Joanna Warszawska

Real-Time Continuous Glucose Monitoring in Critically Ill Patients: A prospective randomized trial

OBJECTIVE To evaluate the impact of real-time continuous glucose monitoring (CGM) on glycemic control and risk of hypoglycemia in critically ill patients. RESEARCH DESIGN AND METHODS A total 124 patients receiving mechanical ventilation were randomly assigned to the real-time CGM group (n = 63; glucose values given every 5 min) or to the control group (n = 61; selective arterial glucose measurements according to an algorithm; simultaneously blinded CGM) for 72 h. Insulin infusion rates were guided according to the same algorithm in both groups. The primary end point was percentage of time at a glucose level <110 mg/dl. Secondary end points were mean glucose levels and rate of severe hypoglycemia (<40 mg/dl). RESULTS Percentage of time at a glucose level <110 mg/dl (59.0 ± 20 vs. 55.0 ± 18% in the control group, P = 0.245) and the mean glucose level (106 ± 18 vs. 111 ± 10 mg/dl in the control group, P = 0.076) could not be improved using real-time CGM. The rate of severe hypoglycemia was lower in the real-time CGM group (1.6 vs. 11.5% in the control group, P = 0.031). CGM reduced the absolute risk of severe hypoglycemia by 9.9% (95% CI 1.2–18.6) with a number needed to treat of 10.1 (95% CI 5.4–83.3). CONCLUSIONS In critically ill patients, real-time CGM reduces hypoglycemic events but does not improve glycemic control compared with intensive insulin therapy guided by an algorithm.

Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes

Macrophages play a key role in responding to pathogens and initiate an inflammatory response to combat microbe multiplication. Deactivation of macrophages facilitates resolution of the inflammatory response. Deactivated macrophages are characterized by an immunosuppressive phenotype, but the lack of unique markers that can reliably identify these cells explains the poorly defined biological role of this macrophage subset. We identified lipocalin 2 (LCN2) as both a marker of deactivated macrophages and a macrophage deactivator. We show that LCN2 attenuated the early inflammatory response and impaired bacterial clearance, leading to impaired survival of mice suffering from pneumococcal pneumonia. LCN2 induced IL-10 formation by macrophages, skewing macrophage polarization in a STAT3-dependent manner. Pulmonary LCN2 levels were tremendously elevated during bacterial pneumonia in humans, and high LCN2 levels were indicative of a detrimental outcome from pneumonia with Gram-positive bacteria. Our data emphasize the importance of macrophage deactivation for the outcome of pneumococcal infections and highlight the role of LCN2 and IL-10 as determinants of macrophage performance in the respiratory tract.

Myeloid PTEN Promotes Inflammation but Impairs Bactericidal Activities during Murine Pneumococcal Pneumonia

Phosphatidylinositol 3-kinase has been described as an essential signaling component involved in the chemotactic cell influx that is required to eliminate pathogens. At the same time, PI3K was reported to modulate the immune response, thus limiting the magnitude of acute inflammation. The precise role of the PI3K pathway and its endogenous antagonist phosphatase and tensin homolog deleted on chromosome 10 (PTEN) during clinically relevant bacterial infections is still poorly understood. Utilizing mice lacking myeloid cell-specific PTEN, we studied the impact of PTEN on the immune response to Streptococcus pneumoniae. Survival analysis disclosed that PTEN-deficient mice displayed less severe signs of disease and prolonged survival. The inflammatory response to S. pneumoniae was greatly reduced in macrophages in vitro and in vivo. Unexpectedly, neutrophil influx to the lungs was significantly impaired in animals lacking myeloid-cell PTEN, whereas the additional observation of improved phagocytosis by alveolar macrophages lacking PTEN ultimately resulted in unaltered lung CFUs following bacterial infection. Together, the absence of myeloid cell-associated PTEN and consecutively enhanced PI3K activity dampened pulmonary inflammation, reduced neutrophil influx, and augmented phagocytic properties of macrophages, which ultimately resulted in decreased tissue injury and improved survival during murine pneumococcal pneumonia.

