Pressure Autoregulation Research Articles

Abstract 063: Impaired Myogenic Response of the Af-art Contributes to the Increased Susceptibility to Hypertension and Diabetic Induced Renal Disease in Milan Normotensive Rats

Previous studies have indicated that Milan normotensive (MNS) rats are more susceptible to the development of hypertension and diabetic induced renal injury than Milan hypertensive (MHS) rats, but the genes and pathways involved are unknown. MNS also develop proteinuria and chronic kidney disease (CKD) as they age, whereas hypertensive MHS do not. We compared the myogenic response of isolated perfused Af-Art and autoregulation of RBF and glomerular capillary pressure in 6-9 week old MNS and MHS rats. The diameter of Af-Art of MNS rats increased from 14.0 ± 0.5 to 14.2 ± 0.6 μm (n=6) when elevation in perfusion pressure from 60 to 120 mmHg. In contrast, the diameter of the Af-Art decreased significantly from 14.3 ± 0.5 to 11.5 ± 0.6 μm (n=6) in MHS rats. In vivo, RBF increased by 26% when RPP was increased from 100 to 140 mmHg in MNS rats but it remained unchanged in MHS rats. Glomerular capillary pressure rose by 11 mmHg in MNS following the elevation in RPP from 100 to 140 mm Hg but not in MHS rats. Protein excretion increased from 8.9 ± 0.7 to 158.2 ± 23.1 mg/day in MNS rats as the increased in age from 3 to 9 months of age but it did not increase in MHS rats. In com-parison to other strains susceptible and resistant to CKD, we noticed that both MNS and Fawn Hooded hypertensive (FHH) rats that do not autoregulate RBF also share the same sequence variant in the Adducin 3 gene. We performed a genetic complementation study to test whether this mutation might be responsible for the impaired myogenic response in MNS. The diameter of the Af-Art isolated from an F1 cross of MNS &FHH rats increased from 17.2 ± 0.9 to 18.5 ± 0.9 μM (n=5) in response to increase in perfusion pressure and RBF was not efficiently autoregulated in these animals. These data indicate a mutation in Adducin 3 which impairs myogenic response of the Af-Art and increased transmission of pressure to the glomerular capillaries may contribute to the development of CKD in MNS rats similar to what is seen in FHH rats.

Assessment of developmental cardiotoxic effects in chick embryonic cardiomyocyte micromass culture and the mouse embryonic stem cell differentiation model of novel phytochemicals

The heart and the vascular system are vulnerable to toxins, which may be environmental (e.g., ambient pollution, heavy metals, plant-based), iatrogenic (e.g., chemotherapy, diphenhydramine, complementary or alternative medicines), or secondary to ingestion of social drugs (e.g., anabolics, energy drinks, illicit drugs). Exposure to toxins may cause structural damage to the cardiovascular system and/or functional disturbances such as decreased cardiac output, electrical conduction system abnormalities, and disruption of systemic arterial pressure autoregulation. Successful treatment necessitates recognition of the cardiovascular effects of the toxin; removal of the toxic agent; and, in some cases, treatment with a known antidote.

Impaired cerebral autoregulation and brain injury in newborns with hypoxic-ischemic encephalopathy treated with hypothermia.

Impaired cerebral autoregulation may contribute to secondary injury in newborns with hypoxic-ischemic encephalopathy (HIE). Continuous, noninvasive assessment of cerebral pressure autoregulation can be achieved with bedside near-infrared spectroscopy (NIRS) and systemic mean arterial blood pressure (MAP) monitoring. This study aimed to evaluate whether impaired cerebral autoregulation measured by NIRS-MAP monitoring during therapeutic hypothermia and rewarming relates to outcome in 36 newborns with HIE. Spectral coherence analysis between NIRS and MAP was used to quantify changes in the duration [pressure passivity index (PPI)] and magnitude (gain) of cerebral autoregulatory impairment. Higher PPI in both cerebral hemispheres and gain in the right hemisphere were associated with neonatal adverse outcomes [death or detectable brain injury by magnetic resonance imaging (MRI), P < 0.001]. NIRS-MAP monitoring of cerebral autoregulation can provide an ongoing physiological biomarker that may help direct care in perinatal brain injury.

