Level Of CPP Research Articles

#3959 ASSOCIATION BETWEEN AMORPHOUS CALCIUM-PHOSPHATE RATIOS IN CIRCULATING CALCIPROTEIN PARTICLES AND PROGNOSTIC BIOMARKERS IN HEMODIALYSIS PATIENTS

Abstract Background and Aims Calciprotein particles (CPPs) are circulating colloidal mineral-protein complexes containing crystalline and/or non-crystalline (amorphous) calcium-phosphate (CaPi). Serum CPP levels correlate with vascular stiffness and calcification in patients with chronic kidney disease (CKD). In vitro studies showed that CPPs containing crystalline CaPi were more arteriosclerogenic and inflammogenic than CPPs without containing crystalline CaPi. Thus, we hypothesized that not only the quantity but also the quality of CPPs (the phase of CaPi) might affect clinical outcomes. Method To test this hypothesis, we quantified amorphous CaPi ratio defined as the ratio of the amorphous CaPi amount to the total CaPi amount in serum CPPs from 183 hemodialysis patients and explored its possible correlation with serum parameters associated with prognosis of hemodialysis patients. Results Multivariate analysis revealed that the amorphous CaPi ratio correlated positively with hemoglobin and negatively with fibroblast growth factor-21 (FGF21), which remained significant after adjusting for the total CaPi amount. Because, low hemoglobin and high FGF21 were associated with increased mortality. Patients with low amorphous CaPi rate tended to have lower 2-year survival rates (p = 0.07). Conclusion This study suggests that low amorphous CaPi ratio in circulating CPPs is associated with poor prognosis in hemodialysis patients. Further investigation of the association with prognosis is warranted.

Neural correlates of cocaine-induced conditioned place preference in the posterior cerebellar cortex.

Addictive drugs are potent neuropharmacological agents capable of inducing long-lasting changes in learning and memory neurocircuitry. With repeated use, contexts and cues associated with consumption can acquire motivational and reinforcing properties of abused drugs, triggering drug craving and relapse. Neuroplasticity underlying drug-induced memories takes place in prefrontal-limbic-striatal networks. Recent evidence suggests that the cerebellum is also involved in the circuitry responsible for drug-induced conditioning. In rodents, preference for cocaine-associated olfactory cues has been shown to correlate with increased activity at the apical part of the granular cell layer in the posterior vermis (lobules VIII and IX). It is important to determine if the cerebellum's role in drug conditioning is a general phenomenon or is limited to a particular sensory modality. The present study evaluated the role of the posterior cerebellum (lobules VIII and IX), together with the medial prefrontal cortex (mPFC), ventral tegmental area (VTA), and nucleus accumbens (NAc) using a cocaine-induced conditioned place preference procedure with tactile cues. Cocaine CPP was tested using ascending (3, 6, 12, and 24 mg/kg) doses of cocaine in mice. Compared to control groups (Unpaired and Saline animals), Paired mice were able to show a preference for the cues associated with cocaine. Increased activation (cFos expression) of the posterior cerebellum was found in cocaine CPP groups and showed a positive correlation with CPP levels. Such increases in cFos activity in the posterior cerebellum significantly correlated with cFos expression in the mPFC. Our data suggest that the dorsal region of the cerebellum could be an important part of the network that mediates cocaine-conditioned behavior.

Ambulatory central BP and arterial stiffness in patients with and without intradialytic hypertension.

