Wolfgang J. Kox

Wasting as independent risk factor for mortality in chronic heart failure

BACKGROUND Wasting in chronic heart failure (CHF) has long been known but is little investigated. We sought to find out whether the cachectic state in CHF provides additional prognostic information about all-cause mortality. METHODS Between June, 1993, and May, 1995, we studied 171 consecutive patients with CHF (mean age 60 years [SD 11; range 27-86]; 17 female). We assessed exercise capacity (peak oxygen consumption; mean 17.5 mL kg-1 min-1 [6.7]), functional status (New York Heart Association [NYHA] class: 21 class I, 63 class II, 68 class III, 19 class IV), and left-ventricular ejection fraction (mean 30% [SD 15]; n = 115). The cachectic status was defined prospectively as a non-intentional documented weight loss of at least 7.5% of previous normal weight (28 patients; range 9-36% or 6-30 kg) during at least 6 months. The Cox proportional-hazards model was used to assess the association of variables with survival, and Kaplan-Meier cumulative survival plots were constructed to estimate the influence of risk factors. FINDINGS At the end of follow-up in November, 1996, 49 patients had died (after a mean 324 days [SD 283]). The mean follow-up of the survivors was 834 days (SD 186; range 549-1269). The cachectic state was predictive of 18-month mortality independent of age, NYHA class, left-ventricular ejection fraction, and peak oxygen consumption. Mortality in the cachectic patients (n = 28) was 18% at 3 months, 29% at 6 months, 39% at 12 months, and 50% at 18 months. Patients who had a peak oxygen consumption below 14 mL kg-1 min-1 (n = 53) had mortality at 3, 6, 12, and 18 months of 19%, 30%, 40%, and 51%. 18-month survival was 23% (95% CI 0-46) for the 13 patients with both of these risk factors (cachexia and low peak oxygen consumption) compared with 93% (88-98) in those (n = 103) with neither risk factor (p < 0.0001). INTERPRETATION The cachectic state is a strong independent risk factor for mortality in patients with CHF. Combined with a low peak oxygen consumption, it identifies a subset of patients at extremely high risk of death. Assessment of cachexia should be included in transplant programmes and studies that investigate the effect of interventions by survival analyses.

Hormonal Changes and Catabolic/Anabolic Imbalance in Chronic Heart Failure and Their Importance for Cardiac Cachexia

BACKGROUND The role of hormonal and cytokine abnormalities in the development of cardiac cachexia remains obscure. METHODS AND RESULTS Healthy control subjects (n=16) and patients with chronic heart failure (CHF), classified clinically as cachectic (8% to 35% weight loss over > or = 6 months before study, n=16) or noncachectic (n=37), were assessed for markers of disease severity (maximal oxygen consumption, left ventricular ejection fraction, NYHA functional class). These markers were compared with plasma concentrations of potentially important anabolic and catabolic factors. The degree of neurohormonal activation and catabolic/anabolic imbalance was closely related to wasting but not to conventional measures of the severity of heart failure. Compared with control subjects and noncachectic patients, cachectic patients had reduced plasma sodium and increased norepinephrine, epinephrine (all P<.0001), cortisol, tumor necrosis factor (TNF)-alpha (both P<.002), and human growth hormone (P<.05). Insulin-like growth factor-1, testosterone, and estrogen were similar in all groups. Insulin was increased only in the noncachectic patients (P<.005 versus control subjects). Dehydroepiandrosterone was reduced in the cachectic patients (P<.02 versus control subjects). Insulin, cortisol, TNF-alpha, and norepinephrine correlated independently with wasting in CHF (P<.05; multiple regression of these four factors versus percent ideal weight, R2=.50, P<.0001). CONCLUSIONS Cachexia is more closely associated with hormonal changes in CHF than conventional measures of the severity of CHF. This study suggests that the syndrome of heart failure progresses to cardiac cachexia if the normal metabolic balance between catabolism and anabolism is altered.

