Constant Pressure Infusion Research Articles

Simulation of gravity- and pump-driven perfusion techniques for measuring outflow facility of ex vivo and in vivo eyes.

Aqueous humor dynamics are commonly assessed by infusing fluid into the eye and measuring intraocular pressure (IOP). From the pressure-flow relationship, conventional outflow facility is estimated to study glaucomatous processes that lower facility or identify therapeutics that enhance facility in hopes of restoring healthy IOP levels. The relative merits and limitations of constant flow (CF), gravity-driven constant pressure (CPg), and pump-driven constant pressure (CPp) infusion techniques were explored via simulations of a lumped parameter viscoelastic model of the eye. Model parameter values were based on published perfusion system properties and outflow facility data from rodents. Step increases in pressure or flow were simulated without and with IOP noise recorded from enucleated eyes, anesthetized animals, and conscious animals. Steady-state response levels were determined using published window and ratio criteria. Model simulations show that all perfusion techniques estimate facility accurately and that ocular fluid dynamics set a hard limit on how fast measurements can be taken. This limit can be approached with CPg and CPp systems by increasing their gain but not with CF systems, which invariably take longest to settle. Facility experiment duration is further lengthened by inclusion of IOP noise, and data filtering is needed for steady-state detection with in vivo noise. The ratio criterion was particularly affected because noise in the flow data is amplified by the higher gain of CPg and CPp systems. A recursive regression method is introduced, which can ignore large transient IOP fluctuations that interfere with steady-state detection by fitting incoming data to the viscoelastic eye model. The fitting method greatly speeds up data collection without loss of accuracy, which could enable outflow facility measurements in conscious animals. The model may be generalized to study response dynamics to fluid infusion in other viscoelastic compartments of the body and model insights extended to optimize experiment design.

Integrated experimental system and method for gas hydrate-bearing sediments considering stress-seepage coupling.

It is of great significance to study the mechanical behavior and permeability properties of hydrate-bearing sediments for a safe, efficient, and sustainable exploitation of hydrate. However, most of the studies conducted so far have focused only on a single stress field or seepage field, which is detached from practical engineering. In this paper, a new integrated experimental system (IES) was proposed, which realizes the coupling study of stress and seepage. The main body of IES is a triaxial subsystem and a seepage subsystem. The triaxial subsystem can realize in situ synthesis and triaxial shear of hydrate-bearing sediments (HBS). Stable seepage can be effectively formed using a constant pressure infusion pump and a back pressure valve. A series of shear-seepage coupling tests were carried out to verify the effectiveness of the IES and explore the stress-seepage coupling characteristics of HBS. The results show that stress has a significant influence on permeability, and its essence is the stress compression on the seepage channel. The stress-strain relationship, volume response, and permeability are related to each other. The permeability will be affected by the coupling of hydrate saturation (pore plugging), effective confining pressure (pore compression), and shear (fracture generation).

Segmental outflow dynamics in the trabecular meshwork of living mice.

Aqueous humour does not drain uniformly through the trabecular meshwork (TM), but rather follows non-uniform or "segmental" routes. In this study, we examined whether segmental outflow patterns in the TM change over time in living mice and whether such changes are affected by age. Segmental outflow patterns were labelled by constant-pressure infusion of fluorescent tracer microparticles into the anterior chamber of anesthetised C57BL/6J mice at 3 or 8 months of age. Two different tracer colours were infused at separate time points with an interval of Δt=0, 2, 7 or 14 days. In a separate experiment, one tracer was infused in vivo while the second tracer was infused ex vivo after 2 days. The spatial relationship between the two tracer patterns was analysed using the Pearson's correlation coefficient, r. In 3-month-old mice, there was a time-dependent decay in r, which was near unity at Δt=0 and near zero at Δt=14 days. In 8-month-old mice, r remained elevated for 14 days. Segmental outflow patterns measured in young mice ex vivo were not significantly different from those measured in vivo after accounting for the expected changes over 2 days. Therefore, segmental outflow patterns are not static in the TM but redistribute over time, achieving near complete loss of correlation by 2 weeks in young healthy mice. There is an age-related decline in the rate at which segmental outflow patterns redistribute in the TM. Further research is needed to understand the dynamic factors controlling segmental outflow.

