BACKGROUND: The assessment of autonomic function is an important tool for risk stratification in critically ill patients. Peripheral cardiac chemoreflex sensitivity has been considered a marker for increased risk of sudden cardiac death. In normals, the evaluation of peripheral cardiac chemoreflex sensitivity is performed under controlled breathing conditions during inhalation of hypoxic gas. Since this is poorly tolerated by patients, they are commonly studied under hyperoxic conditions, which are not physiological. METHODS: We studied 20 healthy volunteers who underwent free and controlled breathing of a hypoxic gas mixture (10% O2 in N2) over 5 min. Values of peripheral cardiac chemoreflex sensitivity, corrected for respiratory influence, were compared with the results obtained experimentally under controlled breathing conditions in the same subjects. RESULTS: We found a substantial difference between values obtained during free and controlled breathing (3.64 +/- 0.81 vs. 1.53 +/- 0.32 ms/mmHg, respectively; P < 0.05). After application of a respiratory correction, described and validated in this article, no significant difference was seen for these values (0.89 +/-0.91 vs. 1.53 +/- 0.32 ms/mmHg, P = 0.46). CONCLUSIONS: This approach allows the evaluation of peripheral cardiac chemoreflex sensitivity in free breathing subjects. This correction could improve the assessment of cardiac chemoreflex sensitivity in patients with cardiorespiratory disorders, who find it difficult to control their breathing according to an experimental protocol.

Adult↗

PubMed2001

Pathophysiology of septic shock and multiple organ dysfunction syndrome and various therapeutic approaches with special emphasis on immunoglobulins.

The pathophysiology of sepsis and septic shock is dominated by an imbalance of pro- and antiinflammatory mediators produced by toxin-activated inflammatory cells. Both the overshooting of proinflammatory mediators as well as the development of immune paralysis are deleterious to the patient. Available therapeutic approaches with monoclonal antibodies and antagonists targeted against toxins and mediators have focused mainly on inhibition of overshooting proinflammation: the results, however, have been disappointing. Due to these disappointing results of specific antiinflammatory regimens, adjuvant treatment of sepsis and septic shock with intravenous immunoglobulins (IVIgs) has regained interest although this indication has at best been validated in part. Likely beneficial mechanisms of action may include the improvement of serum bactericidal activity due to neutralizing and opsonizing IgG and IgM antibodies as well as stimulation of phagocytosis and neutralization of bacterial endo- and exotoxins; another attractive mode of action may represent Ig-mediated modification and specific suppression of proinflammatory cytokine release from endotoxin- and superantigen-activated blood cells. For the total group of patients with sepsis and septic shock, a reduction in mortality by IVIg could not be documented; however, in the SBITS study with 653 patients included, a moderate improvement in sepsis morbidity and multiple organ dysfunction syndrome was demonstrated. In defined sepsis sub-groups, a reduction in mortality by IVIg has been seen in each small, not yet confirmed trial. Thus, IVIg is not a magic bullet of sepsis treatment, but it may reduce morbidity and thereby may be useful in the therapeutic mosaic of sepsis treatment.

Animals↗

PubMed2001

Endogenous nitric oxide and soluble tumor necrosis factor receptor levels are enhanced in infants with congenital heart disease.

OBJECTIVE: This study was designed to investigate cytokine and nitric oxide levels in pediatric patients suffering from chronic heart failure and to investigate effects of beta-blocker treatment on these levels. PATIENTS: Fifteen infants with heart failure resulting from left-to-right shunts with pulmonary overcirculation were compared with 11 infants with cyanotic heart defects with reduced pulmonary blood flow. Four of these patients were finally treated with the beta-blocker propranolol. MEASUREMENTS: Endogenous nitric oxide production was determined by measuring total plasma nitrite/nitrate (Griess method), and levels of soluble tumor necrosis factor receptors type 1 and type 2 (TNF-R1 and TNF-R2, respectively) were measured by commercially available enzyme-linked immunosorbent assay. MAIN RESULTS: In infants with left-to-right shunts, soluble tumor necrosis factor receptor levels were significantly elevated as compared with infants with cyanosis (TNF-R1: 1.7 +/- 0.5 vs. 0.8 +/- 0.3 ng/mL; p =.0003; TNF-R2: 8.1 +/- 4.0 vs. 5.1 +/- 3.2 ng/mL; p =.049). In addition, we found a significant correlation between nitrate/nitrite levels and TNF-R1 (r =.70; p =.0001) or TNF-R2 (r =.62; p =.0013), respectively. Furthermore, the tumor necrosis factor receptor levels in four children after beta-blocker treatment were lower as compared with levels before beta-blocker treatment. CONCLUSIONS: Immune mechanisms, such as cytokine or nitric oxide production, may be involved in pathogenesis of heart failure in children, and may contribute to the beneficial effects of beta-blocker treatment observed in these patients.

