Showing papers by "Peter Pickkers published in 2017"

A guiding map for inflammation

Abstract: Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.

Acute hypoxemic respiratory failure in immunocompromised patients: the Efraim multinational prospective cohort study

Abstract: In immunocompromised patients with acute hypoxemic respiratory failure (ARF), initial management aims primarily to avoid invasive mechanical ventilation (IMV). To assess the impact of initial management on IMV and mortality rates, we performed a multinational observational prospective cohort study in 16 countries (68 centers). A total of 1611 patients were enrolled (hematological malignancies 51.9%, solid tumors 35.2%, systemic diseases 17.3%, and solid organ transplantation 8.8%). The main ARF etiologies were bacterial (29.5%), viral (15.4%), and fungal infections (14.7%), or undetermined (13.2%). On admission, 915 (56.8%) patients were not intubated. They received standard oxygen (N = 496, 53.9%), high-flow oxygen (HFNC, N = 187, 20.3%), noninvasive ventilation (NIV, N = 153, 17.2%), and NIV + HFNC (N = 79, 8.6%). Factors associated with IMV included age (hazard ratio = 0.92/year, 95% CI 0.86–0.99), day-1 SOFA (1.09/point, 1.06–1.13), day-1 PaO2/FiO2 (1.47, 1.05–2.07), ARF etiology (Pneumocystis jirovecii pneumonia (2.11, 1.42–3.14), invasive pulmonary aspergillosis (1.85, 1.21–2.85), and undetermined cause (1.46, 1.09–1.98). After propensity score matching, HFNC, but not NIV, had an effect on IMV rate (HR = 0.77, 95% CI 0.59–1.00, p = 0.05). ICU, hospital, and day-90 mortality rates were 32.4, 44.1, and 56.4%, respectively. Factors independently associated with hospital mortality included age (odds ratio = 1.18/year, 1.09–1.27), direct admission to the ICU (0.69, 0.54–0.87), day-1 SOFA excluding respiratory score (1.12/point, 1.08–1.16), PaO2/FiO2 < 100 (1.60, 1.03–2.48), and undetermined ARF etiology (1.43, 1.04–1.97). Initial oxygenation strategy did not affect mortality; however, IMV was associated with mortality, the odds ratio depending on IMV conditions: NIV + HFNC failure (2.31, 1.09–4.91), first-line IMV (2.55, 1.94–3.29), NIV failure (3.65, 2.05–6.53), standard oxygen failure (4.16, 2.91–5.93), and HFNC failure (5.54, 3.27–9.38). HFNC has an effect on intubation but not on mortality rates. Failure to identify ARF etiology is associated with higher rates of both intubation and mortality. This suggests that in addition to selecting the appropriate oxygenation device, clinicians should strive to identify the etiology of ARF.

The lung is a host defense niche for immediate neutrophil-mediated vascular protection

Abstract: Bloodstream infection is a hallmark of sepsis, a medically emergent condition requiring rapid treatment. However, upregulation of host defense proteins through toll-like receptors and NFκB requires hours after endotoxin detection. Using confocal pulmonary intravital microscopy, we identified that the lung provides a TLR4-Myd88-and abl tyrosine kinase-dependent niche for immediate CD11b-dependent neutrophil responses to endotoxin and Gram-negative bloodstream pathogens. In an in vivo model of bacteremia, neutrophils crawled to and rapidly phagocytosed Escherichia coli sequestered to the lung endothelium. Therefore, the lung capillaries provide a vascular defensive niche whereby endothelium and neutrophils cooperate for immediate detection and capture of disseminating pathogens.