Increased arterial stiffness is suggested to be involved in the pathogenesis of intradialytic-hypertension (IDH). Ambulatory pulse-wave-velocity (PWV) is an independent predictor for all-cause-mortality in haemodialysis and its prognostic power is better than office PWV. This is the first study examining ambulatory central blood pressure (BP) and arterial stiffness parameters in patients with and without IDH. This study examined 45 patients with IDH (SBP rise ≥10 mmHg from pre- to post-dialysis and post-dialysis SBP ≥150 mmHg) in comparison with 197 patients without IDH. All participants underwent 48-h ABPM with Mobil-O-Graph-NG; parameters of central haemodynamics, wave reflection and PWV were estimated. Age, dialysis vintage and interdialytic weight gain did not differ between-groups. IDH patients had higher 48-h cSBP (131.7 ± 16.2 vs. 119.2 ± 15.2 mmHg, p < 0.001), 48-h cDBP (86.7 ± 12.7 vs. 79.6 ± 11.5 mmHg, p < 0.001) and 48-h cPP (45.5 ± 10.4 vs. 39.8 ± 10.0 mmHg, p=0.001) compared to patients without IDH. Similarly, during day- and nighttime periods, cSBP/cDBP and cPP levels were higher in IDH-patients compared to non-IDH. Forty-eight-hour augmentation pressure and index, but not AIx(75) were higher in IDH patients; 48-h PWV (10.0 ± 2.0 vs. 9.2 ± 2.1m/s, p=0.017) was significantly higher in patients with IDH. The two study groups displayed different trajectories in central BP and PWV over the course of the recording; IDH patients had steadily high values of the above variables during the 2 days of the interdialytic-interval, whereas non-IDH patients showed a gradual elevation, with significant increases from the 1st to 2nd 24 h. IDH patients have significantly higher levels of ambulatory central BP and arterial stiffness parameters and a different course over the 48-h period compared with non-IDH patients. Increased arterial stiffness could be a prominent factor associated with the high burden of cardiovascular disease in this population.

COMPARISON OF AMBULATORY CENTRAL HEMODYNAMICS AND ARTERIAL STIFFNESS IN HEMODIALYSIS PATIENTS WITH AND WITHOUT INTRADIALYTIC HYPERTENSION

Objective: Increased arterial stiffness is suggested to be involved in the pathogenesis of intradialytic hypertension (IDH). Ambulatory pulse wave velocity (PWV) is an independent predictor for all-cause-mortality in hemodialysis patients and its prognostic power is better than office PWV. This is the first study comparing ambulatory central blood pressure (BP) and arterial stiffness parameters between patients with and without IDH. Design and method: This study examined 45 patients with IDH (defined as: SBP rise greater than or equal to 10 mmHg from pre- to post-dialysis and post-dialysis SBP greater than or equal to 150 mmHg) in comparison 197 without IDH. All participants underwent 48-h ABPM with the Mobil-O-Graph-NG device; parameters of central hemodynamics [central systolic (cSBP) and diastolic BP (cDBP), pulse pressure (PP)], wave reflection [augmentation index (AIx), and pressure (AP)] and PWV were estimated. Results: Age, dialysis vintage, interdialytic weight gain and prevalence of major comorbidities did not differ between the two study groups. Patients with IDH had higher 44-h cSBP (131.6 ± 16.7 vs. 119.3 ± 15.6, p &lt; 0.001), 44-h cDBP (86.4 ± 12.8 vs. 79.3 ± 11.7, p &lt; 0.001) and 44-h cPP (45.7 ± 10.7 vs. 40.3 ± 10.3, p = 0.002) levels compared to patients without IDH. Similarly, during day- and nighttime periods, cSBP/cDBP and cPP levels were higher in IDH patients compared to non-IDH. 44-h augmentation pressure and index, but not AIx(75) were higher in patients with IDH than those without IDH. 44-h PWV (10.0 ± 2.0 vs. 9.2 ± 2.1 m/s, p = 0.020) was significantly higher in patients with IDH. Conclusions: Patients with IDH have higher ambulatory central BP and increased arterial stiffness, as indicated by higher ambulatory cPP and PWV. Increased arterial stiffness could be a prominent factor associated with the high burden of cardiovascular disease in this population.

Reduced hip bone mineral density is associated with high levels of calciprotein particles in patients with Fabry disease

SummaryCalciprotein particles (CPP) are nanoscale mineralo-protein aggregates that help stabilize excess mineral in the circulation. We examined the relationship between CPP and bone mineral density in Fabry disease patients. We found an inverse correlation with total hip and femoral neck density, but none with lumbar spine.PurposeCalciprotein particles (CPP) are colloidal mineral-protein complexes made up primarily of the circulating glycoprotein fetuin-A, calcium, and phosphate. They form in extracellular fluid and facilitate the stabilization, transport, and clearance of excess minerals from the circulation. While most are monomers, they also exist in larger primary (CPP-I) and secondary (CPP-II) form, both of which are reported to be raised in pathological states. This study sought to investigate CPP levels in the serum of patients with Fabry disease, an X-linked systemic lysosomal storage disorder that is associated with generalized inflammation and low bone mineral density (BMD).MethodsWe compared serum CPP-I and CPP-II levels in 59 patients with Fabry disease (37 female) with levels in an age-matched healthy adult cohort (n=28) and evaluated their association with BMD and biochemical data obtained from routine clinical review.ResultsCPP-I and CPP-II levels were higher in male Fabry disease patients than female sufferers as well as their corresponding sex- and age-matched controls. CPP-II levels were inversely correlated with BMD at the total hip and femoral neck, but not the lumbar spine. Regression analyses revealed that these associations were independent of common determinants of BMD, but at the femoral neck, a significant association was only found in female patients.ConclusionLow hip BMD was associated with high CPP-II in patients with Fabry disease, but further work is needed to investigate the relevance of sex-related differences and to establish whether CPP measurement may aid assessment of bone disease in this setting.

