Microcirculatory dysfunction and tissue oxygenation in critical illness.

Severe sepsis is defined by organ failure, often of the kidneys, heart, and brain. It has been proposed that inadequate delivery of oxygen, or insufficient extraction of oxygen in tissue, may explain organ failure. Despite adequate maintenance of systemic oxygen delivery in septic patients, their morbidity and mortality remain high. The assumption that tissue oxygenation can be preserved by maintaining its blood supply follows from physiological models that only apply to tissue with uniformly perfused capillaries. In sepsis, the microcirculation is profoundly disturbed, and the blood supply of individual organs may therefore no longer reflect their access to oxygen. We review how capillary flow patterns affect oxygen extraction efficacy in tissue, and how the regulation of tissue blood flow must be adjusted to meet the metabolic needs of the tissue as capillary flows become disturbed as observed in critical illness. Using the brain, heart, and kidney as examples, we discuss whether disturbed capillary flow patterns might explain the apparent mismatch between organ blood flow and organ function in sepsis. Finally, we discuss diagnostic means of detecting capillary flow disturbance in animal models and in critically ill patients, and address therapeutic strategies that might improve tissue oxygenation by modifying capillary flow patterns.

Impaired NO-mediated vasodilatation in rat coronary arteries after asphyxial cardiac arrest.

BACKGROUND: Cardiovascular dysfunction after cardiac arrest is a common finding. It is unknown whether altered endothelium-mediated vasoreactivity contributes to this dysfunction. We hypothesised that cardiac arrest and resuscitation results in impaired endothelial function. This was addressed by measurements of inflammatory and endothelial plasma markers and of endothelium-dependent vasodilatation in coronary and mesenteric arteries in rats after cardiac arrest and resuscitation. METHODS: Male Sprague Dawley rats underwent either asphyxia-induced cardiac arrest for 5 min and subsequent resuscitation (n = 30) or a sham procedure (control animals, n = 39). Animals were euthanised after 30 min or 2 h. Blood was analysed for TNF-α, IL-1ß, IL-6, IL-10, sE-selectin, sP-selectin, sVCAM-1, ICAM-1, VEGF-α and vWF. Arterial rings of the left anterior descending coronary artery and mesenteric resistance arteries were mounted in microvascular myographs, and concentration-response curves were constructed. RESULTS: The plasma levels of the endothelial markers, sP-selectin and vWF increased following cardiac arrest at both 30 min and 2 h. Acetylcholine-induced endothelium-dependent and mainly nitric oxide (NO)-mediated vasodilatation was impaired in the coronary arteries at 30 min, but not 2 h after resuscitation. Endothelium-derived hyperpolarisation (EDH)-type vasodilatation induced by NS309 and vasodilatation induced by the NO donor sodium nitroprusside was unaltered. In parallel with systemic hypotension, mesenteric arteries exhibited a larger response to NS309 2 h after resuscitation. CONCLUSION: The present results show marked endothelial alterations after cardiac arrest and resuscitation reflected by increased endothelial plasma markers, impaired NO-mediated coronary vasodilatation in the early post-resuscitation phase and enhanced EDH-type vasodilatation in mesenteric arteries later in the post-resuscitation phase.

Fluctuations in sedation levels may contribute to delirium in ICU patients.

BACKGROUND: Delirium in patients admitted to the intensive care unit (ICU) is a serious complication potentially increasing morbidity and mortality. The aim of this study was to investigate the impact of fluctuating sedation levels on the incidence of delirium in ICU. METHODS: A prospective cohort study of adult patients at three multidisciplinary ICUs. The Richmond Agitation and Sedation Scale (RASS) and the Confusion Assessment Method for the ICU were used at least twice a day. RESULTS: Delirium was detected at least once in 65% of the patients (n = 640). Delirious patients were significantly older, more critically ill, more often intubated, had longer ICU stays, and had higher ICU mortality than non-delirious patients. The median duration of delirium was 3 days (interquartile range: 1;10), and RASS was less than or equal to 0 (alert and calm) 91% of the time. The odds ratio (OR) for development of delirium if RASS changed more than two levels was 5.19 when adjusted for gender, age, severity of illness, and ICU site and setting. Continuous infusion of midazolam was associated with a decrease in delirium incidence (OR: 0.38; P = 0.002). CONCLUSIONS: Fluctuations in sedation levels may contribute to development of delirium in ICU patients. The risk of developing delirium might be reduced by maintaining a stable sedation level or by non-sedation.

Erythropoietin does not attenuate renal dysfunction or inflammation in a porcine model of endotoxemia.