Intercompartmental communication between the cerebrospinal and adjacent spaces during intrathecal infusions in an acute ovine in-vivo model

IntroductionThe treatment of hydrocephalus has been a topic of intense research ever since the first clinically successful use of a valved cerebrospinal fluid shunt 72 years ago. While ample studies elucidating different phenomena impacting this treatment exist, there are still gaps to be filled. Specifically, how intracranial, intrathecal, arterial, and venous pressures react and communicate with each other simultaneously.MethodsAn in-vivo sheep trial (n = 6) was conducted to evaluate and quantify the communication existing within the cranio-spinal, arterial, and venous systems (1 kHz sampling frequency). Standardized intrathecal infusion testing was performed using an automated infusion apparatus, including bolus and constant pressure infusions. Bolus infusions entailed six lumbar intrathecal infusions of 2 mL Ringer’s solution. Constant pressure infusions were comprised of six regulated pressure steps of 3.75 mmHg for periods of 7 min each. Mean pressure reactions, pulse amplitude reactions, and outflow resistance were calculated.ResultsAll sheep showed intracranial pressure reactions to acute increases of intrathecal pressure, with four of six sheep showing clear cranio-spinal communication. During bolus infusions, the increases of mean pressure for intrathecal, intracranial, arterial, and venous pressure were 16.6 ± 0.9, 15.4 ± 0.8, 3.9 ± 0.8, and 0.1 ± 0.2 mmHg with corresponding pulse amplitude increases of 2.4 ± 0.3, 1.3 ± 0.3, 1.3 ± 0.3, and 0.2 ± 0.1 mmHg, respectively. During constant pressure infusions, mean increases from baseline were 14.6 ± 3.8, 15.5 ± 4.2, 4.2 ± 8.2, and 3.2 ± 2.4 mmHg with the corresponding pulse amplitude increases of 2.5 ± 3.6, 2.5 ± 3.0, 7.7 ± 4.3, and 0.7 ± 2.0 mmHg for intrathecal, intracranial, arterial, and venous pulse amplitude, respectively. Outflow resistances were calculated as 51.6 ± 7.8 and 77.8 ± 14.5 mmHg/mL/min for the bolus and constant pressure infusion methods, respectively—showing deviations between the two estimation methods.ConclusionsStandardized infusion tests with multi-compartmental pressure recordings in sheep have helped capture distinct reactions between the intrathecal, intracranial, arterial, and venous systems. Volumetric pressure changes in the intrathecal space have been shown to propagate to the intraventricular and arterial systems in our sample, and to the venous side in individual cases. These results represent an important step into achieving a more complete quantitative understanding of how an acute rise in intrathecal pressure can propagate and influence other systems.

Assessment of intracranial dynamics in hydrocephalus: effects of viscoelasticity on the outcome of infusion tests

The treatment of hydrocephalus requires insight into the intracranial dynamics in the patient. Resistance to CSF outflow (R0) is a clinically obtainable parameter of intracranial fluid dynamics that quantifies the apparent resistance to CSF absorption. It is used as a criterion for the selection of shunt candidates and serves as an indicator of shunt performance. The R0 is obtained clinically by performing 1 of 3 infusion tests: constant flow, constant pressure, or bolus infusion. Among these, the bolus infusion method has the shortest examination times and provides the shortest time of exposure of patients to artificially increased intracranial pressure (ICP) levels. However, for unknown reasons, the bolus infusion method systematically underestimates the R0. Here, the authors have tested and verified the hypothesis that this underestimation is due to lack of accounting for viscoelasticity of the craniospinal space in the calculation of the R0. The authors developed a phantom model of the human craniospinal space in order to reproduce in vivo pressure-volume (PV) relationships during infusion testing. The phantom model followed the Marmarou exponential PV equation and also included a viscoelastic response to volume changes. Parameters of intracranial fluid dynamics, such as the R0, could be controlled and set independently. In addition to the phantom model, the authors designed a computational framework for virtual infusion testing in which viscoelasticity can be turned on or off in a controlled manner. Constant flow, constant pressure, and bolus infusion tests were performed on the phantom model, as well as on the virtual computational platform, using standard clinical protocols. Values for the R0 were derived from each infusion test by using both a standard method based on the Marmarou PV equation and a novel method based on a system identification approach that takes into account viscoelastic behavior. Experiments with the phantom model confirmed clinical observations that both the constant flow and constant pressure infusion tests, but not the bolus infusion test, yield correct R0 values when they are determined with the standard method according to Marmarou. Equivalent results were obtained using the computational framework. When the novel system identification approach was used to determine the R0, all of the 3 infusion tests yielded correct values for the R0. CONCLUSIONS" The authors' investigations demonstrate that intracranial dynamics have a substantial viscoelastic component. When this viscoelastic component is taken into account in calculations, the R0, is no longer underestimated in the bolus infusion test.

