Judith Bellapart

Utility of transcranial Doppler ultrasound for the integrative assessment of cerebrovascular function

There is considerable utility in the use of transcranial Doppler ultrasound (TCD) to assess cerebrovascular function. The brain is unique in its high energy and oxygen demand but limited capacity for energy storage that necessitates an effective means of regional blood delivery. The relative low cost, ease-of-use, non-invasiveness, and excellent temporal resolution of TCD make it an ideal tool for the examination of cerebrovascular function in both research and clinical settings. TCD is an efficient tool to access blood velocities within the cerebral vessels, cerebral autoregulation, cerebrovascular reactivity to CO(2), and neurovascular coupling, in both physiological states and in pathological conditions such as stroke and head trauma. In this review, we provide: (1) an overview of TCD methodology with respect to other techniques; (2) a methodological synopsis of the cerebrovascular exam using TCD; (3) an overview of the physiological mechanisms involved in regulation of the cerebral blood flow; (4) the utility of TCD for assessment of cerebrovascular pathology; and (5) recommendations for the assessment of four critical and complimentary aspects of cerebrovascular function: intra-cranial blood flow velocity, cerebral autoregulation, cerebral reactivity, and neurovascular coupling. The integration of these regulatory mechanisms from an integrated systems perspective is discussed, and future research directions are explored.

Potential use of melatonin in sleep and delirium in the critically ill

Intensive care delirium is a well-recognized complication in critically ill patients. Delirium is an independent risk factor for death in the intensive care unit (ICU), leading to oversedation, increased duration of mechanical ventilation, and increased length of stay. Although there has not been a direct causal relationship shown between sleep deprivation and delirium, many studies have demonstrated that critically ill patients have an altered sleep pattern, abnormal levels of melatonin, and loss of circadian rhythms. Melatonin has a major role in control of circadian rhythm and sleep regulation and other effects on the immune system, neuroprotection, and oxidant/anti-oxidant activity. There has been interest in the use of exogenous melatonin as a measure to improve sleep. However, there are only a few studies of melatonin in ICU patients and these use heterogeneous methodologies. Therefore, it is not possible at this stage to make any clear recommendations regarding the clinical use of melatonin in this setting. There is a need for well-designed randomized controlled trials examining the role of melatonin in ICU.

Characterization of Neurological Injury in Transcatheter Aortic Valve Implantation How Clear Is the Picture

The application of transcatheter aortic valve implantation (TAVI) to high-surgical-risk and inoperable patients with severe aortic stenosis (AS) is gaining widespread acceptance with a burgeoning supportive evidence base.1 The benefits associated with the application of this technique, however, are mitigated by the occurrence of major, disabling stroke with associated increased mortality and early-reduced quality of life.2 Despite this, the risk/benefit ratio has been considered acceptable in appropriately selected patients given the outcomes of alternate management options in these high-risk and inoperable populations.3,4 The incidence of cerebrovascular events (CVEs) subsequent to TAVI exceeds that after any other cardiac intervention or valve surgery, most notably in the acute periprocedural period, diminishing over the subsequent 2 months.5 This elevated early risk reflects the increased incidence of ischemic stroke thought secondary to particulate emboli dislodged by the procedure itself or as a result of thromboembolism.6 In fact, cerebral embolism is a universal finding associated with these procedures.7 Most events, however, are subclinical or silent, with clinically apparent CVEs representing but the tip-of-the-iceberg. As a result of the difficulty ascertaining these subclinical events, the true association between TAVI and neurological injury is unknown and the harm potentially underestimated. This article aims to comprehensively review neurological injury in TAVI, with an emphasis on cerebrovascular disease. Evidence and current concepts regarding pathophysiological mechanisms, risk factors, and prognostic implications will be discussed and risk reduction strategies explored. CVEs post-TAVI are classified based on clinical severity as illustrated in Figure 1. Incomplete reporting and variable definitions of clinically apparent events and disregard of subclinical events have limited the true evaluation of CVEs associated with TAVI. Consequently, in 2011 the Valve Academic Research Consortium published a consensus report on standardized end point definitions, including stroke, which were expanded and refined in …