The Intensive Care Medicine research agenda on critically ill oncology and hematology patients

Abstract: Over the coming years, accelerating progress against cancer will be associated with an increased number of patients who require life-sustaining therapies for infectious or toxic chemotherapy-related events. Major changes include increased number of cancer patients admitted to the ICU with full-code status or for time-limited trials, increased survival and quality of life in ICU survivors, changing prognostic factors, early ICU admission for optimal monitoring, and use of noninvasive diagnostic and therapeutic strategies. In this review, experts in the management of critically ill cancer patients highlight recent changes in the use and the results of intensive care in patients with malignancies. They seek to put forward a standard of care for the management of these patients and highlight important updates that are required to care for them. The research agenda they suggest includes important studies to be conducted in the next few years to increase our understanding of organ dysfunction in this population and to improve our ability to appropriately use life-saving therapies or select new therapeutic approaches that are likely to improve outcomes. This review aims to provide more guidance for the daily management of patients with cancer, in whom outcomes are constantly improving, as is our global ability to fight against what is becoming the leading cause of mortality in industrialized and non-industrialized countries.

Acute kidney injury in the ICU: from injury to recovery: reports from the 5th Paris International Conference

Abstract: The French Intensive Care Society organized its yearly Paris International Conference in intensive care on June 18–19, 2015. The main purpose of this meeting is to gather the best experts in the field in order to provide the highest quality update on a chosen topic. In 2015, the selected theme was: “Acute Renal Failure in the ICU: from injury to recovery.” The conference program covered multiple aspects of renal failure, including epidemiology, diagnosis, treatment and kidney support system, prognosis and recovery together with acute renal failure in specific settings. The present report provides a summary of every presentation including the key message and references and is structured in eight sections: (a) diagnosis and evaluation, (b) old and new diagnosis tools, (c) old and new treatments, (d) renal replacement therapy and management, (e) acute renal failure witness of other conditions, (f) prognosis and recovery, (g) extracorporeal epuration beyond the kidney, (h) the use of biomarkers in clinical practice http://www.srlf.org/5th-paris-international-conference-jeudi-18-et-vendredi-19-juin-2015/.

The intensive care medicine agenda on acute kidney injury.

Abstract: Acute kidney injury (AKI) is a common complication in the critically ill. Current standard of care mainly relies on identification of patients at risk, haemodynamic optimization, avoidance of nephrotoxicity and the use of renal replacement therapy (RRT) in established AKI. The detection of early biomarkers of renal tissue damage is a recent development that allows amending the late and insensitive diagnosis with current AKI criteria. Increasing evidence suggests that the consequences of an episode of AKI extend long beyond the acute hospitalization. Citrate has been established as the anticoagulant of choice for continuous RRT. Conflicting results have been published on the optimal timing of RRT and on the renoprotective effect of remote ischaemic preconditioning. Recent research has contradicted that acute tubular necrosis is the common pathology in AKI, that septic AKI is due to global kidney hypoperfusion, that aggressive fluid therapy benefits the kidney, that vasopressor therapy harms the kidney and that high doses of RRT improve outcome. Remaining uncertainties include the impact of aetiology and clinical context on pathophysiology, therapy and prognosis, the clinical benefit of biomarker-driven interventions, the optimal mode of RRT to improve short- and long-term patient and kidney outcomes, the contribution of AKI to failure of other organs and the optimal approach for assessing and promoting renal recovery. Based on the established gaps in current knowledge the trials that must have priority in the coming 10 years are proposed together with the definition of appropriate clinical endpoints.

Reduced rate of intensive care unit acquired gram-negative bacilli after removal of sinks and introduction of ‘water-free’ patient care

