Pre-admission ambient air pollution and blood soot particles predict hospitalisation outcomes in COVID-19 patients.

BACKGROUND: Air pollution exposure is one of the major risk factors for aggravation of respiratory diseases. We investigated whether exposure to air pollution and accumulated black carbon (BC) particles in blood were associated with coronavirus disease 2019 (COVID-19) disease severity, including the risk for intensive care unit (ICU) admission and duration of hospitalisation. METHODS: From May 2020 until March 2021, 328 hospitalised COVID-19 patients (29% at intensive care) were recruited from two hospitals in Belgium. Daily exposure levels (from 2016 to 2019) for particulate matter with aerodynamic diameter <2.5 µm and <10 µm (PM2.5 and PM10, respectively), nitrogen dioxide (NO2) and BC were modelled using a high-resolution spatiotemporal model. Blood BC particles (internal exposure to nano-sized particles) were quantified using pulsed laser illumination. Primary clinical parameters and outcomes included duration of hospitalisation and risk of ICU admission. RESULTS: Independent of potential confounders, an interquartile range (IQR) increase in exposure in the week before admission was associated with increased duration of hospitalisation (PM2.5 +4.13 (95% CI 0.74-7.53) days, PM10 +4.04 (95% CI 1.24-6.83) days and NO2 +4.54 (95% CI 1.53-7.54) days); similar effects were observed for long-term NO2 and BC exposure on hospitalisation duration. These effect sizes for an IQR increase in air pollution on hospitalisation duration were equivalent to the effect of a 10-year increase in age on hospitalisation duration. Furthermore, for an IQR higher blood BC load, the OR for ICU admission was 1.33 (95% CI 1.07-1.65). CONCLUSIONS: In hospitalised COVID-19 patients, higher pre-admission ambient air pollution and blood BC levels predicted adverse outcomes. Our findings imply that air pollution exposure influences COVID-19 severity and therefore the burden on medical care systems during the COVID-19 pandemic.

The effects of differing anticoagulant regimes on blood quality after cell salvage in coronary artery bypass grafting (CABG): a pilot study.

BACKGROUND: Cell salvage reduces allogenic blood transfusion requirements in surgery. We present a pilot study exploring the impact of anticoagulant choice, citrate or heparin, on the quality of cell salvaged blood in adults undergoing coronary artery bypass grafting (CABG). MATERIALS AND METHODS: Elective on pump CABG patients were randomly allocated to citrate or heparin anticoagulation. We measured red blood cell characteristics and inflammation in both the blood collection reservoir and the washed red blood cell concentrate. Postoperatively, the level of biomarkers and the coagulation profile in the peripheral blood as well as the transfusion requirements of allogenic blood products were studied. RESULTS: Thirty eight patients were included, 19 in the citrate group and 19 in the heparin group. Baseline characteristics were similar. In the washed red blood cell concentrate, Mean Hb (g/dl) and Ht (%) were lower in the citrate group [Hb: 18.1 g/dL (SD 1.3) vs. 21.1 (1.6), p < 0.001; Ht: 59.9% (54.7-60.9) vs. 63.7% (62.3-64.8); p < 0.001]; Mean corpuscular volume (MCV, µm 3) was higher [99.1fL (9.4) vs. 88 (4.2), p < 0.001] and mean corpuscular hemoglobin concentration (MCHC, g/dl) lower in the citrate group [31.9 g/dl (29.6-32.4) vs. 33.6 (33.1-34.0) p < 0.001]. Thrombocyte count (1000/µl) was higher in the citrate group [31.0 (26.0-77.0) vs. 13.0 (10.0-39.0); p = 0.006]. There were no differences in the requirement for allogenic blood products' transfusion (intraoperatively and postoperatively) or in the coagulation parameters after washed red blood cell concentrate infusion. Higher IL-10 was found in the citrate group in the blood collection reservoir, higher neutrophil-derived myeloperoxidase (MPO) in the heparin group after washed red blood cell concentrate infusion. CONCLUSION: Though red blood cells in washed red blood cell concentrate were more swollen and diluted in the citrate group with more residual thrombocytes, published quality guidelines were met in both groups. Our pilot study suggests that differences in inflammatory markers in the blood collection reservoir and after infusion of washed red blood cell concentrate indicate a possible pro-inflammatory effect of heparin compared to citrate. A larger study is warranted to confirm these results and their possible clinical consequences. Trial registration ClinicalTrials.gov : NCT02674906. Registered 5 February 2016.