Transcranial Doppler Assessment of Cerebral Autoregulation

Cerebral autoregulation describes the process by which cerebral blood flow is maintained despite fluctuations in cerebral perfusion pressure. The assessment of cerebral autoregulation is a key to the optimisation of cerebral perfusion pressure in patients with brain injury. This review evaluates the current evidence for transcranial Doppler in the assessment of cerebral autoregulation. The study of cerebral autoregulation classically assesses changes in cerebral perfusion pressure secondary to changes in systemic blood pressure. It is defined static autoregulation if blood pressure changes are progressive, thereby allowing a steady-state autoregulatory response to be completed. For sudden changes in blood pressure, the autoregulatory response is defined as dynamic. The static and dynamic components of cerebral autoregulation have been approached using linear mathematical models (models based in direct correlations). Over the past decade, demonstration of the nonstationary (the property of changing over time or space) behaviour of cerebral autoregulation has emphasised the benefit obtained in using nonlinear statistical models (models based on changeable functions), suggesting that these methods may improve the mathematical representation of cerebral autoregulation. Despite the multiple determinants involved in cerebral autoregulation, it appears feasible to reliably assess cerebral autoregulation through the combination of linear and nonlinear methods. Nonlinear methods appear attractive in the research setting, but the challenge is how to adopt these methods to the clinical setting.

The silent and apparent neurological injury in transcatheter aortic valve implantation study (SANITY): concept, design and rationale.

BackgroundThe incidence of clinically apparent stroke in transcatheter aortic valve implantation (TAVI) exceeds that of any other procedure performed by interventional cardiologists and, in the index admission, occurs more than twice as frequently with TAVI than with surgical aortic valve replacement (SAVR). However, this represents only a small component of the vast burden of neurological injury that occurs during TAVI, with recent evidence suggesting that many strokes are clinically silent or only subtly apparent. Additionally, insult may manifest as slight neurocognitive dysfunction rather than overt neurological deficits. Characterisation of the incidence and underlying aetiology of these neurological events may lead to identification of currently unrecognised neuroprotective strategies.MethodsThe Silent and Apparent Neurological Injury in TAVI (SANITY) Study is a prospective, multicentre, observational study comparing the incidence of neurological injury after TAVI versus SAVR. It introduces an intensive, standardised, formal neurologic and neurocognitive disease assessment for all aortic valve recipients, regardless of intervention (SAVR, TAVI), valve-type (bioprosthetic, Edwards SAPIEN-XT) or access route (sternotomy, transfemoral, transapical or transaortic). Comprehensive monitoring of neurological insult will also be recorded to more fully define and compare the neurological burden of the procedures and identify targets for harm minimisation strategies.DiscussionThe SANITY study undertakes the most rigorous assessment of neurological injury reported in the literature to date. It attempts to accurately characterise the insult and sustained injury associated with both TAVI and SAVR in an attempt to advance understanding of this complication and associations thus allowing for improved patient selection and procedural modification.

Intraaortic Balloon Pump Counterpulsation and Cerebral Autoregulation: an observational study