Epidural analgesia and perioperative kidney function after major liver resection.

Epidural analgesia (EDA) is a common analgesia regimen in liver resection, and is accompanied by sympathicolysis, peripheral vasodilatation and hypotension in the context of deliberate intraoperative low central venous pressure. This associated fall in mean arterial pressure may compromise renal blood pressure autoregulation and lead to acute kidney injury (AKI). This study investigated whether EDA is a risk factor for postoperative AKI after liver surgery. The incidence of AKI was investigated retrospectively in patients who underwent liver resection with or without EDA between 2002 and 2012. Univariable and multivariable analyses were performed including recognized preoperative and intraoperative predictors of posthepatectomy renal failure. A series of 1153 patients was investigated. AKI occurred in 8·2 per cent of patients and was associated with increased morbidity (71 versus 47·3 per cent; P = 0·003) and mortality (21 versus 0·3 per cent; P < 0·001) rates. The incidence of AKI was significantly higher in the EDA group (10·1 versus 3·7 per cent; P = 0·003). Although there was no significant difference in the incidence of AKI between patients undergoing minor hepatectomy with or without EDA (5·2 versus 2·7 per cent; P = 0·421), a substantial difference in AKI rates occurred in patients undergoing major hepatectomy (13·8 versus 5·0 per cent; P = 0·025). In multivariable analysis, EDA remained an independent risk factor for AKI after hepatectomy (P = 0·040). EDA may be a risk factor for postoperative AKI after major hepatectomy.

Normal perfusion pressure breakthrough theory: a reappraisal after 35 years.

The intrinsic ability of the brain to maintain constant cerebral blood flow (CBF) is known as cerebral pressure autoregulation. This ability protects the brain against cerebral ischemia and hyperemia within a certain range of blood pressures. The normal perfusion pressure breakthrough (NPPB) theory described by Spetzler in 1978 was adopted to explain the edema and hemorrhage that sometimes occur after resection of brain arteriovenous malformations (AVMs). The underlying pathophysiology of edema and hemorrhage after AVM resection still remains controversial. Over the last three decades, advances in neuroimaging, CBF, and cerebral perfusion pressure (CPP) measurement have both favored and contradicted the NBBP theory. At the same time, other theories have been proposed, including the occlusive hyperemia theory. We believe that both theories are related and complementary and that they both explain changes in hemodynamics after AVM resection. The purpose of this work is to review the current status of the NBBP theory 35 years after its original description.

Intracranial Pressure and Cerebrovascular Autoregulation in Pediatric Critical Illness

Protecting the brain in vulnerable infants and children with critical illness involving the brain is a central aspect of pediatric intensive care and neurocritical care. Collectively, illness-induced derangements in intracranial pressure, circulatory homeostasis, and pressure autoregulation are all fundamental in informing bedside management. Therefore, this review provides an understanding of these entities and a physiological approach to bedside care and monitoring.

Endothelial nitric oxide synthase mediates the cerebrovascular effects of erythropoietin in traumatic brain injury.

Background: Erythropoietin (Epo) improves post-traumatic cerebral blood flow (CBF), pressure autoregulation, and vascular reactivity to l-arginine. This study examines the dependence of these cerebral hemodynamic effects of Epo on nitric oxide generated by endothelial nitric oxide synthase (eNOS).Methods: Using laser Doppler flow imaging, CBF was monitored in wild-type (WT) and eNOS-deficient mice undergoing controlled cortical impact followed by administration of Epo (5000 U/kg) or normal saline.Results: Cerebral blood flow decreased in all groups post-injury with the greatest reductions occurring at the impact site. Epo administration resulted in significantly higher CBF in the peri-contusional sites in the WT mice [70.2 ± 3.35% in Epo-treated compared to 53 ± 3.3% of baseline in saline-treated mice (p < 0.0001)], but no effect was seen in the eNOS-deficient mice. No CBF differences were found at the core impact site where CBF dropped to 20–25% of baseline in all groups.Conclusion: These differences between eNOS-deficient and WT mice indicate that the Epo mediated improvement in CBF in traumatic brain injury is eNOS dependent.

