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Was ist neu? Monitoring von Analgesie, Sedierung und Delir Voraussetzung für das Monitoring einer zielorientierten Analgosedierung und das Screening auf die Präsenz eines Delirs sind der Einsatz validierter Messinstrumente wie die Richmond-Agitation-and-Sedation-Scale sowie ein adäquater ärztlicher und intensivpflegerischer Betreuungsschlüssel. Durchführung der Analgesie und Sedierung Ziel ist nach Möglichkeit ein wacher, orientierter, kooperativer Patient, der frei von Schmerzen ist. Hierbei kommt der multimodalen analgosedierenden Behandlung eine große Bedeutung zu. Auch bei COVID-19-Patienten sollte eine geringstmögliche Sedierung angestrebt werden, wobei bei invasiv beatmeten COVID-19-Patienten in Bauchlage eine tiefe Sedierung empfohlen wird.

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The prerequisite for monitoring goal-oriented analgesia and screening for the presence of delirium is the use of validated measuring instruments such as the Richmond Agitation and Sedation Scale as well as an adequate medical and intensive care staffing ratio.The goal, if possible, is an awake, oriented, cooperative patient who is free of pain. In this regard, multimodal analgesic treatment is of great importance. The lowest possible sedation should also be aimed for in COVID-19 patients, although deep sedation is recommended for invasively ventilated COVID-19 patients in the prone position.Voraussetzung für das Monitoring einer zielorientierten Analgosedierung und das Screening auf die Präsenz eines Delirs sind der Einsatz validierter Messinstrumente wie die Richmond-Agitation-and-Sedation-Scale sowie ein adäquater ärztlicher und intensivpflegerischer Betreuungsschlüssel. DURCHFüHRUNG DER ANALGESIE UND SEDIERUNG: Ziel ist nach Möglichkeit ein wacher, orientierter, kooperativer Patient, der frei von Schmerzen ist. Hierbei kommt der multimodalen analgosedierenden Behandlung eine große Bedeutung zu. Auch bei COVID-19-Patienten sollte eine geringstmögliche Sedierung angestrebt werden, wobei bei invasiv beatmeten COVID-19-Patienten in Bauchlage eine tiefe Sedierung empfohlen wird.

Background Prevalence of multiple organ failure (MOF) in critically ill patients is increasing and associated mortality remains high. Extracorporeal organ support is a cornerstone in the management of MOF. We report data of an advanced hemodialysis system based on albumin dialysis (ADVOS multi device) that can regulate acid–base balance in addition to the established properties of renal replacement therapy and albumin dialysis systems in critically ill patients with MOF. Methods 34 critically ill patients with MOF received 102 ADVOS treatment sessions in the Department of Intensive Care Medicine of the University Medical Center Hamburg-Eppendorf. Markers of metabolic detoxification and acid–base regulation were collected and blood gas analyses were performed. A subgroup analyses were performed in patients with severe acidemia (pH Results Median number of treatment sessions was 2 (range 1–9) per patient. Median duration of treatment was 17.5 (IQR 11–23) hours per session. Treatment with the ADVOS multi-albumin dialysis device caused a significant decrease in bilirubin levels, serum creatinine, BUN and ammonia levels. The relative elimination rate of bilirubin was concentration dependent. Furthermore, a significant improvement in blood pH, HCO3− and PaCO2, was achieved during ADVOS treatment including six patients that suffered from severe metabolic acidosis refractory to continuous renal replacement therapy. Delta pH, HCO3− and PaCO2 were significantly affected by the ADVOS blood flow rate and pH settings. This improvement in the clinical course during ADVOS treatments allowed a reduction in norepinephrine during ADVOS therapy. Treatments were well tolerated. Mortality rates were 50% and 62% for 28 and 90 days, respectively. Conclusions In this case series in patients with MOF, ADVOS was able to eliminate water-soluble and albumin-bound substances. Furthermore, the device corrected severe metabolic and respiratory acid–base disequilibrium. No major adverse events associated with the ADVOS treatments were observed.

Introduction: Immunomodulatory therapies have shown beneficial effects in patients with severe COVID-19. Patients with hypercytokinemia might benefit from the removal of inflammatory mediators via hemadsorption. Methods: Single-center prospective randomized trial at the University Medical Center Hamburg-Eppendorf (Germany). Patients with confirmed COVID-19, refractory shock (norepinephrine ≥0.2 µg/kg/min to maintain a mean arterial pressure ≥65 mm Hg), interleukin-6 (IL-6) ≥500 ng/L, and an indication for renal replacement therapy or extracorporeal membrane oxygenation were included. Patients received either hemadsorption therapy (HT) or standard medical therapy (SMT). For HT, a CytoSorb® adsorber was used for up to 5 days and was replaced every 18–24 h. The primary endpoint was sustained hemodynamic improvement (norepinephrine ≤0.05 µg/kg/min ≥24 h). Results: Of 242 screened patients, 24 were randomized and assigned to either HT (N = 12) or SMT (N = 12). Both groups had similar severity as assessed by SAPS II (median 75 points HT group vs. 79 SMT group, p = 0.590) and SOFA (17 vs. 16, p = 0.551). Median IL-6 levels were 2,269 (IQR 948–3,679) and 3,747 (1,301–5,415) ng/L in the HT and SMT groups at baseline, respectively (p = 0.378). Shock resolution (primary endpoint) was reached in 33% (4/12) versus 17% (2/12) in the HT and SMT groups, respectively (p = 0.640). Twenty-eight-day mortality was 58% (7/12) in the HT compared to 67% (8/12) in the SMT group (p = 1.0). During the treatment period of 5 days, 6/12 (50%) of the SMT patients died, in contrast to 1/12 (8%) in the HT group. Conclusion: HT was associated with a non-significant trend toward clinical improvement within the intervention period. In selected patients, HT might be an option for stabilization before transfer and further therapeutic decisions. This finding warrants further investigation in larger trials.