The Relationship Between Esophageal Pressure and Diaphragm Thickening Fraction in Spontaneously Breathing Sedated Children: A Feasibility Study.

OBJECTIVES: Diaphragm ultrasound is a novel alternative to esophageal pressure measurements in the evaluation of diaphragm function and activity, but data about its reliability in a pediatric setting are lacking. We aimed to compare the esophageal pressure swing (∆P es , gold standard) with the diaphragmatic thickening fraction (DTF) as a measure of inspiratory effort in sedated children. Additionally, we studied the effect of positive end-expiratory pressure (PEEP) on the end-expiratory thickness of the diaphragm (DT ee ). DESIGN: Prospective open-label non-randomized interventional physiological cohort study. SETTING: Operating room in tertiary academic hospital. PATIENTS: Children 28 days to 13 years old scheduled for elective surgery with general anesthesia, spontaneously breathing through a laryngeal mask airway, were eligible for inclusion. Exclusion criteria were disorders or previous surgery of the diaphragm, anticipated difficult airway or acute cardiopulmonary disease. All measurements were performed prior to surgery. INTERVENTIONS: Patients were subjected to different levels of respiratory load, PEEP and anesthetic depth in a total of seven respiratory conditions. MEASUREMENTS AND MAIN RESULTS: The esophageal pressure and diaphragm thickening fraction were simultaneously recorded for five breaths at each respiratory condition. The relation between ∆P es and DTF was studied in a mixed model. We analyzed 407 breaths in 13 patients. Both DTF ( p = 0.03) and ∆Pes ( p = 0.002) could detect respiratory activity, and ∆P es and DTF were associated across respiratory conditions ( p < 0.001; R2 = 31%). With increasing inspiratory load, ∆P es increased significantly, while DTF did not ( p = 0.08). Additionally, DT ee did not differ significantly between 10, 5, and 0 cm H 2 O PEEP ( p = 0.08). CONCLUSIONS: In spontaneously breathing sedated children and across different respiratory conditions, DTF could differentiate minimal or no inspiratory effort from substantial inspiratory effort and was associated with ∆P es . Increased efforts resulted in higher ∆P es but not larger DTF.

Minimizing Lung Injury During Laparoscopy in Head-Down Tilt: A Physiological Cohort Study.

BACKGROUND: Increased intra-abdominal pressure during laparoscopy induces atelectasis. Positive end-expiratory pressure (PEEP) can alleviate atelectasis but may cause hyperinflation. Cyclic opening of collapsed alveoli and hyperinflation can lead to ventilator-induced lung injury and postoperative pulmonary complications. We aimed to study the effect of PEEP on atelectasis, lung stress, and hyperinflation during laparoscopy in the head-down (Trendelenburg) position. METHODS: An open-label, repeated-measures, interventional, physiological cohort trial was designed. All participants were recruited from a single tertiary Belgian university hospital. Twenty-three nonobese patients scheduled for laparoscopy in the Trendelenburg position were recruited.We applied a decremental PEEP protocol: 15 (high), 10 and 5 (low) cm H 2 O. Atelectasis was studied with the lung ultrasound score, the end-expiratory transpulmonary pressure, the arterial oxygen partial pressure to fraction of inspired oxygen concentration (P ao2 /Fi o2 ) ratio, and the dynamic respiratory system compliance. Global hyperinflation was evaluated by dead space volume, and regional ventilation was evaluated by lung ultrasound. Lung stress was estimated using the transpulmonary driving pressure and dynamic compliance. Data are reported as medians (25th-75th percentile). RESULTS: At 15, 10, and 5 cm H 2 O PEEP, the respective measurements were: lung ultrasound scores (%) 11 (0-22), 27 (11-39), and 53 (42-61) ( P < .001); end-expiratory transpulmonary pressures (cm H 2 O) 0.9 (-0.6 to 1.7), -0.3 (-2.0 to 0.7), and -1.9 (-4.6 to -0.9) ( P < .001); P ao2 /Fi o2 ratios (mm Hg) 471 (435-538), 458 (410-537), and 431 (358-492) ( P < .001); dynamic respiratory system compliances (mL/cm H 2 O) 32 (26-36), 30 (25-34), and 27 (22-30) ( P < .001); driving pressures (cm H 2 O) 8.2 (7.5-9.5), 9.3 (8.5-11.1), and 11.0 (10.3-12.2) ( P < .001); and alveolar dead space ventilation fractions (%) 10 (9-12), 10 (9-12), and 9 (8-12) ( P = .23). The lung ultrasound score was similar between apical and basal lung regions at each PEEP level ( P = .76, .37, and .76, respectively). CONCLUSIONS: Higher PEEP levels during laparoscopy in the head-down position facilitate lung-protective ventilation. Atelectasis and lung stress are reduced in the absence of global alveolar hyperinflation.