Adrenergic beta-Antagonists↗

PubMed2001

Interleukin-1 and related proteins in cardiovascular disease in adults and children.

Interleukin-1 (IL-1) is a key mediator in the cytokine network, controlling important functions in the immune system, during development, infection, inflammation, cell-differentiation, tissue remodelling, and even cell death. The agonistic isoforms of IL-1 (i.e., IL-1alpha and IL-1beta), the IL-1 receptor antagonists, the receptors and receptor-associated proteins, as well as the recently identified IL-18 and its receptor belong to the IL-1 family of proteins. Activation of the IL-1beta and IL-18 precursors is performed enzymatically by caspase-1, previously termed IL-1beta-converting enzyme (ICE). This molecule is the founding member of the caspase family of enzymes, which are involved in maturation of cytokines and in initiation and execution of apoptotic processes. It has been suggested that cytokines and apoptosis are involved in pathogenesis of cardiovascular diseases such as atherosclerosis, chronic heart failure, myocarditis, cardiomyopathy, or stroke. Since IL-1, like TNF, is a central mediator in the cytokine network, it may act as a potent activator of cardiovascular cells. We know that cells of the vessel wall and the heart can produce IL-1 and respond to this mediator by production of other cytokines or regulation of other cardiovascular cell functions. Thus, this report summarizes general information about the molecules of the IL-1 family of proteins, including the caspases, as well as data regarding these proteins in relation to the vessel wall and the heart and their role in cardiovascular disease in adults and children. The summarized information indicates a role of these molecules in regulation of local inflammatory responses during cardiovascular disease.

Adult↗

PubMed2001

Autonomic dysfunction in the ICU patient.

The sympathetic-parasympathetic balance may be altered in critically ill patients. Assessment of autonomic function provides information concerning prognosis, pathogenesis, and treatment strategies in ICU-relevant disorders. Proven tools are heart rate variability, baroreflex sensitivity, and, with limitations, cardiac chemoreflex sensitivity. New nonlinear methods are being evaluated that may predict risk more precisely in critically ill patients. This article summarizes application of these tools in the ICU. In addition, a model is introduced for investigating the impaired autonomic function in multiple organ dysfunction syndrome and sepsis, integrating extrinsic mechanisms and factors that are intrinsic to the cardiac tissue. By this combined approach, the authors hope to gain insight into the pathogenesis of multiple organ dysfunction syndrome. New pathophysiologic concepts are needed for the development of treatment strategies for this life-threatening disease.

Autonomic Nervous System↗

PubMed2001

Intravenous immunoglobulin for prophylaxis and therapy of sepsis.

Intravenous immunoglobulins (IVIg) are widely used as prophylaxis against and as supplemental treatment of sepsis and septic shock, although this concept does not belong to the currently approved medical indications for IVIg products. A reduction in mortality by pooled IVIgGMA more than by IVIgG alone was reported in the recent Cochrane database (eight trials, 492 patients). However, the failure to reduce mortality by IVIgG in the score-based immunoglobulin treatment in sepsis study (653 patients) seriously questions whether IVIgG may reduce mortality. Patients with streptococcal toxic shock syndrome might benefit from IVIg, although it remains questionable whether large controlled trials will ever be available. Intravenous immunoglobulin prophylaxis can undoubtedly reduce the occurrence of infections-especially pneumonias-in at-risk patients. More data are necessary to ascertain whether this beneficial effect is linked with a reduction of infection-related morbidity and mortality. Ongoing studies will document whether cardiac surgery patients with escalating systemic inflammatory response syndrome or mediastinitis will benefit from IVIg. IgM-specific complement inactivation may further stimulate the discussion of IVIgGMA superiority over IVIgG.