Background: Critical Care Providers (CCPs) experience situations that challenge their ethics and professional standards and may entail moral distress (MD). Aim: To analyze MD perceived by CCPs in intensive care units (ICUs) or emergency departments (EDs) and further clarify whether CCPs who rely on spiritual resources differ in their perception of MD from those who do not utilize these resources. Methods: A cross-sectional anonymous survey was administered using a modified version of the German language version of the Moral Distress Scale (MDS) with 2 × 12 items to assess the frequency and the respective perceived burden of specific situations by applying a 5-point Likert scale. Explorative factor analysis was performed and the sub-constructs of the respective items regarding MD frequency and burden were identified. Job burden and professional satisfaction were measured using visual analogue scales (VAS) and a four-point Likert scale, respectively. The 15-item SpREUK questionnaire was applied to measure spiritual attitudes and behaviours and to differentiate between religious and spiritual persons. Data from 385 German-speaking CCPs were included (55% physicians, 45% nurses). Results: Conflict situations are similar for physicians and nurses although they are perceived as more burdensome by nurses. Among physicians, the MDS factor Looking away/Resignation scores highest for assistant physician residents, whereas distress caused by looking away is more often perceived by specialist physicians without a managerial position. Work satisfaction is inversely associated with MD and emotional exhaustion is positively associated with it. Participants’ spirituality is marginally associated with MD. The best predictors of both MD frequency and burden are emotional exhaustion with further influences of work satisfaction, being a nurse, and being a non-believer on the frequency of MD perception. Being a nurse, participants’ experience in ICU/ED, and being of the male gender are further predictors of MD burden. Conclusions: MD is experienced differently by different groups of CCPs depending on their place in the hierarchy of responsibility. As MD perception is best predicted by emotional exhaustion, these situations should be avoided. Although some CCPs may rely on spiritual resources, all need individual and team support to cope with MD.

Extracorporeal membrane oxygenation (ECMO) represents a viable therapy option for patients with refractory acute respiratory distress syndrome (ARDS). Currently, veno-venous (vv) ECMO is frequently used in patients suffering from coronavirus disease 2019 (COVID-19). VV-ECMO was also frequently utilised during the influenza pandemic and experience with this complex and invasive treatment has increased worldwide since. However, data on comparison of clinical characteristics and outcome of patients with COVID-19 and influenza-related severe ARDS treated with vv-ECMO are scarce. This is a retrospective analysis of all consecutive patients treated with vv/(veno-arterial)va-ECMO between January 2009 and January 2021 at the University Medical Centre Hamburg-Eppendorf in Germany. All patients with confirmed COVID-19 or influenza were included. Patient characteristics, parameters related to ICU and vv/va-ECMO as well as clinical outcomes were compared. Mortality was assessed up to 90 days after vv/va-ECMO initiation. Overall, 113 patients were included, 52 (46%) with COVID-19 and 61 (54%) with influenza-related ARDS. Median age of patients with COVID-19 and influenza was 58 (IQR 53–64) and 52 (39–58) years (p < 0.001), 35% and 31% (p = 0.695) were female, respectively. Charlson Comorbidity Index was 3 (1–5) and 2 (0–5) points in the two groups (p = 0.309). Median SAPS II score pre-ECMO was 27 (24–36) vs. 32 (28–41) points (p = 0.009), and SOFA score was 13 (11–14) vs. 12 (8–15) points (p = 0.853), respectively. Median P/F ratio pre-ECMO was 64 (46–78) and 73 (56–104) (p = 0.089); pH was 7.20 (7.16–7.29) and 7.26 (7.18–7.33) (p = 0.166). Median days on vv/va-ECMO were 17 (7–27) and 11 (7–20) (p = 0.295), respectively. Seventy-one percent and sixty-nine percent had renal replacement therapy (p = 0.790). Ninety-four percent of patients with COVID-19 and seventy-seven percent with influenza experienced vv/va-ECMO-associated bleeding events (p = 0.004). Thirty-four percent and fifty-five percent were successfully weaned from ECMO (p = 0.025). Ninety-day mortality was 65% and 57% in patients with COVID-19 and influenza, respectively (p = 0.156). Median length of ICU stay was 24 (13–44) and 28 (16–14) days (p = 0.470), respectively. Despite similar disease severity, the use of vv/va-ECMO in ARDS related to COVID-19 and influenza resulted in similar outcomes at 90 days. A significant higher rate of bleeding complications and thrombosis was observed in patients with COVID-19.

Purpose: Immunomodulatory therapies have shown beneficial effects in patients with severe COVID-19. Patients with hypercytokinemia might benefit from removal of inflammatory mediators via hemadsorption.Methods: Single-center prospective randomized trial at the University Medical Center Hamburg-Eppendorf (Germany). Patients with confirmed COVID-19, refractory shock (norepinephrine ≥0.2 μg/kg/min to maintain a mean arterial pressure ≥ 65 mmHg), IL-6≥500 ng/l and an indication for renal replacement therapy (RRT) or extracorporeal membrane oxygenation (ECMO) were included. Patients received either hemadsorption therapy (HT) or standard medical therapy (SMT). For HT, a CytoSorb® adsorber was used for up to 5 days and was replaced every 18–24 hours. The primary endpoint was sustained hemodynamic improvement (norepinephrine ≤0.05 µg/kg/min≥24h). Secondary endpoints included 28-day mortality, SOFA, and reduction of IL-6, PCT, and MR-proADM. Results: Of 242 screened patients, 24 were randomized and assigned to either HT (N=12) or SMT (N=12). Both groups had similar severity as assessed by SAPS II (median 75 points HT group vs. 79 SMT group, p=0.590) and SOFA (17 vs. 16, p=0.551). At randomization, 22 (92%) patients were on RRT and 11 (46%) had vv-ECMO. Median IL-6 levels were 2269 (IQR 948–3679) and 3747 (1301–5415) ng/l in the HT and SMT group at baseline, respectively (p=0.378). Serum IL-6 reduction in the first 24h of treatment compared between both groups was 83% vs. 46% (p=0.235). Shock resolution (primary endpoint) was reached in 33% (4/12) vs. 17% (2/12) in the HT and SMT group, respectively (p=0.640). 28-day mortality was 58% (7/12) in the HT compared to 67% (8/12) in the SMT group (p=1.0).Conclusion: HT was associated with a non-significant trend towards clinical improvement within the intervention period including reduction of IL-6 levels and shock resolution. In selected patients, HT might therefore be an option for stabilization and bridge to transfer and decision. (Trial registration: ClinicalTrials.gov: NCT04344080, https://clinicaltrials.gov/ct2/show/NCT04344080, trial registration date 04/14/2020)]