Reoperation for bleeding after cardiac surgery.

BACKGROUND: Postoperative cardio-surgical haemostatic management is centre-specific and experience-based, which leads to a variability in patient care. This study aimed to identify which postoperative haemostatic interventions may reduce the need for reoperation after cardiac surgery in adults. METHODS: A retrospective case-control study in a tertiary centre. Adult, elective, primary cardiac surgical patients were selected (n = 2098); cases (n = 42) were patients who underwent reoperation within 72 h after the initial surgery. Interventions administered to control surgical bleeding were compared for the need to re-operate using multiple logistic regression. RESULTS: Rate of cardiac surgical reoperation was 2% in the study population. Three variables were found to be associated with cardiac reoperation: preoperative administration of fresh frozen plasma (OR 5.45, CI 2.34-12.35), cumulative volume of chest tube drainage and cumulative count of packed red blood cells transfusion on ICU (OR 1.98, CI 1.56-2.51). CONCLUSION: No significant difference among specific types of postoperative haemostatic interventions was found between patients who needed reoperation and those who did not. Perioperative transfusion of fresh frozen plasma, postoperative transfusion of packed cells and cumulative volume of chest tube drainage were associated with reoperation after cardiac surgery. These variables could help predict the need for reoperation.

Life-Saving Emergency Adrenalectomy in a Pheochromocytoma Crisis with Cardiogenic Shock.

Cardiogenic shock during a pheochromocytoma crisis is a life-threatening disorder. This case report illustrates a 49-year-old male with profound cardiogenic shock, extreme hemodynamic instability (systolic blood pressure ranging from 45 up to 290 mmHg in a cyclic pattern), and progressive multiple organ failure in the presence of a unilateral adrenal mass. Emergency adrenalectomy led to rapid hemodynamic stabilization. Histological investigation confirmed the diagnosis of pheochromocytoma. This case indicates that emergency adrenalectomy, although usually not considered first choice, is a valid option in cardiogenic shock and extremely fluctuating hemodynamics due to a pheochromcytoma-induced catecholamine storm.

Beta-Trace Protein as a Potential Marker of Acute Kidney Injury: A Pilot Study.

INTRODUCTION: Acute kidney injury (AKI) is a frequent complication among patients in the intensive care unit (ICU). The limitations of serum Cr (sCr) in timely detecting AKI are well known. Beta-trace protein (BTP) is emerging as a novel endogenous glomerular filtration rate marker. The aim of this study was to explore the role of BTP as a marker of AKI. METHODS: Patients admitted to the ICU undergoing surgery were included. BTP, sCr, Cystatin C (CysC), and neutrophil gelatinase-associated lipocalin (NGAL) were measured preoperatively, postoperatively (post-op), and at the first (D1) and second (D2) post-op day. AKI was defined as an increase of sCr to ≥1.5-fold from baseline within 2 days after surgery. RESULTS: Of the 52 patients studied, 10 patients (19%) developed AKI. Patients with AKI were older (69.6 ± 10.7 vs. 58.1 ± 16.7 years, p = 0.043) and had a longer length of ICU stay (13 [IQR 6-49] vs. 6 [IQR 5-8] days, p = 0.032). Between the 2 groups, the evolution of BTP, sCr, CysC, and NGAL over time differed significantly, with overall higher values in the AKI group. ROC analysis for the detection of AKI within 2 days after surgery showed a great accuracy for BTP. The area under the curve (AUC) for BTP post-op; D1; and D2 was, respectively, 0.869 ± 0.049; 0.938 ± 0.035; and 0.943 ± 0.032. The discriminative power of a BTP measurement on D1 was superior in detecting AKI compared to NGAL (adjusted p value = 0.027). We could not detect a significant difference between the AUCs of other biomarkers (NGAL, sCr, and CysC). CONCLUSION: Serum BTP is a promising marker for diagnosing AKI in ICU patients undergoing surgery.