First-Breath-Induced Type 2 Pathways Shape the Lung Immune Environment

Summary From birth onward, the lungs are exposed to the external environment and therefore harbor a complex immunological milieu to protect this organ from damage and infection. We investigated the homeostatic role of the epithelium-derived alarmin interleukin-33 (IL-33) in newborn mice and discovered the immediate upregulation of IL-33 from the first day of life, closely followed by a wave of IL-13-producing type 2 innate lymphoid cells (ILC2s), which coincided with the appearance of alveolar macrophages (AMs) and their early polarization to an IL-13-dependent anti-inflammatory M2 phenotype. ILC2s contributed to lung quiescence in homeostasis by polarizing tissue resident AMs and induced an M2 phenotype in transplanted macrophage progenitors. ILC2s continued to maintain the M2 AM phenotype during adult life at the cost of a delayed response to Streptococcus pneumoniae infection in mice. These data highlight the homeostatic role of ILC2s in setting the activation threshold in the lung and underline their implications in anti-bacterial defenses.

Sustained PI3K Activation exacerbates BLM-induced Lung Fibrosis via activation of pro-inflammatory and pro-fibrotic pathways

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with limited treatment options. Additionally, the lack of a complete understanding of underlying immunological mechanisms underscores the importance of discovering novel options for therapeutic intervention. Since the PI3K/PTEN pathway in myeloid cells influences their effector functions, we wanted to elucidate how sustained PI3K activity induced by cell-type specific genetic deficiency of its antagonist PTEN modulates IPF, in a murine model of bleomycin-induced pulmonary fibrosis (BIPF). We found that myeloid PTEN deficient mice (PTENMyKO), after induction of BIPF, exhibit increased TGF-β1 activation, mRNA expression of pro-collagens and lysyl oxidase as well as augmented collagen deposition compared to wild-type littermates, leading to enhanced morbidity and decreased survival. Analysis of alveolar lavage and lung cell composition revealed that PTENMyKO mice exhibit reduced numbers of macrophages and T-cells in response to bleomycin, indicating an impaired recruitment function. Interestingly, we found dysregulated macrophage polarization as well as elevated expression and release of the pro-fibrotic cytokines IL-6 and TNF-α in PTENMyKO mice during BIPF. This might point to an uncontrolled wound healing response in which the inflammatory as well as tissue repair mechanisms proceed in parallel, thereby preventing resolution and at the same time promoting extensive fibrosis.

The triggering receptor expressed on myeloid cells 2 inhibits complement component 1q effector mechanisms and exerts detrimental effects during pneumococcal pneumonia

Phagocytosis and inflammation within the lungs is crucial for host defense during bacterial pneumonia. Triggering receptor expressed on myeloid cells (TREM)-2 was proposed to negatively regulate TLR-mediated responses and enhance phagocytosis by macrophages, but the role of TREM-2 in respiratory tract infections is unknown. Here, we established the presence of TREM-2 on alveolar macrophages (AM) and explored the function of TREM-2 in the innate immune response to pneumococcal infection in vivo. Unexpectedly, we found Trem-2 −/− AM to display augmented bacterial phagocytosis in vitro and in vivo compared to WT AM. Mechanistically, we detected that in the absence of TREM-2, pulmonary macrophages selectively produced elevated complement component 1q (C1q) levels. We found that these increased C1q levels depended on peroxisome proliferator-activated receptor-δ (PPAR-δ) activity and were responsible for the enhanced phagocytosis of bacteria. Upon infection with S. pneumoniae, Trem-2 −/− mice exhibited an augmented bacterial clearance from lungs, decreased bacteremia and improved survival compared to their WT counterparts. This work is the first to disclose a role for TREM-2 in clinically relevant respiratory tract infections and demonstrates a previously unknown link between TREM-2 and opsonin production within the lungs.

Bβ15-42 Protects against Acid-induced Acute Lung Injury and Secondary Pseudomonas Pneumonia In Vivo

RATIONALE Acute lung injury (ALI) is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of ALI. The fibrin-derived peptide Bbeta(15-42) was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of Bbeta(15-42) in ALI has not been addressed so far. OBJECTIVES To investigate the therapeutic potential of Bbeta(15-42) in ALI and secondary pneumonia induced by Pseudomonas aeruginosa. METHODS The effect of the fibrin-derived peptide Bbeta(15-42) was studied in models of ALI, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels, and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with P. aeruginosa 24 hours after induction of aspiration pneumonitis and effects of Bbeta(15-42) on inflammation, bacterial clearance, and survival were evaluated. MEASUREMENTS AND MAIN RESULTS After LPS or acid inhalation, proinflammatory cytokine levels, neutrophil influx, and vascular leak were found diminished in mice treated with Bbeta(15-42). Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received Bbeta(15-42) during acid aspiration and were subsequently challenged with bacteria displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival. CONCLUSIONS The fibrin-derived peptide Bbeta(15-42) exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginosa pneumonia.