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the coronavirus disease 2019 (COVID-19) led to an ongoing pandemic with a surge of critically ill patients. Very little is known about the occurrence and characteristic of cardiac arrest in critically ill patients with COVID-19 treated at the intensive care unit (ICU). The aim was to investigate the incidence and outcome of intensive care unit cardiac arrest (ICU-CA) in critically ill patients with COVID-19. This was a retrospective analysis of prospectively recorded data of all consecutive adult patients with COVID-19 admitted (27 February 2020–14 January 2021) at the University Medical Centre Hamburg-Eppendorf (Germany). Of 183 critically ill patients with COVID-19, 18% (n = 33) had ICU-CA. The median age of the study population was 63 (55–73) years and 66% (n = 120) were male. Demographic characteristics and comorbidities did not differ significantly between patients with and without ICU-CA. Simplified Acute Physiological Score II (SAPS II) (ICU-CA: median 44 points vs. no ICU-CA: 39 points) and Sequential Organ Failure Assessment (SOFA) score (median 12 points vs. 7 points) on admission were significantly higher in patients with ICU-CA. Acute respiratory distress syndrome (ARDS) was present in 91% (n = 30) with and in 63% (n = 94) without ICU-CA (p = 0.002). Mechanical ventilation was more common in patients with ICU-CA (97% vs. 67%). The median stay in ICU before CA was 6 (1–17) days. A total of 33% (n = 11) of ICU-CAs occurred during the first 24 h of ICU stay. The initial rhythm was non-shockable (pulseless electrical activity (PEA)/asystole) in 91% (n = 30), 94% (n = 31) had sustained return of spontaneous circulation (ROSC). The median time to ROSC was 3 (1–5) minutes. Patients with ICU-CA had significantly higher ICU mortality (61% vs. 37%). Multivariable logistic regression showed that the presence of ARDS (odds ratio (OR) 4.268, 95% confidence interval (CI) 1.211–15.036, p = 0.024) and high SAPS II (OR 1.031, 95% CI 0.997–1.065, p = 0.077) were independently associated with the occurrence of ICU-CA. A total of 18% of critically ill patients with COVID-19 suffered from a cardiac arrest within the intensive care unit. The occurrence of ICU-CA was associated with presence of ARDS and severity of illness.

About 20% of ICU patients with COVID-19 require renal replacement therapy (RRT). Mid-regional pro-adrenomedullin (MR-proADM) might be used for risk assessment. This study investigates MR-proADM for RRT prediction in ICU patients with COVID-19.We analysed data of consecutive patients with COVID-19, requiring ICU admission at a university hospital in Germany between March and September 2020. Clinical characteristics, details on AKI, and RRT were assessed. MR-proADM was measured on admission.64 patients were included (49 (77%) males). Median age was 62.5y (54-73). 47 (73%) patients were ventilated and 50 (78%) needed vasopressors. 25 (39%) patients had severe ARDS, and 10 patients needed veno-venous extracorporeal membrane oxygenation. 29 (45%) patients required RRT; median time from admission to RRT start was 2 (1-9) days. MR-proADM on admission was higher in the RRT group (2.491 vs. 1.23 nmol/l;AKI requiring RRT is frequent in ICU patients with COVID-19. MR-proADM on admission was able to predict RRT requirement, which may be of interest for risk stratification and management.

Background SARS-CoV-2 caused a pandemic and global threat for human health. Presence of liver injury was commonly reported in patients with coronavirus disease 2019 (COVID-19). However, reports on severe liver dysfunction (SLD) in critically ill with COVID-19 are lacking. We evaluated the occurrence, clinical characteristics and outcome of SLD in critically ill patients with COVID-19. Methods Clinical course and laboratory was analyzed from all patients with confirmed COVID-19 admitted to ICU of the university hospital. SLD was defined as: bilirubin ≥ 2 mg/dl or elevation of aminotransferase levels (> 20-fold ULN). Results 72 critically ill patients were identified, 22 (31%) patients developed SLD. Presenting characteristics including age, gender, comorbidities as well as clinical presentation regarding COVID-19 overlapped substantially in both groups. Patients with SLD had more severe respiratory failure (paO2/FiO2: 82 (58–114) vs. 117 (83–155); p p p = 0.106), vasopressor (95% vs. 72%; p p p p = 0.002). Occurrence of SLD was independently associated with presence of viremia [OR 6.359; 95% CI 1.336–30.253; p p p p Conclusion One-third of critically ill patients with COVID-19 suffer from SLD, which is associated with high mortality. Occurrence of viremia and severity of illness seem to contribute to occurrence of SLD and underline the multifactorial cause.

Background There are large uncertainties with regard to the outcome of patients with coronavirus disease 2019 (COVID-19) and mechanical ventilation (MV). High mortality (50–97%) was proposed by some groups, leading to considerable uncertainties with regard to outcomes of critically ill patients with COVID-19. Objectives The aim was to investigate the characteristics and outcomes of critically ill patients with COVID-19 requiring intensive care unit (ICU) admission and MV. Methods A multicentre retrospective observational cohort study at 15 hospitals in Hamburg, Germany, was performed. Critically ill adult patients with COVID-19 who completed their ICU stay between February and June 2020 were included. Patient demographics, severity of illness, and ICU course were retrospectively evaluated. Results A total of 223 critically ill patients with COVID-19 were included. The majority, 73% (n = 163), were men; the median age was 69 (interquartile range = 58–77.5) years, with 68% (n = 151) patients having at least one chronic medical condition. Their Sequential Organ Failure Assessment score was a median of 5 (3–9) points on admission. Overall, 167 (75%) patients needed MV. Noninvasive ventilation and high-flow nasal cannula were used in 31 (14%) and 26 (12%) patients, respectively. Subsequent MV, due to noninvasive ventilation/high-flow nasal cannula therapy failure, was necessary in 46 (81%) patients. Renal replacement therapy was initiated in 33% (n = 72) of patients, and owing to severe respiratory failure, extracorporeal membrane oxygenation was necessary in 9% (n = 20) of patients. Experimental antiviral therapy was used in 9% (n = 21) of patients. Complications during the ICU stay were as follows: septic shock (40%, n = 90), heart failure (8%, n = 17), and pulmonary embolism (6%, n = 14). The length of ICU stay was a median of 13 days (5–24), and the duration of MV was 15 days (8–25). The ICU mortality was 35% (n = 78) and 44% (n = 74) among mechanically ventilated patients. Conclusion In this multicentre observational study of 223 critically ill patients with COVID-19, the survival to ICU discharge was 65%, and it was 56% among patients requiring MV. Patients showed high rate of septic complications during their ICU stay.