Effect of resting pressure on the estimate of cerebrospinal fluid outflow conductance

BackgroundA lumbar infusion test is commonly used as a predictive test for patients with normal pressure hydrocephalus and for evaluation of cerebrospinal fluid (CSF) shunt function. Different infusion protocols can be used to estimate the outflow conductance (Cout) or its reciprocal the outflow resistance (Rout), with or without using the baseline resting pressure, Pr. Both from a basic physiological research and a clinical perspective, it is important to understand the limitations of the model on which infusion tests are based. By estimating Cout using two different analyses, with or without Pr, the limitations could be explored. The aim of this study was to compare the Cout estimates, and investigate what effect Prhad on the results.MethodsSixty-three patients that underwent a constant pressure infusion protocol as part of their preoperative evaluation for normal pressure hydrocephalus, were included (age 70.3 ± 10.8 years (mean ± SD)). The analysis was performed without (Cexcl Pr) and with (Cincl Pr) Pr. The estimates were compared using Bland-Altman plots and paired sample t-tests (p < 0.05 considered significant).ResultsMean Cout for the 63 patients was: Cexcl Pr = 7.0 ± 4.0 (mean ± SD) μl/(s kPa) and Cincl Pr = 9.1 ± 4.3 μl/(s kPa) and Rout was 19.0 ± 9.2 and 17.7 ± 11.3 mmHg/ml/min, respectively. There was a positive correlation between methods (r = 0.79, n = 63, p < 0.01). The difference, ΔCout= -2.1 ± 2.7 μl/(s kPa) between methods was significant (p < 0.01) and ΔRout was 1.2 ± 8.8 mmHg/ml/min). The Bland-Altman plot visualized that the variation around the mean difference was similar all through the range of measured values and there was no correlation between ΔCout and Cout.ConclusionsThe difference between Cout estimates, obtained from analyses with or without Pr, needs to be taken into consideration when comparing results from studies using different infusion test protocols. The study suggests variation in CSF formation rate, variation in venous pressure or a pressure dependent Cout as possible causes for the deviation from the CSF absorption model seen in some patients.

Reference values for CSF outflow resistance and intracranial pressure in healthy elderly

The intracranial pressure (ICP) and CSF outflow resistance (R(out)) are essential to describe the dynamics of the CSF system. R(out) affects ICP, pulse amplitudes, CSF absorption, and the compliance of the system. The objective of this study was to determine the reference values in healthy elderly subjects. Elderly people (60-82 years), who considered themselves healthy, were recruited through an advertisement in the local newspaper. All were evaluated with a 3-T MRI. Subjects were eligible if they did not have any psychiatric or neurologic disorder or signs of advanced atherosclerotic disease. CSF resting pressure (ICP) and R(out) were determined by a constant pressure infusion method with the patient in the supine position. The study population consisted of 40 subjects (mean age 70 years; 23 women). The median ICP was 11.6 mm Hg (15.8 cmH(2)O) and the reference interval was ICP 7.8-14.3 mm Hg (10.6-19.4 cmH(2)O) (defined as 5th to 95th percentiles). The median R(out) was 8.6 mm Hg/mL/min. The variation in R(out) was large and not normally distributed. The 90th percentile of R(out) was 17.4 mm Hg/mL/min. This study reports reference values for ICP and R(out) and should be used for comparison when investigating disorders with suspected CSF dynamic disturbances in the elderly. ICP was in the same range as that reported in the young and middle-aged. The upper limit of R(out) was higher than previously believed to be the upper limit of normal for this age group.