BackgroundThe use of Intra-aortic counterpulsation is a well established supportive therapy for patients in cardiac failure or after cardiac surgery. Blood pressure variations induced by counterpulsation are transmitted to the cerebral arteries, challenging cerebral autoregulatory mechanisms in order to maintain a stable cerebral blood flow. This study aims to assess the effects on cerebral autoregulation and variability of cerebral blood flow due to intra-aortic balloon pump and inflation ratio weaning.MethodsCerebral blood flow was measured using transcranial Doppler, in a convenience sample of twenty patients requiring balloon counterpulsation for refractory cardiogenic shock (N = 7) or a single inotrope to maintain mean arterial pressure following an elective placement of an intra-aortic balloon pump for cardiac surgery (N = 13). Simultaneous blood pressure at the aortic root was recorded via the intra-aortic balloon pump. Cerebral blood flow velocities were recorded for six minute intervals at a 1:1 balloon inflation-ratio (augmentation of all cardiac beats) and during progressive reductions of the inflation-ratio to 1:3 (augmentation of one every third cardiac beat). Real time comparisons of peak cerebral blood flow velocities with systolic blood pressure were performed using cross-correlation analysis. The primary endpoint was assessment of cerebral autoregulation using the time delay between the peak signals for cerebral blood flow velocity and systolic blood pressure, according to established criteria. The variability of cerebral blood flow was also assessed using non-linear statistics.ResultsDuring the 1:1 inflation-ratio, the mean time delay between aortic blood pressure and cerebral blood flow was -0.016 seconds (95% CI: -0.023,-0.011); during 1:3 inflation-ratio mean time delay was significantly longer at -0.010 seconds (95% CI: -0.016, -0.004, P < 0.0001). Finally, upon return to a 1:1 inflation-ratio, time delays recovered to those measured at baseline. During inflation-ratio reduction, cerebral blood flow irregularities reduced over time, whilst cerebral blood flow variability at end-diastole decreased in patients with cardiogenic shock.ConclusionsWeaning counterpulsation from 1:1 to 1:3 inflation ratio leads to a progressive reduction in time delays between systolic blood pressure and peak cerebral blood flow velocities suggesting that although preserved, there is a significant delay in the establishment of cerebral autoregulatory mechanisms. In addition, cerebral blood flow irregularities (i.e. surrogate of flow adaptability) decrease and a loss of cerebral blood flow chaotic pattern occurs during the end-diastolic phase of each beat in patients with cardiogenic shock.

The effect of Ventricular Assist Devices on cerebral autoregulation: A preliminary study

BackgroundThe insertion of Ventricular Assist Devices is a common strategy for cardiovascular support in patients with refractory cardiogenic shock. This study sought to determine the impact of ventricular assist devices on the dynamic relationship between arterial blood pressure and cerebral blood flow velocity.MethodsA sample of 5 patients supported with a pulsatile ventricular assist device was compared with 5 control patients. Controls were matched for age, co-morbidities, current diagnosis and cardiac output state, to cases. Beat-to-beat recordings of mean arterial pressure and cerebral blood flow velocity, using transcranial Doppler were obtained. Transfer function analysis was performed on the lowpass filtered pressure and flow signals, to assess gain, phase and coherence of the relationship between mean arterial blood pressure and cerebral blood flow velocity. These parameters were derived from the very low frequency (0.02-0.07 Hz), low frequency (0.07-0.2 Hz) and high frequency (0.2-0.35 Hz).ResultsNo significant difference was found in gain and phase values between the two groups, but the low frequency coherence was significantly higher in cases compared with controls (mean ± SD: 0.65 ± 0.16 vs 0.38 ± 0.19, P = 0.04). The two cases with highest coherence (~0.8) also had much higher spectral power in mean arterial blood pressure.ConclusionsPulsatile ventricular assist devices affect the coherence but not the gain or phase of the cerebral pressure-flow relationship in the low frequency range; thus whether there was any significant disruption of cerebral autoregulation mechanism was not exactly clear. The augmentation of input pressure fluctuations might contribute in part to the higher coherence observed.

Pharmacokinetics of a novel dosing regimen of oral melatonin in critically ill patients