Monitoring of cerebral autoregulation.

Pressure autoregulation is an important hemodynamic mechanism that protects the brain against inappropriate fluctuations in cerebral blood flow in the face of changing cerebral perfusion pressure (CPP). Static autoregulation represents how far cerebrovascular resistance changes when CPP varies, and dynamic autoregulation represents how fast these changes happen. Both have been monitored in the setting of neurocritical care to aid prognostication and contribute to individualizing CPP targets in patients. Failure of autoregulation is associated with a worse outcome in various acute neurological diseases. Several studies have used transcranial Doppler ultrasound, intracranial pressure (ICP with vascular reactivity as surrogate measure of autoregulation), and near-infrared spectroscopy to continuously monitor the impact of spontaneous fluctuations in CPP on cerebrovascular physiology and to calculate derived variables of autoregulatory efficiency. Many patients who undergo such monitoring demonstrate a range of CPP in which autoregulatory efficiency is optimal. Management of patients at or near this optimal level of CPP is associated with better outcomes in traumatic brain injury. Many of these studies have utilized the concept of the pressure reactivity index, a correlation coefficient between ICP and mean arterial pressure. While further studies are needed, these data suggest that monitoring of autoregulation could aid prognostication and may help identify optimal CPP levels in individual patients.

The Upper Limit of Cerebral Blood Flow Autoregulation Is Decreased With Elevations in Intracranial Pressure

The upper limit of cerebrovascular pressure autoregulation (ULA) is inadequately characterized. To delineate the ULA in an infant swine model. Neonatal piglets with sham surgery (n = 9), interventricular fluid infusion (INF) (n = 10), controlled cortical impact (CCI) (n = 10), or CCI + INF (n = 11) had intracranial pressure monitoring and bilateral cortical laser-Doppler flowmetry recordings during arterial hypertension to lethality using an aortic balloon catheter. An increase of red cell flux as a function of cerebral perfusion pressure was determined by piecewise linear regression, and static rates of autoregulation were determined above and below this inflection. The ULA was rendered as the first instance of an upward deflection of Doppler flux causing a static rate of autoregulation decrease greater than 0.5. ULA was identified in 55% of piglets after sham surgery, 70% after INF, 70% after CCI, and 91% after CCI with INF (P = .36). When identified, the median (interquartile range) ULA was as follows: sham group, 102 mm Hg (97-109 mm Hg); INF group, 75 mm Hg (52-84 mm Hg); CCI group, 81 mm Hg (69-101 mm Hg); and CCI + INF group, 61 mm Hg (52-57 mm Hg) (P = .01). In post hoc analysis, both groups with interventricular INF had significantly lower ULA than that observed in the sham group. Neonatal piglets without intracranial pathology tolerated acute hypertension with minimal perturbation of cerebral blood flow. Piglets with acutely increased intracranial pressure with or without trauma demonstrated loss of autoregulation when subjected to arterial hypertension.

A conceptual approach to managing severe traumatic brain injury in a time of uncertainty.

