 h at the General Clinical Research Center on three occasions: control, one 30-min bout of exercise, and three 10-min bouts of exercise. Twenty-four hour GH secretion was measured. Compared with unstimulated 24-h GH secretion, both intermittent and continuous exercise, at constant exercise intensity, resulted in severalfold elevation of 24-h integrated serum GH concentrations in young adults. Basal and pulsatile modes of GH secretion were attenuated both at rest and during exercise in obese subjects. The present data suggest that continuous and intermittent exercise training should be comparably effective in increasing 24-h GH secretion.

The Capability of Trapping Gaseous Microemboli of Two Pediatric Arterial Filters With Pulsatile and NonPulsatile Flow in a Simulated Infant CPB Model

The study objective was to test the capability of Medtronic Affinity and Terumo Capiox pediatric arterial filters to trap gaseous microemboli in a simulated infant cardiopulmonary bypass (CPB) model. The filters were used in parallel pattern. The circuit was primed with lactated ringer's solution (700 ml) and postfilter pressure was maintained at 100 mm Hg using a Hoffman clamp. Trials were conducted at flow rates ranging from 500 to 1,250 ml/min. After introducing 20 ml air into the venous line via an 18-G needle, 2-minute segments of data were recorded. This entire process was repeated 6 times for each unique combination of arterial filter, flow rate and perfusion mode, yielding a total of 96 experiments. More than 80% of gaseous microemboli were trapped by the two pediatric arterial filters. With increased flow rates and pulsatile mode, more gaseous microemboli passed through the arterial filters. There were no differences in terms of the percentage of gaseous microemboli trapped and pressure drops between Medtronic Affinity and Terumo Capiox pediatric arterial filters. Results demonstrated that Medtronic Affinity and Terumo Capiox pediatric arterial filters could trap the majority of gaseous microemboli in this particular setting of an open arterial filter purge line in a simulated infant CPB circuit with pulsatile and nonpulsatile flow.

A Hemodynamic Evaluation of the Medos Deltastream DP1 Rotary Pump and Jostra HL-20 Roller Pump Under Pulsatile and Nonpulsatile Perfusion in an Infant Cardiopulmonary Bypass Model—A Pilot Study

This study aims to compare the Jostra HL-20 roller pump to the Medos DeltaStream DP1 rotary pump in terms of pressure and flow waveforms, as well as calculated energies based on pressure/flow relationships, in a simulated pediatric cardiopulmonary perfusion system. The flow rate was set at 1,000 ml/min for each pump, under both pulsatile and nonpulsatile perfusion modes. Mean arterial pressure (MAP) was maintained at 40 mm Hg. Pressure and flow measurements and waveforms were recorded at precannula site in the bypass circuit. Blood analog test fluid was used to simulate blood properties. A total of 24 experiments were performed (n = 12 nonpulsatile and n = 12 pulsatile). A significant increase in surplus hemodynamic energy (SHE) was observed in both pumps under pulsatile perfusion. In contrast, nonpulsatile perfusion generated very little SHE in the Jostra roller pump, whereas no SHE was generated in the Medos rotary pump. However, under pulsatile perfusion, the Medos rotary pump generated more than twice the amount of SHE or "extra" energy than the Jostra roller pump. The total hemodynamic energy was also significantly higher in the Medos rotary pump than the Jostra roller pump, under pulsatile perfusion. This pilot study suggests that the Medos DeltaStream DP1 rotary pump may produce greater hemodynamic energy levels and higher quality physiologic pressure/flow waveforms than the Jostra roller pump. Further investigation of the Medos DeltaStream DP1 rotary pump is necessary to evaluate hemodynamic energy generation under various pump settings, in contrast to different flow rates.

Effect of Continuous and Pulsatile Flow Left Ventricular Assist on Pulsatility in a Pediatric Animal Model of Left Ventricular Dysfunction: Pilot Observations