Key Points Patients with acute leukemia present with a prolonged and severe course of COVID-19, which is paralleled by high rates of viremia. Low-intensive chemotherapy seems to be more feasible in patients with acute myeloid leukemia and concomitant SARS-CoV-2 infection., Visual Abstract

The spread of SARS-CoV-2 caused a worldwide healthcare threat. High critical care admission rates related to Coronavirus Disease 2019 (COVID-19) respiratory failure were observed. Medical advances helped increase the number of patients surviving the acute critical illness. However, some patients require prolonged critical care. Data on the outcome of patients with a chronic critical illness (CCI) are scarce. Single-center retrospective study including all adult critically ill patients with confirmed COVID-19 treated at the Department of Intensive Care Medicine at the University Medical Center Hamburg-Eppendorf, Germany, between 1 March 2020 and 8 August 2021. We identified 304 critically ill patients with COVID-19 during the study period. Of those, 55% (n = 167) had an ICU stay ≥21 days and were defined as chronic critical illness, and 45% (n = 137) had an ICU stay

Background— Organ transplantation has seen an increased use of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplantation outcomes when older donor organs are used represent a growing challenge. Methods and Results— Here, we characterize the impact of donor age on solid-organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when older hearts were used. Shorter graft survival of older hearts was independent of organ age per se, because chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c + dendritic cells augmenting CD4 + and CD8 + T-cell proliferation and proinflammatory cytokine production, particularly that of interleukin-17A. Of note, depletion of donor CD11c + dendritic cells before engraftment, neutralization of interleukin-17A, or transplantation of older hearts into IL-17A −/− mice delayed rejection and reduced alloimmune responses to levels observed when young hearts were transplanted. Conclusions— These results demonstrate a critical role of old donor CD11c + dendritic cells in mounting age-dependent alloimmune responses with an augmented interleukin-17A response in recipient animals. Targeting interleukin-17A may serve as a novel therapeutic approach when older organs are transplanted.

Costimulatory molecules, such as the programmed death ligand (PD-L1), might exert differential effects on T-cell function, depending on the clinical setting and/or immunological environment. Given the impact of T cells on bronchiolitis obliterans (BO) in lung transplantation, we used an established tracheal transplant model inducing BO-like lesions to investigate the impact of PD-L1 on alloimmune responses and histopathological outcome in BO. In contrast to other transplant models in which PD-L1 generally shows protective functions, we demonstrated that PD-L1 has divergent effects depending on its location in donor versus recipient tissue. Although PD-L1 deficiency in donor tissue worsened histopathological outcome, and increased systemic inflammatory response, recipient PD-L1 deficiency induced opposite effects. Mechanistic studies revealed PD-L1–deficient recipients were hyporesponsive toward alloantigen, despite increased numbers of CD8 + effector T cells. The function of PD-L1 on T cells after unspecific stimulation was dependent on both cell type and strength of stimulation. This novel function of recipient PD-L1 may result from the high degree of T-cell activation within the highly immunogenic milieu of the transplanted tissue. In this model, both decreased T-cell alloimmune responses and the reduction of BO in PD-L1–deficient recipients suggest a potential therapeutic role of selectively blocking PD-L1 in the recipient. Further investigation is warranted to determine the impact of this finding embedded in the complex pathophysiological context of BO.

TIM-3 is constitutively expressed on subsets of macrophages and dendritic cells. Its expression on other cells of the innate immune system and its role in fetomaternal tolerance has not yet been explored. In this study, we investigate the role of TIM-3–expressing innate immune cells in the regulation of tolerance at the fetomaternal interface (FMI) using an allogeneic mouse model of pregnancy. Blockade of TIM-3 results in accumulation of inflammatory granulocytes and macrophages at the uteroplacental interface and upregulation of proinflammatory cytokines. Furthermore, TIM-3 blockade inhibits the phagocytic potential of uterine macrophages resulting in a build up of apoptotic bodies at the uteroplacental interface that elicits a local immune response. In response to inflammatory cytokines, Ly-6ChiGneg monocytic myeloid–derived suppressor cells expressing inducible NO synthase and arginase 1 are induced. However, these suppressive cells fail to downregulate the inflammatory cascade induced by inflammatory granulocytes (Ly-6CintGhi) and apoptotic cells; the increased production of IFN-γ and TNF-α by inflammatory granulocytes leads to abrogation of tolerance at the FMI and fetal rejection. These data highlight the interplay between cells of the innate immune system at the FMI and their influence on successful pregnancy in mice.

The elimination of substances between 10 and 50 kDa by conventional high-flux membranes is not satisfactory. We investigated in vivo the elimination of middle-sized uremic solutes by conventional polyflux (PF) and modified high-cut-off (HCO) membranes. All 12 patients underwent four treatments, two with the HCO dialyzer and two with the PF dialyzer, each in either a haemodialysis (HD) or haemodiafiltration (HDF) mode. The reduction ratio of urea, creatinine, β2-microglobulin (β2M), leptin, soluble TNF-RI, complement factor D, IL-6, sIL-6 receptor, advanced glycation end-products (AGEs) and albumin was determined. In addition, the amount removed was determined in the dialysate for β2M, complement factor D, AGEs and albumin. Treatment with HCO removed β2M, sTNF-RI, factor D, and high molecular AGE significantly better than conventional high-flux membranes. The albumin loss was higher when using HCO membranes. HCO membranes are a promising approach to improve removal of uremic toxins not affected by conventional high-flux membranes.

Co-stimulatory molecules are a heterogenous group of cell surface molecules that act to amplify or counteract the initial activating signals provided to T cells from the T cell receptor (TCR) following its interaction with an antigen/major histocompatibility complex (MHC), thereby influencing T cell differentiation and fate. While co-stimulation was previously thought to be indispensable for T cell activation at all stages of development, it is now known that the requirements for co-stimulation, and co-stimulatory molecules involved, vary according to the stage of T cell differentiation. The ability to influence T cell fate is of paramount interest in the field of transplantation as we seek therapeutic options that inhibit detrimental alloimmune responses whilst simultaneously promoting allograft tolerance. As with many immune mechanisms, there is a degree of functional overlap between certain co-stimulatory molecules, while some have diametrically opposite effects on different T cell subsets despite sharing common ligands. This is a critical point when considering these molecules as therapeutic targets in transplantation, as blockade of a co-stimulatory pathway, while desirable in itself, may prevent the ligation of an essential regulatory co-inhibitory molecule. This review discusses the T helper cell lineages pertinent to transplantation and the co-stimulatory molecules involved in their differentiation.

