Dynamic cerebral autoregulation is preserved during orthostasis and intrathoracic pressure regulation in healthy subjects: A pilot study.

Resistance breathing may restore cardiac output (CO) and cerebral blood flow (CBF) during hypovolemia. We assessed CBF and cerebral autoregulation (CA) during tilt, resistance breathing, and paced breathing in 10 healthy subjects. Blood velocities in the internal carotid artery (ICA), middle cerebral arteries (MCA, four subjects), and aorta were measured by Doppler ultrasound in 30° and 60° semi-recumbent positions. ICA blood flow and CO were calculated. Arterial blood pressure (ABP, Finometer), and end-tidal CO2 (ETCO2) were recorded. ICA blood flow response was assessed by mixed-models regression analysis. The synchronization index (SI) for the variable pairs ABP-ICA blood velocity, ABP-MCA velocities in 0.005-0.08 Hz frequency interval was calculated as a measure of CA. Passive tilting from 30° to 60° resulted in 12% decrease in CO (p = 0.001); ICA blood flow tended to fall (p = 0.04); Resistance breathing restored CO and ICA blood flow despite a 10% ETCO2 drop. ETCO2 and CO contributed to ICA blood flow variance (adjusted R2: 0.9, p < 0.0001). The median SI was low (<0.2) indicating intact CA, confirmed by surrogate date testing. The peak SI was transiently elevated during resistance breathing in the 60° position. Resistance breathing may transiently reduce CA efficiency. Paced breathing did not restore CO or ICA blood flow.

Dysfunctional arteriovenous anastomoses in hands of systemic sclerosis patients with digital ulcers.

OBJECTIVES: Previous studies indicate that the arteriovenous anastomoses (AVAs) and the arterioles with the nutritive flow are involved in the pathophysiologic process disturbing hand blood flow in systemic sclerosis (SSc). However, impact of different part of the microvascular system involved in digital ulcers (DU) is not well known. Here, we aimed to assess the vasomotor activity of the AVAs in the hands of patients with and without DU in SSc. METHODS: Simultaneous recordings were made of laser Doppler flux in the finger pulp and thenar eminence, together with ipsilateral radial artery blood velocity and mean arterial blood pressure (MAP) in 22 non-smoking SSc patients and 13 aged-matched healthy controls. RESULTS: AVA responses in the finger pulp to spontaneous vasoconstrictor nerve impulses were abolished in 64% of the SSc patients. Correlation and cross-spectra analysis showed positive correlation between blood flow changes and MAP changes, indicating a passive vascular bed in the SSc finger pulp with blood flow variations depending on short-term variability in MAP. Dysfunctional AVAs were identified in all the patients with a history of DU (n=8), while none of the patients with normal AVA function had episodes of DU (n=8) (p= 0.017). CONCLUSIONS: We found that in SSc patients with DU there is a dysfunction of the AVAs of the finger pulp. This proof-of-concept study supports the notion that AVA dysfunction may play a critical role in SSc related DU. AVA dysfunction may be a part of autonomic dysfunction in SSc.

Hypothermia makes cerebral resistance index a poor prognostic tool in encephalopathic newborns.

BACKGROUND: Severe neonatal encephalopathy (NE) of hypoxic-ischaemic origin may cause death or life-long disability. Acute encephalopathy may also affect cerebrovascular control. Pourcelot's cerebrovascular resistance index (RI) ≤0.55 was predictive of poor outcome in normothermic NE infants. Recent studies have questioned its predictive power during therapeutic hypothermia (HT). OBJECTIVE: To assess the predictive power of RI during HT and after rewarming. METHODS: 45 infants with NE treated with HT for 72 h had their RI calculated during early (median 11 h) and late (median 62 h) cooling and after rewarming (median 89 h). Poor outcome was defined as death or abnormalities on day 10 magnetic resonance imaging shown to predict severe neuromotor disability. RESULTS: RI ≤0.55 during cooling did not differentiate between good and poor outcome (late cooling, p = 0.08), but was powerful after rewarming (p = 0.004). RI ≤0.55 predicted true poor outcome in 43% (95% confidence interval (CI): 12, 80) during late cooling and in 100% (95% CI: 31, 100) after rewarming. RI >0.55 predicted good outcome in 86% (95% CI: 69, 95) during late cooling and in 89% (95% CI: 74, 96) after rewarming. CONCLUSIONS: Low RI is not predictive of poor outcome during HT in NE infants, but regains the predictive power seen in normothermic infants after rewarming.