The pulsatility curve—the relationship between mean intracranial pressure and pulsation amplitude

The amplitude of cardiac-related pulsations in intracranial pressure has recently been suggested as useful for selecting patients for shunt surgery in hydrocephalus. To better understand how shunting affects these pulsations, we aim to model the relationship between mean pressure and pulsation amplitude in a wide range, including low pressures typically found after shunt surgery. Twenty-five patients with probable idiopathic normal pressure hydrocephalus were examined with lumbar constant pressure infusion investigations including drainage of cerebrospinal fluid. Mean pressure and pulsation amplitude were determined for consecutive 1.5 s intervals, starting at peak pressure (ca 35 mmHg), after infusion, continuing during spontaneous return to baseline and drainage to 0 mmHg. The amplitude versus pressure relationship revealed a linear phase at higher pressures (14–32 mmHg, lack of fit test: p = 0.79), a transitional phase and an essentially constant phase at low pressures (0–10 mmHg, slope = −0.02, lack of fit test: p = 0.88). Individual patients' baseline values were found in all three phases. The model and methodology presented in this paper can be used to preoperatively identify patients with potential for postoperative amplitude decrease and to predict how much the amplitude can be reduced.

Comparison between 3 infusion methods to measure cerebrospinal fluid outflow conductance

There are several infusion methods available to estimate the outflow conductance (Cout) or outflow resistance (Rout=1/Cout) of the CSF system. It has been stated that for unknown reasons, the bolus infusion method estimates a higher C(out) than steady-state infusion methods. The aim of this study was to compare different infusion methods for estimation of Cout. The following 3 different infusion methods were used: the bolus infusion method (Cout bol); the constant flow infusion method, both static (Cout stat) and dynamic (Cout dyn) analyses; and the constant pressure infusion method (Cout cpi). Repeated investigations were performed on an experimental model with well-known characteristics, with and without physiological pressure variations (B-waves, breathing, and so on). All 3 methods were also performed in a randomized order during the same investigation in 20 patients with probable or possible idiopathic normal-pressure hydrocephalus; 6 of these patients had a shunt and 14 did not. Without the presence of physiological pressure variations, the concordance in the experimental model was good between all methods. When they were added, the repeatability was better for the steady-state methods and a significantly higher Cout was found with the bolus method in the region of clinically relevant Cout (p<0.05). The visual fit for the bolus infusion was dependent on subjective assessment by the operator. This experimental finding was confirmed by the clinical results, where significant differences were found in the investigations in patients without shunts between Cout of the visual bolus method and Cout stat, Cout dyn, and Cout cpi (4.58, 4.18, and 6.12 μl/[second×kPa], respectively). This study emphasized the necessity for standardization of Cout measurements. An experienced operator could partly compensate for difficulties in correctly estimating the pressure parameters for the bolus infusion method, but for the general user this study suggests a steady-state method for estimating Cout.

Real-time estimation of cerebrospinal fluid system parameters via oscillating pressure infusion

Hydrocephalus is related to a disturbed cerebrospinal fluid (CSF) system. For diagnosis, lumbar infusion test are performed to estimate outflow conductance, C (out), and pressure volume index, PVI, of the CSF system. Infusion patterns and analysis methods used in current clinical practice are not optimized. Minimizing the investigation time with sufficient accuracy is of major clinical relevance. The aim of this study was to propose and experimentally evaluate a new method, the oscillating pressure infusion (OPI). The non-linear model of the CSF system was transformed into a linear time invariant system. Using an oscillating pressure pattern and linear system identification methods, C (out) and PVI with confidence intervals, were estimated in real-time. Forty-two OPI and constant pressure infusion (CPI) investigations were performed on an experimental CSF system, designed with PVI = 25.5 ml and variable C (out). The ARX model robustly estimated C (out) (mean C (out,OPI) - C (out,CPI) = 0.08 μl/(s kPa), n = 42, P = 0.68). The Box-Jenkins model proved most reliable for PVI (23.7 ± 2.0 ml, n = 42). The OPI method, with its oscillating pressure pattern and new parameter estimation methods, efficiently estimated C (out) and PVI as well as their confidence intervals in real-time. The results from this experimental study show potential for the OPI method and supports further evaluation in a clinical setting.

Outflow facility in mice with a targeted type I collagen mutation.