Early treatment with IgM-enriched intravenous immunoglobulin does not mitigate critical illness polyneuropathy and/or myopathy in patients with multiple organ failure and SIRS/sepsis: a prospective, randomized, placebo-controlled, double-blinded trial

IntroductionCritical illness polyneuropathy and/or myopathy (CIPNM) is a severe complication of critical illness. Retrospective data suggest that early application of IgM-enriched intravenous immunoglobulin (IVIG) may prevent or mitigate CIPNM. Therefore, the primary objective was to assess the effect of early IgM-enriched IVIG versus placebo to mitigate CIPNM in a prospective setting.MethodsIn this prospective, randomized, double-blinded and placebo-controlled trial, 38 critically ill patients with multiple organ failure (MOF), systemic inflammatory response syndrome (SIRS)/sepsis, and early clinical signs of CIPNM were included. Patients were randomly assigned to be treated either with IgM-enriched IVIG or placebo over a period of three days. CIPNM was measured by the CIPNM severity sum score based on electrophysiological stimulation of the median, ulnar, and tibial nerves on days 0, 4, 7, 14 and on the histological evaluation of muscle biopsies on days 0 and 14 and ranged from 0 (no CIPNM) to 8 (very severe CIPNM).ResultsA total of 38 critically ill patients were included and randomized to receive either IgM-enriched IVIG (n = 19) or placebo (n = 19). Baseline characteristics were similar between the two groups. CIPNM could not be improved by IVIG treatment, represented by similar CIPNM severity sum scores on day 14 (IVIG vs. placebo: 4.8 ± 2.0 vs. 4.5 ± 1.8; P = 0.70). CIPNM severity sum score significantly increased from baseline to day 14 (3.5 ± 1.6 vs. 4.6 ± 1.9; P = 0.002). After an interim analysis the study was terminated early due to futility in reaching the primary endpoint.ConclusionsEarly treatment with IVIG did not mitigate CIPNM in critically ill patients with MOF and SIRS/sepsis.Trial registrationClinicaltrials.gov: NCT01867645

Storage of bronchoalveolar lavage fluid and accuracy of microbiologic diagnostics in the ICU: a prospective observational study

IntroductionEarly initiation of appropriate antimicrobial treatment is a cornerstone in managing pneumonia. Because microbiologic processing may not be available around the clock, optimal storage of specimens is essential for accurate microbiologic identification of pathogenetic bacteria. The aim of our study was to determine the accuracy of two commonly used storage approaches for delayed processing of bronchoalveolar lavage in critically ill patients with suspected pneumonia.MethodsThis study included 132 patients with clinically suspected pneumonia at two medical intensive care units of a tertiary care hospital. Bronchoalveolar lavage samples were obtained and divided into three aliquots: one was used for immediate culture, and two, for delayed culture (DC) after storage for 24 hours at 4°C (DC4) and -80°C (DC-80), respectively.ResultsOf 259 bronchoalveolar lavage samples, 84 (32.4%) were positive after immediate culture with 115 relevant culture counts (≥104 colony-forming units/ml). Reduced (<104 colony-forming units/ml) or no growth of four and 57 of these isolates was observed in DC4 and DC-80, respectively. The difference between mean bias of immediate culture and DC4 (-0.035; limits of agreement, -0.977 to 0.906) and immediate culture and DC-80 (-1.832; limits of agreement, -4.914 to 1.267) was -1.788 ± 1.682 (P < 0.0001). Sensitivity and negative predictive value were 96.5% and 97.8% for DC4 and 50.4% and 75.4% for DC-80, respectively; the differences were statistically significant (P < 0.0001).ConclusionsBronchoalveolar lavage samples can be processed for culture when stored up to 24 hours at 4°C without loss of diagnostic accuracy. Delayed culturing after storage at -80°C may not be reliable, in particular with regard to Gram-negative bacteria.