Minimum alveolar concentration (MAC) for sevoflurane and xenon at normothermia and hypothermia in newborn pigs.

BACKGROUND: Neuroprotection from therapeutic hypothermia increases when combined with the anaesthetic gas xenon in animal studies. A clinical feasibility study of the combined treatment has been successfully undertaken in asphyxiated human term newborns. It is unknown whether xenon alone would be sufficient for sedation during hypothermia eliminating or reducing the need for other sedative or analgesic infusions in ventilated sick infants. Minimum alveolar concentration (MAC) of xenon is unknown in any neonatal species. METHODS: Eight newborn pigs were anaesthetised with sevoflurane alone and then sevoflurane plus xenon at two temperatures. Pigs were randomised to start at either 38.5°C or 33.5°C. MAC for sevoflurane was determined using the claw clamp technique at the preset body temperature. For xenon MAC determination, a background of 0.5 MAC sevoflurane was used, and 60% xenon added to the gas mixture. The relationship between sevoflurane and xenon MAC is assumed to be additive. Xenon concentrations were changed in 5% steps until a positive clamp reaction was noted. Pigs' temperature was changed to the second target, and two MAC determinations for sevoflurane and 0.5 MAC sevoflurane plus xenon were repeated. RESULTS: MAC for sevoflurane was 4.1% [95% confidence interval (CI): 3.65-4.50] at 38.5°C and 3.05% (CI: 2.63-3.48) at 33.5°C, a significant reduction. MAC for xenon was 120% at 38.5°C and 116% at 33.5°C, not different. CONCLUSION: In newborn swine sevoflurane, MAC was temperature dependent, while xenon MAC was independent of temperature. There was large individual variability in xenon MAC, from 60% to 120%.

Respiratory variations in pulmonary and systemic blood flow in healthy humans.

AIM: Cardiovascular oscillations are tightly coupled to respiration. Respiratory sinus arrhythmia (RSA) is an important part of heart rate variability with unknown function. Stroke volumes from the right (r-SV) and left (l-SV) side of the heart are assumed to vary differently with respiration, but have not previously been recorded non-invasively and simultaneously in humans. The present study introduces an improved technique for capturing respiratory variations in r-SV. METHODS: Six young volunteers were investigated during spontaneous and metronome-paced breathing in the left lateral decubitus position. Heart rate (HR, from ECG), l-SV (from finger blood arterial pressure curve) and r-SV (pulsed ultrasound Doppler) were recorded. Left and right cardiac outputs (l-CO and r-CO) were calculated beat by beat from HR, l-SV and r-SV. Respiratory variations in cardiovascular variables and phase angles were estimated by spectral analysis at respiratory frequency (0.15-0.40 Hz). RESULTS: The amplitude of respiratory variations in l-CO was 17% of r-CO (94% CI (6%, 35%), P=0.03). The amplitude of the respiratory variations in l-SV was not different from r-SV (74%, 94% CI (50%, 127%) non-significant). Increases in HR and r-SV were in phase with inspiration, while l-SV decreased during inspiration. CONCLUSION: The amplitude of respiratory variations in l-CO is significantly smaller than in r-CO. Respiratory variations in HR and in l-SV are in inverse phase; thus, RSA buffers respiratory variations in l-SV. RSA plays an important role in reducing oscillations in systemic blood flow resulting from respiratory changes in venous return.

Stroke volume decreases during mild dynamic and static exercise in supine humans.

AIM: The contributions of cardiac output (CO) and total peripheral resistance to changes in arterial blood pressure are debated and differ between dynamic and static exercise. We studied the role stroke volume (SV) has in mild supine exercise. METHODS: We investigated 10 healthy, supine volunteers by continuous measurement of heart rate (HR), mean arterial blood pressure, SV (ultrasound Doppler) and femoral beat volume (ultrasound Doppler) during both dynamic mild leg exercise and static forearm exercise. This made it possible to study CO, femoral flow (FF) and both total and femoral peripheral resistance beat-by-beat. RESULTS: During a countdown period immediately prior to exercise, HR and mean arterial pressure increased, while SV decreased. During mild supine exercise, SV decreased by 5-8%, and most of this was explained by increased mean arterial pressure. Dynamic leg exercise doubled femoral beat volume, while static hand grip decreased femoral beat volume by 18%. FF is tightly regulated according to metabolic demand during both dynamic leg exercise and static forearm exercise. CONCLUSION: Our three major findings are, firstly, that SV decreases during both dynamic and static mild supine exercise due to an increase in mean arterial pressure. Secondly, femoral beat volume decreases during static hand grip, but FF is unchanged due to the increase in HR. Finally, anticipatory responses to exercise are apparent prior to both dynamic and static exercise. SV changes contribute to CO changes and should be included in studies of central haemodynamics during exercise.

