Jesper Qvist

Elderly Humans Show Prolonged In Vivo Inflammatory Activity during Pneumococcal Infections

Levels of circulating cytokines were measured in 22 hospitalized patients with pneumococcal infections during the first week after admission, to test for age-associated differences. Twenty-two healthy age- and sex-matched subjects were included as controls. Concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-1 receptor antagonist, soluble TNF receptor I (sTNFR-I), and IL-10 were increased on admission (P<.05), but macrophage inflammatory protein (MIP)-1beta was not. Whereas levels of cytokines were similar on admission, levels of TNF-alpha and sTNFR-I after 1 week were higher (P<.05) in elderly (68-91 years) than in young (37-55 years) patients. Furthermore, plasma levels of IL-10 and sTNFR-I after 1 week were positively correlated with age, and the declines in sTNFR-I and in the TNFalpha/IL-10 ratio from day 0 to day 7 were correlated with age. Thus, aging was associated with prolonged inflammatory activity. This may reflect decreased ability to control the infection or a dysregulated cytokine response.

Ageing Is Associated with a Prolonged Fever Response in Human Endotoxemia

ABSTRACT The purpose of this study was to investigate whether an age-associated impaired acute-phase response exists. Nine healthy elderly volunteers (median, 66 years; range, 61 to 69 years) and eight young controls (median, 24 years; range, 20 to 27 years) were given an intravenous bolus of endotoxin (2 ng/kg). The rectal temperature was monitored continuously, and blood samples for cytokine measurements were obtained before endotoxin administration as well as 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 24 h after the injection. The elderly subjects showed a more prolonged fever response compared to the young controls. Levels of tumor necrosis factor alpha (TNF-α), soluble TNF receptors (sTNFR-I), interleukin-6 (IL-6), IL-8, IL-10, and IL-1 receptor antagonist (IL-1ra) in plasma increased markedly following endotoxin administration in both groups. The elderly group showed larger initial increases in TNF-α and sTNFR-I levels and prolonged increased levels of sTNFR-I. Monocyte concentrations decreased in both groups, with the elderly group showing a more rapid decrease and a slower subsequent increase than did the young group. Furthermore, the elderly group had a more rapid increase in C-reactive protein levels than did the young group. In conclusion, ageing is associated with an altered acute-phase response including initial hyperreactivity, prolonged inflammatory activity, and prolonged fever response.

Cerebral Blood Flow and Oxidative Metabolism During Human Endotoxemia

The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α), has been suggested to mediate septic encephalopathy through an effect on cerebral blood flow (CBF) and metabolism. The effect of an intravenous bolus of endotoxin on global CBF, metabolism, and net flux of cytokines and catecholamines was investigated in eight healthy young volunteers. Cerebral blood flow was measured by the Kety-Schmidt technique at baseline (during normocapnia and voluntary hyperventilation for calculation of subject-specific cerebrovascular CO2 reactivity), and 90 minutes after an intravenous bolus of a reference Escherichia coli endotoxin. Arterial TNF-α peaked at 90 minutes, coinciding with a peak in subjective symptoms. At this time, CBF and Paco2 were significantly reduced compared to baseline; the CBF decrease was readily explained by hypocapnia. The cerebral metabolic rate of oxygen remained unchanged, and the net cerebral flux of TNF-α, interleukin (IL)-1β, and IL-6 did not differ significantly from zero. Thus, high circulating levels of TNF-α during human endotoxemia do not induce a direct reduction in cerebral oxidative metabolism.

Dependency of cerebral blood flow on mean arterial pressure in patients with acute bacterial meningitis.