Transgenic Col1a1(r/r) mice develop elevated intraocular pressure (IOP) with an open angle and progressive optic nerve axon loss. The present study was undertaken to evaluate aqueous outflow facility and its age dependence in these mice. Homozygous B6;129S4-Col1a1(tm1Jae) mice and corresponding wild-type Col1a1(+/+) mice from 12 to 56 weeks of age were anesthetized, and IOP was measured with a microneedle. Outflow facility was determined by a two-level, constant-pressure infusion Type I collagen, subunit alpha1 was assessed in sclera and choroid by Western blot analysis. The mean IOP in 12- to 36-week-old transgenic Col1a1(r/r) mice was 25.1% higher than in control Col1a1(+/+) mice (P < 0.01), whereas the mean outflow facility was 25.4% lower than in control mice (P < 0.01). After this period, the mean IOP in 42- to 56-week-old transgenic mice returned to normal levels, whereas outflow facility increased by 36.0%. Over the 12- to 56-week study period, IOP and outflow facility in the transgenic mice were inversely correlated (r(2) = -0.702, P < 0.01). Collagen I alpha1 content was greater in 37- and 43-week-old transgenic mice than in age-matched wild-type control mice. Outflow facility is reduced in transgenic Col1a1(r/r) mice with IOP elevation. The inverse correlation of IOP elevation to facility reduction indicates that increased resistance in the aqueous outflow pathway contributes to ocular hypertension in Col1a1(r/r) mice. These mice may be useful as a model for open-angle glaucoma, as well as for assessing the relationship between collagen type I metabolism and aqueous outflow.

Constant pressure fluid infusion into rat neocortex from implantable microfluidic devices

Implantable electrode arrays capable of recording and stimulating neural activity with high spatial and temporal resolution will provide a foundation for future brain computer interface technology. Currently, their clinical impact has been curtailed by a general lack of functional stability, which can be attributed to the acute and chronic reactive tissue responses to devices implanted in the brain. Control of the tissue environment surrounding implanted devices through local drug delivery could significantly alter both the acute and chronic reactive responses, and thus enhance device stability. Here, we characterize pressure-mediated release of test compounds into rat cortex using an implantable microfluidic platform. A fixed volume of fluorescent cell marker cocktail was delivered using constant pressure infusion at reservoir backpressures of 0, 5 and 10 psi. Affected tissue volumes were imaged and analyzed using epifluorescence and confocal microscropies and quantitative image analysis techniques. The addressable tissue volume for the 5 and 10 psi infusions, defined by fluorescent staining with Hoescht 33342 dye, was significantly larger than the tissue volume addressed by simple diffusion (0 psi) and the tissue volume exhibiting insertion-related cell damage (stained by propidium iodide). The results demonstrate the potential for using constant pressure infusion to address relevant tissue volumes with appropriate pharmacologies to alleviate reactive biological responses around inserted neuroprosthetic devices.

Assessment of cerebrospinal fluid outflow conductance using an adaptive observer—experimental and clinical evaluation

Idiopathic normal pressure hydrocephalus (INPH) patients have a disturbance in the dynamics of the cerebrospinal fluid (CSF) system. The outflow conductance, C, of the CSF system has been suggested to be prognostic for positive outcome after treatment with a CSF shunt. All current methods for estimation of C have drawbacks; these include lack of information on the accuracy and relatively long investigation times. Thus, there is a need for improved methods. To accomplish this, the theoretical framework for a new adaptive observer (OBS) was developed which provides real-time estimation of C. The aim of this study was to evaluate the OBS method and to compare it with the constant pressure infusion (CPI) method. The OBS method was applied to data from infusion investigations performed with the CPI method. These consisted of repeated measurements on an experimental set-up and 30 patients with suspected INPH. There was no significant difference in C between the CPI and the OBS method for the experimental set-up. For the patients there was a significant difference, −0.84 ± 1.25 µl (s kPa)−1, mean ± SD (paired sample t-test, p < 0.05). However, such a difference is within clinically acceptable limits. This encourages further development of this new real-time approach for estimation of the outflow conductance.

Adaptive method for assessment of cerebrospinal fluid outflow conductance

Outflow conductance (C(out)) is important for predicting shunt responsiveness in patients with suspected idiopathic adult hydrocephalus syndrome (IAHS). C (out) is determined by performing an infusion test into the cerebrospinal fluid system, and the reliability of the test is dependent on the measurement time. The objective of this study was to develop an adaptive signal analysis method to reduce the investigation time, by taking the individual intracranial pressure variations of the patient into consideration. The method was evaluated on 28 patients with suspected IAHS. The results from full time investigations (60 min) were compared to the results of the new algorithm. Applying the new adaptive method resulted in a reduction of mean investigation time by 14.3 +/- 5.9 min (mean +/- SD), p<0.01. The reduction of reliability in the C(out) estimation was found clinically negligible. We thus recommend this adaptive method to be used when performing constant pressure infusion tests.