Dysregulated activities of proline-specific enzymes in septic shock patients (sepsis-2).

The proline-specific enzymes dipeptidyl peptidase 4 (DPP4), prolylcarboxypeptidase (PRCP), fibroblast activation protein α (FAP) and prolyl oligopeptidase (PREP) are known for their involvement in the immune system and blood pressure regulation. Only very limited information is currently available on their enzymatic activity and possible involvement in patients with sepsis and septic-shock. The activity of the enzymes was measured in EDTA-plasma of patients admitted to the intensive care unit (ICU): 40 septic shock patients (sepsis-2) and 22 ICU control patients after major intracranial surgery. These data were used to generate receiver operating characteristic (ROC) curves. A survival analysis (at 90 days) and an association study with other parameters was performed. PRCP (day 1) and PREP (all days) enzymatic activities were higher in septic shock patients compared to controls. In contrast, FAP and DPP4 were lower in these patients on all studied time points. Since large differences were found, ROC curves were generated and these yielded area under the curve (AUC) values for PREP, FAP and DPP4 of 0.88 (CI: 0.80-0.96), 0.94 (CI: 0.89-0.99) and 0.86 (CI: 0.77-0.95), respectively. PRCP had a lower predicting value with an AUC of 0.71 (CI: 0.58-0.83). A nominally significant association was observed between survival and the DPP4 enzymatic activity at day 1 (p<0.05), with a higher DPP4 activity being associated with an increase in survival. All four enzymes were dysregulated in septic shock patients. DPP4, FAP and PREP are good in discriminating between septic shock patients and ICU controls and should be further explored to see whether they are already dysregulated in earlier stages, opening perspectives for their further investigation as biomarkers in sepsis. DPP4 also shows potential as a prognostic biomarker. Additionally, the associations found warrant further research.

Clinical- and surgery-specific risk factors for post-operative sepsis: a systematic review and meta-analysis of over 30 million patients.

Post-operative sepsis is a severe complication of surgery, which often worsens the clinical outcomes. While several risk factors have been identified, the importance of others remains uncertain. This systematic review and meta-analysis aimed to determine patient and surgery-related risk factors for post-operative sepsis. We reviewed Medline, the Web of Science, and the Cochrane library, systematically, for articles describing risk factors for sepsis. The role of eligible risk factors was investigated using a random-effects model, while analyzing univariate and multivariate data separately. Among 193 pro- and retrospective articles, comprising over 30 million patients, 38 eligible risk factors were selected for this meta-analysis. The patient-related risk factors associated with post-operative sepsis included male gender (odds ratio, OR 1.41), pre-existing heart failure (OR 2.53), diabetes (OR 1.41), and chronic kidney disease (OR 1.26). The surgery-related risk factors identified included emergency surgery (OR 3.38), peri-operative blood transfusion (OR 1.90), inpatient hospital stay (OR 2.31), and open surgery (OR 1.80). The adjusted overall incidence of surgical sepsis was 1.84%. In conclusion, multiple-patient and surgery-related risk factors are associated with the development of post-operative sepsis. Recognizing these risk factors could assist in the pre-operative identification of patients at risk of post-operative sepsis.

154 compared to 54 mmol per liter of sodium in intravenous maintenance fluid therapy for adult patients undergoing major thoracic surgery (TOPMAST): a single-center randomized controlled double-blind trial.