Abstract: Sinks in patient rooms are associated with hospital-acquired infections. The aim of this study was to evaluate the effect of removal of sinks from the Intensive Care Unit (ICU) patient rooms and the introduction of ‘water-free’ patient care on gram-negative bacilli colonization rates. We conducted a 2-year pre/post quasi-experimental study that compared monthly gram-negative bacilli colonization rates pre- and post-intervention using segmented regression analysis of interrupted time series data. Five ICUs of a tertiary care medical center were included. Participants were all patients of 18 years and older admitted to our ICUs for at least 48 h who also received selective digestive tract decontamination during the twelve month pre-intervention or the twelve month post-intervention period. The effect of sink removal and the introduction of ‘water-free’ patient care on colonization rates with gram-negative bacilli was evaluated. The main outcome of this study was the monthly colonization rate with gram-negative bacilli (GNB). Yeast colonization rates were used as a ‘negative control’. In addition, colonization rates were calculated for first positive culture results from cultures taken ≥3, ≥5, ≥7, ≥10 and ≥14 days after ICU-admission, rate ratios (RR) were calculated and differences tested with chi-squared tests. In the pre-intervention period, 1496 patients (9153 admission days) and in the post-intervention period 1444 patients (9044 admission days) were included. Segmented regression analysis showed that the intervention was followed by a statistically significant immediate reduction in GNB colonization in absence of a pre or post intervention trend in GNB colonization. The overall GNB colonization rate dropped from 26.3 to 21.6 GNB/1000 ICU admission days (colonization rate ratio 0.82; 95%CI 0.67–0.99; P = 0.02). The reduction in GNB colonization rate became more pronounced in patients with a longer ICU-Length of Stay (LOS): from a 1.22-fold reduction (≥2 days), to a 1.6-fold (≥5 days; P = 0.002), 2.5-fold (for ≥10 days; P < 0.001) to a 3.6-fold (≥14 days; P < 0.001) reduction. Removal of sinks from patient rooms and introduction of a method of ‘water-free’ patient care is associated with a significant reduction of patient colonization with GNB, especially in patients with a longer ICU length of stay.

Monocyte Subsets Are Differentially Lost from the Circulation during Acute Inflammation Induced by Human Experimental Endotoxemia

Abstract: Three human monocyte subsets are recognized with different functions in the immune system: CD14++/CD16- classical monocytes (CM), CD14++/CD16+ intermediate monocytes (IM) and CD14+/CD16++ non-classical monocytes (NCM). Increased IM and NCM percentages have been reported under inflammatory conditions, yet little is known about monocyte subsets at the onset of inflammation. The human endotoxemia model is uniquely capable of studying the first phases of acute inflammation induced by intravenous injection of 2 ng/kg bodyweight lipopolysaccharide (LPS) into healthy volunteers. After that, monocyte subset counts, activation/differentiation status and chemokine levels were studied over 24 h. The numbers of all subsets were decreased by >95% after LPS injection. CM numbers recovered first (3- 6 h), followed by IM (6-8 h) and NCM numbers (8-24 h). Similarly, increased monocyte counts were observed first in CM (8 h), followed by IM and NCM (24 h). Monocytes did not display a clear activated phenotype (minor increase in CD11b and CD38 expression). Plasma levels of CCL2, CCL4 and CX3CL1 closely resembled the cell numbers of CM, IM and NCM, respectively. Our study provides critical insights into the earliest stages of acute inflammation and emphasizes the necessity to stain for different monocyte subsets when studying the role of monocytes in disease, as neither function nor kinetics of the subsets overlap.

Characterization of a model of systemic inflammation in humans in vivo elicited by continuous infusion of endotoxin.

Abstract: Investigating the systemic inflammatory response in patients with critical illness such as sepsis, trauma and burns is complicated due to uncertainties about the onset, duration and severity of the insult. Therefore, in vivo models of inflammation are essential to study the pathophysiology and to evaluate immunomodulatory therapies. Intravenous bolus administration of endotoxin to healthy volunteers is a well-established model of a short-lived systemic inflammatory response, characterized by increased plasma cytokine levels, flu-like symptoms and fever. In contrast, patients suffering from systemic inflammation are often exposed to inflammatory stimuli for an extended period of time. Therefore, continuous infusion of endotoxin may better reflect the kinetics of the inflammatory response encountered in these patients. Herein, we characterize a novel model of systemic inflammation elicited by a bolus infusion of 1 ng/kg, followed by a 3hr continuous infusion of 1 ng/kg/h of endotoxin in healthy volunteers, and compared it with models of bolus administrations of 1 and 2 ng/kg of endotoxin. The novel model was well-tolerated and resulted in a more pronounced increase in plasma cytokine levels with different kinetics and more prolonged symptoms and fever compared with the bolus-only models. Therefore, the continuous endotoxin infusion model provides novel insights into kinetics of the inflammatory response during continuous inflammatory stimuli and accommodates a larger time window to evaluate immunomodulating therapies.

37th International Symposium on Intensive Care and Emergency Medicine (part 1 of 3)

Abstract: Introduction Imbalance in cellular energetics has been suggested to be an important mechanism for organ failure in sepsis and septic shock. We hypothesized that such energy imbalance would either be caused by metabolic changes leading to decreased energy production or by increased energy consumption. Thus, we set out to investigate if mitochondrial dysfunction or decreased energy consumption alters cellular metabolism in muscle tissue in experimental sepsis. Methods We submitted anesthetized piglets to sepsis (n = 12) or placebo (n = 4) and monitored them for 3 hours. Plasma lactate and markers of organ failure were measured hourly, as was muscle metabolism by microdialysis. Energy consumption was intervened locally by infusing ouabain through one microdialysis catheter to block major energy expenditure of the cells, by inhibiting the major energy consuming enzyme, N+/K + -ATPase. Similarly, energy production was blocked infusing sodium cyanide (NaCN), in a different region, to block the cytochrome oxidase in muscle tissue mitochondria. Results All animals submitted to sepsis fulfilled sepsis criteria as defined in Sepsis-3, whereas no animals in the placebo group did. Muscle glucose decreased during sepsis independently of N+/K + -ATPase or cytochrome oxidase blockade. Muscle lactate did not increase during sepsis in naïve metabolism. However, during cytochrome oxidase blockade, there was an increase in muscle lactate that was further accentuated during sepsis. Muscle pyruvate did not decrease during sepsis in naïve metabolism. During cytochrome oxidase blockade, there was a decrease in muscle pyruvate, independently of sepsis. Lactate to pyruvate ratio increased during sepsis and was further accentuated during cytochrome oxidase blockade. Muscle glycerol increased during sepsis and decreased slightly without sepsis regardless of N+/K + -ATPase or cytochrome oxidase blocking. There were no significant changes in muscle glutamate or urea during sepsis in absence/presence of N+/K + -ATPase or cytochrome oxidase blockade. Conclusions These results indicate increased metabolism of energy substrates in muscle tissue in experimental sepsis. Our results do not indicate presence of energy depletion or mitochondrial dysfunction in muscle and should similar physiologic situation be present in other tissues, other mechanisms of organ failure must be considered.

Spleen-derived IFN-γ induces generation of PD-L1+-suppressive neutrophils during endotoxemia.

Abstract: The immune inhibitory checkpoint molecule programmed death ligand (PD-L)-1 is increasingly recognized as an important player in the immune suppression observed in patients with sepsis, but its role has mainly been studied in monocytes. In an earlier study, we demonstrated that experimental human endotoxemia results in mobilization of a subset of PD-L1-expressing neutrophils displaying an IFN-γ-induced transcriptome profile. Herein, we identify the source of IFN-γ production during murine endotoxemia and its role in the generation of PD-L1+-suppressive neutrophils. We demonstrate that, similar to what we found in humans, murine endotoxemia results in the influx of a subset of PD-L1+ neutrophils in the circulation, and incubation of mouse neutrophils with recombinant IFN-γ profoundly increases PD-L1 expression. Furthermore, administration of anti-IFN-γ abrogated the generation of PD-L1+ neutrophils in endotoxemic mice. The critical involvement of the spleen is illustrated by the fact that splenectomy nullified circulating IFN-γ levels and substantially reduced the abundance of PD-L1+ neutrophils, whereas cotreatment with recombinant IFN-γ resulted in complete restoration of generation of PD-L1+ neutrophils in splenectomized mice. Finally, the functional importance of spleen-derived PD-L1+ neutrophils is exemplified by the finding that the profound decrease in T-lymphocyte proliferation observed in cells from endotoxemic mice was attenuated in cells from splenectomized animals. We demonstrated that spleen-derived IFN-γ induces generation of PD-L1+-suppressive neutrophils, implying that the spleen is critically involved in immune suppression during inflammatory diseases such as sepsis. Furthermore, our data suggest that IFN-γ plays a dual role by enhancing innate immunity and at the same time suppressing adaptive immune responses.