Assessment of cerebrospinal fluid outflow conductance using constant-pressure infusion—a method with real time estimation of reliability

The outflow conductance (Cout) of the cerebrospinal fluid (CSF) system is a parameter considered to be predictive in selection for hydrocephalus surgery. Cout can be determined through an infusion test. A new apparatus for performing infusion tests in a standardized and automated way was developed. The objective was to evaluate repetitiveness as well as to propose and evaluate a method for real time estimation of the reliability of individual Cout investigations. Repeated investigations were performed on an experimental model simulating the CSF system, and on 14 patients with hydrocephalus. ΔCout, calculated as the 95% confidence interval of Cout, was introduced as an estimate of the reliability of individual Cout investigations. On the model, no significant difference was found between ΔCout and the actual Cout variation in repeated investigations (p = 0.135). The correlation between the first and the second patient investigation was high (R = 0.99, p < 0.05), although there was a significant difference between the investigations (p < 0.05). The standard deviation of difference was 2.60 µl (s kPa)−1. The repetitiveness of Cout with the new apparatus was high, and ΔCout reflected the reliability of each investigation. This feature has to be taken into account in every individual case, before making a decision or performing research based on measurements of Cout in the future.

CSF Pulse Pressure and B Waves

Abstract Object. The appearance of numerous B waves during intracranial pressure (ICP) registration in patients with idiopathic adult hydrocephalus syndrome (IAHS) is considered to predict good outcome after shunt surgery. The aim of this study was to describe which physical parameters of the cerebrospinal fluid (CSF) system B-waves reflect and to find a method that could replace long-term B-wave analysis. Methods. Ten patients with IAHS were subjected to long-term registration of ICP and a lumbar constant-pressure infusion test. The B-wave presence, CSF outflow resistance (Rout), and relative pulse pressure coefficient (RPPC) were assessed using computerized analysis. The RPPC was introduced as a parameter reflecting the joint effect of elastance and pulsatory volume changes on ICP and was determined by relating ICP pulse amplitudes to mean ICP. Conclusions. The B-wave presence on ICP registration correlates strongly with RPPC (r = 0.91, p &lt; 0.001, 10 patients) but not with CSF Rout. This correlation indicates that B waves—like RPPC—primarily reflect the ability of the CSF system to reallocate and store liquid rather than absorb it. The RPPC-assessing lumbar short-term CSF pulse pressure method could replace the intracranial long-term B-wave analysis.

Brain energy metabolism and intracranial pressure in idiopathic adult hydrocephalus syndrome

Background: The symptoms in idiopathic adult hydrocephalus syndrome (IAHS) are consistent with pathology involving the periventricular white matter, presumably reflecting ischaemia and CSF hydrodynamic disturbance. Objective: To investigate whether a...

Cerebrospinal fluid pulse pressure method: a possible substitute for the examination of B waves

The appearance of numerous B waves during intracranial pressure (ICP) registration in patients with idiopathic adult hydrocephalus syndrome (IAHS) is considered to predict good outcome after shunt surgery. The aim of this study was to describe which physical parameters of the cerebrospinal fluid (CSF) system B-waves reflect and to find a method that could replace long-term B-wave analysis. Ten patients with IAHS were subjected to long-term registration of ICP and a lumbar constant-pressure infusion test. The B-wave presence, CSF outflow resistance (R(out)), and relative pulse pressure coefficient (RPPC) were assessed using computerized analysis. The RPPC was introduced as a parameter reflecting the joint effect of elastance and pulsatory volume changes on ICP and was determined by relating ICP pulse amplitudes to mean ICP. The B-wave presence on ICP registration correlates strongly with RPPC (r = 0.91, p < 0.001, 10 patients) but not with CSF R(out). This correlation indicates that B waves-like RPPC-primarily reflect the ability of the CSF system to reallocate and store liquid rather than absorb it. The RPPC-assessing lumbar short-term CSF pulse pressure method could replace the intracranial long-term B-wave analysis.