Pediatric ventricular assist devices are being developed that can produce pulsatile flow (PF) or continuous flow (CF). An important aspect of choosing between these two modes is understanding the consequences of each mode on pediatric vascular pulsatility. Differences in vascular pulsatility generated by PF and CF operation of the 3-inch pediatric cardiopulmonary assist system (pCAS, Ension, Inc., Pittsburgh, PA) were investigated while providing left atrium-to-aorta left ventricular assist (LVA), using an infant animal model of left ventricular dysfunction. Hemodynamic data were digitally recorded with the pCAS providing LVA at incremental flow rates while operating in continuous mode, pulsatile mode at 100 bpm, and pulsatile mode at 140 bpm. These data were used to calculate vascular input impedance (Zart), energy equivalent pressure, and surplus hemodynamic energy as indices of pulsatility for partial (50% of maximum) and maximum LVA flow. Both CF and PF LVA by the pCAS resulted in favorable hemodynamic rectification of left ventricular dysfunction while generating equivalent flows. PF LVA maintained a greater degree of pulsatility compared with CF, as evidenced by increasing energy equivalent pressure and a lesser drop in surplus hemodynamic energy with increasing pCAS flow. Differences in Zart modulus and phase were indiscernible. The selection of flow mode may have long-term consequences on Zart and end-organ perfusion affecting clinical outcomes in pediatric patients.

Novel concepts about normal sexual differentiation of reproductive neuroendocrine function and the developmental origins of female reproductive dysfunction: the sheep model

The neuroendocrine regulation of GnRH secretion plays a central role in timing gamete release in both sexes. This regulation is more complex in the female because the discontinuous release of ova is more complex than the continuous release of spermatozoa. This review provides an evolving understanding of the sex differences in reproductive neuroendocrine controls and how these differences arise. The rules for sexual differentiation of steroid feedback control of GnRH secretion conceptually parallel the well-established principles that underlie the sexual differentiation of the internal and external genitalia. In the context of the neuroendocrine regulation of the ovarian cycle, and using the sheep as a model, four steroid feedback controls for GnRH secretion are inherent (default). They require no ovarian developmental input to function appropriately during adulthood. Two steroid feedback controls regulate the preovulatory surge mode of GnRH secretion, and two regulate the pulsatile mode. If the individual is a male, three steroid feedback controls of GnRH secretion become unnecessary or irrelevant, and these are abolished or become functionally inoperative through programmed reductions in hypothalamic sensitivity. This central programming occurs through exposure of presynaptic GnRH neurons in the developing male brain to the androgenic and estrogenic actions of testicular steroids. In precocial species such as ruminants, this programming begins well before birth. Understanding how GnRH secretion normally becomes sexually differentiated is of practical importance to determining how inappropriate hormonal environments during development can variously malprogram the neuroendocrine system to produce a variety of reproductive dysfunctions relating to patterning of gonadotropin secretion.

The Effect of the Presence and Pattern of Luteinizing Hormone Stimulation on Ovulatory Follicle Development in Sheep1

The aim of this study was to examine the role of LH on the growth of the large preovulatory follicle and its secretion of hormones in sheep. Ewes with ovarian autotransplants were treated with GnRH-antagonist at the time of luteal regression and different LH regimes applied for 60-66 h before administration of an ovulatory stimulus (hCG). In Experiment 1 (N = 24; n = 8), ewes received either no LH or constant or pulsatile infusion of LH at the same dose (1.25 microg/h). In Experiment 2 (N = 12, n = 6), LH was constantly infused at a rate of 1.25 microg or 2.5 microg oLH/h. In Experiment 1, animals receiving either pulsatile or constant LH exhibited increases in estradiol and inhibin A secretion (P < 0.001) and a depression in FSH (P < 0.001) that resembled the normal follicular phase. Similarly in Experiment 2, doubling the dose of LH resulted in a two-fold increase in ovarian estradiol secretion (P < 0.05) but no other changes. All animals receiving LH, regardless of the pattern of stimulation, ovulated and established a normal luteal phase. In contrast, no LH treatment resulted in constant immuno-active LH without pulses, unchanged FSH and inhibin A concentrations (P < 0.05), and basal estradiol secretion (P < 0.001). Morphologically normal large antral follicles were observed in this group and although corpora lutea formed in response to hCG, progesterone profiles were abnormal. In conclusion, these results suggest that LH is an essential requirement for normal ovulatory follicle development and subsequent luteal function and show that a pulsatile mode of LH stimulation is not required by ovulatory follicles.