Stress-Hyperglykämie – Einfluss auf Morbidität und Mortalität beim Akutpatienten

Die Stress-Hyperglykämie wurde bereits vor 130 Jahren von Claude Bernard in seinen Beobachtungen beim Blutungsschock erstmals ausführlich beschrieben [1]. Bis vor wenigen Jahren waren wir der Meinung, dass bei Intensivpatienten diese Stress-Hyperglykämie als adaptives Epiphänomen im Sinne einer physiologischen Gegenregulation zu akzeptieren ist und Blutzuckerwerte um 200 mg/dl sogar positive Effekte auf den Stoffwechsel des Intensivpatienten haben. Zu diesem gestörten Glukosestoffwechsel kommt es bei akuten Erkrankungen unabhängig von vorbestehenden Glukosestoffwechsel-Erkrankungen wie Diabetes mellitus. Dabei spielt die periphere Insulinresistenz, die durch eine Hyperinsulinämie, eine beeinträchtigte periphere Insulin-mediierte Glukoseaufnahme ins Muskelgewebe und eine gleichzeitig erhöhte hepatische Glukoneogenese charakterisiert ist, die zentrale Rolle [2]. Zahlreiche klinische Studien zeigen jedoch, dass diese Stress-Hyperglykämie nicht nur ein Epiphänomen darstellt, sondern negative Auswirkungen auf Morbidität und Mortalität aufweisen. Eine rezente Untersuchung bei 6187 Patienten auf einer Notfallaufnahme in Australien zeigte eindrucksvoll, dass der Blutzuckerwert bei der Aufnahme ein unabhängiger Prädiktor für die Mortalität darstellt [3]. Je höher der Blutzuckerspiegel war, umso höher war die Mortalität. Pro Anstieg des Blutzuckerspiegels um 1 mmol/l stieg die Hasard-Ratio zu versterben signifikant um 1,04 an. Auffallend war aber vor allem, dass dieser Zusammenhang nur bei jenen Patienten bestand, die keinen vorbestehenden Diabetes mellitus hatten, nicht jedoch bei jenen Patienten mit bekanntem Diabetes mellitus. Auch für spezielle Krankheitsbilder konnten ähnliche Zusammenhänge zwischen Blutzuckerspiegel und Morbidität beziehungsweise Mortalität gezeigt werden. Eine Metaanalyse ergab für den akuten Myokardinfarkt eine sehr enge Korrelation zwischen dem Ausmaß der StressHyperglykämie und der Entwicklung eines kardiogenen Schock, Herzversagens und erhöhter Spitalsmortalität [4]. Auch bei kardiochirurgischen Patienten ist eine perioperative Hyperglykämie mit einer erhöhten Mortalität assoziiert [5]. Ähnliche Ergebnisse zeigen sich auch bei Trauma-Patienten, bei denen die Hyperglykämie mit einer erhöhten Mortalität, verlängerter Liegedauer und erhöhter Infektionsrate assoziiert ist [6]. Auch bei Schlaganfallpatienten bewirkt eine Hyperglykämie ein höheres Risiko zu versterben und bei jenen Patienten, die überleben, ist die neurologische Rehabilitation umso schlechter, je ausgeprägter in der Akutphase die Hyperglykämie war [7]. In dieser Ausgabe der Wiener Klinischen Wochenschrift wird nun erstmals der Zusammenhang zwischen Vorhofflimmern bei akutem Myokardinfarkt und einer Stress-Hyperglykämie beschrieben [8]. Die Autoren führten eine retrospektive Analyse bei 543 Patienten mit akutem Myokardinfarkt durch und zeigten eindrucksvoll, dass eine Stress-Hyperglykämie mit einer erhöhten Prävalenz von Vorhofflimmern assoziiert ist. Jene Patientengruppe mit einer Stress-Hyperglykämie über 8 mmol/l und Vorhofflimmern hatten eine 14.5 fach höhere Spitalsmortalität als jene Patientengruppe ohne Stress-Hyperglykämie und Vorhofflimmern. Während eine Stress-Hyperglykämie in einer multivariaten Regressionsanalyse ein unabhängiger Prädiktor für eine erhöhte Mortalität war, stellte hingegen Vorhofflimmern keinen unabhängigen Risikofaktor dar. Diese Ergebnisse werfen drei wichtige Fragen auf: