Critical Closing Pressure Research Articles

Genesis of Antibiotic Resistance (AR) LXXI: Turbulence Modeling of Hemodynamics in Simplified Severe Sepsis Protocol‐2 (SSSP‐2) ‐ NCT01663701: Activated E‐Oligomer Complex Elicit Rapid Leucocyte‐Platelets‐Erythrocytes (LPE) Aggregation and Occlusion of Capillary by Impairing Energy Cascading and Starling Forces (Net Filtration Pressure)

Here we present a rationale for the fluid overload-induced accelerated LPE aggregates to occlude the arterial end of the capillary bed resulting in critical closing pressure (CCP). It is known that native purine/pyrimidine receptors have yet to be purified to homogeneity and characterization of receptor-ligand kinetics. Recombinant purine/pyrimidine receptors knockout genotype mice are not embryonic lethal, while its characterization in vivo is dependent of multifactorial factors of epigenetic origin namely (post-translational modification, lineage-specific developmental and hemodynamic heterogeneity; ex: meaning age, gender, morphological attribute(s) of the platelet(s), viscosity, and hematocrit). Every attempt to purify Ca2+ /Mg2+ ecto-ATPase (EC 3.6.1.15) to homogeneity, showed co-purification of CD36, PMID: 9925363); cell-CAM105 (PMID: 1637321 PMCID: PMC1132742, PMID: 8387753, PMID: 1985902); mmCGM1a (PMID: 1633107); PECAM-1,(PMID: 19558578); CBATP, (PMID: 9218468); BgP (PMID: 2527235); caldesmon (PMID: 1930128); NCAM (PMID: 8262246, PMID: 7804134); Ig gene superfamily (PMID: 2141577), Cadherin (PMID: 8489264); and chicken gizzard ecto-ATPase amino acid similarity to CD39 (PMID: 8995405). The fact remain that native CD39 has never been tested for mM [Ca2+] or [Mg2+] ecto-ATPase (EC 3.6.1.15) or E-NTPDase (NTPDase1) (EC 3.6.1.6) (PMID: 1672348, PMID: 1721639). Further, neither CAM nor CD39 knockout genotype is embryonic lethal. Experimental evidence shows that differential regulation of CD38, integrin's (CD11), and CD39 in the liver allograft, implicit of interdependency in host immune response (PMID: 31511354). We have obtained evidence that the phylogenetic tree analysis, neighbor-joining tree without distance correlation among CD36, CD38, CD39, CAM, P2Y/P2, and corona #2, receptors. The cladogram show a marked evolutionary conservancy between CD39 & P2X, CD36 & Corona virus-2, CAM & P2Y &cadherin, with a possibility of existence as an oligomer (ECpx). Taken together, it is hypothesized that nucleotide receptors (P2Y/P2X), CAM, and ectonucleotidases family of a protein complex (E-Cpx) could possibly exist as a membrane-bound oligomer. Subsequent activation of E-Cpx on LPE, aggregation, and rapid occlusion of the capillary by forming T-S waves, 3D distortion of T-S waves, in phase arrays of hairpin K-type vortices, turbulent spot formation, merging of turbulent spot formation, without energy cascading among the LPE aggregates and adherence to the damaged endothelial cells at the arterial end of the capillary, Refer Fig: 3.4, 3.5, 3.6 3.8; (ISBN: 978-0-13-127498-3), a robust anaerobic /aerobic persister (s) colonization eliciting CCP. In turn, a progressive hypotensive state induced endothelial damage and abrupt collapse of interstitial space would result in CCP ensuing hypoxia. Such a scenario may have been the cause for exacerbated mortality among the sepsis cohort in NCT01663701-SSSP-2 (PMID: 28973227).

Critical Closing Pressure by Diffuse Correlation Spectroscopy in a Neonatal Piglet Model.

The critical closing pressure (CrCP) of the cerebral vasculature is the arterial blood pressure (ABP) at which cerebral blood flow (CBF) ceases. Because the ABP of preterm infants is low and close to the CrCP, there is often no CBF during diastole. Thus, estimation of CrCP may become clinically relevant in preterm neonates. Transcranial Doppler (TCD) ultrasound has been used to estimate CrCP in preterm infants. Diffuse correlation spectroscopy (DCS) is a continuous, noninvasive optical technique that measures microvascular CBF. Our objective was to compare and validate CrCP measured by DCS versus TCD ultrasound. Hemorrhagic shock was induced in 13 neonatal piglets, and CBF was measured continuously by both modalities. CrCP was calculated using a model of cerebrovascular impedance, and CrCP determined by the two modalities showed good correlation by linear regression, median r 2 = 0.8 (interquartile range (IQR) 0.71-0.87), and Bland-Altman analysis showed a median bias of -3.5 (IQR -4.6 to -0.28). This is the first comparison of CrCP determined by DCS versus TCD ultrasound in a neonatal piglet model of hemorrhagic shock. The difference in CrCP between the two modalities may be due to differences in vasomotor tone within the microvasculature of the cerebral arterioles versus the macrovasculature of a major cerebral artery.