Current controversies in the literature suggest that a reassessment of the current management of severe traumatic brain injury (sTBI) is necessary. This article presents a conceptual framework toward individualizing sTBI treatment with respect to targeting thresholds and strategies on the basis of known physiologic processes and available monitors. Intracranial pressure (ICP) is modeled as an epiphenomenon of cerebral compliance and herniation tendency, as well as cerebral ischemia. By combining serial neurological examinations, imaging studies, and ICP measurements (values, trends, and area-under-the-curve calculations) over time, evidence can be accrued on the necessity of maintaining ICP at a given threshold in the realm of physical changes in the brain. Similarly, by collecting and trending clinical, imaging, and monitoring data on the status of cerebral blood flow, the balance of oxygen consumption and delivery, and the status of cerebral static pressure autoregulation, and analyzing them with respect to measured parameters, such as blood pressure, ICP, and cerebral perfusion pressure, one can attempt to fine-tune these variables as well. Such individualization of management optimizes the possibility of successfully treating demonstrated pathophysiological processes while avoiding unnecessary interventions and treatment toxicity. Monitor values must not be seen as targets but rather as indicators of targetable pathology.

The ontogeny of cerebrovascular pressure autoregulation in premature infants.

To quantify cerebrovascular autoregulation as a function of gestational age (GA) and across the phases of the cardiac cycle. The present study is a hypothesis-generating re-analysis of previously published data. Premature infants (n=179) with a GA range of 23 to 33 weeks were monitored with umbilical artery catheters and transcranial Doppler insonation of the middle cerebral artery for 1-h sessions over the first week of life. Autoregulation was quantified by three methods, as a moving correlation coefficient between: (1) systolic arterial blood pressure (ABP) and systolic cerebral blood flow (CBF) velocity (Sx); (2) mean ABP and mean CBF velocity (Mx); and (3) diastolic ABP and diastolic CBF velocity (Dx). Comparisons of individual and cohort cerebrovascular pressure autoregulation were made across GA for each aspect of the cardiac cycle. Systolic, mean and diastolic ABP increased with GA (r=0.3, 0.4 and 0.4; P<0.0001). Systolic CBF velocity was pressure-passive in infants with the lowest GA, and Sx decreased with advancing GA (r=-0.3; P<0.001), indicating increased capacity for cerebral autoregulation during systole during development. By contrast, Dx was elevated, indicating dysautoregulation, in all subjects and showed minimal change with advancing GA (r=-0.06; P=0.05). Multivariate analysis confirmed that both GA (P<0.001) and 'effective cerebral perfusion pressure' (ABP minus critical closing pressure (CrCP); P<0.01) were associated with Sx. Premature infants have low and usually pressure-passive diastolic CBF velocity. By contrast, the regulation of systolic CBF velocity by pressure autoregulation developed in this cohort between 23 and 33 weeks GA. Elevated effective cerebral perfusion pressure derived from the CrCP was associated with dysautoregulation.

Role of 20-HETE in the impaired myogenic and TGF responses of the Af-Art of Dahl salt-sensitive rats

The present study examined whether 20-HETE production is reduced in the renal vasculature and whether this impairs myogenic or tubuloglomerular feedback (TGF) responses of the afferent arteriole (Af-Art). The production of 20-HETE was 73% lower in renal microvessels of Dahl salt-sensitive rats (SS) rats than in SS.5(BN) rats, in which chromosome 5 from the Brown Norway (BN) rat containing the CYP4A genes was transferred into the SS genetic background. The luminal diameter of the Af-Art decreased by 14.7 ± 1.5% in SS.5(BN) rats when the perfusion pressure was increased from 60 to 120 mmHg, but it remained unaltered in SS rats. Administration of an adenosine type 1 receptor agonist (CCPA, 1 μM) reduced the diameter of the Af-Art in the SS.5(BN) rats by 44 ± 2%, whereas the diameter of the Af-Art of SS rats was unaltered. Autoregulation of renal blood flow (RBF) and glomerular capillary pressure (PGC) was significantly impaired in SS rats but was intact in SS.5(BN) rats. Administration of a 20-HETE synthesis inhibitor, HET0016 (1 μM), completely blocked the myogenic and adenosine responses in the Af-Art and autoregulation of RBF and PGC in SS.5(BN) rats, but it had no effect in SS rats. These data indicate that a deficiency in the formation of 20-HETE in renal microvessels impairs the reactivity of the Af-Art of SS rats and likely contributes to the development of hypertension induced renal injury.