MO089: Comparison of Ambulatory Central Hemodynamics and Arterial Stiffness in Hemodialysis Patients With And Without Intradialytic Hypertension

Abstract BACKGROUND AND AIMS Increased arterial stiffness is suggested to be involved in the pathogenesis of intradialytic hypertension (IDH). Ambulatory pulse wave velocity (PWV) is an independent predictor for all-cause-mortality in hemodialysis patients and its prognostic power is better than office PWV. This is the first study comparing ambulatory central blood pressure (BP) and arterial stiffness parameters between patients with and without IDH. METHOD This study examined 45 patients with IDH (defined as: SBP rise ≥ 10 mmHg from pre- to post-dialysis and post-dialysis SBP ≥ 150 mmHg) in comparison 197 without IDH. All participants underwent 48-h ABPM with the Mobil-O-Graph-NG device; parameters of central hemodynamics [central systolic (cSBP) and diastolic BP (cDBP), pulse pressure (PP)], wave reflection [augmentation index (AIx) and pressure (AP)] and PWV were estimated. RESULTS Age, dialysis vintage, interdialytic weight gain and prevalence of major comorbidities did not differ between the two study groups. Patients with IDH had higher 44-h cSBP (131.6 ± 16.7 versus 119.3 ± 15.6, P &amp;lt; 0.001), 44-h cDBP (86.4 ± 12.8 versus 79.3 ± 11.7, P &amp;lt; 0.001) and 44-h cPP (45.7 ± 10.7 versus 40.3 ± 10.3, P = 0.002) levels compared with patients without IDH. Similarly, during day- and nighttime periods, cSBP/cDBP and cPP levels were higher in IDH patients compared with non-IDH. 44-h augmentation pressure and index, but not AIx(75) were higher in patients with IDH than those without IDH. 44-h PWV (10.0 ± 2.0 vs. 9.2 ± 2.1 m/s, P = 0.020) was significantly higher in patients with IDH. CONCLUSION Patients with IDH have higher ambulatory central BP and increased arterial stiffness, as indicated by higher ambulatory cPP and PWV. Increased arterial stiffness could be a prominent factor associated with the high burden of cardiovascular disease in this population.

Individualized blood pressure targets in the postoperative care of patients with intracerebral hemorrhage.

Recent guidelines recommend targeting a systolic blood pressure (SBP) < 140 mm Hg in the early management of patients with spontaneous intracerebral hemorrhage (ICH). The optimal SBP targets for ICH patients after hematoma evacuation (HE) remain unclear. Here, the authors aimed to define the optimal SBP range based on multimodal neuromonitoring data. Forty poor-grade ICH patients who had undergone HE and then monitoring of intracerebral pressure, brain tissue oxygen tension (PbtO2), and cerebral metabolism (via cerebral microdialysis [CMD]) were prospectively included. Episodes of brain tissue hypoxia (BTH) (1-hour averaged PbtO2 < 20 mm Hg) and metabolic distress (CMD-lactate/pyruvate ratio [LPR] ≥ 40) were identified and linked to corresponding parameters of hemodynamic monitoring (SBP and cerebral perfusion pressure [CPP]). Multivariable regression analysis was performed using generalized estimating equations to identify associations between SBP levels, PbtO2, and brain metabolism. The mean patient age was 60 (range 51-66) years and the median [IQR] initial ICH volume was 47 [29-60] ml. In multivariable models adjusted for Glasgow Coma Scale score, probe location, ICH volume, and age, lower SBP was independently associated with a higher risk of BTH (≤ 120 mm Hg: adjusted OR 2.9, p = 0.007; 120-130 mm Hg: adj OR 2.4, p = 0.002; 130-140 mm Hg: adj OR 1.6, p = 0.017) compared to a reference range of 140-150 mm Hg at the level of the foramen interventriculare Monroi, which corresponded to a CPP of 70-80 mm Hg and SBP levels between 150 and 160 mm Hg at the heart level. After exclusion of episodes with mitochondrial dysfunction, SBP targets < 140 mm Hg were associated with higher odds of cerebral metabolic distress (≤ 130 mm Hg: OR 2.5, p = 0.041; 130-140 mm Hg: OR 2.3, p = 0.033). Patients with a modified Rankin Scale score ≥ 5 at neurological ICU discharge more often exhibited BTH than patients with better outcomes (51% vs 10%, p = 0.003). These data suggest that lower SPB and CPP levels are associated with a higher risk for BTH. Further studies are needed to evaluate whether a higher SPB target may prevent BTH and improve outcomes.