Objective: Patients with acute bacterial meningitis are often treated with sympathomimetics to maintain an adequate mean arterial pressure (MAP). We studied the influence of such therapy on cerebral blood flow (CBF). Design: Prospective physiologic trial. Setting: The Department of Infectious Diseases, Copenhagen University Hospital, Denmark. Patients: Sixteen adult patients with acute bacterial meningitis. Intervention: Infusion of norepinephrine to increase MAP. Measurements: During a rise in MAP induced by norepinephrine infusion, we measured relative changes in CBF by transcranial Doppler ultrasonography of the middle cerebral artery, recording mean flow velocity (Vmean), and by the arterial to jugular oxygen saturation difference. In 10 out of 16 patients, serial measurements were performed until recovery or death. Individual autoregulation curves were analyzed by a computer program. Autoregulation was classified as impaired if Vmean increased by >10% per 30 mm Hg increase in MAP and if no lower limit of autoregulation was identified by the computer program; otherwise, autoregulation was classified as preserved. Main Results: Initially, Vmean increased from a median value of 46 cm/sec (range, 30‐87 cm/sec) to 63 cm/sec (33‐105 cm/sec) (p < .0001), and arterial to jugular oxygen saturation difference decreased from 0.28 (0.16‐0.51) to 0.21 (0.08‐0.39) (p < .001) when MAP was raised from 69 mm Hg (55‐102 mm Hg) to 110 mm Hg (93‐129 mm Hg). CBF autoregulation was restored in eight of ten patients undergoing serial examination after 7 (range, 2‐10) days. Six of these patients had an uncomplicated course, one had a protracted recovery, and one died. Autoregulation was not restored in two patients; one died and one had a protracted recovery. Conclusion: In patients in the early phase of acute bacterial meningitis, CBF autoregulation is impaired. With recovery from meningitis, the cerebral vasculature regains the ability to maintain cerebral perfusion at a constant level despite variations in MAP.

Epidemiology of intensive care.

It is difficult to study the epidemiology of ICUs, as they lack a uniform nomenclature and/or classification. The organization and distribution of intensive care medicine depend on the size and function of the hospital. The patients in ICUs are predominantly men, with a high proportion of elderly patients (greater than or equal to 70 years) constituting 25-30% of the total. Case-mix, severity of illness and outcome differ from one unit to another, and can be compared only if the patients are classified with a common classification system. Most survivors of intensive care seem to return to normal or near normal functional level within one year. Compared to Western Europe, the United States has more ICU beds and a nearly ten times higher admission rate to intensive care. These variations can be seen as a result of a fundamental difference in the attitudes toward withdrawing or withholding life support.

Activated T Lymphocytes Disappear from Circulation during Endotoxemia in Humans

ABSTRACT Seventeen volunteers received an intravenous bolus of endotoxin (2 ng/kg of body weight). Endotoxin-induced lymphopenia was constituted mainly by cells with an immature phenotype (CD45RA+ CD45RO−) that were less likely to undergo apoptosis (CD28+), whereas cells with the highest rates of disappearance were characterized by an activated phenotype (CD45RA− CD45RO+) as well as a phenotype linked to apoptosis (CD95+ CD28−). In conclusion, endotoxin-induced lymphopenia reflects the disappearance from the circulation of activated lymphocytes prone to undergo apoptosis.

Adrenaline‐induced mobilization of T cells in HIV‐infected patients

The present study aimed to investigate lymphocyte mobilization from peripheral cell reservoirs in HIV‐infected patients. Nine HIV‐infected patients on stable highly active anti‐retroviral therapy (HAART), eight treatment‐naive HIV‐infected patients and eight HIV− controls received a 1‐h adrenaline infusion. The adrenaline infusion induced a three‐fold increase in the concentration of lymphocytes in all three groups. All HIV‐infected patients mobilized significantly higher numbers of CD8+ cells but less CD4+ cells. All subjects mobilized CD45RA+CD62L+ and CD8+CD28+ cells to a lesser extent than CD45RO+CD45RA− and CD8+CD28−cells. Furthermore, high numbers of CD8+CD38+ cells were mobilized only in the HIV‐infected patients. It was therefore predominantly T cells with an activated phenotype which were mobilized after adrenaline stimulation. It is concluded that the HIV‐associated immune defect induced an impaired ability to mobilize immune‐competent cells in response to stress stimuli. Furthermore, the study does not support the idea that CD4+ T cells are trapped in lymph nodes by HIV antigens, because untreated and HAART‐treated HIV‐infected patients mobilized similar numbers of CD4+ T cells. Finally, no evidence was found for the existence of a HAART‐induced non‐circulating pool of CD4+ T cells.

Circulating levels of vasoactive peptides in patients with acute bacterial meningitis

PurposeThe underlying mechanisms for cerebral blood flow (CBF) abnormalities in acute bacterial meningitis (ABM) are largely unknown. Putative mediators include vasoactive peptides, e.g. calcitonin-gene related peptide (CGRP), vasoactive intestinal peptide (VIP), and endothelin-1 (ET-1), all of which may be affected by therapeutic interventions used in the intensive care unit. We measured arterial levels as well as the net cerebral flux of these peptides in patients with ABM, and in healthy volunteers undergoing interventions relevant to intensive care.MethodsSeven patients with severe ABM and sepsis and fifteen healthy volunteers were included after informed consent. The net cerebral fluxes of vasoactive peptides were measured by the Kety-Schmidt technique in ABM patients (baseline study only), as well as in volunteers at baseline, during voluntary hyperventilation, after an intravenous injection of lipopolysaccharide (LPS), and during norepinephrine infusion.ResultsThe arterial levels of CGRP, but not of VIP or ET-1, were elevated in patients with ABM, but no net cerebral flux was present. CGRP levels decreased during hyperventilation and after LPS injection. No net cerebral flux of VIP occurred in any group at any time. A cerebral efflux of ET-1, which occurred in volunteers at baseline, was neither present in volunteers after LPS injection nor in patients with ABM.ConclusionThe arterial concentration of the vasodilatory peptide, CGRP, but of neither VIP nor the vasoconstrictor ET-1, is elevated in patients with ABM and sepsis. A constitutive cerebral output of ET-1 appears to be present in healthy humans, but is abolished after LPS injection.

Cardiovascular adjustments to pulmonary vascular injury in dogs.

The hemodynamic effects of blood volume augmentation and mechanical ventilation (MV) with positive end-expiratory pressure (PEEP) were studied in nine Beagles anesthetized with halothane before and after thrombin-induced pulmonary hypertension. The effect of therapy with dopamine, norepinephrine with and without nitroglycerine (NTG), and intraaortic balloon pumping (IABP) were studied in a second series of six Beagles. Before thrombin, dextran (35 ml · kg−1) caused a significant increase in right and left ventricular end-diastolic and end-systolic volumes (RV and LVEDV, and RV and LVESV). However, RV and LV performance, as estimated by ejection fraction, was unchanged during volume loading and MV with PEEP when the pulmonary vasculature was intact. The response to volume loading and MV with PEEP was altered significantly once PVR bad been increased with the administration of thrombin. Stroke volumes were decreased, and remained so, despite volume loading and MV with PEEP. LVEDV decreased without a decrease in LVEDP, indicating a decreased LV compliance. Dopamine and norepinephrine with and without NTG increased stroke volumes and RV ejection fraction in contrast to IABP. Assessment of LV performance, according to the Frank-Starling mechanism, requires a measure of end-diastolic volume when diffuse pulmonary vasoconstriction leads to RV distension and LV hypovolemia secondary to septal shift. Measurement of LV filling pressures can provide misleading values to estimate changes in LV volume in this setting. Measurement of ventricular volumes is required for optimal management of patients with severe acute respiratory failure and pulmonary hypertension.

Pulmonary hypertension in a patient with ARDS—a possible side-effect of dopamine treatment

A patient with severe acute pulmonary failure developed pulmonary hypertension with worsening of right ventricular failure during treatment with dopamine. Ventricular failure was demonstrated by changes in cardiac filling pressures, pulmonary vascular resistance and ventricular volumes. By changing from dopamine to isoproterenol infusion central hemodynamic parameters normalized within a few hours.