Headache, Blurred Vision and Seizure in Hemodialysis Patient

A 53-year-old man with severe headache, blurred vision, and single generalized tonic-clonic seizure during hemodialysis presented to the emergency department (ED). On admission to the ED, the patient was in postictal state and measured at the following levels: blood pressure 203/113 mmHg, pulse rate 80/ min, respiratory rate of 17/min, body temperature of 36,5 °C, peripheral O2 saturation of 96%, and GCS of 9. Neurologic examination revealed no focal deficit. Bedside finger-stick glucose test was detected at 59 mg/dl. ECG of the patient was in normal sinus rhythm and revealed no ischemic sign. Intravenous 25 g glucose was administered to the patient and control of finger stick glucose test was detected at 281 mg/dl. However, the mental status of the patient did not improve. The patient had complaints of headache and blurred vision for at least one day according to family members. The patient had chronic renal failure and hemodialysis for 1.5 years and was on eye drops for glaucoma. On fundoscopic examination, acute pathology was not detected. Noncontrast enhanced cranial computerized tomography (CT) was performed and CT revealed no acute pathology. Laboratory tests of the patient showed creatinin 5.8 and urea 79 mg/dl and no electrolyte imbalance, leucositosis, or thrombocytopenia. GCS of the patient was detected at 14 without focal deficits at two hours after admission to the ED. Contrast enhanced magnetic resonance imaging (MRI) of cranial and diffusion MRI was also performed (Figure 1). Figure 1 The patient's flair (a) and T2-weighted (b, c) cranial MRI images. DIAGNOSIS: Posterior Reversible Encephalopathy Syndrome MRI revealed hyperintensity compatible with vasogenic edema on FLAIR and t2 weighted sequences in the bilateral occipital, parietal, and frontal region (Figure 2). After magnetic resonance imaging, the patient had generalized tonic-clonic seizures. Reduction of the patient's blood pressure from 203/113 mmHg to 179/95 mmHg did not cause any clinical improvement. Loading dose of valproic acid was given intravenously to the patient. The patient was intubated due to uncontrolled seizures and shallow breathing and was admitted to intensive care unit. The patient died after 6 days due to intracranial hemorrhage. Figure 2 MRI of cranial showed hyperintensity on FLAIR (a) and t2 weighted sequences (b, c) in the posterior, frontal, occipital ve parietal region. Posterior reversible encephalopathy syndrome (PRES), initially described in 1996 by Hinchey et al., is a clinical-neuroradiological entity characterized by headache, vomiting, altered mental status, blurred vision, and seizures.[1] This syndrome is most commonly encountered in association with acute hypertension, preeclampsia or eclampsia, autoimmune diseases, renal failure, post-transplantation, sepsis, shock, and exposure to immunosuppressants.2, 3, 4 Although the lesions in PRES are due to vasogenic edema, the mechanism responsible for the imaging appearance remains unclear and controversial.1, 2 There are two main hypotheses: 1) Cerebral hypoperfusion related to disruption of the blood-brain barrier results in vasogenic edema (e.g. eclampsia/preeclampsia, cyclosporine toxicity, and infection/sepsis/septic shock), and 2) Cerebral hyperperfusion results in vasogenic edema by exceeding the capacity for autoregulation of perfusion pressure (e.g. acute hypertension).[5] In our patient, we considered that hypertension induced by renal failure led to regional dysautoregulation, consequently causing hypoperfusion. Radiologic findings of PRES are best seen on MRI of the brain. The typical imaging findings of PRES are most apparent as hyperintensity on FLAIR and t2 weighted sequences of cranial MRI in the parietooccipital and posterior, frontal, cortical, and subcortical white matter and are reversible with appropriate management.4, 5 The treatment is based in the management or withdrawal of the triggering factor. Hypoglycemia should be looked for routinely and corrected. Antiepileptic treatment should be initiated at the emergency department. Control of hypertensive emergency is an important part of the symptomatic management.1, 5 Mortality has been reported in 15% of patients. Cause of death in PRES may be due to the underlying disease, increased cerebral edema, and intracerebral hemorrhage.[6] The early recognition and treatment of PRES is important to prevent permanent neurological sequelae. Awareness of the clinical and radiographic findings of acute PRES is essential to avoid misdiagnosis and treatment delay.