Respiratory sinus arrhythmia: opposite effects on systolic and mean arterial pressure in supine humans.

1. Are arterial blood pressure fluctuations buffered or reinforced by respiratory sinus arrhythmia (RSA)? There is still considerable debate about this simple question. Different results have been obtained, triggering a discussion as to whether or not the baroreflexes are responsible for RSA. We suspected that the measurements of different aspects of arterial pressure (mean arterial pressure (MAP) and systolic pressure (SP)) can explain the conflicting results. 2. Simultaneous recordings of beat-to-beat MAP, SP, left cardiac stroke volume (SV, pulsed ultrasound Doppler), heart rate (HR) and respiration (RE) were obtained in 10 healthy young adults during spontaneous respiration. In order to eliminate HR variations at respiratory frequency we used propranolol and atropine administration in the supine and tilted positions. Respiration-synchronous variation in the recorded variables was quantified by spectral analysis of the recordings of each of these variables, and the phase relations between them were determined by cross-spectral analysis. 3. MAP fluctuations increased after removing heart rate variations in both supine and tilted position, whereas SP fluctuations decreased in the supine position and increased in the head-up tilted position. 4. RSA buffers respiration-synchronous fluctuations in MAP in both positions. However, fluctuations in SP were reinforced by RSA in the supine and buffered in the tilted position.

Alveolar haemorrhage in a case of high altitude pulmonary oedema.

A case of high altitude pulmonary oedema (HAPE) in a climber who made a rapid ascent on Mt McKinley (Denali), Alaska is described. The bronchoalveolar lavage (BAL) fluid contained increased numbers of red blood cells and an abundance of haemosiderin laden macrophages consistent with alveolar haemorrhage. The timing of this finding indicates that alveolar haemorrhage began early during the ascent, well before the onset of symptoms. Although evidence of alveolar haemorrhage has been reported at necropsy in individuals dying of HAPE, previous reports have not shown the same abundance of haemosiderin laden macrophages in the BAL fluid. These findings suggest that alveolar haemorrhage is an early event in HAPE.

Acid-fast-positive Legionella pneumophila: a possible pitfall in the cytologic diagnosis of mycobacterial infection in pulmonary specimens.

The acid-fast stain is commonly used in the rapid cytologic assessment of bronchoalveolar lavage (BAL) fluid to detect pulmonary mycobacterial infections, particularly in immunocompromised patients. The identification of acid-fast, rod-shaped organisms may be taken as presumptive evidence of such an infection, in the appropriate clinical setting. However, this determination is made less specific by the occasional acid-fast positivity of microorganisms other than mycobacteria. We report on the occurrence of a fatal pneumonia caused by acid-fast positive Legionella pneumophila detected by BAL. This is a potential pitfall in the rapid diagnosis of pulmonary mycobacterial infections.

Radiation therapy for tracheobronchial amyloidosis.

A 67-year-old man presented with localized tracheobronchial amyloidosis involving the distal trachea and the right-sided airways. The disease caused right middle lobe collapse and threatened the right upper and lower lobes. A variety of bronchoscopic methods, including Nd:YAG laser resection, dilation, and stenting, were used as temporizing methods. External beam radiation therapy, considered because of disease progression, caused a measurable local response. Radiation therapy should be considered as a treatment option for localized tracheobronchial amyloidosis causing airway obstruction.

Inhaled nitric oxide versus conventional therapy: effect on oxygenation in ARDS.