Proenkephalin (PENK) as a Novel Biomarker for Kidney Function

Abstract: Background: The assessment of kidney function and detection of acute kidney injury (AKI) remain cumbersome. On the one hand, because of limited accuracy of established tests: The most widely used methods are creatinine based, which lack in sensitivity, as creatinine is not purely filtrated by the kidney and rises relatively late after onset of AKI. On the other hand, because of labor-intensiveness: Gold standard inulin clearance and comparable methods involve intravenous compound infusion, blood sampling at several time points, and have error-sensitive determination methods. In recent years, several biomarkers have been put forward (e.g., NGAL, KIM-1, TIMP-2*IGFBP-7), but clinical implementation is limited up to now. Content: Proenkephalin (PENK) represents a new candidate to determine kidney function. This peptide is cleaved from the precursor peptide preproenkephalin A alongside enkephalins (endogenous opioids) and is filtrated in the glomerulus. PENK plasma concentration appears to accurately represent glomerular filtration rate in patients diagnosed with sepsis or cardiac diseases. Moreover, increased PENK concentration is found to be associated with longer-term outcome concerning AKI and cardiac diseases. Lastly, the predominant receptor of enkephalins, the δ-opioid receptor, is expressed with the highest density in the kidney, suggesting that enkephalins could also exert a direct effect on kidney function. Summary: In this review, we present an overview of enkephalins and the assessment of kidney function using this possible new functional biomarker PENK and compare it with established and novel biomarkers.

A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia.

Abstract: The use of acetylsalicylic acid (ASA) is associated with improved outcome in patients with sepsis, and P2Y12 inhibitors have been suggested to also have immunomodulatory effects. Therefore, we evaluated the effects of clinically relevant combinations of antiplatelet therapy on the immune response in experimental endotoxaemia in humans in vivo. Forty healthy subjects were randomised to seven days of placebo, placebo with ASA, ticagrelor and ASA, or clopidogrel and ASA treatment. Systemic inflammation was elicited at day seven by intravenous administration of Escherichia coli endotoxin. ASA treatment profoundly augmented the plasma concentration of pro-inflammatory cytokines, but did not affect anti-inflammatory cytokines. Addition of either P2Y12 antagonist to ASA did not affect any of the circulating cytokines, except for an attenuation of the ASA-induced increase in TNFα by ticagrelor. Systemic inflammation increased plasma adenosine, without differences between groups, and although P2Y12 inhibition impaired platelet reactivity, there was no correlation with cytokine responses.

Patterns in Bacterial- and Viral-Induced Immunosuppression and Secondary Infections in the ICU

Abstract: Immunosuppression renders the host increased susceptible for secondary infections. It is becoming increasingly clear that not only bacterial sepsis, but also respiratory viruses with both severe and mild disease courses such as influenza, respiratory syncytial virus, and the human rhinovirus may induce immunosuppression. In this review, the current knowledge on (mechanisms of) bacterial- and virus-induced immunosuppression and the accompanying susceptibility toward various secondary infections is described. In addition, the frequently encountered secondary pathogens and their preferred localizations are presented. Finally, future perspectives in the context of the development of diagnostic markers and possibilities for personalized therapy to improve the diagnosis and treatment of immunocompromised patients are discussed.

Towards precision medicine for sepsis patients.

Abstract: Over the last decade it has become clear that the immunological response and clinical course in sepsis patients is too complex to simply regard it as ‘hyperinflammation-induced organ failure’. In contrast to the previous belief that patients mainly suffer from an exaggerated pro-inflammatory response, it has now become evident that a pro- and anti-inflammatory response are mounted simultaneously [1, 2]. Whether pro-inflammation or anti-inflammation is the overruling immune response may differ between patients and evolve over time in an individual patient [2], and this may explain why all previous clinical studies in sepsis patients using interventions to attenuate the immune response are negative [3]. Greater appreciation for the role of the dysregulated immune response is represented in the new definition of sepsis [4], defining sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection.

Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients

Abstract: To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies. Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations. A two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V 1 and V 2 were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration–time curve over 24 h (interquartile range) on day 14 for regimens I–V were 91 (67–122), 183 (135–244), 91 (67–122), 137 (101–183) and 183 (135–244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration–time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration–time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016. The licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.

Ethylene, an early marker of systemic inflammation in humans

Abstract: Ethylene is a major plant hormone mediating developmental processes and stress responses to stimuli such as infection. We show here that ethylene is also produced during systemic inflammation in humans and is released in exhaled breath. Traces of ethylene were detected by laser spectroscopy both in vitro in isolated blood leukocytes exposed to bacterial lipopolysaccharide (LPS) as well as in vivo following LPS administration in healthy volunteers. Exposure to LPS triggers formation of ethylene as a product of lipid peroxidation induced by the respiratory burst. In humans, ethylene was detected prior to the increase of blood levels of inflammatory cytokines and stress-related hormones. Our results highlight that ethylene release is an early and integral component of in vivo lipid peroxidation with important clinical implications as a breath biomarker of bacterial infection.

Markers of Intestinal Damage and their Relation to Cytokine Levels in Cardiac Surgery Patients.

Abstract: OBJECTIVES: In patients undergoing cardiac surgery, both extracorporeal circulation (ECC) and intraoperative mesenterial hypoperfusion may account for increased cytokine levels and lead to postoperative gastrointestinal (GI) symptoms. METHODS: We investigated levels of the intestinal damage markers intestinal fatty acid binding protein (I-FABP in plasma [n = 72] and urine [n = 37]), citrulline (in plasma [n = 35]), and claudin-3 (in urine [n = 37]) in patients undergoing aortic or mitral valve surgery with or without coronary artery bypass grafting. Furthermore, the relationship between these markers and the surgery-induced cytokine response was explored by measuring serial plasma levels of tumor necrosis factor-alpha, interleukin (IL)-6, IL-8, and IL-10 (n = 35). Finally, the relationship between markers of intestinal damage and GI-symptoms (abdominal pain, ileus, vomiting, diarrhea, time to first defecation) was assessed. RESULTS: Plasma and urinary I-FABP levels, and urinary claudin-3 levels peaked at the end of surgery, while citrulline levels were not influenced by surgery. ECC duration correlated with plasma I-FABP levels (r = 0.31, P = 0.007). Plasma levels of all measured cytokines increased during surgery, with peak levels observed either at the end of surgery or on the first postoperative day. While ECC duration correlated with IL-6 and IL-8 release (r = 0.43, P = 0.01 and r = 0.36, P = 0.04 respectively), there was no direct relationship between I-FABP and claudin-3 levels and cytokine concentrations. No patients developed significant GI or non-GI complications, and I-FABP and claudin-3 release appeared not to be related to postoperative GI symptoms, although the incidence of these symptoms may have limited a reliable assessment. CONCLUSIONS: Longer duration of ECC is associated with a more pronounced release of intestinal injury markers and inflammatory cytokines, but intestinal injury markers are not directly related to the observed increase in cytokine levels or GI-symptoms. These findings indicate that ECC duration contributes to the cytokine response observed in cardiac surgery patients and that intestinal injury itself is not a causative factor for this response.

Norepinephrine Contributes to Enterocyte Damage in Septic Shock Patients: A Prospective Cohort Study.

Abstract: Objectives:In septic patients, both systemic inflammation and splanchnic hypoperfusion may cause enterocyte damage. Catecholamines may exert additional detrimental effects on mesenteric blood flow in these patients, and thereby contribute to this damage. Enterocyte damage itself results in i

Development and implementation of a clinical pathway for cardiac surgery in the intensive care unit: Effects on protocol adherence.