Dose-Response Relationship, Drug↗

PubMed2000

[Anaphylactic shock].

IgE-dependent and IgE-independent hypersensitivity reactions, the latter due to physical, chemical or hyperosmolar stimuli, may evolve as anaphylaxis or an anaphylactoid reaction, by an escalating release of mediators from mast cells and basophils. Without immediate treatment, anaphylaxis goes along with substantial morbidity (shock, multiple organ failure) and mortality; within minutes this explosive clinical response can be fatal. The severity of anaphylactic/anaphylactoid reactions is graded from stages 0 to IV in order to guide the management of this disease, stage III corresponding to anaphylactic shock. Severe anaphylactic reactions may take a progressive course despite adequate therapy; even in the case of an initial favourable response to treatment measures life-threatening symptoms may recur; there may be late-phase reactions 6 to 12 hours after the initial reaction. For the initial emergency management a differentiation between IgE-mediated and IgE-independent anaphylactoid reactions is not required. These are the pertinent principles of therapy in hypotensive and hypoxic patients: removal of the likely noxious agent at the site of introduction, provision of a patent airway, 100% oxygen supplementation, intravenous fluid therapy and pharmacological support with catecholamines. After primary care the monitoring and therapy of the patient with anaphylactic shock has to be continued on the intensive care unit. Guidelines for management of acute anaphylaxis referring to both the stage of disease including shock and the main clinical manifestation (cutaneous, pulmonary, cardiovascular) have been established by a German interdisciplinary consensus conference and were published in 1994; consensus guidelines for emergency medical treatment have been communicated by the ILCOR (1997) and the Project Team of the Resuscitation Council (UK) (1999).

Acute Disease↗

PubMed2000

Heterogeneity of cardiac rat and human elongation factor 2.

Elongation factor 2 (EF-2) catalyses the last step of the elongation cycle, translocation, in the course of protein biosynthesis. A system for analyzing post-translational modifications of EF-2, which is a single polypeptide of 857 amino acids, is reported and its application to cytosolic extracts of cultured neonatal rat heart myocytes, neonatal and adult rat cardiac tissue, and extracts of human left ventricular myocardium is described. Comparing different pH ranges in immobilized pH gradient-isoelectric focusing (IPG-IEF), a range of pH 3 - 10 and 4 - 9 resulted in a highly defined and reproducible resolution of six different EF-2 variants of all extracts in the first dimension. These six variants were detected by the "imaging plate" (phosphor radiation image sensor) after specific labeling with Pseudomonas exotoxin A catalyzed [32P]ADP-ribosylation. This finding could be confirmed in Western blot analysis with a specific polyclonal rabbit antibody. Using two-dimensional polyacrylamide gel electrophoresis (2-D-PAGE), five to six EF-2 variants could be demonstrated in all extracts. By application of a second IPG indicator strip to the 2-D gel, they could be aligned with corresponding spots in a silver-stained 2-D separation of human myocardial tissue, revealing that the EF-2 variants belong to the group of low-abundance proteins.

Adenosine Diphosphate Ribose↗

PubMed2000

Processing of interleukin-18 by human vascular smooth muscle cells.

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Caspase 1↗

PubMed2000

Immune modulation by catecholamines--a potential mechanism of cytokine release in heart failure?

Cytokine blood levels are found to be moderately elevated in chronic heart failure, as a function of severity of disease. The source of these cytokines and the trigger mechanisms stimulating cytokine release are a matter of intense research. Potential players include bacterial endotoxin from intestinal translocation, a neurohumoral dysbalance with an enhanced sympathetic tone or an overspill of cytokines from the failing heart itself. We present arguments in favor of a direct link between the chronically enhanced sympathetic tone in heart failure and the clinically overt activation of the immune system, particularly interleukin 6 release.

Catecholamines↗

PubMed2000

[Therapy of acute heart failure. Emergency therapy].

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Acute Disease↗