A randomized, controlled clinical trial was performed with patients with acute respiratory distress syndrome (ARDS) to compare the effect of conventional therapy or inhaled nitric oxide (iNO) on oxygenation. Patients were randomized to either conventional therapy or conventional therapy plus iNO for 72 h. We tested the following hypotheses: (1) that iNO would improve oxygenation during the 72 h after randomization, as compared with conventional therapy; and (2) that iNO would increase the likelihood that patients would improve to the extent that the FI(O2) could be decreased by > or = 0.15 within 72 h after randomization. There were two major findings. First, That iNO as compared with conventional therapy increased Pa(O2)/FI(O2) at 1 h, 12 h, and possibly 24 h. Beyond 24 h, the two groups had an equivalent improvement in Pa(O2)/FI(O2). Second, that patients treated with iNO therapy were no more likely to improve so that they could be managed with a persistent decrease in FI(O2) > or = 0.15 during the 72 h following randomization (11 of 20 patients with iNO versus 9 of 20 patients with conventional therapy, p = 0.55). In patients with severe ARDS, our results indicate that iNO does not lead to a sustained improvement in oxygenation as compared with conventional therapy.

Signal-dependent translation of a regulatory protein, Bcl-3, in activated human platelets.

Circulating human platelets lack nuclei, cannot synthesize mRNA, and are considered incapable of regulated protein synthesis. We found that thrombin-activated, but not resting, platelets synthesize Bcl-3, a member of the IkappaB-alpha family of regulatory proteins. The time- and concentration-dependent generation of Bcl-3 in platelets signaled by thrombin was blocked by translational inhibitors, by rapamycin, and by inhibitors of phosphatidylinositol-3-kinase, indicating that it occurs via a specialized translational control pathway that involves phosphorylation of the inhibitory protein 4E-BP1. After its synthesis in activated platelets Bcl-3 binds to the SH3 domain of Fyn (p59(fyn)), a Src-related tyrosine kinase. This, along with its expression in anucleate cells, suggests that Bcl-3 has previously unrecognized functions aside from modulation of transcription. We also demonstrate that platelets synthesize and secrete numerous proteins besides Bcl-3 after they adhere to fibrinogen, which mediates adhesion and outside-in signaling of these cells by engagement of alphaIIb/beta3 integrin. Taken together, these data demonstrate that regulated synthesis of proteins is a signal-dependent activation response of human platelets.

Succinylcholine-induced hyperkalemia following prolonged pharmacologic neuromuscular blockade.

While being treated for the acute respiratory distress syndrome, a 27-year-old woman developed profound hyperkalemia and cardiac arrest following the administration of succinylcholine chloride (SCh). She had none of the risk factors previously described for development of severe hyperkalemia following SCh administrations; however, she had been intermittently treated with nondepolarizing neuromuscular blocking drugs throughout the course of her illness. We suggest that immobilization of critically ill patients with pharmacologic neuromuscular blockade may predispose them to severe hyperkalemia and cardiac arrest following administration of SCh. SCh should be used with great caution in such patients.

Activated platelets signal chemokine synthesis by human monocytes.

Human blood monocytes adhere rapidly and for prolonged periods to activated platelets that display P-selectin, an adhesion protein that recognizes a specific ligand on leukocytes, P-selectin glycoprotein-1. We previously demonstrated that P-selectin regulates expression and secretion of cytokines by stimulated monocytes when it is presented in a purified, immobilized form or by transfected cells. Here we show that thrombin-activated platelets induce the expression and secretion of monocyte chemotactic protein-1 and IL-8 by monocytes. Enhanced monokine synthesis requires engagement of P-selectin glycoprotein-1 on the leukocyte by P-selectin on the platelet. Secretion of the chemokines is not, however, directly signaled by P-selectin; instead, tethering of the monocytes by P-selectin is required for their activation by RANTES (regulated upon activation normal T cell expressed presumed secreted), a platelet chemokine not previously known to induce immediate-early gene products in monocytes. Adhesion of monocytes to activated platelets results in nuclear translocation of p65 (RelA), a component of the NF-kappaB family of transcription factors that binds kappaB sequences in the regulatory regions of monocyte chemotactic protein-1, IL-8, and other immediate-early genes. However, expression of tissue factor, a coagulation protein that also has a kappaB sequence in the 5' regulatory region of its gene, is not induced in monocytes adherent to activated platelets. Thus, contact of monocytes with activated platelets differentially affects the expression of monocyte products. These experiments suggest that activated platelets regulate chemokine secretion by monocytes in inflammatory lesions in vivo and provide a model for the study of gene regulation in cell-cell interactions.

Platelet-activating factor (PAF): signalling and adhesion in cell-cell interactions.