Tolerance induction protocols have been successfully tested in animal models, yet their compatibility with immunosuppressive drugs remains to be fully elucidated. Our own previous data have indicated that cyclosporine A (CsA) affects the balance of effector and regulatory mechanisms with low-dose CsA doses promoting hyporesponsiveness. Here, we present a fully mismatched rat kidney model in which low-dose CsA treatment induces donor hyporesponsiveness to secondary renal allografts. Lewis recipients of DA kidney grafts received low, medium or high doses of CsA × 10 days. By 30 days, the primary transplant was removed and a second transplant of donor origin was engrafted. Following low-dose CsA, but not high-dose CsA treatment of the primary recipient, secondary transplants were accepted long-term in the absence of immunosuppression. Regulatory T-cell function was unimpaired and independent of the CyA dosage. Of note, low-dose CsA significantly reduced alloantibody titers in primary recipients. Adoptive transfer of graft infiltrating cells or splenocytes from hyporesponsive recipients supported long-term acceptance of donor kidney allografts. These results demonstrate a dose-dependent and transferable “pro-tolerogenic” effect of low-dose CsA treatment. This model is of clinical relevance to test the interference of CsA with tolerance induction in the absence of additional immunosuppression.

The addition of low, nondepleting doses of rabbit antithymocyte globulin (ATG) to human peripheral blood mononuclear cells has been shown to expand functional CD4(+) CD25(+) FoxP3(+) regulatory T cells (Tregs) in vitro. This report is the first to elucidate the exact cellular mechanisms of ATG-mediated Treg expansion. CD4(+) T cells require monocytes, but not other antigen presenting cell subsets, to be present in coculture to expand Tregs. However, T cells do not require direct cell-cell contact with monocytes, suggesting the importance of soluble factors. Moreover, ATG initially "reprograms" CD4(+) T cells, but not monocytes, and induces STAT3 and STAT5 signaling in CD4(+) cells. These reprogrammed CD4(+) T cells subsequently secrete GM-CSF and IL-10 only in case of intact STAT3 signaling, which in turn promote the generation of tolerogenic CD14(+) CD11c(+) dendritic cells characterized by enhanced IL-10 and decreased IL-12 production. Treg expansion following ATG treatment is accompanied by enhanced gene expression of both GM-CSF and Bcl-2, but not TGF-β, in peripheral blood mononuclear cells. These results demonstrate that ex vivo expansion of human Tregs by ATG is due to its ability to reprogram CD4(+) T cells in a STAT3-dependent but TGF-β-independent manner, leading to the generation of monocyte-derived dendritic cells with a tolerogenic cytokine profile.

We have previously reported that peri-transplant conditioning leads to successful induction of renal allograft tolerance via the mixed chimerism approach in nonhuman primates (NHP) and humans. However, this strategy requires treatments beginning six days prior to transplantation, which limits its relevance only to living donor transplant recipients. To extend the clinical applicability of this approach, we developed a novel regimen “delayed tolerance,” with which the recipient initially undergoes organ transplantation with conventional immunosuppression, followed by conditioning and donor bone marrow transplantation (DBMT) at a later date. This approach might be likened to “planting flowers in a battle field.” That is, the recipient’s immunologic environment after organ transplantation is like a battlefield filled with hostile innate and adaptive immune-responses directed against donor antigeneic specificities. Implanting fragile donor hematopoietic progenitors into this environment and encouraging them to bloom in this vicious field requires special treatments. In our NHP studies recently published in The American Journal of Transplantation, we showed that such “delayed tolerance,” in fact, can be induced in NHP through the mixed chimerism approach, if specific modifications to overcome/avoid donor-specific memory T cell responses are provided. These modifications include adequate depletion of CD8 memory T cells and timing of donor bone marrow administration to minimize levels of pro-inflammatory cytokines. This article addendum will provide a short summary of the original paper with our additional insights and interpretations.

CD4 + T cells contribute to the pathogenesis of ischemia-reperfusion injury, which is the primary cause of delayed graft failure after kidney transplantation. The TIM-1:TIM-4 pathway participates in the activation/differentiation of CD4 + T cells, suggesting that it may modulate ischemia-reperfusion injury. Here, we studied the role of TIM-1 in a murine uninephrectomized renal ischemia-reperfusion injury model. Blocking the TIM-1:TIM-4 pathway with an antagonistic monoclonal antibody protected renal function and diminished reperfusion injury resulting from 30 minutes of ischemia. Histologic examination showed significantly less evidence of renal damage as evidenced by diminished tubular necrosis, preservation of the brush border, fewer cast formations, and less tubular dilation. Blocking TIM-1 also reduced the number of apoptotic cells and diminished local inflammation within ischemic kidneys, the latter shown by decreased recruitment of macrophages, neutrophils, and CD4 + T cells and by reduced local production of proinflammatory cytokines. Furthermore, TIM-1 blockade significantly improved survival after ischemia-reperfusion injury. Taken together, these data suggest that the TIM-1:TIM-4 pathway enhances injury after renal ischemia-reperfusion injury and may be a therapeutic target.

B7 ligands deliver both costimulatory and coinhibitory signals to the CD28 family of receptors on T lymphocytes, the balance between which determines the ultimate immune response. Although B7-H4, a recently discovered member of the B7 family, is known to negatively regulate T cell immunity in autoimmunity and cancer, its role in solid organ allograft rejection and tolerance has not been established. Targeting the B7-H4 molecule by a blocking antibody or use of B7-H4(-/-) mice as recipients of fully MHC-mismatched cardiac allografts did not affect graft survival. However, B7-H4 blockade resulted in accelerated allograft rejection in CD28-deficient recipients. B7-1/B7-2-double-deficient recipients are truly independent of CD28/CTLA-4:B7 signals and usually accept MHC-mismatched heart allografts. Blockade of B7-H4 in these mice also precipitated rejection, demonstrating regulatory function of this molecule independent of an intact CD28/CTLA-4:B7 costimulatory pathway. Accelerated allograft rejection was always accompanied by increased frequencies of alloreactive IFN-γ-, IL-4- and Granzyme B-producing splenocytes. Finally, intact recipient, but not donor, B7-H4 is essential for prolongation of allograft survival by blocking CD28/CTLA4:B7 pathway using CTLA4-Ig. These data are the first to provide evidence of the regulatory effects of B7-H4 in alloimmune responses in a murine model of solid organ transplantation.