Comparison of hollow-fiber membrane oxygenators with different perfusion modes during normothermic and hypothermic CPB in a simulated neonatal model

The objectives of this investigation were (1) to compare two hollow-fiber membrane oxygenators (Capiox Baby RX versus Lilliput 1-D901) in terms of pressure drops and surplus hemodynamic energy (SHE) during normothermic and hypothermic cardiopulmonary bypass (CPB) in a simulated neonatal model; and (2) to evaluate pulsatile and non-pulsatile perfusion modes for each oxygenator in terms of SHE levels. In a simulated patient, CPB was initiated at a constant pump flow rate of 500 mL/min. The circuit was primed with fresh bovine blood. After 5 min of normothermic CPB, the pseudo-patient was cooled down to 25 degrees C for 10 min followed by 30 min of hypothermic CPB. The pseudo-patient then underwent 10 min of rewarming and 5 min of normothermic CPB. At each experimental site (pre- and post-oxygenator and pre-aortic cannula), SHE was calculated using the following formula {SHE (ergs/cm3) = 1332 [((integralfpdt)/(integralfdt)) - mean arterial pressure]} (f = pump flow and p = pressure). A linear mixed-effects model that accounts for the correlation among repeated measurements was fit to the data to assess differences in SHE between oxygenators, pumps, and sites. Tukey's multiple comparison procedure was used to adjust p-values for post-hoc pairwise comparisons. The pressure drops in the Capiox group compared to the Lilliput group were significantly lower during hypothermic non-pulsatile (21.3 +/- 0.5 versus 50.7 +/- 0.9 mmHg, p < 0.001) and pulsatile (22 +/- 0.0 versus 53.3 +/- 0.5 mmHg, p < 0.001) perfusion, respectively. Surplus hemodynamic energy levels were significantly higher in the pulsatile group compared to the non-pulsatile group, with Capiox (1655 +/- 92 versus 10008 +/- 1370 ergs/cm3, p < 0.001) or Lilliput (1506 +/- 112 versus 7531 +/- 483 ergs/cm3, p < 0.001) oxygenators. During normothermic CPB, both oxygenators had patterns similar to those observed under hypothermic conditions. The Capiox oxygenator had a significantly lower pressure drop in both pulsatile and non-pulsatile perfusion modes. For each oxygenator, the SHE levels were significantly higher in the pulsatile mode.

Quantification of Perfusion Modes in Terms of Surplus Hemodynamic Energy Levels in a Simulated Pediatric CPB Model

The objective of this investigation was to compare pulsatile versus nonpulsatile perfusion modes in terms of surplus hemodynamic energy (SHE) levels during cardiopulmonary bypass (CPB) in a simulated neonatal model. The extracorporeal circuit consisted of a Jostra HL-20 heart-lung machine (for both pulsatile and nonpulsatile modes of perfusion), a Capiox Baby RX hollow-fiber membrane oxygenator, a Capiox pediatric arterial filter, 5 feet of arterial tubing and 6 feet of venous tubing with a quarter-inch diameter. The circuit was primed with a lactated Ringers solution. The systemic resistance of a pseudo-patient (mean weight, 3 kg) was simulated by placing a clamp at the end of the arterial line. The pseudo-patient was subjected to five pump flow rates in the 400 to 800 ml/min range. During pulsatile perfusion, the pump rate was kept constant at 120 bpm. Pressure waveforms were recorded at the preoxygenator, postoxygenator, and preaortic cannula sites. SHE was calculated by use of the following formula {SHE (ergs/cm) = 1,332 [((integral fpdt) / (integral fdt)) - Mean Arterial Pressure]} (f = pump flow and p = pressure). A total of 60 experiments were performed (n = 6 for nonpulsatile and n = 6 for pulsatile) at each of the five flow rates. A linear mixed-effects model, which accounts for the correlation among repeated measurements, was fit to the data to assess differences in SHE between flows, pumps, and sites. The Tukey multiple comparison procedure was used to adjust p values for post hoc pairwise comparisons. With a pump flow rate of 400 ml/min, pulsatile flow generated significantly higher surplus hemodynamic energy levels at the preoxygenator site (23,421 +/- 2,068 ergs/cm vs. 4,154 +/- 331 ergs/cm, p < 0.0001), the postoxygenator site (18,784 +/- 1,557 ergs/cm vs. 3,383 +/- 317 ergs/cm, p < 0.0001), and the precannula site (6,324 +/- 772 ergs/cm vs. 1,320 +/- 91 ergs/cm, p < 0.0001), compared with the nonpulsatile group. Pulsatile flow produced higher SHE levels at all other pump flow rates. The Jostra HL-20 roller pump generated significantly higher SHE levels in the pulsatile mode when compared with the nonpulsatile mode at all five pump flow rates.