Cerebral Critical Closing Pressure in Concomitant Traumatic Brain Injury and Intracranial Hematomas.

The results of the treatment of 90 patients with severe to moderate сTBI were studied (male/female - 49:41). The average age was 34.2±14.4years. Depending on the presence of ICH, patients were divided into two groups. All patients were subjected to transcranial Doppler of the both middle cerebral arteries, and evaluation of mean arterial pressure (MAP). Based on data obtained, the CrCPs were calculated. Significance was preset to p<0.05. The mean CrCP values in each group appeared to be significantly higher than a referral value (р<0.05). The mean CrCP values in the perifocal zone of removed hematoma were significantly higher than in TBI patients without ICH (р=0.015 and р=0.048, respectively). Analysis of CrCP values in various types of ICH showed no statistically significant differences (р>0.05). The CrCP significantly differs in the groups of TBI patients with and without ICH. The comparability of the groups in respect to the concomitant injury structure proves that the revealed CrCP changes result from the traumatic compression of the brain.

Cerebrovascular Consequences of Elevated Intracranial Pressure After Traumatic Brain Injury.

We compared various descriptors of cerebral hemodynamics in 517 patients with traumatic brain injury (TBI) who had, on average, elevated (>23mmHg) or normal (<15mmHg) intracranial pressure (ICP). In a subsample of 193 of those patients, transcranial Doppler ultrasound (TCD) recordings were made. Arterial blood pressure (ABP), cerebral blood flow velocity (CBFV), cerebral autoregulation indices based on TCD (the mean flow index (Mx; the coefficient of correlation between the the cerebral perfusion pressure CPP and flow velocity) and the autoregulation index (ARI)), and the pressure reactivity index (PRx) were compared between groups. We also analyzed the TCD-based cerebral blood flow (CBF) index (diastolic CBFV/mean CBFV), the spectral pulsatility index (sPI), and the critical closing pressure (CrCP). Finally, we also looked at brain tissue oxygenation (cerebral oxygen partial tension (PbtO2)) in 109 patients. The mean cerebral perfusion pressure (CPP) was lower in the group with elevated ICP (p<0.01), despite a higher mean arterial pressure (MAP) (p<0.005) and worse autoregulation (as assessed with the Mx, ARI, and PRx indices), greater CrCP, a lower CBF index, and a higher sPI (all with p values of <0.001). Neither the mean CBFV nor PbtO2 reached significant differences between groups. Mortality in the group with elevated ICP was almost three times greater than that in the group with normal ICP (45% versus 17%). Elevated ICP affects cerebral autoregulation. When autoregulation is not working properly, the brain is exposed to ischemic insults whenever CPP falls.

Impacts of a Pressure Challenge on Cerebral Critical Closing Pressure and Effective Cerebral Perfusion Pressure in Patients with Traumatic Brain Injury.

Cerebral critical closing pressure (CrCP) comprises intracranial pressure (ICP) and arteriolar wall tension (WT). It is the arterial blood pressure (ABP) at which small vessels close and circulation stops. We hypothesized that the increase in WT secondary to a systemic hypertensive challenge would lead to an increase in CrCP and that the "effective" cerebral perfusion pressure (CPPeff; calculated as ABP-CrCP) would give more complete information than the "conventional" cerebral perfusion pressure (CPP; calculated as ABP-ICP). This study aimed to compare CrCP, CPP, and CPPeff changes during a hypertensive challenge in patients with a severe traumatic brain injury. Data on ABP, ICP, and cerebral blood flow velocity, measured by transcranial Doppler ultrasound, were acquired simultaneously for 30 min both basally and during a hypertensive challenge. An impedance-based CrCP model was used. The following values are expressed as median (interquartile range). There were 11 patients, aged 29 (14) years. CPP increased from 73 (17) to 102 (26) mmHg (P≤0.001). ICP did not change. CrCP changed from 23 (11) to 27 (10) mmHg (P≤0.001). WT increased from 7 (5) to 11 (7) mmHg (P ˂ 0.005). CPPeff changed less than CPP. The CPP change was greater than the CPPeff change, mainly because CrCP increased simultaneously with the WT increase as a result of the autoregulatory response. CPPeff provides information about the real driving force generating blood movement.

Sex differences in the autonomic and cerebrovascular responses to upright tilt.