CD8(+) memory T cells endanger allograft survival by causing acute and chronic rejection and prevent tolerance induction. We explored the role of CD27:CD70 T-cell costimulatory pathway in alloreactive CD8(+)/CD4(+) T-cell activation. CD27-deficient (CD27(-/-)) and wild-type (WT) B6 mice rejected BALB/c cardiac allografts at similar tempo, with or without depletion of CD4(+) or CD8(+) T cells, suggesting that CD27 is not essential during primary T-cell alloimmune responses. To dissect the role of CD27 in primed effector and memory alloreactive T cells, CD27(-/-) or WT mice were challenged with BALB/c hearts either 10 or 40 days after sensitization with donor-type skin grafts. Compared to WT controls, allograft survival was prolonged in day 40- but not day 10-sensitized CD27(-/-) recipients. Improved allograft survival was accompanied by diminished secondary responsiveness of memory CD8(+) T cells, which resulted from deficiency in memory formation rather than their lack of secondary expansion. Chronic allograft vasculopathy and fibrosis were diminished in CD27(-/-) recipients of class I- but not class II-mismatched hearts as compared to WT controls. These data establish a novel role for CD27 as an important costimulatory molecule for alloreactive CD8(+) memory T cells in acute and chronic allograft rejection.

Survival of renal allografts is limited by chronic allograft deterioration resulting from processes that are difficult to detect in their early stages, when therapeutic interventions would be most effective. Predictive biomarkers from easily accessible specimens, such as blood or urine, might improve early diagnosis of smoldering graft-damaging processes and help with the identification of patients at particularly high risk of sustained injury, thereby helping to tailor therapy and appropriate follow-up screening.This article reviews recently investigated biomarkers for the prediction of renal allograft failure, outlines the new '-omic' technologies as a potential source for the identification of new predictive biomarkers and judges the practical value of predictive biomarkers at the present timepoint.A literature search was performed using the medical database PubMed. No general restrictions (e.g., year of publication) were applied, but the focus was set on more recently published articles.Despite a large number of interesting studies, none of the investigated candidate biomarkers is robustly established for widespread clinical use or able to replace biopsies for graft assessment.

T cell Ig mucin 1 (TIM-1) plays an important role in regulating immune responses in autoimmune and asthma models, and it is expressed on both Th1 and Th2 cells. Using an antagonistic TIM-1-specific antibody, we studied the role of TIM-1 in alloimmunity. A short course of TIM-1-specific antibody monotherapy prolonged survival of fully MHC-mismatched vascularized mouse cardiac allografts. This prolongation was associated with inhibition of alloreactive Th1 responses and preservation of Th2 responses. TIM-1-specific antibody treatment was more effective in Th1-type cytokine-deficient Stat4(-/-) recipients as compared with Th2-type cytokine-deficient Stat6(-/-) recipients. Subtherapeutic doses of rapamycin plus TIM-1-specific antibody resulted in allograft acceptance and prevented the development of chronic allograft vasculopathy. Allograft survival via this treatment was accompanied by a Th1- to Th2-type cytokine switch. Depletion of natural Tregs abrogated the graft-protecting effect of the TIM-1-specific antibody. Importantly, CD4(+)CD25(+) Tregs obtained from long-term survivors had enhanced regulatory activity as compared with naive CD4(+)CD25(+) Tregs. Consistent with this, TIM-1-specific antibody treatment both preserved Tregs and prevented the expansion of alloreactive effector Th1 cells in an alloreactive TCR transgenic adoptive transfer model. These studies define previously unknown functions of TIM-1 in regulating alloimmune responses in vivo and may provide a novel approach to promoting transplantation tolerance.

The increasing use of high-flux membranes for hemodialysis (HD) has raised concerns that these membranes may confer a higher risk of exposure to cytokine-inducing, bacterial substances (CIS) in the dialysate. Several studies, however, reported higher transfer of CIS through low-flux cellulosic than high-flux synthetic membranes. This surprising paradox was explained by adsorption of CIS to certain high-flux membranes. In order to investigate flux and membrane type independently, we studied two synthetic Polyflux (PF) membranes of the same type but with different flux properties and compared them to a cellulosic membrane (Cuprophan). Three different approaches were employed: (1) cytokine induction in whole blood during in vitro HD contaminated with bacterial filtrates, (2) removal of recombinant C5a, and (3) transfer of purified lipopolysaccharide (LPS). After 90 min recirculation of whole blood, the appearance of IL-6-inducing substances on the blood side was lowest with high-flux PF (1.1 ± 0.2 ng/ml), slightly higher with low-flux PF (1.9 ± 0.7 ng/ml) and highest with Cuprophan (4.1 ± 1 ng/ml). Recombinant C5a added to plasma on the blood side was markedly removed by high-flux PF (by 83%), to a lesser degree and only in the presence of ultrafiltration with low-flux PF (by 54%) and not significantly with Cuprophan (by 11%). Significant transfer of purified LPS from the dialysate onto the blood side was only observed with the cellulosic membrane. We conclude that in contrast to cellulosic membranes, certain synthetic membranes do not permit transfer of LPS. Cytokine induction on the blood side is further reduced by the use of high-flux membranes due to removal of activated complement factors.

To investigate the effect of low-dose hydrocortisone on time to shock reversal, the cytokine profile, and its relation to adrenal function in patients with early septic shock.Prospective, randomized, double-blind, single-center study.Medical intensive care unit of a university hospital.Forty-one consecutive patients with early hyperdynamic septic shock.After inclusion and a short adrenocorticotropic hormone test, all patients were randomized to receive either low-dose hydrocortisone (50-mg bolus followed by a continuous infusion of 0.18 mg/kg body of weight/hr) or matching placebo. After shock reversal, the dose was reduced to 0.06 mg/kg/hr and afterward slowly tapered. Severity of illness was estimated using Acute Physiology and Chronic Health Evaluation II score and Sequential Organ Failure Assessment score.Time to cessation of vasopressor support (primary end point) was significantly shorter in hydrocortisone-treated patients compared with placebo (53 hrs vs. 120 hrs, p.02). This effect was more profound in patients with impaired adrenal reserve. Irrespective of endogenous steroid production, cytokine production was reduced in the treatment group with lower plasma levels of interleukin-6 and a diminished ex vivo lipopolysaccharide-stimulated interleukin-1 and interleukin-6 production. Interleukin-10 levels were unaltered. Adverse events were not more frequent in the treatment group.Treatment with low-dose hydrocortisone accelerates shock reversal in early hyperdynamic septic shock. This was accompanied by reduced production of proinflammatory cytokines, suggesting both hemodynamic and immunomodulatory effects of steroid treatment. Hemodynamic improvement seemed to be related to endogenous cortisol levels, whereas immune effects appeared to be independent of adrenal reserve.