Signalling by PAF is closely linked to adhesive interactions between cells of the inflammatory and vascular systems. It acts as a juxtacrine signal that alters the activity of beta 2 integrins on myeloid leukocytes (Figure 1), and works in concert with P-selectin at the surfaces of endothelial cells (Figure 2 and text). Observations in models of flow and in vivo support the original experiments using cultured endothelium under static conditions that indicated that PAF acts at this vascular interface. P-selectin modifies and integrates signals delivered through the PAF receptor on monocytes (Figure 4). Adhesion via P-selectin and engagement of beta 2 integrins modify signals leading to PAF synthesis (text and Figure 5). The intimate relationship between adhesive events and signalling by PAF may be a critical determinant in its roles in physiologic and pathologic responses.

P-selectin regulates platelet-activating factor synthesis and phagocytosis by monocytes.

Adhesion molecules on endothelial cells or platelets may regulate localization and activation of leukocytes at sites of tissue injury, infection, or thrombosis. In these studies, we found that human peripheral blood monocytes adhered specifically to immobilized P-selectin (CD62P), Chinese hamster ovary cells transfected with a cDNA for P-selectin, or endothelial cells stimulated to express P-selectin on the cell surface. P-selectin did not directly stimulate synthesis of the lipid autoacoid platelet-activating factor (PAF); however, incubation on immobilized P-selectin primed monocytes for increased synthesis of PAF in response to opsonized zymosan particles. P-selectin did not stimulate increased surface expression of integrin CD11b/CD18 and did not enhance binding of iC3b-coated erythrocytes, a CD11b/CD18-mediated functional response. P-selectin increased PAF production by monocytes incubated with unopsonized zymosan particles that stimulate this response by interaction with the beta-glucan receptor. Further, phagocytosis of unopsonized zymosan particles, another response triggered by the beta-glucan receptor, was increased following the adherence of monocytes to P-selectin. These data suggested that P-selectin primed monocytes for increased PAF synthesis through regulation of the beta-glucan receptor or regulation of signal transduction mechanisms that are linked to the receptor. P-selectin expressed on endothelial cells or platelets may serve both to localize monocytes at sites of vascular inflammation or thrombosis and to prime the cells for subsequent responses that augment inflammation.

The interaction of leukocytes with platelets in blood coagulation.

The concept that leukocytes play an active role in hemostasis and thrombosis has only recently been accepted. Leukocytes may influence coagulation directly, by the production of procoagulant and anticoagulant molecules, or indirectly, by actions on vascular cells including platelets, endothelial cells, and other leukocytes. This review examines the role of leukocytes in coagulation with an emphasis on regulation of leukocyte function by interactions, with platelets. Activated platelets may serve both to localize leukocytes in areas of thrombosis and to modulate their function. Over the past year, several in vitro studies further defined molecular mechanisms by which leukocytes may regulate coagulation. Further, in vivo studies have provided support for the relevance of these mechanisms in pathophysiologic coagulation.

CD11b/CD18 integrin and a beta-glucan receptor act in concert to induce the synthesis of platelet-activating factor by monocytes.

We determined the mechanism by which opsonized zymosan particles, which are derived from yeast and composed of carbohydrate polymers, stimulate platelet-activating factor (PAF) synthesis by monocytes. A role for CD11b/CD18 was demonstrated because antibodies to this integrin decreased PAF synthesis, zymosan bearing only a ligand for CD11b/CD18 (iC3b) induced the synthesis of PAF, and monocytes that did not express CD11b/CD18 produced much less PAF than control monocytes. Ligation of CD11b/CD18 was not sufficient for PAF synthesis suggesting that an additional receptor was involved. Monocytes are known to bind beta-glucan which is a major component of zymosan. Opsonized beta-glucan particles stimulated the synthesis of PAF, and a soluble form of beta-glucan partially inhibited PAF synthesis in response to opsonized zymosan. Two lines of evidence suggested that the beta-glucan receptor mediating this response was distinct from CD11b/CD18. First, CD11b/CD18-deficient monocytes produced PAF when stimulated by zymosan opsonized with isolated C3b, a molecule that binds to complement receptor type 1 (CD35). Second, inducing contact of monocytes with zymosan by centrifugation resulted in PAF synthesis that was not inhibited by antibodies to CD11b/CD18. The combination of soluble beta-glucan and antibodies to CD11b/CD18 completely blocked PAF synthesis in response to opsonized zymosan. Together, these results demonstrate that induction of maximal PAF synthesis by serum-opsonized zymosan requires the concerted interactions of monocyte receptors for iC3b and beta-glucan. Additionally, they suggest that CD11b/CD18 facilitates binding of the particle and that a beta-glucan receptor transduces the activation signal.