Sex differences in the regulation of autonomic and cerebrovascular responses to orthostatic stress remain unclear. The objectives of this study were to concurrently investigate autonomic control and cerebrovascular resistance indices, including critical closing pressure (CrCP) and resistance area product (RAP), during upright tilt in men and women. In 13 women and 14 men (18-29years), ECG, non-invasive blood pressure, middle cerebral artery blood velocity, and end-tidal CO2 (ETCO2) were continuously measured during supine rest and 70° tilt. Heart rate variability (HRV), cardiovagal baroreflex sensitivity (cBRS), and transfer function parameters of dynamic cerebral autoregulation were calculated. Compared to supine, upright tilt increased the low frequency-to-high frequency ratio of HRV in men only (P=0.044), and decreased cBRS more in women (P=0.001). Cerebrovascular resistance index (CVRi) increased during tilt only in men (sex-by-time interaction: P=0.004). RAP was lower in women throughout tilt (main effect of sex: P=0.022). CrCP decreased during tilt in both sexes (main effect of time: P<0.001). Normalizing to ETCO2 did not alter the effect of tilt on cerebrovascular resistance. Men displayed a greater increase of sympathetic indices and CVRi during tilt while women had greater parasympathetic withdrawal. We hypothesize that increased sympathetic activity in men may drive sex differences in the cerebrovascular response to upright posture.

The critical closing pressure contribution to dynamic cerebral autoregulation in humans: influence of arterial partial pressure of CO2.

Dynamic cerebral autoregulation (CA) is often expressed by the mean arterial blood pressure (MAP)-cerebral blood flow (CBF) relationship, with little attention given to the dynamic relationship between MAP and cerebrovascular resistance (CVR). In CBF velocity (CBFV) recordings with transcranial Doppler, evidence demonstrates that CVR should be replaced by a combination of a resistance-area product (RAP) with a critical closing pressure (CrCP) parameter, the blood pressure value where CBFV reaches zero due to vessels collapsing. Transfer function analysis of the MAP-CBFV relationship can be extended to the MAP-RAP and MAP-CrCP relationships, to assess their contribution to the dynamic CA response. During normocapnia, both RAP and CrCP make a significant contribution to explaining the MAP-CBFV relationship. Hypercapnia, a surrogate state of depressed CA, leads to marked changes in dynamic CA, that are entirely explained by the CrCP response, without further contribution from RAP in comparison with normocapnia. Dynamic cerebral autoregulation (CA) is manifested by changes in the diameter of intra-cerebral vessels, which control cerebrovascular resistance (CVR). We investigated the contribution of critical closing pressure (CrCP), an important determinant of CVR, to explain the cerebral blood flow (CBF) response to a sudden change in mean arterial blood pressure (MAP). In 76 healthy subjects (age range 21-70years, 36 women), recordings of MAP (Finometer), CBF velocity (CBFV; transcranial Doppler ultrasound), end-tidal CO2 (capnography) and heart rate (ECG) were performed for 5min at rest (normocapnia) and during hypercapnia induced by breathing 5% CO2 in air. CrCP and the resistance-area product (RAP) were obtained for each cardiac cycle and their dynamic response to a step change in MAP was calculated by means of transfer function analysis. The recovery of the CBFV response, following a step change in MAP, was mainly due to the contribution of RAP during both breathing conditions. However, CrCP made a highly significant contribution during normocapnia (P<0.0001) and was the sole determinant of changes in the CBFV response, resulting from hypercapnia, which led to a reduction in the autoregulation index from 5.70±1.58 (normocapnia) to 4.14±2.05 (hypercapnia; P<0.0001). In conclusion, CrCP makes a very significant contribution to the dynamic CBFV response to changes in MAP and plays a major role in explaining the deterioration of dynamic CA induced by hypercapnia. Further studies are needed to assess the relevance of CrCP contribution in physiological and clinical studies.

Cerebral Hemodynamics Are Not Affected by the Size of the Patent Ductus Arteriosus

Introduction: Although patent ductus arteriosus (PDA) has been implicated to play a role in the development of cerebral ischemia and intraventricular hemorrhage (IVH) through a cerebral steal phenomenon, there is conflicting data on the impact of PDA size on cerebral blood flow (CBF). Cerebral autoregulation is the brain’s innate protective mechanism to maintain constant CBF despite changes in blood pressure, and it is unclear if it is influenced by PDA hemodynamics. Objective: To delineate the relationship between PDA size and CBF velocity (CBFv) in premature infants. Methods: 113 premature infants born at 23–29 weeks’ gestation had echocardiograms performed during the first week after birth to evaluate for PDA. The infants were divided into 3 groups according to PDA size: none-to-small, moderate, or large. All infants had continuous recordings of umbilical artery blood pressure (ABP) and CBFv during the first week after birth. Critical closing pressure (CrCP) was calculated from ABP and CBFv tracings. Diastolic closing margin (DCM), defined as diastolic blood pressure minus CrCP, was calculated as a marker for the risk of developing IVH. Results: Infants with a large PDA (n = 16) had the lowest ABP across all phases of the cardiac cycle (systole [p = 0.003], mean [p = 0.005], and diastole [p = 0.012]) compared to infants with a moderate (n = 19) or none-to-small PDA (n = 78). Despite blood pressure being different, systolic, mean, and diastolic CBFv were not different across groups. Cerebral autoregulation, as measured during systole, was intact regardless of the PDA size. CrCP and DCM were also not different across groups. Conclusions: In this cohort, CBFv and cerebral autoregulation during systole were not influenced by PDA size. Intact cerebral autoregulation may play a role in maintaining CBFv regardless of PDA size and differences in ABP.

Genesis of Antibiotic Resistance (AR) LIV: “Confounder Effect”: Sepsis with Comorbidity ‐ An Indomitable Turbulence Modeling Consignment

To delineate the hemodynamic basis of exacerbated mortality rate in Early Resuscitation Protocol (ERP) for sepsis with comorbidity, here we present the results of a comparative simulation analysis of “Net Filtration Pressure” (NFP) at homeostasis (Laminar) vs Sepsis with comorbidity (Laminar‐transition‐turbulence‐collapse) in the contexture of Fahraeus – Lindqvist Effect (FLE), plasma skimming, swirling &amp; sigma effect and its role in Critical Closing Pressure (CCP) (Transition to Turbulence consequent collapse). At homeostasis, Starling Forces: NFP= (BHP+IFOP) − (BCOP+IFHP)] at the arterial end, net pressure is outward at 10 mmHg (filtration) and at the venous end, net pressure is inward at −9 mmHg (reabsorption). [Starling equation: Jv = Kf ([Pc − Pi] − σ [πc − πi]), where Jv is the net fluid movement between compartments and [Pc − Pi] − σ [πc − πi] is the net driving force, Pc is the capillary hydrostatic pressure, Pi is the interstitial hydrostatic pressure, πc is the capillary oncotic pressure, πi is the interstitial oncotic pressure, Kf is the filtration coefficient – a proportionality constant, and σ is the reflection coefficient (Fig 3a ‐ Ind J Ana. 2019; 63(1):6). The ERP, NCT01663701 (JAMA.2017;318(13):1233) based sepsis cohort data are sepsis‐ suspected infection plus ≥2 (SIRS), MAP &lt; 65mmHg, sepsis‐induced hypotension 89mmHg/55mmHg (~ 2 liters of bolus administered within 1 hr of enrollment, edema, hypoxemia, hypoperfusion, tachypnea, and respiratory failure due to a lack of ventilator support. For simulation of Starling forces, the impact of FLE, plasma skimming effect, sigma effect (blood flow is not continuum), loss and/or dysfunctional glycocalyx (Crit Care. 2019;23(1):259) (substituting πg = 0mmHg (null &amp; void) instead of πi, revised starling equation: Jv = Kf ([Pc − Pi] − σ [πc − πg] (Br J Ana. 2012 Mar;108(3):384) induce sustained leakage &amp; hemoconcentration cellular aggregates (RBC, WBC, thrombocytes) – large eddies, CCP derived based on Law of La Place, and swirling effect (variable Schmidt number) were considered. Based on the simulation analysis, the prediction of NFP at arterial and venous end would be ~ +10mmHg favoring fluid filtration into the interstitial space causing edema, intra vascular hypotension, hypoperfusion and rheological factors predicted to be PI &lt;1.05%, SpO2≦95%, PaO2 of 55 mmHg, SaO2&lt;90%, SvO2&lt;90%, StO2 below normal, DO2I below normal range, FiO2 &lt;0.21(21%), PaCO2&lt; 38 – 42 mmHg and PaO2/FiO2 &lt;200mmHg. If numerous thrombi are forming simultaneously (equivalent to large‐eddy: Laminar to turbulence transition, then coagulation factors and platelets can become depleted (plasma skimming) causing hemorrhage (septic embolism tend to break up but not in this instance since glycocalyx is null and void) analogous to large‐eddy cascading in to smaller eddies (Fully Turbulent flow). Absence of cascading would likely to obstruct the blood flow and induce ischemia‐induced infarcts in the capillary bed. Though the “Counter‐Inflammatory response syndrome” would likely to mitigate thrombosis, plasma skimming/sigma effect on the cellular aggregates, would lead to thrombosis (large eddies) and CCP.Support or Funding InformationSupported by professional development funds provided by SWTJC to Subburaj Kannan

Genesis of Antibiotic Resistance (AR) LII: Laminar to Turbulent flow transition triggered by “Physiological Shunt” Induce Hypoxia (Anoxia?) Augmenting AR Clinical Persister (S) (ARCP)

The mechanism(s) of biosimilar induced adverse clinical events in inflammatory disorders and its impact on the evolution of ARCP inherent on the incidence of morbidity and the mortality rate remains to be substantiated. A biosimilar to Neulasta (Pegfilgrastim) administered for myelosuppressive chemotherapy has been reported to have a clinically significant incidence of febrile neutropenia. Similar modalities with other biosimilars have also been presented (Int J Hematol.2010 Dec;92(5):765–8; Case Rep Nephrol Urol. 2012 Jul–Dec; 2(2): 165–171); The contraindication for the original formulation is reported to be acute respiratory distress syndrome (ARDS), Glomerulonephritis (GN), Leukocytosis, and Capillary Leak Syndrome (CLS). As per the differential diagnosis for the febrile neutropenia could be of acute respiratory distress syndrome (ARDS) with or without pulmonary edema. Under such clinical presentation tissue hypoxia (Stagnant anoxia (Hypoxicischemic injury), Anoxic anoxia?) with or without “Sweet Syndrome” with an unknown etiology waning the ventilation‐perfusion coupling in patients undergoing chemo/radiation therapy for clinical oncology modalities (J. Clin. Med. 2019, 8(2), 143). CLS has been ascribed with reversible plasma extravasation and loss of net filtration pressure gradient (NFP) in the microcirculation which is analogous to sepsis, septic shock, septicemia impelled hypotension possibly (hypovolemic shock?) with the end result of multiple organ failure (Kidney International, 2017: 92:1, 37). It is hypothesized that such clinical presentation of ensuing hypoxia (plausibly systemic anoxia?) causing VA/Q (VA = alveolar ventilation; Q= blood flow) is below normal which is about 2% of cardiac output (CO) referred to as “shunted blood” (deoxygenated). The total amount of “shunted blood” in the capillary bed – microcirculation per minute is “Physiological shunt” with dysregulated net filtration pressure (NFP) potentially a state of critical closing pressure (CCP) ebb the capillary exchange. Under such physiological sate declining perfusion pressure / perfusion index (PI) and tissue pO2 causing progressive hypoxia and/or anoxia. It is suggested that hypoxia serve as a trigger for generating an adverse pressure gradient impacting the expression pattern of antibiotic resistance gene(s) repertoire (ARCP). Altered ARGR expression profile is known to cause selection pressure on ARCP. In particular, ensuing anaerobic milieu in vivo, engender selection pressure on anaerobic AR pathogens including Gram negative rods, Gram‐positive cocci, Gram‐positive spore‐ and non‐spore‐forming bacilli and Gram‐negative cocci resulting in an aberrant expression pattern of ARGR. Taken together, such the clinical presentation would likely to lead to patients treated with biosimilar(s) become unresponsive to antibiotic therapy leading to an emergence of ARCP impairing the ability for clinical stratification and a defined point of clinical intervention preempting an instant CCP subsequent emergence Antibiotic Resistance Pandemic (ARP).Support or Funding InformationSupported by professional development funds by SWTJC to Subburaj Kannan

Critical closing pressure during experimental intracranial hypertension: comparison of three calculation methods

ABSTRACT Objectives: The critical closing pressure (CrCP) defines arterial blood pressure below which cerebral arteries collapse. It represents a clinically relevant parameter for the estimation of cerebrovascular tone. Although there are few methods to assess CrCP, there is no consensus which of them estimates this parameter most accurately. The aim of present retrospective, experimental study was to compare three methods of CrCP estimation: conventional Aaslid’s formula and methods based on the cerebrovascular impedance: the established continuous flow forward (CFF) and a new pulsatile flow forward (PFF) model. Methods: The effects of the following physiological manoeuvres on the CrCP were studied in New Zealand white rabbits: lumbar infusion of Hartmann’s solution to induce mild intracranial hypertension, sympathetic blockade to induce arterial hypotension, and modulation of respiratory tidal volume to induce hypocapnia or hypercapnia. Results: During intracranial hypertension, all CrCP estimates were significantly higher than at baseline, decreased with decreasing ABP and increased with gradual hypocapnia. During hypercapnia, all CrCP estimates were significantly decreased but only in the case of CrCPA the negative, non-physiological values were observed (16% of the cases). The Bland–Altman analysis revealed that a good agreement between each impedance method and Aaslid’s method deteriorated significantly in the low range of the average numerical value of the estimates. Discussion: Our results confirm the limited usage of Aaslid’s formula for the calculation of CrCP. Although both impedance methods seem to be equivalent, the fact that PFF model better describes cerebrovascular hemodynamic allows the recommendation of this model for the calculation of CrCP.

Non-invasive estimation of cerebral perfusion pressure using transcranial Doppler ultrasonography in children with severe traumatic brain injury.

ObjectiveTo identify if cerebral perfusion pressure (CPP) can be non-invasively estimated by either of two methods calculated using transcranial Doppler ultrasound (TCD) parameters.DesignRetrospective review of previously prospectively gathered data.SettingPediatric intensive care unit in a tertiary care referral hospital.PatientsTwenty-three children with severe traumatic brain injury (TBI) and invasive intracranial pressure (ICP) monitoring in place.InterventionsTCD evaluation of the middle cerebral arteries was performed daily. CPP at the time of the TCD examination was recorded. For method 1, estimated cerebral perfusion pressure (CPPe) was calculated as: CPPe = MAP × (diastolic flow (Vd)/mean flow (Vm)) + 14. For method 2, critical closing pressure (CrCP) was identified as the intercept point on the x-axis of the linear regression line of blood pressure and flow velocity parameters. CrCP/CPPe was then calculated as MAP-CrCP.Measurements and main resultsOne hundred eight paired measurements were available. Using patient averaged data, correlation between CPP and CPPe was significant (r = 0.78, p = < 0.001). However, on Bland-Altman plots, bias was 3.7 mmHg with 95% limits of agreement of − 17 to + 25 for CPPe. Using patient averaged data, correlation between CPP and CrCP/CPPe was significant (r = 0.59, p = < 0.001), but again bias was high at 11 mmHg with wide 95% limits of agreement of − 15 to + 38 mmHg.ConclusionsCPPe and CrCP/CPPe do not have clinical value to estimate the absolute CPP in pediatric patients with TBI.

Measurement of Critical Closing Pressure (Pcrit) During Drug-Induced Sleep Endoscopy (DISE)

Measurement of Critical Closing Pressure (Pcrit) During Drug-Induced Sleep Endoscopy (DISE)

Determining differences between critical closing pressure and resistance-area product: responses of the healthy young and old to hypocapnia.

Healthy ageing has been associated with lower cerebral blood flow velocities (CBFVs); however, the behaviour of hemodynamic parameters associated with cerebrovascular tone (critical closing pressure, CrCP) and cerebrovascular resistance (resistance-area product, RAP) remains unclear. Specifically, evidence supports ageing being associated with greater cerebrovascular tone and resistance during exercise with elevated CrCP and RAP in older individuals at rest and during exercise. Comprehensive hemodynamic assessment of CrCP and RAP during hyperventilation-induced hypocapnia in two distinct age groups (young ≤ 49 and old > 50) has not been described. CBFV in the middle cerebral artery (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were recorded in 104 healthy individuals (43 young [age 33.8 (9.3) years], 61 old [age 64.1 (8.5) years]) during a minimum of 60s of metronome-driven hyperventilation-induced hypocapnia. Autoregulation index was calculated as a function of time, using a moving window autoregressive-moving average model. CBFV was reduced in response to age (p < 0.0001) and hypocapnia (p = 0.023) (young 57.3 (14.4) vs. 44.9cms-1 (11.1), old 51.7 (12.9) vs. 37.8cms-1 (9.6)). Critical closing pressure (CrCP) increased significantly in response to hypocapnia (young 37.6 (18.5) vs. 39.7mmHg (16.0), old 33.9 (13.5) vs. 39.3mmHg (11.4); p < 0.0001). Resistance-area product was increased in response to age (p = 0.001) and hypocapnia (p = 0.004) (young 1.02 (0.40) vs. 1.09mmHgcms-1 (11.07), old 1.16 (0.34) vs. 1.34mmHgcms-1 (0.39)). RAP and not CrCP mediates differences in cerebrovascular resistance responses to hypocapnia between the healthy young and old individuals.

Abstract TP490: Analysis of Cerebral Hemodynamics and Interaction of 0.1-hz Oscillations of Hemodynamic Parameters in Postural Orthostatic Tachycardia Syndrome

Background: POTS is defined as heart rate increase of more than 30 beats within the first minutes of standing upright. The aim of this study was to analyze causal connectivity among cerebral hemodynamic changes in head-up tilt test (HUT) of POTS using TCD and Finometer between normal and POTS. Methods: Normal (n=20) and POTS (n=20) were enrolled to monitor the beat-to-beat arterial blood pressure (ABP) using Finometer and Cerebral blood flow velocity (CBFV) in right MCA using TCD. Subjects rested in supine position for 5 min and subjects were abruptly positioned at 80 o from horizontal on a tilt table. Beat-to-Beat ABP pulse intervals (HR) were calculated using foot points of each pulse. We divided HUT into early tilt stage (ETS) and late tilt stage (LTS). We analyzed several variables including ABP, HR, systolic CBFV, critical closing pressure (CrCP) between normal and POTS. To analyze effects of intrinsic spontaneous oscillations known as ‘Mayer waves’, in ABP, CBFV, and HR, the frequency component from 0.06Hz to 0.15Hz was extracted using FIR filter. Then Granger causality was calculated to analyze the changes of causal connectivity of each signal by HUT effects. Results: CrCP during HUT in POTS was significantly larger than normal. Compared with normal, POTS showed significantly increased causal flow of ABP◊HR and HR◊CBFV during ETS and causal flow of CBFV◊ABP during LTS. In paired t-test of state change from supine to ETS, while causal flow of ABP◊CBFV in normal was significantly increased during supine, causal flow of ABP◊CBFV and ABP◊HR in POTS were significantly increased during ETS. In paired t-test of state change from ETS to LTS, while causal flow of HR◊CBFV in normal was significantly increased during ETS, causal flow of ABP◊CBFV and HR◊CBFV in POTS were significantly decreased during LTS. In POTS, causal density of HR◊BP during spine was significantly increased and causal density of HR◊CBFV and BP◊CBFV were significantly decreased during LTS. Discussion: This study showed that increased CrCP during HUT is related with increased coupling of 0.1-Hz oscillations from ABP to HR and from HR to CBFV in POTS. Increased CrCP during HUT may cause the excessive blood pooling and the low effective circulating volume in the central vasculature and can explain symptom of POTS.