Dear Editor, Invasive mechanical ventilation with or without additional extracorporeal membrane oxygenation (ECMO) support represents standard treatment for patients with acute respiratory distress syndrome (ARDS). An ‘‘awake ECMO’’ strategy in order to avoid intubation and mechanical ventilation has been implemented as a bridge to lung transplantation in patients with chronic lung disease [1, 2] but has been used only occasionally in patients with ARDS [3]. We conducted a single-center, uncontrolled pilot trial designed to assess the feasibility of veno-venous ECMO in awake, non-intubated, spontaneously breathing patients with ARDS (www.clinical.govNCT01669 863 ). Patients between 18 and 75 years old presenting with moderate or severe ARDS were eligible. The main exclusion criteria were severe bleeding disorders and uncontrolled sepsis with multi-organ failure involving at least two organ systems. The Institutional Review Board (IRB) of Hannover Medical School approved and supervised the study and all patients provided written informed consent prior to ECMO insertion. Six patients with severe ARDS were enrolled as planned; four of them were immunocompromised. Patient characteristics and outcome parameters are shown in Table 1. All patients suffered from severe ARDS with PaO2/FiO2 ratios at most 100 mmHg while receiving noninvasive ventilation. Gas exchange patterns improved immediately after ECMO insertion and noninvasive ventilation could be stopped within 1 h in two patients. Three patients (patients 1, 4, and 5) were successfully weaned from ECMO after 10, 5, and 7 days, respectively, and discharged from the ICU without needing invasive mechanical ventilation. Patient 2 was also successfully weaned from ECMO support but developed respiratory failure due to an iatrogenic pneumothorax 2 days later and required intubation as a result. A protracted ICU course ensued, complicated by ventilatorassociated pneumonia and sepsis. The patient was eventually discharged from the ICU after 50 days. Patient 3 improved rapidly on ECMO support, but became increasingly agitated and confused. On the 7th day on ECMO support, he intentionally removed his jugular cannula, resulting in emergency intubation and brief cardiopulmonary resuscitation. He subsequently died 10 days later from

Background Despite significant nephrotoxicity, calcineurin inhibitors (CNIs) remain the cornerstone of immunosuppression in solid organ transplantation. We, along with others, have reported tolerogenic properties of anti-thymocyte globulin (ATG, Thymoglobulin®), evinced by its ability both to spare Tregs from depletion in vivo and, when administered at low, non-depleting doses, to expand Tregs ex vivo. Clinical trials investigating B7/CD28 blockade (LEA29Y, Belatacept) in kidney transplant recipients have proven that the replacement of toxic CNI use is feasible in selected populations. Methods Rabbit polyclonal anti-murine thymocyte globulin (mATG) was administered as induction and/or prolonged, low-dose therapy, in combination with CTLA4-Ig, in a stringent, fully MHC-mismatched murine skin transplant model to assess graft survival and mechanisms of action. Results Prolonged, low-dose mATG, combined with CTLA4-Ig, effectively promotes engraftment in a stringent transplant model. Our data demonstrate that mATG achieves graft acceptance primarily by promoting Tregs, while CTLA4-Ig enhances mATG function by limiting activation of the effector T cell pool in the early stages of treatment, and by inhibiting production of anti-rabbit antibodies in the maintenance phase, thereby promoting regulation of alloreactivity. Conclusion These data provide the rationale for development of novel, CNI-free clinical protocols in human transplant recipients.

Background One hallmark of uremia is the impairment of neuro-cognitive function. Anecdotal clinical description from the early days of chronic dialysis therapy impressively illustrates the improvement of those functions by chronic hemodialysis treatment. Fortunately, today, uremia is only rarely observed in industrialized countries as many patients seek medical/nephrological attention prior to the occurrence of deadly complications of uremia. Case presentation We report a rare case of severe uremia and describe the day to day improvement in neuro-cognitive function by dialysis using state of the arte test battery – starting at a serum creatinine of 2443 μmol/l. Conclusions Especially executive functions, which are assumed to be localized in the frontal cerebral regions, are impaired in severe uremia and improve remarkably with the correction of severe uremia, i.e. initiation of dialysis.

Background Organs from DCD (donation after cardiac death) donors are increasingly used for transplantation. The impact of advanced donor age and warm ischemia on the immune response of the recipient has not been studied. We developed a novel and clinically relevant model of DCD kidney transplantation and investigated the effects of donor age and prolonged warm ischemia on the recipient immune response after following DCD kidney transplantation. Methods DCD grafts from young and old F-344 donor rats were engrafted into LEW recipients who were nephrectomized bilaterally after a short (20 minutes) or prolonged (45 minutes) warm ischemia time. Results Analysis of the recipient's immune response early after transplantation showed an enhanced innate and adaptive immune response when old DCD kidneys were engrafted. Next, we studied DCD recipients with a supportive, contralateral native kidney in place, which allowed the recovery of the transplanted DCD kidney. Old DCD kidneys, demonstrated an impaired renal function associated with pronounced histomorphologic graft deterioration and an enhanced immune response by day 100 after transplantation. Interestingly, young DCD kidneys with a long warm ischemic time recovered from acute tubular necrosis and did not stimulate the long-term immune response. Conclusion Our observations emphasize that prolonged warm ischemic time and advanced donor age augment the immune response after transplantation of DCD grafts. These results provide an experimental model and a mechanistic framework of clinically relevant aspects in DCD donation.