Effect of Sevelamer on Calciprotein Particles in Hemodialysis Patients: The Sevelamer Versus Calcium to Reduce Fetuin-A-Containing Calciprotein Particles in Dialysis (SCaRF) Randomized Controlled Trial

IntroductionCalciprotein particles (CPPs) are potentially modifiable mediators of phosphate toxicity in patients with kidney disease. We compared the effects of calcium carbonate (CC) and the non–calcium-based phosphate binder sevelamer on CPP levels in patients undergoing hemodialysis (HD). We hypothesized that treatment with sevelamer would achieve greater reductions in amorphous calcium phosphate–containing CPP (CPP-1) and hydroxyapatite-containing CPP (CPP-2) owing to reduced calcium loading and anti-inflammatory pleiotropic effects.MethodsWe conducted an open-label, randomized controlled trial (RCT) in which 31 stable prevalent HD patients were allocated to receive either sevelamer hydrochloride (SH), sevelamer carbonate (SC), or CC for 24 weeks. Dual primary endpoints were the between groups differences in serum CPP-1 and CPP-2 levels at 24 weeks in SH + SC–treated versus CC-treated patients. Effects on aortic pulse wave velocity (aPWV), inflammatory cytokines (interleukin-6 and -8), and effects across individual treatment arms were also assessed.ResultsSerum CPP-1, but not CPP-2, levels were lower in those randomly assigned to the sevelamer (SH + SC) group compared with the CC group at 24 weeks (–70%, 95% confidence interval [CI] –90% to –15%, P = 0.02). In subgroup analysis, this effect was confined to those receiving SC (–83.4%, 95% CI –95.7% to –36.8%, P = 0.01). aPWV and interleukin-8 levels were also lower in those who received sevelamer compared with CC at 24 weeks (–2.0 m/s, 95% CI –2.9 to –1.1; –57%, 95% CI –73% to –30%, respectively, both P = 0.01). Conventional markers of mineral metabolism remained stable across all treatment groups.DiscussionCompared with treatment with CC, use of sevelamer for 24 weeks was associated with lower serum CPP-1 levels and a reduction in aPWV and systemic inflammation.

Investigation of copeptin levels in foetal congenital central nervous system anomalies

Copeptin has been shown to be associated with central nervous system pathologies. The aim of this study was to investigate the relationship between serum CCP levels and central nervous system (CNS) anomalies. In this case-control study, those at 9–14 weeks of gestation serum levels of copeptin, were assessed in pregnant women whose foetuses subsequently developed CNS anomalies (group 1: n = 60) and compared with gestational age-matched pregnant women who exhibited normal pregnancy outcomes (group 2: n = 48). The mean copeptin levels were 1.58 ± 0.40 ng/mL and 1.11 ± 0.36 ng/mL in the CNS anomalies and control groups, respectively (p < .0001). An increased level of copeptin independently predicts development of CNS anomalies, suggesting that copeptin can be used for prediction and discrimination of CNS anomalies in normal pregnancies at 9–14 weeks of gestation. Impact statement What is already known on this subject? There is no test or method to diagnose CNS anomalies in the first trimester of pregnancy. This study presents the first and new information on the relationship between serum copeptin levels and central nervous system anomalies in pregnant women whose foetuses subsequently developed CNS anomalies. What do the results of this study add? I have strongly demonstrated differences in maternal CPP levels between CNS anomalous pregnancies and healthy controls. What are the implications of these findings for clinical practice and/or further research? It has been thought that copeptin appears to be an ideal marker for central nervous system anomaly prediction at 9–14 weeks of gestational age and if confirmed in larger prospective studies. Finally, these results could not be used as parameters for prenatal CNS screening. Advanced studies, well-structured and conducted on larger populations are needed to investigate the issue further.

Mid-term predictive value of calciprotein particles in maintenance hemodialysis patients based on a gel-filtration assay

Background and aimsCalciprotein particles (CPPs), nano-aggregates containing fetuin-A-bound calcium-phosphate, are associated with aortic stiffness and coronary calcification in maintenance hemodialysis patients. A novel gel-filtration assay can detect low-density small CPPs, which are actually a major form of circulating CPPs in vivo. We sought to investigate whether circulating CPP levels measured by gel-filtration method would accurately predict hard endpoints in maintenance hemodialysis patients. MethodsThis study used a prospective, multicenter, longitudinal, and observational design. One-hundred eight patients enrolled in this study were followed-up for about 2 years. We reported all-cause death and cardiovascular events, which included major adverse cardiac, cerebrovascular, and limb events. ResultsKaplan-Meier analysis showed no significant difference between patients with the higher (>median) and lower (<median) CPP levels with regard to all-cause death. However, the higher CPP group showed a higher incidence of cardiovascular events (log-rank test χ2 = 4.41, p = 0.036). Univariate Cox regression analysis revealed that CPP levels were not associated with all-cause death, but were significantly associated with higher incidence of cardiovascular events (hazard ratio (HR) 1.03, 95% confidence interval (CI) [1.02–1.05], p < 0.001) for every thousand CPP increase. Multivariate Cox regression analysis revealed that CPP levels were not associated with all-cause death, but were independently associated with cardiovascular events (HR 1.03, 95% CI [1.01–1.04], p < 0.001) for every thousand CPP. ConclusionsThis finding suggests a potential predictive value of CPPs in maintenance hemodialysis patients.

P102 Young Investigator, Top Clinical Abstract Combined therapy with adalimumab and mesenchymal stromal cells contributes to reduction in the degree of inflammation in ulcerative colitis

BACKGROUND: One of the new promising methods of treatment of patients with ulcerative colitis (UC) is biological therapy using bone marrow mesenchymal stromal cells (MCS). In some cases, simultaneously with MCS, patients receive concomitant anticytokine therapy. Currently, a new strategy for UC therapy is to achieve a deep remission of the disease. Objective: to compare the level of immunobiological and histological markers of inflammation – C-reactive protein (CRP), the Histological Geboes Score (GS) and fecal calprotectin (FCP) - in patients with UC receiving cell therapy MSC, anticytokine therapy with adalimumab (ADA) and combined therapy of bone marrow MSC and ADA. METHODS: 60 patients with total ulcerative colitis of moderate severity were divided into groups depending on the therapy. The first group of patients with UC aged from 19 to 56 years (Me-29) (n = 20) received anti-inflammatory therapy with the use of the culture of 2 million MSC/kg according to the scheme the second group of patients with UC (n = 20) aged 23 to 62 years (Me-41) received ADA in accordance with the recommended scheme, the third group of patients with UC (n = 20) aged 20 to 59 years (Me-33) received the MSC + ADA. The level of CRP, PCF and is was assessed 26 weeks after initiation of therapy. The baseline CRP was 25.0 ± 1.9; 26.5 ± 2.1 and 24.0 ± 2.4 mg/L, respectively. Baseline GS in the groups of patients was 4.4 ± 0.2; 4.35 ± 0.2 and 4.5 ± 0.3 points, respectively. The initial level of the FCP made 890.8 ± 88,8; 850.3 ± 83.9 and 910.5 ± 120.5 μg/g, respectively. RESULTS: After 26 weeks from the start of therapy in the 1-st group of patients, the level of CPP was 6.8 ± 1.1 mg/L, in the 2-nd group-7.4 ± 1.3 mg/L, in the 3-rd group-7.9 ± 1.0 mg/L (P &gt; 0.05). After 26 weeks from the start of therapy in the 1-st group of patients, the level of FCP was 108.8 ± 9.3 μg/g, in the 2-nd group-90.6 ± 6.5 μg/g, in the 3-rd group - 96.8 ± 6.3 μg/g (P &lt; 0.05 compared to the 1-st and 2-nd groups). After 26 weeks from the start of therapy in the 1-st group of patients with GS was 0.7 ± 0.1 points, in the 2-nd group-0.65 ± 0.1 points, in the 3-rd-0.5 ± 0.06 points (P &lt; 0.001 compared with the 1-st and 2-nd groups). CONCLUSION(S): Combined cell and anti-cytokine therapy with adalimumab contributes to a more pronounced reduction in the degree of inflammation of the intestinal mucosa.

Increased risk of critical CBF levels in SAH patients with actual CPP below calculated optimal CPP

BackgroundCerebral pressure autoregulation can be quantified with the pressure reactivity index (PRx), based on the correlation between blood pressure and intracranial pressure. Using PRx optimal cerebral perfusion pressure (CPPopt) can be calculated, i.e., the level of CPP where autoregulation functions best. The relation between cerebral blood flow (CBF) and CPPopt has not been examined. The objective was to assess to which extent CPPopt can be calculated in SAH patients and to investigate CPPopt in relation to CBF.MethodsRetrospective study of prospectively collected data. CBF was measured bedside with Xenon-enhanced CT (Xe-CT). The difference between actual CPP and CPPopt was calculated (CPP∆). Correlations between CPP∆ and CBF parameters were calculated with Spearman’s rank order correlation coefficient (rho). Separate calculations were done using all patients (day 0–14 after onset) as well as in two subgroups (day 0–3 and day 4–14).ResultsEighty-two patients with 145 Xe-CT scans were studied. Automated calculation of CPPopt was possible in adjunct to 60% of the Xe-CT scans. Actual CPP < CPPopt was associated with higher numbers of low-flow regions (CBF <10 ml/100 g/min) in both the early phase (day 0–3, n = 39, Spearman’s rho = −0.38, p = 0.02) and late acute phase of the disease (day 4–14, n = 35, Spearman’s rho = −0.39, p = 0.02). CPP level per se was not associated with CBF.ConclusionsCalculation of CPPopt is possible in a majority of patients with severe SAH. Actual CPP below CPPopt is associated with low CBF.

Alteration and clinical significance of cfDNA and CRP in children patients with hand-foot-and-muoth disease

Objective To explore the clinical significance of changes of serum cfDNA and CRPin patients with hand-foot-and-muoth disease. Methods Serum levels of cfDNA, CPP were measured with fluorescent quantitation PCR and immunoturbidime, respectively in 108 cases of children patients with hand-foot-and-muoth and 108 healthy subjects children as control group. Results Serum cf DNA and CPP levels with hand-foot-andmuoth group(523.45±42.31)mg/L,(22.57±5.52)mg/L were significantly higher than those of control group detection results(260.18±20.56)mg/L,(2.88±0.82)mg/L(t=58.16,36.85,all P<0.05).And we observed the serum cf DNA and CPP levels in different severity extent of pneumonia,the results show that the serum increased gradually with the increase of the severity(t=29.80,13.68,all P<0.05).and the serum level of cfDNA was positive correlation with CRP(r=0.730,P<0.01). Conclusion The serum.cf DNA and CRP reflect situation of patients and extent of hand-foot-and-muoth disease, which have a close relationship between the clinical process of hand-foot-and-muoth disease and have significance value to evaluate the pathogenetic condition and prognosis. Key words: Hand foot and muoth disease; Deoxyribonucleic acid; C reactive protein

Favorable Outcome in Traumatic Brain Injury Patients With Impaired Cerebral Pressure Autoregulation When Treated at Low Cerebral Perfusion Pressure Levels

Cerebral pressure autoregulation (CPA) is defined as the ability of the brain vasculature to maintain a constant blood flow over a range of different systemic blood pressures by means of contraction and dilatation. To study CPA in relation to physiological parameters, treatment, and outcome in a series of traumatic brain injury patients. In this prospective observational study, 44 male and 14 female patients (age, 15-72 years; mean, 38.7 years; Glasgow Coma Scale score, 4-13; median, 7) were analyzed. Patients were divided into groups on the basis of status of CPA (more pressure active vs more pressure passive) and level of cerebral perfusion pressure (CPP; low vs high CPP). The proportions of favorable outcome in the groups were assessed. Differences in physiological variables in the different groups were analyzed. Patients with more impaired CPA treated at CPP levels below median had a significantly higher proportion of favorable outcome compared with patients with more impaired CPA treated at CPP levels above median. No significant difference in outcome was seen between patients with more intact CPA when divided by level of CPP. In patients with more impaired CPA, CPP<50 mm Hg and CPP<60 mm Hg were associated with favorable outcome, whereas CPP>70 mm Hg and CPP>80 mm Hg were associated with unfavorable outcome. In patients with more intact CPA, no difference in physiological variables was seen between patients with favorable and unfavorable outcomes. Our results support that in traumatic brain injury patients with impaired CPA, CPP should not be elevated.