PURPOSE: To determine the effects of the sodium content of maintenance fluid therapy on cumulative fluid balance and electrolyte disorders. METHODS: We performed a randomized controlled trial of adults undergoing major thoracic surgery, randomly assigned (1:1) to receive maintenance fluids containing 154 mmol/L (Na154) or 54 mmol/L (Na54) of sodium from the start of surgery until their discharge from the ICU, the occurrence of a serious adverse event or the third postoperative day at the latest. Investigators, caregivers and patients were blinded to the treatment. Primary outcome was cumulative fluid balance. Electrolyte disturbances were assessed as secondary endpoints, different adverse events and physiological markers as safety and exploratory endpoints. FINDINGS: We randomly assigned 70 patients; primary outcome data were available for 33 and 34 patients in the Na54 and Na154 treatment arms, respectively. Estimated cumulative fluid balance at 72 h was 1369 mL (95% CI 601-2137) more positive in the Na154 arm (p < 0.001), despite comparable non-study fluid sources. Hyponatremia < 135 mmol/L was encountered in four patients (11.8%) under Na54 compared to none under Na154 (p = 0.04), but there was no significantly more hyponatremia < 130 mmol/L (1 versus 0; p = 0.31). There was more hyperchloremia > 109 mmol/L under Na154 (24/35 patients, 68.6%) than under Na54 (4/34 patients, 11.8%) (p < 0.001). The treating clinicians discontinued the study due to clinical or radiographic fluid overload in six patients receiving Na154 compared to one patient under Na54 (excess risk 14.2%; 95% CI - 0.2-30.4%, p = 0.05). CONCLUSIONS: In adult surgical patients, sodium-rich maintenance solutions were associated with a more positive cumulative fluid balance and hyperchloremia; hypotonic fluids were associated with mild and asymptomatic hyponatremia.

Respiratory muscle activity after spontaneous, neostigmine- or sugammadex-enhanced recovery of neuromuscular blockade: a double blind prospective randomized controlled trial.

BACKGROUND: The use of neostigmine after neuromuscular blockade (NMB) has been associated with postoperative respiratory complications. In previous studies, we found lower diaphragmatic activity after neostigmine reversal of NMB, compared to sugammadex. It is still unclear whether the adequate use of neostigmine guarantees normal respiratory muscle function after NMB. In this study, we wanted to assess the effect of commonly used degrees of NMB and their possible reversal strategies on respiratory muscle activity after the return of normal neuromuscular transmission. METHODS: This is a randomized, controlled, parallel-group, single-centre, double-blind study in patients scheduled for intracranial surgery at a tertiary academic hospital in Belgium. All participants received target controlled propofol/remifentanil anesthesia and were randomized into one of five groups, receiving either a shallow NMB with no reversal (shallow/saline), a shallow NMB with sugammadex reversal (shallow/sugammadex), a moderate NMB with neostigmine reversal (moderate/neostigmine), a moderate NMB with sugammadex reversal (moderate/sugammadex), or a deep NMB with sugammadex reversal (deep/sugammadex). Primary and secondary outcome parameters were diaphragm and intercostal electromyographic (EMG) activity at the moment of resumed spontaneous breathing activity, defined as a maximal interval of 10 min after the first spontaneous breath. RESULTS: For the five groups, a total of 55 patients could be included in the final analysis. Median time of spontaneous breathing analyzed was 5 min (IQR 3-9.5 min). Both the moderate/sugammadex and the moderate/neostigmine groups had lower levels of diaphragm EMG compared to the shallow/sugammadex group. The moderate/neostigmine group had lower levels of intercostal EMG activity compared to the shallow/saline group. CONCLUSIONS: In this study, the depth of neuromuscular blockade and type of reversal strategy impacts respiratory muscle activity at the moment of resumed spontaneous breathing and recovery of neuromuscular blockade. Both groups that received moderate NMB had lower levels of diaphragm EMG, compared to the shallow NMB group with sugammadex reversal. Compared to the shallow NMB group with no reversal, the moderate NMB with neostigmine reversal group had lower intercostal EMG activity. TRIAL REGISTRATION: Clinicaltrials.gov NCT01962298 on October 9, 2013 and EudraCT 2013-001926-25 on October 10, 2013.

Maintenance fluid therapy and fluid creep impose more significant fluid, sodium, and chloride burdens than resuscitation fluids in critically ill patients: a retrospective study in a tertiary mixed ICU population.