The proinflammatory cytokine IL-6 plays an important role in controlling T-cell differentiation, especially the development of Th17 and regulatory T cells. To determine the function of IL-6 in regulating allograft rejection and tolerance, BALB/c cardiac grafts were transplanted into wild-type or IL-6-deficient C57BL/6 mice. We observed that production of IL-6 and IFN-γ was upregulated during allograft rejection in untreated wild-type mice. In IL-6-deficient mice, IFN-γ production was greater than that observed in wild-type controls, suggesting that IL-6 production affects Th1/Th2 balance during allograft rejection. CD28-B7 blockade by CTLA4-Ig inhibited IFN-γ production in C57BL/6 recipients, but had no effect on the production of IL-6. Although wild-type C57BL/6 recipients treated with CTLA4-Ig rejected fully MHC-mismatched BALB/c heart transplants, treatment of IL-6-deficient mice with CTLA4-Ig resulted in graft acceptance. Allograft acceptance appeared to result from the combined effect of costimulatory molecule blockade and IL-6-deficiency, which limited the differentiation of effector cells and promoted the migration of regulatory T cells into the grafts. These data suggest that the blockade of IL-6, or its signaling pathway, when combined with strategies that inhibit Th1 responses, has a synergistic effect on the promotion of allograft acceptance. Thus, targeting the effects of IL-6 production may represent an important part of costimulation blockade-based strategies to promote allograft acceptance and tolerance.

A 55-year-old, previously healthy man was admitted to another hospital with deep-venous thrombosis in both legs and massive pulmonary embolism verified by chest computed tomography (CT). He presented with severe dyspnea and hypotension refractory to inotropes. Fibrinolytic therapy with recombinant tissue plasminogen activator was initiated, but the patient further deteriorated and required cardiopulmonary resuscitation for a period of 30 minutes. After return of spontaneous circulation, he remained in cardiogenic shock despite the use of inotropes and vasopressors, which is why our hospital was contacted. Our mobile extracorporeal membrane oxygenation (ECMO) team was dispatched and the patient received veno-arterial ECMO support with a 24 French venous cannula inserted via the right femoral vein and advanced into the right atrium and a 17 French arterial cannula inserted into the right femoral artery and advanced into the right iliacal artery. With an ECMO blood flow of 4.5 L/min, hemodynamics stabilized and the patient was transported to Hannover Medical School. Here, the patient was mechanically ventilated with an inspiratory oxygen fraction of 1.0 …

Blockade of the B7: CD28 costimulatory pathway has emerged as a promising therapy to prevent allograft rejection. However, this pathway has also been demonstrated to be important for the generation and maintenance of regulatory T cells. In this study, we investigated the role of the B7: CD28 pathway in the 'bm12 into B6' MHC class II-mismatched vascularized cardiac transplant model of chronic rejection. Allograft rejection was remarkably accelerated in B6 background B7DKO and CD28KO recipients compared with B6 wild-type (WT) recipients. Allograft rejection was associated with a significantly enhanced Th1/Th2 alloreactivity and marked reduction in the ratio of regulatory T cells to CD4(+) effector/memory cells. We noted that administration of anti-B7-1 and anti-B7-2 mAb prior to transplantation also accelerated allograft rejection. Furthermore, depleting CD25(+) cells in B6 WT recipients of bm12 hearts prior to transplant also precipitated rejection at a similar rate. Neither B7/CD28 deficiency nor CD25 depletion affected graft survival in single MHC class I-mismatched (bm1 into B6) recipients. This study highlights the paradoxical functions of B7: CD28 costimulation in a MHC class II-mismatched model, in which the B7: CD28 pathway is demonstrated to be important in preventing rejection through the generation and maintenance of Tregs.

Mannose-binding lectin (MBL) mediates important functions within the innate immune system, and its deficiency was associated with infectious complications. However, in adults without concomitant immunodeficiency the clinical relevance of MBL deficiency remains controversial. We analyzed the distribution of MBL deficiency and its association with concomitant immunodeficiency in 228 adult Caucasian patients with a history of recurrent and/or severe infections. Two hundred forty-one unrelated Caucasians without recurrent or severe infections served as control subjects. The frequency of severe MBL deficiency (plasma levels

Purpose of review Negative T-cell costimulatory pathways regulate T-cell responses and are of great interest in the development of tolerance-inducing strategies in transplantation. This article provides an update of major contributions to the understanding of the known negative costimulatory pathways, and reviews recent studies on the effects of targeting of these pathways in alloimmunity. Recent findings Graft tissue expression of negative costimulatory molecules, especially programmed death receptor ligand 1, plays a major role in regulation of alloimmune responses. The recently demonstrated programmed death receptor ligand 1:B7-1 interaction highlights the complexity and possible redundancy/hierarchy of the functions of these pathways in vivo. CD160 was identified as a ligand of Herpes virus entry mediator and has been established as a new coinhibitory molecule. A soluble form of B7-H3 with possible functional roles has been identified in mice and humans. Summary The understanding of negative costimulatory pathways is embarrassed by complex interactions between simultaneously activated positive and negative costimulatory pathways among themselves and with immunosuppressive agents, differential expression of these molecules on different immune cell subsets as well as their expression in parenchymal cells of transplanted tissues, all of them clearly affecting their functions. Further elucidation of these novel concepts is pertinent for targeting these pathways in translational studies in near future.

Introduction Hyperglycemia is associated with negative outcomes in various settings of critical illness; infectious complications, especially, seem to be increased. On the other hand, intensive insulin therapy (IIT) has been shown to improve outcome in clinical trials. Whether normoglycemia itself or the application of insulin is responsible for the observed findings is unknown. We therefore tested the effect of glucose and insulin on various immune functions in vitro. Methods Human peripheral blood mononuclear cells (PBMCs) were incubated ex vivo with low doses of lipopolysaccharide (LPS). PBMCs were incubated with various osmotic agents, insulin, or a combination of both. Interleukin (IL)-6 and IL-1 cytokine response was measured by enzyme-linked immunosorbent assay. In addition, we investigated the effects of glucose on phagocytosis and oxidative burst in human granulocytes. Results Increasing concentrations of both glucose and mannitol significantly enhanced LPS-induced cytokine production. Insulin alone did not alter cytokine production and had only a minor influence in combination with glucose. Phagocytosis and oxidative burst were significantly reduced with increasing concentrations of glucose and mannitol. Conclusion Hyperglycemia may lead to inflammation by enhancing cytokine production via the direct effects of hyperosmotic stress. Impaired phagocytosis and oxidative burst under hyperglycemia may weaken defense mechanisms of the host. Our in vitro findings may help to explain the beneficial effects of IIT not only in diabetic but also in critically ill patients.