Abstract: Rationale, aims and objectives Cardiac surgery (CS) is facilitated by multiple perioperative guidelines and protocols. Use of a clinical pathway (CP) may facilitate the care of these patients. Methods This is a pre-post design study in the ICU of a tertiary referral centre. A CP for CS patients in the ICU was developed by ICU-nurses and enabled them to execute proactively predefined actions in accordance with and within the preset boundaries which were part of a variance report. A tailored implementation strategy was used. Primary outcome measure was protocol adherence above 80% on the domains of blood pressure control, action on chest tube blood loss and electrolyte control within the CP. Results In a 4-month period, 84 consecutive CP patients were included and compared with 162 matched control patients admitted in the year before implementation; 3 patients were excluded. Propensity score was used as matching parameter. CP patients were more likely to receive early adequate treatment for derangements in electrolytes (96% vs 47%, P < .001), blood pressure (90% vs 49%, P < .001) and adequate treatment for chest tube blood loss (90% vs 10%, P < .001). We found no differences in hospital and ICU LOS, ICU readmission or mortality. Conclusion Use of the CP improved postoperative ICU treatment for cardiac surgical patients. Implementation of a CP and the use of a special variance report could be a blueprint for the implementation and use of a CP in low-volume high complex surgery.

Development of Endotoxin Tolerance Does Not Influence the Response to a Challenge with the Mucosal Live-Attenuated Influenza Vaccine in Humans In Vivo.

Abstract: Introduction: The effects of bacterial infections on the response to subsequent viral infections are largely unknown. This is important to elucidate to increase insight into the pathophysiology of bacterial and viral co-infections, and to assess whether bacterial infections may influence the course of viral infections. Methods: Healthy male subjects received either bacterial endotoxin [Escherichia coli-derived lipopolysaccharide (LPS), 2 ng/kg, n = 15] or placebo (n = 15) intravenously, followed by intranasal Fluenz (live-attenuated influenza vaccine) 1 week later. Results: LPS administration resulted in increased plasma cytokine levels and development of endotoxin tolerance in vivo and ex vivo, illustrated by attenuated cytokine production upon rechallenge with LPS. Following Fluenz administration, infectivity for the Fluenz A/B strains was similar between the LPS-Fluenz and placebo-Fluenz groups (13/15 subjects in both groups). Also, the Fluenz-induced increase in temperature and IL-6, G-CSF and IP-10 concentrations in nasal wash were similar between both groups. Conclusion: While endotoxemia profoundly attenuates the immune response upon a second LPS challenge, it does not influence the Fluenz-induced immune response. These results suggest immune suppression after bacterial infection does not alter the response to a subsequent viral infection.

Vasopressors Do Not Influence Cerebral Critical Closing Pressure During Systemic Inflammation Evoked by Experimental Endotoxemia and Sepsis in Humans.

Abstract: AIM The aim of this study was to investigate the effects of different vasopressors on the cerebral vasculature during experimental human endotoxemia and sepsis. We used the critical closing pressure (CrCP) as a measure of cerebral vascular tone. METHODS We performed a prospective pilot study, at the intensive care department (ICU) of a tertiary care university hospital in the Netherlands, in 40 healthy male subjects during experimental human endotoxemia (administration of bacterial lipopolysaccharide [LPS]) and in 10 patients with severe sepsis or septic shock.Subjects in the endotoxemia study were randomized to receive a 5 h infusion of either 0.05 μg/kg/min noradrenaline (n = 10, "LPS-nor"), 0.5 μg/kg/min phenylephrine (n = 10, "LPS-phenyl"), 0.04 IU/min vasopressin (n = 10, "LPS-AVP"), or saline (n = 10, "LPS-placebo") starting 1 h before intravenous administration of 2 ng/kg LPS. In patients with sepsis, fluid resuscitation and vasopressor use was at the discretion of the medical team, aiming at normovolemia and a mean arterial pressure (MAP) > 65 mm Hg, using noradrenaline.The mean flow velocity in the middle cerebral artery (MFVMCA) was measured by transcranial Doppler (TCD) with simultaneously recording of heart rate, arterial blood pressure, respiratory rate, and oxygen saturation. CrCP was estimated using the cerebrovascular impedance model. RESULTS The CrCP decreased in the LPS-placebo group from 52.6 [46.6-55.5] mm Hg at baseline to 44.1 [41.2-51.3] mm Hg at 270 min post-LPS (P = 0.03). Infusion of phenylephrine increased the CrCP in the period before LPS administration from 46.9 [38.8-53.4] to 53.8 [52.9-60.2] mm Hg (P = 0.02), but after LPS administration, a similar decrease was observed compared with the LPS-placebo group. Noradrenaline or vasopressin prior to LPS did not affect the CrCP. The decrease in CrCP after LPS bolus was similar in all treatment groups. The CrCP in the sepsis patients equaled 35.7 [34.4-42.0] mm Hg, and was lower compared with that in the LPS-placebo subjects from baseline until 90 min after LPS (P < 0.01). CONCLUSIONS Experimental human endotoxemia results in a decreased CrCP due to a loss of vascular resistance of the arterial bed. Vasopressors did not prevent this decrease in CrCP. Findings in patients with sepsis are comparable to those found in subjects after LPS administration.Patients with sepsis, despite treatment with vasopressors, have a risk for low cerebral blood flow and ischemia.