BACKGROUND: Erythropoietin (EPO) is a multifunctional cytokine with anti-apoptotic, anti-inflammatory, and organ protective effects. EPO protects against ischemia-reperfusion injuries, and recent reports suggest that EPO also prevents organ dysfunction in experimental sepsis. The aims of this study were to determine whether EPO prevents endotoxemia-induced organ dysfunction in a porcine model and to characterize the immunomodulatory and anti-apoptotic effects of EPO. METHODS: Twenty-eight pigs were randomly assigned to three groups: (1) endotoxemia treated with EPO 5000 IU/kg, (2) endotoxemia treated with placebo, and (3) a sham group anesthetized and submitted to sham operation without treatment. A laparotomy was performed, and a flow probe was placed around the left renal artery, which allowed renal blood flow (RBF) measurements. Endotoxemia was induced by an infusion of lipopolysaccharide. After 2 h, the infusion was reduced to a maintenance dose and the animals were fluid resuscitated. The glomerular filtration rate (GFR), RBF, renal oxygen consumption, and plasma cytokines [interleukin (IL)-1ß, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha] were analyzed. Renal biopsies were analyzed for cytokine content and apoptosis. RESULTS: Endotoxemia elicited impaired renal function, estimated as GFR, and increased the levels of renal apoptotic cells, with no modifying effect of EPO. Furthermore, EPO had no effect on RBF, renal oxygen consumption, or the systemic hemodynamic response to endotoxemia. EPO did not modify the inflammatory response, measured as changes in cytokine levels in plasma and organs. CONCLUSION: EPO did not confer renal protection in this fluid-resuscitated porcine model of endotoxemia, and EPO did not modify the inflammatory response.

Erythropoietin administration is associated with short-term improvement in glomerular filtration rate after ischemia-reperfusion injury.

BACKGROUND: Erythropoietin (EPO) is a cytokine with organ-protective properties. We hypothesized that EPO could attenuate acute renal dysfunction and inflammation in a porcine model of ischemia-reperfusion (IR). Furthermore, we aimed to characterize the impact of EPO on systemic and renal hemodynamics, and renal oxygen consumption. METHODS: Twenty-four pigs were randomly assigned to three groups: (1) EPO (5000 IU/kg) administered intravenously before IR (n=9), (2) placebo administered before IR (n=9), or (3) sham group, anesthetized and operated on only (n=6). IR was induced by clamping the left renal artery for 45 min. Hemodynamics and renal blood flow (RBF) were analyzed continuously. Glomerular filtration rate (GFR), renal oxygen consumption, and plasma cytokines (IL-1ß, IL-6, IL-8, IL-10, and TNF-α) were analyzed hourly. Renal biopsies were analyzed for cytokine content and apoptosis. RESULTS: GFR was higher during reperfusion in the EPO group than in the placebo group (P<0.01). No differences between the IR groups were found in hemodynamics, RBF, oxygen consumption, or renal apoptosis. The levels of TNF-α in the plasma (P=0.036) and the levels of TNF-α and IL-10 in the renal cortex (P=0.04 and P=0.01, respectively) were lower in the EPO group compared with the sham group. CONCLUSION: EPO attenuated the renal dysfunction as estimated as GFR. This effect was not related to changes in the hemodynamics. The immunomodulatory effects of EPO were manifested as decreased levels of TNF-α and IL-10 in renal biopsies and TNF-α levels in plasma.

Brief report: biomarkers of aortic vascular prosthetic graft infection in a porcine model with Staphylococcus aureus.

Aortic vascular prosthetic graft infection (AVPGI) with Staphylococcus aureus is a feared post-operative complication. This study was conducted to evaluate the clinical signs and potential biomarkers of infection in a porcine AVPGI model. The biomarkers evaluated were: C-reactive protein (CRP), fibrinogen, white blood cells (WBC), major histocompatibility complex II (MHC II) density, lymphocyte CD4:CD8 ratio and tumour necrosis factor-alpha (TNF-α) in vitro responsiveness. Sixteen pigs were included in the study, and randomly assigned into four groups (n = 4): "SHAM" pigs had their infra-renal aorta exposed by laparotomy; "CLEAN" pigs had an aortic graft inserted; "LOW" and "HIGH" pigs had an aortic graft inserted and, subsequently, S. aureus were inoculated on the graft material (5 × 10(4) colony-forming units [CFU] and 1 × 10(6) CFU, respectively). Biomarkers were evaluated prior to surgery and on day 2, 5, 7, and 14 post-operatively in blood samples. Of all biomarkers evaluated, CRP was superior for diagnosing S. aureus AVPGI in pigs, with a sensitivity of 0.86 and a specificity of 0.75.

[Continuous venovenous hemodiafiltration in critically ill patients with acute renal failure]. / Kontinuerlig venovenøs haemodiafiltration til kritisk syge patienter med akut nyresvigt.