Monocyte deactivation : rationale for a new therapeutic strategy in sepsis

Inflammatory cells, in particular monocytes/macrophages, release pro-inflammatory mediators in response to several infectious and non-infectious stimuli. The excessive release of these mediators, resulting in the development of whole body inflammation, may play an important role in the pathogenesis of sepsis and septic shock. TNF-alpha, acting synergistically with cytokines such as IL-1, GM-CSF and IFN-gamma, is the key mediator in the induction process of septic shock, as shown in several experimental models. Based on this concept and on the encouraging results obtained in several experimental models, a number of clinical sepsis trials targeting the production or action of TNF-alpha or IL-1 have been performed in recent years. Unfortunately, these trials have failed to demonstrate a therapeutic benefit. One reason for this may be the lack of exact immunologic analyses during the course of septic disease. Recently, we demonstrated that there is a biphasic immunologic response in sepsis: an initial hyperinflammatory phase is followed by a hypo-inflammmatory one. The latter is associated with immunodeficiency which is characterized by monocytic deactivation, which we have called “immunoparalysis”. While anti-inflammatory therapy (e.g. anti-TNF antibodies, IL-1 receptor antagonist, IL-10) makes sense during the initial hyperinflammatory phase, immune stimulation by removing inhibitory factors (plasmapheresis) or the administration of monocyte activating cytokines (IFN-gamma, GM-CSF) may be more useful during “immunoparalysis”.

Invariant reversible QEEG effects of anesthetics

Continuous recordings of brain electrical activity were obtained from a group of 176 patients throughout surgical procedures using general anesthesia. Artifact-free data from the 19 electrodes of the International 10/20 System were subjected to quantitative analysis of the electroencephalogram (QEEG). Induction was variously accomplished with etomidate, propofol or thiopental. Anesthesia was maintained throughout the procedures by isoflurane, desflurane or sevoflurane (N = 68), total intravenous anesthesia using propofol (N = 49), or nitrous oxide plus narcotics (N = 59). A set of QEEG measures were found which reversibly displayed high heterogeneity of variance between four states as follows: (1) during induction; (2) just after loss of consciousness (LOC); (3) just before return of consciousness (ROC); (4) just after ROC. Homogeneity of variance across all agents within states was found. Topographic statistical probability images were compared between states. At LOC, power increased in all frequency bands in the power spectrum with the exception of a decrease in gamma activity, and there was a marked anteriorization of power. Additionally, a significant change occurred in hemispheric relationships, with prefrontal and frontal regions of each hemisphere becoming more closely coupled, and anterior and posterior regions on each hemisphere, as well as homologous regions between the two hemispheres, uncoupling. All of these changes reversed upon ROC. Variable resolution electromagnetic tomography (VARETA) was performed to localize salient features of power anteriorization in three dimensions. A common set of neuroanatomical regions appeared to be the locus of the most probable generators of the observed EEG changes.

Immunomodulatory therapies in sepsis

Abstract Despite advances in critical care medicine, mortality from sepsis in ICU patients remains high. In response to several infectious and non-infectious stimuli, monocytes/macrophages release a number of mediators, including cytokines, involved in the proinflammatory response that underlies sepsis. The excessive release of these mediators results in the development of whole body inflammation, and plays an important role in the pathogenesis of sepsis and septic shock. In addition, patients with sepsis also undergo an anti-inflammatory phase (the compensatory anti-inflammatory response syndrome) and at times, a mixed response with both pro-and anti-inflammatory components (the mixed antagonistic response syndrome). The initial systemic hyperinflammation is caused by production of inflammatory cytokines, especially tumour necrosis factor-α (TNF-α), and also interleukin-1 (IL-1), IL-6, and interferon gamma, which act synergistically with TNF-α in inducing shock in animal models. However, clinical trials aimed at downregulating these mediators using antibodies against endotoxin, TNF-α, antagonists of IL-1 or platelet activating factor have proved to be uniformly disappointing. Not only have these agents been found to have no effect, but they may also increase mortality. One of the reasons for such failure may be the lack of precise immunological monitoring during the course of sepsis.¶We have recently demonstrated that sepsis shows a biphasic immunological pattern during the initial and later phase: the early hyperinflammatory phase is counterbalanced by an anti-inflammatory response which may lead to a hypoinflammatory state. The latter is associated with immunodeficiency that is characterised by monocytic deactivation, so-called immunoparalysis. Interferon gamma-1 b has an immunoregulatory effect in patients with immunoparalysis during the compensatory anti-inflammatory response syndrome, not only restoring levels of HLA-DR expression but also re-establishing the ability of monocytes to secrete cytokines such as TNF-α. By monitoring immune status in septic patients, targeted intervention may lead to more success in immunomodulation of sepsis.

Bispectral index-guided sedation with dexmedetomidine in intensive care : a prospective, randomized, double blind, placebo-controlled phase II study

ObjectiveTo compare dexmedetomidine vs. placebo with respect to the amount of additional propofol and morphine used for bispectral index-guided sedation and analgesia in mechanically ventilated, intensive care patients after surgery. DesignProspective, randomized, double blind, placebo-controlled, phase II clinical trial. SettingGeneral surgical and cardiac surgical intensive care units. PatientsThirty patients scheduled for major surgery requiring mechanical ventilation for a minimum of 6 hrs were included in the study. InterventionsPatients were assigned randomly to receive either dexmedetomidine (loading infusion, 6.0 &mgr;g·kg−1·hr−1 for 10 mins; maintenance infusion, 0.1–0.7 &mgr;g·kg−1·hr−1) or placebo after intensive care unit admission. Measurements and Main ResultsSedation was guided by using the electroencephalographic parameter bispectral index, a new noninvasive method to estimate the level of sedation. We aimed at maintaining bispectral index ranges between 60 and 70 during mechanical ventilation before starting weaning, 65 and 95 during weaning, and 85 to 95 postextubation. Additional sedative and analgesic medication was given (propofol and morphine) as clinically indicated and within the previously mentioned bispectral index ranges. Patients receiving dexmedetomidine required significantly less propofol during mechanical ventilation (0.87 ± 0.21 vs. 1.52 ± 0.30 mg·kg−1·hr−1;p < .01) and weaning (0.17 ± 0.06 vs. 0.62 ± 0.21 mg·kg−1·hr−1;p < .001) to maintain the target bispectral index range. During study drug administration, morphine requirements for dexmedetomidine-treated patients were reduced by 58% (p = .05). Hemodynamic stability during weaning and after extubation was better maintained in patients receiving dexmedetomidine. ConclusionsDexmedetomidine reduced propofol requirements and improved hemodynamic stability during bispectral index-guided intensive care unit sedation.

Altered cell-mediated immunity and increased postoperative infection rate in long-term alcoholic patients.

Background: Preoperative alteration of T cell–mediated immunity as well as an altered immune response to surgical stress were found in long-term alcoholic patients. The aim of this study was to evaluate perioperative T cell–mediated immune parameters as well as cytokine release from whole blood cells after lipopolysaccharide stimulation and its association with postoperative infections. Methods: Fifty-four patients undergoing elective surgery of the aerodigestive tract were included in this prospective observational study. Long-term alcoholic patients (n = 31) were defined as having a daily ethanol consumption of at least 60 g and fulfilling the Diagnostic and Statistical Manual of Mental Disorders for either alcohol abuse or alcohol dependence. The nonalcoholic patients (n = 23) were defined as drinking less than 60 g ethanol/day. Blood samples to analyze the immune status were obtained on morning before surgery and on the morning of days 1, 3, and 5 after surgery. Results: Basic patient characteristics did not differ between groups. Before surgery, the T helper 1:T helper 2 ratio (Th1: Th2) was significantly lower (P < 0.01), whereas plasma interleukin 1β and lipopolysaccharide-stimulated interleukin 1ra from whole blood cells were increased in long-term alcoholic patients. After surgery, a significant suppression of the cytotoxic lymphocyte ratio (Tc1:Tc2), the interferon γ:interleukin 10 ratio from lipopolysaccharide-stimulated whole blood cells, and a significant increase of plasma interleukin 10 was observed. Long-term alcoholics had more frequent postoperative infections compared with nonalcoholic patients (54%vs. 26%; P = 0.03). Conclusions: T helper cell–mediated immunity was significantly suppressed before surgery and possibly led to inadequate cytotoxic lymphocyte and whole blood cell response in long-term alcoholic patients after surgery. This altered cell-mediated immunity might have accounted for the increased infection rate in long-term alcoholic patients after surgery.

Hyperprocalcitonemia in patients with noninfectious SIRS and pulmonary dysfunction associated with cardiopulmonary bypass

Background The incidence of noninfectious systemic inflammatory response syndrome (SIRS) associated with coronary artery bypass surgery and the potential role of several inflammatory parameters as early markers of pulmonary dysfunction induced by cardiopulmonary bypass (CPB) were investigated. Methods Forty patients undergoing elective coronary artery bypass surgery were studied prospectively. Perioperative lung function was monitored using the lung injury score introduced by Murray and colleagues, by measuring venous admixture (Qs/Qt), and, in some cases, by measuring extravascular lung water. Serum concentrations of the inflammatory parameters (procalcitonin, interleukin‐6, sL‐selectin, leukocyte elastase, neopterin, leukocyte counts, and C‐reactive protein) were determined sequentially. The American College of Chest Physicians‐Society of Critical Care Medicine classification system was used to diagnose SIRS. Results According to the entry criteria, SIRS developed in 17 (42%) patients after operation. Nine patients of this group showed signs of acute pulmonary impairment, whereas patients without SIRS had no lung injury. In all patients with acute lung injury, distinct increases in procalcitonin concentrations ranging from 5.1 to 14.3 ng/ml were measured. In patients with SIRS but without acute lung injury and in patients without SIRS, none or only negligible increases in serum concentrations of procalcitonin were seen. Compared with procalcitonin, other inflammatory parameters investigated were less sensitive and less specific to indicate pulmonary dysfunction secondary to CPB. Conclusions Procalcitonin seems to be an appropriate parameter indicating the early development of severe noninfectious SIRS and for predicting pulmonary dysfunction secondary to CPB.

Thoracic Epidural Anesthesia Combined with General Anesthesia: The Preferred Anesthetic Technique for Thoracic Surgery

Thoracic epidural anesthesia (TEA) combined with general anesthesia (GA) as well as total-IV anesthesia (TIVA) are both established anesthetic managements for thoracic surgery. We compared them with respect to hypoxic pulmonary vasoconstriction, shunt fraction and oxygenation during one-lung ventilation. Fifty patients, ASA physical status II-III undergoing pulmonary resection were randomly allocated to two groups. In the TIVA group, anesthesia was maintained with propofol and fentanyl. In the TEA group, anesthesia was maintained with TEA (bupivacaine 0.5%) combined with low-dose concentration 0.3–0.5 vol% of isoflurane (end-tidal). Changing from two-lung ventilation to one-lung ventilation caused a significant increase in cardiac output (CO) in the TIVA group, whereas no change was observed in the TEA group. One-lung ventilation caused significant increases in shunt fraction in both groups which was associated per definition with a significant decrease in Pao2 in both groups but Pao2 remained significantly increased in the TEA group (P < 0.05). We conclude that both anesthetic regimens are safe intraoperatively. However, TEA in combination with GA did not impair arterial oxygenation to the same extent as TIVA, which might be a result of the changes in CO. Therefore, patients with preexisting cardiopulmonary disease and impaired oxygenation before one-lung ventilation might benefit from TEA combined with GA.

Oxidized proteins as a marker of oxidative stress during coronary heart surgery

The measurement of the degree of oxidative stress in patients often causes problems because of the lack of useful parameters. Therefore, we used an ELISA technique to evaluate serum protein carbonyls as a parameter of oxidative stress in patients during coronary heart surgery. Protein carbonyls were detected in serum samples of 14 patients undergoing coronary surgery and cardiopulmonary artery bypass grafting. A clear 2- to 3-fold increase in protein carbonyls in serum samples taken from human venous coronary sinus could be detected in the reperfusion period of the heart. We compared these data with markers of oxidative stress previously used, such as the glutathione status and the lipid peroxidation product malondialdehyde (MDA). Strong correlations of the protein carbonyl formation with MDA (r2 = 0.86) and oxidized glutathione (r2 = 0.81) were found in the early reperfusion stage. Increased levels of oxidized glutathione and MDA were detected only in the early reperfusion period. In contrast, the serum protein carbonyl content remained elevated for several hours, indicating a considerably slower serum clearance of oxidized proteins compared with that of lipid peroxidation products and the normalization of the glutathione status. We therefore concluded that the measurement of serum carbonyls by this ELISA technique is suitable to detect oxidative stress in serum samples of patients. The relative stability of the parameter makes the protein carbonyl detection even more valuable for clinical purposes.