Pressure autoregulation monitoring and cerebral perfusion pressure target recommendation in patients with severe traumatic brain injury based on minute-by-minute monitoring data.

In severe traumatic brain injury, a universal target for cerebral perfusion pressure (CPP) has been abandoned. Attempts to identify a dynamic CPP target based on the patient's cerebrovascular autoregulatory capacity have been promising so far. Bedside monitoring of pressure autoregulatory capacity has become possible by a number of methods, Czosnyka's pressure reactivity index (PRx) being the most frequently used. The PRx is calculated as the moving correlation coefficient between 40 consecutive 5-second averages of intracranial pressure (ICP) and mean arterial blood pressure (MABP) values. Plotting PRx against CPP produces a U-shaped curve in roughly two-thirds of monitoring time, with the bottom of this curve representing a CPP range corresponding with optimal autoregulatory capacity (CPPopt). In retrospective series, keeping CPP close to CPPopt corresponded with better outcomes. Monitoring of PRx requires high-frequency signal processing. The aim of the present study is to investigate how the processing of the information on cerebrovascular pressure reactivity that can be obtained from routine minute-by-minute ICP and MABP data can be enhanced to enable CPPopt recommendations that do not differ from those obtained by the PRx method, show the same associations with outcome, and can be generated in more than two-thirds of monitoring time. The low-frequency autoregulation index (LAx) was defined as the moving minute-by-minute ICP/MABP correlation coefficient calculated over time intervals varying from 3 to 120 minutes. The CPPopt calculation was based on LAx-CPP plots and done for time windows between 1 and 24 hours and for each LAx type. The resulting matrix of CPPopts were then averaged in a weighted manner, with the weight based on the goodness of fit of a U-shape and the lower value of the LAx corresponding to the U-bottom, to result in a final CPPopt recommendation. The association between actual CPP/CPPopt and outcome was assessed in the multicenter Brain Monitoring with Information Technology Research Group (BrainIT) database (n = 180). In the Leuven-Tübingen database (60-Hz waveform data, n = 21), LAx- and PRx-based CPPopts were compared. In the BrainIT database, CPPopt recommendations were generated in 95% of monitoring time. Actual CPP being close to LAx-based CPPopt was associated with increased survival. In a multivariate model using the Corticosteroid Randomization After Significant Head Injury (CRASH) model as covariates, the average absolute difference between actual CPP and CPPopt was independently associated with increased mortality. In the high-frequency data set no significant difference was observed between PRx-based and LAx-based CPPopts. The new method issued a CPPopt recommendation in 97% of monitoring time, as opposed to 44% for PRx-based CPPopt. Minute-by-minute ICP/MABP data contain relevant information for autoregulation monitoring. In this study, the authors' new method based on minute-by-minute data resolution allowed for CPPopt calculation in nearly the entire monitoring time. This will facilitate the use of pressure reactivity monitoring in all ICUs.

Loss of cerebral blood flow autoregulation and assessment of the critical cerebral perfusion pressure at high ICP (674.14)

Objective: To study the effect of increased intracranial pressure (ICP) on the critical cerebral perfusion pressure (CPP) and its relationship to the loss of cerebral blood flow (CBF) autoregulation.Background: Earlier studies showed that the critical cerebral perfusion pressure (CPP) fell from 60 to 30 mmHg as determined by decreasing arterial pressure as opposed to increasing intracranial pressure (ICP), respectively. We hypothesized that the decrease in the critical CPP at high ICP was due to microvascular shunting resulting in a pathological higher CBF at a lower CPP.Methods: Using two‐photon laser scanning microscopy (2PLSM) we measured microvascular (3‐25 m diam) flow velocity in rat cerebral cortex by increasing ICP or decreasing arterial blood pressure. In separate studies we also increased ICP progressively while monitoring the capillary (CAP) to microvascular shunt (MVS) ratio to study the effect of increasing ICP on the development of microvascular shunts.Results: The reduction in critical CPP with increasing ICP was due to increased microvascular shunting resulting in a sustained CBF at a lower critical CPP, which therefore decreased the critical CPP from 60 to 30 mmHg and associated with increased microvascular shunting. A progressive increase in ICP resulted in a parallel increase in the ratio of MVS/CAP ratio.Conclusion: The decrease in critical CPP obtained when ICP is increased as opposed to decreasing arterial pressure is due to the opening of microvascular shunts thereby creating low resistance microvascular conduits through the brain. The progressive increase in MVS with increasing ICP leads to the loss of CBF autoregulation, which differs from that observed at high CO2.Grant Funding Source: NIH RO3 NS051639;AHA 2BGIA11730011

Improvement of mild retinopathy in type 2 diabetic patients correlates with narrowing of retinal arterioles. A prospective observational study

Diabetic retinopathy is one of the leading causes of blindness in the Western world. The disease is characterized by morphological lesions secondary to disturbances in retinal blood flow assumed to be related to disturbances in retinal autoregulation. However, there is a need for elucidating the relation between disturbances in diameter regulation of retinal vessels and the development of diabetic retinopathy in longitudinal studies. Sixty-four patients with type 2 diabetes mellitus were subjected to measurement of pressure autoregulation of retinal arterioles using the Dynamic Vessel Analyzer (DVA) and measurement of retinal thickness using OCT scanning, and after a mean of 6.8 years, 42 of the patients were re-examined. The vascular response was compared in patients in whom retinopathy had disappeared, was unchanged, or had worsened. At baseline, hemoglobin A1c (HbA1c) was significantly higher in the patients who would later experience worsening of diabetic retinopathy than in the other groups, but had been reduced at the follow-up examination. During the follow-up period, the resting diameter of retinal arterioles decreased significantly in the patients who experienced improvement in diabetic retinopathy but was unchanged in the other groups, whereas both the diameter response of retinal arterioles to isometric exercise and retinal thickness increased non-significantly with worsening of retinopathy. The development of diabetic retinopathy is related to the diameter of retinal arterioles. Future clinical intervention studies should aim at investigating the effects of normalizing arteriolar diameters in diabetic retinopathy.

Nonstationary multivariate modeling of cerebral autoregulation during resting state and hypercapnia (1184.10)

We examined the time‐varying characteristics of cerebral autoregulation and hemodynamics during resting state and hypercapnia by using recursively estimated multivariate (two‐input) models which quantify the dynamic effects of mean arterial blood pressure (ABP) and end‐tidal CO2 tension (PETCO2) on middle cerebral artery blood flow velocity (CBFV). Experimental measurements of spontaneous variations of these signals were obtained from thirteen healthy subjects under normal, free‐breathing conditions. Beat‐to‐beat values of ABP and CBFV, as well as breath‐to‐breath values of PETCO2 were also obtained in 8 female subjects during baseline and sustained euoxic hypercapnia. The multiple‐input, single‐output linear models used to describe the relationship between ABP, PETCO2 and CBFV were based on the Laguerre expansion technique. In order to account for the different dynamics associated with each input, the model parameters were updated using a recursive least squares scheme with constant and adaptive multiple forgetting factors. The results reveal the presence of nonstationarities that are more pronounced in the very low frequency range. By comparing one‐input (MABP) and two‐input (MABP and PETCO2) models, our results point out that the incorporation of PETCO2 as an additional input yields less time‐varying estimates of dynamic pressure autoregulation obtained from single‐input (MABP‐CBFV) models, suggesting the important role of PETCO2 and the possible shortcomings of assessing dynamic autoregulation using such models.

An optimal frequency range for assessing the pressure reactivity index in patients with traumatic brain injury

The objective of this study was to identify the optimal frequency range for computing the pressure reactivity index (PRx). PRx is a clinical method for assessing cerebral pressure autoregulation based on the correlation of spontaneous variations of arterial blood pressure (ABP) and intracranial pressure (ICP). Our hypothesis was that optimizing the methodology for computing PRx in this way could produce a more stable, reliable and clinically useful index of autoregulation status. The patients studied were a series of 131 traumatic brain injury patients. Pressure reactivity indices were computed in various frequency bands during the first 4 days following injury using bandpass filtering of the input ABP and ICP signals. Patient outcome was assessed using the extended Glasgow Outcome Scale (GOSe). The optimization criterion was the strength of the correlation with GOSe of the mean index value over the first 4 days following injury. Stability of the indices was measured as the mean absolute deviation of the minute by minute index value from 30-min moving averages. The optimal index frequency range for prediction of outcome was identified as 0.018-0.067 Hz (oscillations with periods from 55 to 15 s). The index based on this frequency range correlated with GOSe with ρ=-0.46 compared to -0.41 for standard PRx, and reduced the 30-min variation by 23%.

Nonstationary multivariate modeling of cerebral autoregulation during hypercapnia

We examined the time-varying characteristics of cerebral autoregulation and hemodynamics during a step hypercapnic stimulus by using recursively estimated multivariate (two-input) models which quantify the dynamic effects of mean arterial blood pressure (ABP) and end-tidal CO2 tension (PETCO2) on middle cerebral artery blood flow velocity (CBFV). Beat-to-beat values of ABP and CBFV, as well as breath-to-breath values of PETCO2 during baseline and sustained euoxic hypercapnia were obtained in 8 female subjects. The multiple-input, single-output models used were based on the Laguerre expansion technique, and their parameters were updated using recursive least squares with multiple forgetting factors. The results reveal the presence of nonstationarities that confirm previously reported effects of hypercapnia on autoregulation, i.e. a decrease in the MABP phase lead, and suggest that the incorporation of PETCO2 as an additional model input yields less time-varying estimates of dynamic pressure autoregulation obtained from single-input (ABP–CBFV) models.

Theoretical Analysis of Vascular Regulatory Mechanisms Contributing to Retinal Blood Flow Autoregulation

To study whether impaired retinal autoregulation is a risk factor for glaucoma, the relationship between vascular regulatory mechanisms and glaucoma progression needs to be investigated. In this study, a vascular wall mechanics model is used to predict the relative importance of regulatory mechanisms in achieving retinal autoregulation. Resistance vessels are assumed to respond to changes in pressure, shear stress, carbon dioxide (CO2), and the downstream metabolic state communicated via conducted responses. Model parameters governing wall tension are fit to pressure and diameter data from porcine retinal arterioles. The autoregulation pressure range for control and elevated levels of IOP is predicted. The factor by which flow changes as the blood pressure exiting the central retinal artery is varied between 28 and 40 mm Hg is used to indicate the degree of autoregulation (1 indicates perfect autoregulation). In the presence of only the myogenic response mechanism, the factor is 2.06. In the presence of the myogenic and CO2 responses, the factor is 1.22. The combination of myogenic, shear, CO2, and metabolic responses yields the best autoregulation (factor of 1.10). Model results are compared with flow and pressure data from multiple patient studies, and the combined effects of the metabolic and CO2 responses are predicted to be critical for achieving retinal autoregulation. When IOP is elevated, the model predicts a decrease in the autoregulation range toward low perfusion pressure, which is consistent with observations that glaucoma is associated with decreased perfusion pressure.