The development of computerized machines with a simple user-friendly interface to perform continuous venovenous hemodiafiltration (CVVHDF) has resulted in a break-through of CVVHDF in the treatment of acute renal failure (ARF) in Danish intensive care units. During CVVHDF the blood is submitted to a combination of dialysis and ultrafiltration. In contrast to intermittent haemodialysis (HD), CVVHDF can be used in critically ill patients with unstable circulation. Biocompatible membranes are used. During treatment with CVVHDF, cytokines are removed from the blood partly by ultrafiltration, partly by adsorption to the filter. The clinical importance of this is not yet known. Patients with ARF treated with CVVHDF seem to be more likely to show renal recovery than those treated with HD. There are few prospective investigations of the effect of CVVHDF on mortality, but all comparisons of CVVHDF with HD indicate a trend in favor of CVVHDF.

[Antibiotic prophylaxis in adult critically ill patients in intensive care units]. / Profylaktisk antibiotikabehandling til kritisk syge patienter indlagt på intensiv afdeling.

OBJECTIVES: To determine whether antibiotic prophylaxis reduces respiratory tract infections (RTI) and overall mortality in an unselected adults intensive care population. SEARCH STRATEGY: Systematic literature search in peer-reviewed journals indexed in MEDLINE, examination of relevant proceedings of scientific meetings and personal contact with trialists. SELECTION CRITERIA: All randomised clinical trials (RCTs), published and unpublished, comparing different forms of antibiotic prophylaxis used to reduce RTIs and mortality in unselected adult intensive care units (ICUs) populations. DATA COLLECTION AND ANALYSIS: Out of the 32 RCTs eligible for this review data have been extracted from published reports and then complemented with information provided by study investigators for 29 trials. Data were available only from published reports in the remaining three RCTs. For each trial the following information has been sought: a) method of randomisation; b) use of blinding techniques; c) number of randomised patients; d) number of patients with RTIs; e) number of deaths; f) number of patients excluded from the published analysis; g) number of RTIs and number of deaths among excluded patients. Pooled estimates of treatment effects across trials have been calculated after grouping RCTs in two main, mutually exclusive, categories: a) 15 trials testing the effect of a combination of a topical and a systemic antibiotic against no prophylactic treatment; b) 17 trials where the experimental treatment was a topical antimicrobial preparation. Crude proportions of RTIs and mortality were used to calculate the overall treatment effect. We also computed the number of ICU patients who need to be treated in order to prevent one infection and one death. MAIN RESULTS: Overall 32 RCTs including 5639 patients were identified. Pooled estimates of the 15 RCTs (including 3273 patients) testing the effect of the topical and systemic antibiotic combination indicate a strong significant reduction of both RTIs (OR = 0.36, 95% CI = 0.30-0.43) and total mortality (OR = 0.80, 95% CI = 0.68-0.93). Five and 23 patients need to be treated to prevent one infection and one death, respectively, using this treatment. When data on the effect of the combination based on topical antimicrobials were pooled from the 17 available trials (including 2366 patients) a marked reduction on RTIs (OR = 0.57, 95% CI = 0.46-0.69) also emerged but no corresponding effect on overall mortality (OR = 1.01; 95% CI = 0.84-1.22) was found. CONCLUSIONS: After 15 years of clinical research this meta-analysis of 32 RCTs shows that a regimen of antibiotic prophylaxis based on a combination of a systemic and topical antibiotic can reduce both RTIs and overall mortality in ICU patients in a way that is both statistically significant and humanly worthwhile. Over and above their personal opinions intensivists should take this evidence into account when defining their policies.

[Artificial respiration in patients with acute severe asthma. Mode of ventilation and survival]. / Respiratorbehandling af patienter med akut svaer astma. Ventilationsstrategi og overlevelse.

The purpose of the study was to register the treatment, mode of ventilation and mortality of patients with acute severe asthma treated with intermittent positive pressure ventilation (IPPV) in a Danish intensive care unit (ICU) during a ten-year period. Fifty-seven patients underwent ventilation on 78 occasions. Fifty-three patients were ventilated with controlled hypoventilation and low PEEP, while four patients were treated with high PEEP. One of the 53 patients receiving controlled hypoventilation and two of the four patients who received high PEEP developed a pneumothorax. All the patients were treated with intravenous steroid and infusion of a beta 2-agonist. Eighty-eight point three per cent received an infusion of theophylline whereas only 16.9% were treated with inhalation of a beta 2-agonist. Eight patients already had irreversible brain damage due to cardiac arrest before arrival to the ICU. Seven of these patients died due to brain damage. All the patients who reached the ICU without brain damage survived. After discharge from the hospital increased mortality was observed among these patients. Some of the patients died due to underestimation from doctors as well as patients of the severity of the asthma. Patients with acute severe asthma requiring IPPV should be ventilated with controlled hypoventilation. A high PEEP is associated with an increased risk of barotrauma. Continuing education of doctors and patients is necessary to increase the use of objective airflow measurement.