PURPOSE: Research on intravenous fluid therapy and its side effects, volume, sodium, and chloride overload, has focused almost exclusively on the resuscitation setting. We aimed to quantify all fluid sources in the ICU and assess fluid creep, the hidden and unintentional volume administered as a vehicle for medication or electrolytes. METHODS: We precisely recorded the volume, sodium, and chloride burdens imposed by every fluid source administered to 14,654 patients during the cumulative 103,098 days they resided in our 45-bed tertiary ICU and simulated the impact of important strategic fluid choices on patients' chloride burdens. In septic patients, we assessed the impact of the different fluid sources on cumulative fluid balance, an established marker of morbidity. RESULTS: Maintenance and replacement fluids accounted for 24.7% of the mean daily total fluid volume, thereby far exceeding resuscitation fluids (6.5%) and were the most important sources of sodium and chloride. Fluid creep represented a striking 32.6% of the mean daily total fluid volume [median 645 mL (IQR 308-1039 mL)]. Chloride levels can be more effectively reduced by adopting a hypotonic maintenance strategy [a daily difference in chloride burden of 30.8 mmol (95% CI 30.5-31.1)] than a balanced resuscitation strategy [daily difference 3.0 mmol (95% CI 2.9-3.1)]. In septic patients, non-resuscitation fluids had a larger absolute impact on cumulative fluid balance than did resuscitation fluids. CONCLUSIONS: Inadvertent daily volume, sodium, and chloride loading should be avoided when prescribing maintenance fluids in view of the vast amounts of fluid creep. This is especially important when adopting an isotonic maintenance strategy.

Introducing TOPMAST, the first double-blind randomized clinical trial specifically dedicated to perioperative maintenance fluid therapy in adults.

BACKGROUND: Although prescribed to every patient undergoing surgery, maintenance fluid therapy is a poorly researched part of perioperative fluid therapy. The tonicity of the chosen solutions, could be an important cause of morbidity, with hyponatremia being a potential side effect of hypotonic solutions, where isotonic solution could lead to fluid overload. METHODS: The TOPMAST-trial is an ongoing prospective single-center double-blind randomized trial comparing an isotonic and a hypotonic maintenance fluid strategy during and after surgery in patients undergoing different types of major thoracic surgery. Patients receive NaCl 0.9% in glucose 5% with an added 40 mmol L-1 of potassium chloride or a premixed solution containing 54 mmol L-1 sodium, 55 mmol L-1 chloride and 26 mmol of potassium at a rate of 27 mL per kg of body weight per day. The primary hypothesis is that isotonic maintenance solutions cause a more positive perioperative fluid balance than hypotonic fluids. Different secondary safety endpoints will be explored, especially the effect of the study treatments on the occurrence electrolyte disturbances (e.g. hyponatremia, hyperchloremia) and a set of clinical endpoints. Efficacy endpoints include the need for resuscitation fluids and assessment of renal and hormonal adaptive mechanisms. An anticipated 68 patients will be included between March 2017 and January 2018. DISCUSSION: The study will provide the most comprehensive evaluation of clinically important outcomes associated with the choice of perioperative maintenance fluid therapy.

Dendritic cell vaccination as postremission treatment to prevent or delay relapse in acute myeloid leukemia.

Relapse is a major problem in acute myeloid leukemia (AML) and adversely affects survival. In this phase 2 study, we investigated the effect of vaccination with dendritic cells (DCs) electroporated with Wilms' tumor 1 (WT1) messenger RNA (mRNA) as postremission treatment in 30 patients with AML at very high risk of relapse. There was a demonstrable antileukemic response in 13 patients. Nine patients achieved molecular remission as demonstrated by normalization of WT1 transcript levels, 5 of which were sustained after a median follow-up of 109.4 months. Disease stabilization was achieved in 4 other patients. Five-year overall survival (OS) was higher in responders than in nonresponders (53.8% vs 25.0%; P = .01). In patients receiving DCs in first complete remission (CR1), there was a vaccine-induced relapse reduction rate of 25%, and 5-year relapse-free survival was higher in responders than in nonresponders (50% vs 7.7%; P < .0001). In patients age ≤65 and >65 years who received DCs in CR1, 5-year OS was 69.2% and 30.8% respectively, as compared with 51.7% and 18% in the Swedish Acute Leukemia Registry. Long-term clinical response was correlated with increased circulating frequencies of polyepitope WT1-specific CD8+ T cells. Long-term OS was correlated with interferon-γ+ and tumor necrosis factor-α+ WT1-specific responses in delayed-type hypersensitivity-infiltrating CD8+ T lymphocytes. In conclusion, vaccination of patients with AML with WT1 mRNA-electroporated DCs can be an effective strategy to prevent or delay relapse after standard chemotherapy, translating into improved OS rates, which are correlated with the induction of WT1-specific CD8+ T-cell response. This trial was registered at www.clinicaltrials.gov as #NCT00965224.

Prognosis and treatment of FOLFOX therapy related interstitial pneumonia: a plea for multimodal immune modulating therapy in the respiratory insufficient patient.