Nitric oxide and cyclic GMP enhance aqueous humor outflow facility in rabbits

Purpose. Nitric oxide (NO) may control intraocular pressure (IOP)-regulating mechanisms physiologically and in ocular diseases such as glaucoma. The aim of the present study was to clarify whether an increase in aqueous humor outflow facility could explain the IOP-lowering effect of the NO/cyclic GMP pathway we recently described. Methods. Test compounds were administered to anesthetized rabbits (New Zealand White, n = 6) intracamerally (5µl) in the following doses: nitrosocaptopril 12.3µg, captopril 10.9µg, sodium nitroprusside (SNP) 13.1µg and 8-Brc-GMP 22.3µg. Outflow facility (C) was determined by the two-level constant pressure infusion method. Outflow facility, C 1 and C 2, was measured at lower and higher pressure levels, respectively. Results. Outflow facility was increased after treatment with SNP (increase in C in the experimental eye as compared to the control eye C 1 80% and C 2 74%), nitrosocaptopril (C 1 69% and C 2 64%) and 8-Br-cGMP (C 1 35% and C 2 33%). Captopril had no effect on outflow facility (C 1 -12% and C 2 2%). Blood pressure was not affected by the drugs. Conclusions. We conclude that enhancement of outflow facility by nitrosocaptopril, SNP and 8-Br-cGMP, their second messenger derivative, at least partly explains the IOP-lowering effect of NO releasing compounds.

Myocardial protection with oxygenated esmolol cardioplegia during prolonged normothermic ischemia in the rat

Objective: We previously showed that arrest with multidose infusions of high-dose (1 mmol/L) esmolol (an ultra-short-acting β-blocker) in oxygenated Krebs-Henseleit buffer (esmolol cardioplegia) provided complete myocardial protection after 40 minutes of normothermic (37°C) global ischemia in isolated rat hearts. In this study we investigated the importance of oxygenation for protection with esmolol cardioplegia, compared it with that of St Thomas' Hospital cardioplegia, and determined the protective efficacy of multidose esmolol cardioplegia for extended ischemic durations. Methods: Isolated rat hearts (n = 6/group) were perfused in the Langendorff mode at constant pressure (75 mm Hg) with oxygenated Krebs-Henseleit bicarbonate buffer at 37°C. The first part of the first study had four groups: (i) multidose (every 15 minutes) oxygenated (95% oxygen/5% carbon dioxide) Krebs-Henseleit buffer during 60 minutes of global ischemia, (ii) multidose deoxygenated (95% nitrogen/5% carbon dioxide) Krebs-Henseleit buffer during 60 minutes of global ischemia, (iii) multidose oxygenated esmolol cardioplegia during 60 minutes of global ischemia, and (iv) multidose deoxygenated esmolol cardioplegia during 60 minutes of global ischemia. The second part of the first study had three groups: (v) multidose St Thomas' Hospital solution during 60 minutes of global ischemia, (vi) multidose oxygenated St Thomas' Hospital solution during 60 minutes of global ischemia, and (vii) multidose oxygenated esmolol cardioplegia during 60 minutes of global ischemia. In the second study, hearts were randomly assigned to 60, 75, 90, or 120 minutes of global ischemia and at each ischemic duration were subjected to multidose oxygenated constant flow or constant pressure infusion of (i) Krebs-Henseleit buffer (constant flow), (ii) Krebs-Henseleit buffer (constant pressure), (iii) esmolol cardioplegia (constant flow), or (iv) esmolol cardioplegia (constant pressure). All hearts were reperfused for 60 minutes, and recovery of function was measured. Results: Multidose infusion of oxygenated esmolol cardioplegia completely protected the hearts (97% ± 5%) after 60 minutes of 37°C global ischemia. Deoxygenated esmolol cardioplegia was significantly less protective (45% ± 8%). Oxygenation of St Thomas' Hospital solution did not alter its protective efficacy in this study (70% ± 4% vs 69% ± 7%). Infusion of esmolol cardioplegia at constant pressure provided complete protection for 60, 75, and 90 minutes (104% ± 5%, 95% ± 5%, and 95% ± 3%, respectively), whereas protection with constant-flow esmolol cardioplegic infusion was significantly decreased at ischemic durations longer than 60 minutes. This decrease in efficacy of constant-flow esmolol cardioplegia was associated with increasing coronary perfusion pressure leading to myocardial injury. Conclusions: Oxygenation of esmolol cardioplegia (Krebs-Henseleit buffer plus 1.0 mmol/L esmolol) was essential for optimal myocardial protection. Multidose infusion of oxygenated esmolol cardioplegia provided good myocardial protection during extended periods of normothermic ischemia. Esmolol cardioplegia may provide an efficacious alternative to hyperkalemia.J Thorac Cardiovasc Surg 2002;124:340-51