Abstract Background: Loss of circadian rhythms and reduced concentrations of endogenous melatonin are common in critically ill patients. After exogenous administration, supra-physiological concentrations in serum are only ephemeral, which may explain the absence of significant therapeutic effect on sleep. The aim of this study is to describe the pharmacokinetics of enteral melatonin in critically ill patients administered in a novel regimen aiming to simulate endogenous release. Methods: Thirteen patients in the recovery phase of critical illness were randomised to receive enteral melatonin or placebo. In the melatonin group, a total of 6 mg was administered as solution through their feeding tube, commencing with a 3 mg loading dose at 9 pm and six subsequent 0.5 mg doses hourly. The placebo was administered using a similar regimen. Serial blood samples were taken and measured using a validated chromatographic method. The concentration-time data for serum melatonin concentrations were described using non-linear mixed-effects modelling. Results: The observed concentrations in the melatonin patients were significantly higher than that observed in the placebo patients. The concentrations in the patients administered melatonin were also higher than endogenous melatonin concentrations previously reported in non-critically ill patients. The patients administered melatonin had a mean clearance, volume of distribution and absorption rate constant of melatonin was 55.2 L/h, 767 L and 0.76 h–1, respectively. Conclusions: Exogenous administration of melatonin with a loading dose of 3 mg followed by an hourly dose of 0.5 mg demonstrates good oral bioavailability and results in supra-physiological and sustained concentrations of serum melatonin during 12 h overnight.

Intracardiac echocardiography guided transeptal catheter injection of microspheres for assessment of cerebral microcirculation in experimental models.

The use of microspheres for the determination of regional microvascular blood flow (RMBF) has previously used different approaches. This study presents for the first time the intracardiac injection of microspheres using transeptal puncture under intracardiac echocardiography guidance. Five Merino sheep were instrumented and cardiovascularly supported according to local guidelines. Two catheter sheaths into the internal jugular vein facilitated the introduction of an intracardiac probe and transeptal catheter, respectively. Five million colour coded microspheres were injected into the left atrium via this catheter. After euthanasia the brain was used as proof of principle and the endpoint for determination of microcirculation at different time points. Homogeneous allocation of microspheres to different regions of the brain was found over time. Alternate slices from both hemispheres showed the following flow ranges: for slice 02; 0.57–1.02 mL/min/g, slice 04; 0.45–1.42 mL/min/g, slice 06; 0.35–1.87 mL/min/g, slice 08; 0.46–1.77 mL/min/g, slice 10; 0.34–1.28 mL/min/g. A mixed effect regression model demonstrated that the confidence interval did include zero suggesting that the apparent variability intra- and intersubject was not statistically significant, supporting the stability and reproducibility of the injection technique. This study demonstrates the feasibility of the transeptal injection of microspheres, showing a homogeneous distribution of blood flow through the brain unchanged over time and has established a new interventional model for the measurement of RMBF in ovine models.

Intraoperative Cerebral Perfusion Disturbances During Transcatheter Aortic Valve Replacement

BACKGROUND Transcatheter aortic valve replacement entails profound and unavoidable hemodynamic perturbations that may contribute to the neurological injury associated with the procedure. METHODS Thirty-one patients were monitored with cerebral oximetry as a surrogate marker of perfusion while undergoing transcatheter aortic valve replacement via a transfemoral approach under general anesthesia to detect intraoperative hypoperfusion insult. Serial neurologic, cognitive, and cerebral magnetic resonance imaging assessments were administered to objectively quantify perioperative neurologic injury and ascertain any association with significant cerebral oximetry disturbances. RESULTS Cerebral oximetry reacted promptly to rapid ventricular pacing with significant cerebral desaturation, relative to baseline, of greater than 12% and greater than 20% in 12 of 31 (68%) and 9 of 31 (29%) patients, respectively; or to an absolute measurement of less than 50% in 10 of 31 (33%) patients. Hyperemia occurred immediately following relief of aortic stenosis exceeding baseline by greater than 10% and greater than 20% in 14 of 31 (45%) and 5 of 31 (16%) patients. Postoperative cognitive dysfunction was evident in 3 of 31 (10%) patients and new magnetic resonance imaging-defined ischemic lesions were seen in 17 of 28 (61%) patients. No patient experienced clinically apparent stroke. CONCLUSIONS Cerebral oximetry reacted promptly to rapid ventricular pacing with significant desaturation and hyperemia a common occurrence. However, no association between this intraoperative insult and objective neurologic injury was detected.