BACKGROUND: The FOLFOX regimen, i.e., folinic acid (FOL), fluorouracil (F) and oxaliplatin (OX), is a drug cocktail that is used to treat gastric and colorectal cancers. Despite the concomitant improvements in response rate, duration of response and patient survival, reports of serious toxic pulmonary side effects have progressively emerged. CASE PRESENTATION: We describe a patient who was treated with FOLFOX as an adjuvant to a rectosigmoidal resection of a rectosigmoidal carcinoma and who developed respiratory insufficiency requiring mechanical ventilation. Computed tomography (CT) imaging and open lung biopsy findings were compatible with interstitial pneumonia (IP). She received multimodal combination treatment (acetylcysteine, corticosteroids, immune globulins and cyclophosphamide) and survived. We performed a systematic literature search and reviewed all 45 reported cases of FOLFOX-related lung toxicity and/or pulmonary fibrosis for their clinical characteristics and their outcomes related to therapy. CONCLUSIONS: We found that for the 45 cases with available data, the median age was 70 years, and the male-female ratio was 3.5: 1. In the patients exhibiting only mild respiratory symptoms, discontinuation of the culprit drug (oxaliplatin) resulted in a 100% regression of the symptoms. However the prognosis of the respiratory insufficient patient proved to be grim: death occurred in 76.9% of the cases despite conventional treatment with corticosteroids. We therefore urge oncologists and critical care specialists not to limit their interventions to the discontinuation of chemotherapy, artificial ventilation, corticosteroids and glutathione replenishment and to consider the gradual introduction of additional immune-modulating agents whenever life-threatening respiratory symptoms in oxaliplatin-treated patients do not subside; all the more so considering the fact that our analysis showed that every patient who survived intubation and mechanical ventilation experienced a full clinical recovery.

Biofilm-Induced Type 2 Innate Immunity in a Cystic Fibrosis Model of Pseudomonas aeruginosa.

Biofilm-producing strains of Pseudomonas aeruginosa are a major cause of morbidity and mortality in cystic fibrosis (CF) patients. In these patients, increased levels of IL-17 as well as of IL-5 and IL-13 along with arginase (Arg)-positive macrophages have been observed in bronchoalveolar lavage fluid. While IL-17 is a strong proinflammatory cytokine associated with host defense against bacterial and fungal infections and is also elevated in several autoimmune diseases, IL-5/IL-13 and Arg1-positive M2 macrophages are part of the anti-inflammatory type 2 (Th2) immunity. To study whether increased IL-5 and IL-13 levels are related to biofilm formation, which is frequently observed in CF patients colonized by P. aeruginosa, we utilized an agarose bead-embedded P. aeruginosa rat model commonly employed in in vivo biofilm studies. We showed that "sterile" agarose bead instillation in rat notably increased lung transcript levels of IL-5 and IL-13 at two post-instillation study-points, day 1 and day 3. Concurrently, increased infiltration of type 2 innate cells such as eosinophils and Arg1 positive M2 activated macrophages (Arg1+CD68+) was also observed both at day 1 and day 3 while the proportion of M1 activated macrophages (iNOS+CD68+) at these time-points decreased. In contrast, P. aeruginosa-loaded beads caused a drastic elevation of proinflammatory Th1 (IFNγ, TNFα, IL-12a) and antibacterial Th17 (IL-17a, IL-17f, IL-22, IL-23a) cytokines along with a high influx of neutrophils and M1 macrophages, while Th2 cytokines (IL-5 and IL-13) drastically declined at day 1 post-infection. Interestingly, at day 3 post-infection, both Th1 and Th17 cytokines sharply declined and corroborated with decreased M1 and increased M2 macrophages. These data suggest that while IL-17 is linked to episodes of acute exacerbations of infection in CF patients, the increased Th2 cytokines and M2 macrophages observed in these patients are largely due to the biofilm matrix. The data presented here has important implications for clinical management of CF patients.

Animal models of hospital-acquired pneumonia: current practices and future perspectives.