Dynamic Cerebral Autoregulation and Critical Closing Pressure in Experimental Human Endotoxemia and Sepsis Patients

Background: To investigate the influence of systemic inflammation on dynamic cerebral autoregulation and vascular tone during experimental human endotoxemia and sepsis. Methods: Healthy volunteers received 3 h continuous infusion of LPS (c-LPS, 4 ng/kg, n = 11, Clinicaltrials.gov NCT02922673) or a bolus of LPS (b-LPS, 2 ng/kg, n = 8, Clinicaltrials.gov NCT02675868) and 10 sepsis patients were studied. Mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV) were monitored simultaneously. Cerebral autoregulation was analysed by transfer function analysis (TFA). Critical closing pressure (CrCP) was estimated as a measure of cerebral vascular tone. Results: c-LPS resulted in a more pronounced and prolonged plasma cytokine response compared with b-LPS. MAP decreased from 89 ± 3 to 75 ± 2 mmHg (p < 0.05) and from 91 ± 2 to 77 ± 3 mmHg (p < 0.001) in the c-LPS and b-LPS groups, respectively. MAP in sepsis patients was 65 ± 4 mmHg. TFA in both LPS groups showed no significant changes over time in coherence, gain and phase. Phase in sepsis patients was lower compared with both LPS groups (7 (2 to 33) [median (interquartile range)] in sepsis versus 57 (36 to 74) in the c-LPS (p = 0.02) and 53 (43 to 64) degrees in the b-LPS group (p = 0.01)). CrCP decreased from 49 ± 2 to 41 ± 2 mmHg (p = 0.16) in the c-LPS and from 50 ± 2 to 42 ± 2 mmHg in the b-LPS group (p < 0.01), and was 36 ± 2 mmHg in sepsis patients. Conclusions: Dynamic cerebral autoregulation is impaired in sepsis patients, but remains intact during experimental human endotoxemia. CrCP decreased during endotoxemia and was low in sepsis, reflecting decreased vascular tone. This indicates activation of a cerebrovascular adaptive process, also during experimental endotoxemia with intact cerebral autoregulation. Trial Registration: Clinicaltrials.gov NCT02922673 and Clinicaltrials.gov NCT02675868

Cerebrovascular assessment of patients undergoing shoulder surgery in beach chair position using a multiparameter transcranial Doppler approach

Although the beach-chair position (BCP) is widely used during shoulder surgery, it has been reported to associate with a reduction in cerebral blood flow, oxygenation, and risk of brain ischaemia. We assessed cerebral haemodynamics using a multiparameter transcranial Doppler-derived approach in patients undergoing shoulder surgery. 23 anaesthetised patients (propofol (2 mg/kg)) without history of neurologic pathology undergoing elective shoulder surgery were included. Arterial blood pressure (ABP, monitored with a finger-cuff plethysmograph calibrated at the auditory meatus level) and cerebral blood flow velocity (FV, monitored in the middle cerebral artery) were recorded in supine and in BCP. All subjects underwent interscalene block ipsilateral to the side of FV measurement. We evaluated non-invasive intracranial pressure (nICP) and cerebral perfusion pressure (nCPP) calculated with a black-box mathematical model; critical closing pressure (CrCP); diastolic closing margin (DCM—pressure reserve available to avoid diastolic flow cessation); cerebral autoregulation index (Mxa); pulsatility index (PI). Significant changes occured for DCM [mean decrease of 6.43 mm Hg (p = 0.01)] and PI [mean increase of 0.11 (p = 0.05)]. ABP, FV, nICP, nCPP and CrCP showed a decreasing trend. Cerebral autoregulation was dysfunctional (Mxa > 0.3) and PI deviated from normal ranges (PI > 0.8) in both phases. ABP and nCPP values were low (< 60 mm Hg) in both phases. Changes between phases did not result in CrCP reaching diastolic ABP, therefore DCM did not reach critical values (≤ 0 mm Hg). BCP resulted in significant cerebral haemodynamic changes. If left untreated, reduction in cerebral blood flow may result in brain ischaemia and post-operative neurologic deficit.

Neurovascular coupling response to cognitive examination in healthy controls: a multivariate analysis.