Differences in NMDA Receptor Antagonist‐Induced Locomotor Activity and [3H]MK‐801 Binding Sites in Short‐Sleep and Long‐Sleep Mice

Short-Sleep (SS) and Long-Sleep (LS) mice differ in initial sensitivity to ethanol. Ethanol acts as an antagonist at N-methyl D-aspartate receptors (NMDARs). Therefore, we tested whether SS and LS mice also differ in initial sensitivity to NMDAR antagonists. Systemic injection (intraperitoneal) of either the noncompetitive NMDAR antagonist MK-801 (dizocilpine) or the competitive NMDAR antagonist 2-carboxypiperazin-4-yl-propyl-1-phosphonic acid (CPP) produced similar results. At lower drug doses, SS mice showed greater locomotor activation than LS mice; and at higher doses, SS mice continued to be activated whereas LS mice became sedated. Brain levels of [3H]MK-801 were 40% higher in SS, compared with LS, mice. However, blood levels of [3H]MK-801 and [3H]CPP and brain levels of [3H]CPP were similar in the two lines. NMDARs were measured using quantitative autoradiographic analysis of in vitro [3H]MK-801 binding to SS and LS mouse brains. Significantly higher (20 to 30%) receptor densities were observed in the hippocampus and cerebral cortex of SS mice. Our results support the hypothesis that SS and LS mice differ in initial sensitivity to NMDAR antagonists and suggest that the line differences in the dose-response relationships for MK-801- and CPP-induced locomotor activity are qualitatively similar to those reported for ethanol. Differences in pharmacokinetics and number of NMDARs may contribute to, but are unlikely to entirely account for, the differential behavioral responsiveness of SS and LS mice to MK-801 and CPP.

Determining cerebral perfusion pressure thresholds in severe head trauma.

Laboratory studies suggest the pulsatile component of the transcranial doppler (TCD) waveform may be useful in determining lower autoregulatory threshold. This study aimed to assess the effect of increasing CPP on jugular bulb oximetry (SjO2) and middle cerebral artery (MCA) TCD flow velocities in the early management of severe head injury. 16 severely head injured patients (GCS < or = 8), had intracranial pressure (ICP), mean arterial pressure, SjO2 and MCA Doppler velocity monitored continuously. CPP was increased by intravenous fluids (right atrial pressure approximately equal to 10) and supplemented with adrenaline infusion until TCD pulsatility (Gosling pulsatility index [PI] reached a plateau. The mean CPP at which SjO2 surpassed 55% was 62 +/- 6.2 mm Hg. TCD PI did not plateau until a significantly higher mean CPP of 74 +/- 5.1 mm Hg was achieved (p < 0.01). In 8 cases, increased CPP was associated with a fall in ICP, ranging from 1 to 8 mm Hg. We conclude that a critically low level of SjO2 is a late indicator of failed autoregulation. CPP values associated with intact autoregulation identified by TCD assessment of MCA flow are significantly higher than those indicated by SjO2 monitoring. MCA Doppler flow assessment may be useful in determining the level of CPP at which therapy should be aimed in the early resuscitation of head trauma.

Testing of cerebral autoregulation in head injury by waveform analysis of blood flow velocity and cerebral perfusion pressure.

Thirty five head injured patients were subjected to day-by-day monitoring of intracranial pressure (ICP), arterial blood pressure (ABP) and blood flow velocity (FV) in middle cerebral artery. Parameters describing cerebral autoregulation: flow velocity time average, systolic, diastolic values, pulsatility index (PI), estimate of cerebrovascular resistance (CVR = CPP/FV) etc. were analyzed as functions of CPP (ABP-ICP). The results show that for CPP below 55 mmHg the evidence of exhausted autoregulation can be observed in FV, CVR, PI. The method is helpful in assessment ot the optimal level of CPP in order to reduce the probability of ischaemic brain insults.