Leukocyte phosphodiesterase expression after lipopolysaccharide and during sepsis and its relationship with HLA-DR expression

Abstract: Phosphodiesterases (PDEs) may modulate inflammatory pathways, but PDE expression is poorly documented in humans with sepsis. Using quantitative PCR on whole blood leukocytes, we characterized PDE mRNA expression in healthy volunteers (n = 20), healthy volunteers given lipopolysaccharide (LPS; n = 18), and critically ill patients with (n = 20) and without (n = 20) sepsis. PDE4B protein expression was also studied in magnetic-activated cell sorting (MACS)-isolated CD15+ neutrophils (from 7 healthy volunteers, 5 patients without and 5 with sepsis). We studied relationships between PDE expression, HLA-DR (mRNA and expression on CD14+ monocytes), tumor necrosis factor (TNF)-α, and interleukin (IL)-10 levels. LPS administration in volunteers was associated with increases in PDE4B and PDE4D and decreases in PDE4A and PDE7A mRNAs. The observed global down-regulation of the HLA-DR complex was correlated with PDE7A. Critically ill patients had lower TNF-α/IL-10 mRNA ratios than the volunteers had and global down-regulation of the HLA-DR complex. Septic patients had persistently lower mRNA levels of PDE7A, PDE4A, and 4B (also at a protein level) and decreasing levels of PDE4D over time. Low PDE4D mRNA levels correlated negatively with HLA-DMA and HLA-DMB. LPS administration and sepsis are, therefore, associated with different PDE mRNA expression patterns. The effect of PDE changes on immune dysfunction and HLA-DR expression requires further investigation.

Crew Resource Management in the trauma room: a prospective 3-year cohort study.

Abstract: OBJECTIVE Human factors account for the majority of adverse events. Human factors awareness training entitled Crew Resource Management (CRM) is associated with improved safety and reduced complications and mortality in critically ill patients. We determined the effects of CRM implementation in the trauma room of an Emergency Department (ED). PATIENTS AND METHODS A prospective 3-year cohort study was carried out in a level 1 ED, admitting more than 12 000 patients annually (>1500 trauma related). At the end of the baseline year, CRM training was performed, followed by an implementation year. The third year was defined as the clinical effect year. The primary outcomes were safety climate, measured using the Safety Attitudes Questionnaire, and ED length of stay. The secondary outcome measures were hospital length of stay and 48-h crude mortality of trauma patients. RESULTS All 5070 trauma patients admitted to the ED during the study period were included. Following CRM implementation, safety climate improved significantly in three out of six Safety Attitudes Questionnaire domains, both at the end of the implementation and clinical effect years: teamwork climate, safety climate, and stress recognition. ED length of stay of these patients increased from 141 (102-192) in the baseline year to 161 (116-211) and 170 (128-223) min in the implementation and clinical effect years, respectively (P<0.05 vs. baseline). Hospital length of stay was prolonged by 1 day in the implementation and clinical effect years (P<0.05 vs. baseline), whereas mortality was unaltered. CONCLUSION Although CRM implementation in the ED was associated with an improved safety climate, the time spent by trauma patients in the ED increased.