Cognitive testing with transcranial Doppler ultrasonography (TCD) has been used to assess neurovascular coupling (NVC), but few studies address its multiple contributions. Subcomponent analysis considers the relative myogenic (resistance area product, RAP) and metabolic (critical closing pressure (CrCP)) contributors. The aim of this study was to investigate the changes in subcomponents that occur with cognitive stimulation with the Addenbrooke's Cognitive Examination (ACE‐III) in healthy controls. Healthy volunteers underwent continuous recording of bilateral TCD, heart rate (HR, three‐lead ECG), end‐tidal CO 2 (ETCO 2, capnography), and mean arterial pressure (MAP, Finometer). The study comprised a 5‐min baseline recording, followed by all 20 paradigms from the ACE‐III. The cerebral blood flow velocity (CBFv) response was decomposed into the relative contributions (subcomponents); V BP (MAP), V CrCP (CrCP), and V RAP (RAP). Data are presented as peak population normalized mean changes from baseline, and median area under the curve (AUC). Forty bilateral datasets were obtained (27 female, 37 right hand dominant). V BP increased at task initiation in all paradigms but differed between tasks (range (SD): 4.06 (8.92)–16.04 (12.23) %, P < 0.05). HR, but not ETCO 2, also differed significantly (P < 0.05). Changes in V RAP reflected changes in MAP, but in some paradigms atypical responses were seen. V CrCP AUC varied significantly within paradigm sections (range [SD]: 18.4 [24.17] to 244.21 [243.21] %*s, P < 0.05). All paradigms demonstrated changes in subcomponents with cognitive stimulation, and can be ranked based on their relative presumed metabolic demand. The integrity of NVC requires further investigation in patient populations.

Modelling the cerebral haemodynamic response in the physiological range of PaCO2

Objective: Arterial CO2 (PaCO2) has a strong effect on cerebral blood flow (CBF), but its influence on CBF regulatory mechanisms and circulatory systemic variables has not been fully described over the entire physiological range of PaCO2. Approach: CBF velocity (CBFV, transcranial Doppler), blood pressure (BP, Finometer) and end-tidal CO2 (EtCO2, capnography) were measured in 45 healthy volunteers (19 male, mean age 37.5 years, range 21–71) at baseline, and in response to hypo- (−5 mm Hg and −10 mm Hg below baseline) and hypercapnia (5% and 8% CO2), applied in random order. Main results: CBFV, cerebral dynamic autoregulation index (ARI), heart rate (HR), arterial blood pressure (ABP), critical closing pressure (CrCP) and resistance-area product (RAP) changed significantly (all p < 0.0001) for hypo- and hyper-capnia. These parameters were shown to follow a logistic curve relationship representing a ‘dose-response’ curve for the effects of PaCO2 on the cerebral and systemic circulations. The four logistic model parameters describing each ‘dose-response’ curve were specific to each of the modelled variables (ANOVA p < 0.0001). Significance: The ability to model the CBFV, ARI, HR, ABP, CrCP and RAP dependency of PaCO2 over its entire physiological range is a powerful tool for physiological and clinical studies, including the need to perform adjustments in disease populations with differing values of baseline PaCO2.

Vasopressors Do Not Influence Cerebral Critical Closing Pressure During Systemic Inflammation Evoked by Experimental Endotoxemia and Sepsis in Humans.

The aim of this study was to investigate the effects of different vasopressors on the cerebral vasculature during experimental human endotoxemia and sepsis. We used the critical closing pressure (CrCP) as a measure of cerebral vascular tone. We performed a prospective pilot study, at the intensive care department (ICU) of a tertiary care university hospital in the Netherlands, in 40 healthy male subjects during experimental human endotoxemia (administration of bacterial lipopolysaccharide [LPS]) and in 10 patients with severe sepsis or septic shock.Subjects in the endotoxemia study were randomized to receive a 5 h infusion of either 0.05 μg/kg/min noradrenaline (n = 10, "LPS-nor"), 0.5 μg/kg/min phenylephrine (n = 10, "LPS-phenyl"), 0.04 IU/min vasopressin (n = 10, "LPS-AVP"), or saline (n = 10, "LPS-placebo") starting 1 h before intravenous administration of 2 ng/kg LPS. In patients with sepsis, fluid resuscitation and vasopressor use was at the discretion of the medical team, aiming at normovolemia and a mean arterial pressure (MAP) > 65 mm Hg, using noradrenaline.The mean flow velocity in the middle cerebral artery (MFVMCA) was measured by transcranial Doppler (TCD) with simultaneously recording of heart rate, arterial blood pressure, respiratory rate, and oxygen saturation. CrCP was estimated using the cerebrovascular impedance model. The CrCP decreased in the LPS-placebo group from 52.6 [46.6-55.5] mm Hg at baseline to 44.1 [41.2-51.3] mm Hg at 270 min post-LPS (P = 0.03). Infusion of phenylephrine increased the CrCP in the period before LPS administration from 46.9 [38.8-53.4] to 53.8 [52.9-60.2] mm Hg (P = 0.02), but after LPS administration, a similar decrease was observed compared with the LPS-placebo group. Noradrenaline or vasopressin prior to LPS did not affect the CrCP. The decrease in CrCP after LPS bolus was similar in all treatment groups. The CrCP in the sepsis patients equaled 35.7 [34.4-42.0] mm Hg, and was lower compared with that in the LPS-placebo subjects from baseline until 90 min after LPS (P < 0.01). Experimental human endotoxemia results in a decreased CrCP due to a loss of vascular resistance of the arterial bed. Vasopressors did not prevent this decrease in CrCP. Findings in patients with sepsis are comparable to those found in subjects after LPS administration.Patients with sepsis, despite treatment with vasopressors, have a risk for low cerebral blood flow and ischemia.