Cerebrovascular response to changes of cerebral venous pressure and cerebrospinal fluid pressure

Using parietal cranial windows and multichannel videoangiometry, pial vessel responses were studied in cats during stepwise elevation of superior sagittal sinus pressure (Psss) to a level of 50 mmHg or reduction of CSF-pressure (PCSF). PCSF was monitored via a needle in the great cistern, known from previous studies to be identical to supratentorial CSF-pressure. During elevation of PSSS, large and small pial veins dilated by 14 +/- 6.1% from resting diameter. Small arteries remained unresponsive until they were dilated by 9 +/- 2.1% at the level of PSSS 50 mmHg. Large arteries dilated by 18 +/- 5.5% at the level of PSSS 50 mmHg. PSSS was always approximately twice as high as PCSF during increase of PSSS. During reduction of PCSF to -5 mmHg, pial veins also dilated, by 7.4 +/- 1% on the average. This observation suggests that normal PCSF is a result of mainly venous vascular pressure, and that the level of normal venous pressure is not dictated by PCSF but by the function and architecture of the cerebral vasculature. Since the rapid reduction of cerebral perfusion pressure CPP by elevation of venous pressure does not induce autoregulatory adjustment according to the level of CPP, but to the level of arterial transmural pressure, it is concluded, that the basic mechanism underlying autoregulation of CBF is myogenic.

Some Observations on Cerebral Perfusion During Cardiopulmonary Bypass

Blood flow was recorded with an electromagnetic flow probe on one internal carotid artery (ICA) during cardiopulmonary bypass (CPB) in 5 patients. The ICA flow was monitored continuously along with arterial blood pressure, epidural intracranial pressure, and cerebral electrical activity using a cerebral function monitor (3 patients). The ICA flow increased by 50 to 100% at the inception of extracorporeal circulation. This rapid enhancement of flow occurred within a thirty-second period and was due to rapid arterial hemodilution caused by introduction of the priming solution. A transitory fall in ICA flow was observed during subsequent minutes when the well-recognized drop in blood pressure took place and the cerebral perfusion pressure (CPP = blood pressure - epidural intracranial pressure) was reduced to less than 30 mm Hg. In only one instance, however, when CPP fell to 15 mm Hg, was the fall in flow lower than the prebypass level. Throughout the rest of CPB, with steady-state hemodilution and CPP levels in the range of 30 to 50 mm Hg, ICA flow was markedly enhanced (50 to 100% above the prebypass level). The flow pattern, however, disclosed a pressure-passive system, indicating that cerebral autoregulation was impaired or that the CPP levels were lower than the individual lower limit of cerebral autoregulation during the period of steady-state hemodilution on CPB. A transient depression of cerebral electrical activity was seen in 2 patients shortly after the introduction of CPB. This phenomenon is suggestive of qualitatively insufficient perfusion and was observed even when ICA bulk flow was increased (hematocrit values, 13 to 17%).

Some Observations on Cerebral Perfusion during Cardiopulmonary Bypass

Blood flow was recorded with an electromagnetic flow probe on one internal carotid artery (ICA) during cardiopulmonary bypass (CPB) in 5 patients. The ICA flow was monitored continuously along with arterial blood pressure, epidural intracranial pressure, and cerebral electrical activity using a cerebral function monitor (3 patients). The ICA flow increased by 50 to 100% at the inception of extracorporeal circulation. This rapid enhancement of flow occurred within a thirty-second period and was due to rapid arterial hemodilution caused by introduction of the priming solution. A transitory fall in ICA flow was observed during subsequent minutes when the well-recognized drop in blood pressure took place and the cerebral perfusion pressure (CPP = blood pressure – epidural intracranial pressure) was reduced to less than 30 mm Hg. In only one instance, however, when CPP fell to 15 mm Hg, was the fall in flow lower than the prebypass level. Throughout the rest of CPB, with steady-state hemodilution and CPP levels in the range of 30 to 50 mm Hg, ICA flow was markedly enhanced (50 to 100% above the prebypass level). The flow pattern, however, disclosed a pressure-passive system, indicating that cerebral autoregulation was impaired or that the CPP levels were lower than the individual lower limit of cerebral autoregulation during the period of steady-state hemodilution on CPB. A transient depression of cerebral electrical activity was seen in 2 patients shortly after the introduction of CPB. This phenomenon is suggestive of qualitatively insufficient perfusion and was observed even when ICA bulk flow was increased (hematocrit values, 13 to 17%).