Lower respiratory tract infections are amongst the leading causes of mortality and morbidity worldwide. Especially in hospital settings and more particularly in critically ill ventilated patients, nosocomial pneumonia is one of the most serious infectious complications frequently caused by opportunistic pathogens. Pseudomonas aeruginosa is one of the most important causes of ventilator-associated pneumonia as well as the major cause of chronic pneumonia in cystic fibrosis patients. Animal models of pneumonia allow us to investigate distinct types of pneumonia at various disease stages, studies that are not possible in patients. Different animal models of pneumonia such as one-hit acute pneumonia models, ventilator-associated pneumonia models and biofilm pneumonia models associated with cystic fibrosis have been extensively studied and have considerably aided our understanding of disease pathogenesis and testing and developing new treatment strategies. The present review aims to guide investigators in choosing appropriate animal pneumonia models by describing and comparing the relevant characteristics of each model using P. aeruginosa as a model etiology for hospital-acquired pneumonia. Key to establishing and studying these animal models of infection are well-defined end-points that allow precise monitoring and characterization of disease development that could ultimately aid in translating these findings to patient populations in order to guide therapy. In this respect, and discussed here, is the development of humanized animal models of bacterial pneumonia that could offer unique advantages to study bacterial virulence factor expression and host cytokine production for translational purposes.

Impact of chloride and strong ion difference on ICU and hospital mortality in a mixed intensive care population.

BACKGROUND: Abnormal chloride levels are commonly observed in critically ill patients, but their clinical relevance remains a matter of debate. We examined the association between abnormal chloremia and ICU and hospital mortality. To further refine findings and integrate them into the ongoing discussion on the detrimental effects of chloride-rich solutions, the impact of strong ion difference (SID) on the same end points was assessed. METHODS: Retrospective cohort study in an academic tertiary intensive care unit on 8830 adult patients who stayed at least 24 h in the ICU was carried out. Patients admitted after elective cardiac surgery were treated as a separate subgroup (n = 2350). Analyses were performed using multivariable logistic regression. All statistical models were extensively adjusted for confounders, including comorbidity, admission diagnosis, other electrolytes and acid-base parameters. RESULTS: Severe hyperchloremia (>110 mmol/L), but not low (SID) was significantly associated with increased mortality in the ICU (odds ratio vs. normochloremia 1.81; 95 % CI 1.32-2.50; p < 0.001) and the hospital (odds ratio 1.49; 95 % CI 1.14-1.96; p = 0.003). Hyperchloremia and low (SID) were encountered in the majority of patients admitted after cardiac surgery (in 86.9 and 47.2 %, respectively), but were not negatively associated with mortality. CONCLUSIONS: In the ICU, hyperchloremia at admission was associated with negative outcome. On the other hand, decreased strong ion difference did not have an impact on mortality, precluding a simple extrapolation of these findings to the ongoing discussion on the detrimental effects of chloride-rich solutions. This notion is fueled by the finding that hyperchloremia after cardiac surgery, frequently encountered and probably fluid-induced, did not seem to be deleterious.

A Preliminary Link between Hydroxylated Metabolites of Polychlorinated Biphenyls and Free Thyroxin in Humans.

BACKGROUND: Polychlorinated biphenyls (PCBs) and their hydroxylated metabolites (HO-PCBs) interfere with thyroid hormone action both in vitro and in vivo. However, epidemiologic studies on the link between PCB exposure and thyroid function have yielded discordant results, while very few data are available for HO-PCBs. OBJECTIVES: Our study aimed at investigating the relationship between clinically available markers of thyroid metabolism and serum levels of both PCBs and HO-PCBs. SUBJECTS AND METHODS: In a group of 180 subjects, thyroid-stimulating hormone (TSH) and free thyroxin (fT4), 29 PCBs (expressed both in lipid weight and in wet weight) and 18 HO-PCBs were measured in serum. RESULTS: In regression models, adjusted for gender, age, current smoking behavior, BMI and total lipid levels, serum levels of 3HO-PCB118 and 3HO-PCB180, and PCB95(lw), PCB99(lw) and PCB149(lw) were independent, significant predictors of fT4. A stepwise, multiple regression with gender, age, current smoking behavior, BMI and total lipid levels and all five previously identified significant compounds retained age, BMI, PCB95(lw), PCB99(lw) and 3HO-PCB180 as significant predictors of fT4. TSH levels were not predicted by serum levels of any of the PCBs or HO-PCBs. CONCLUSIONS: Our study indicates that in vivo, circulating fT4 levels can be linked to serum levels of several PCBs and hydroxylated PCB metabolites.