Matthew Exline

A comparison of zinc metabolism, inflammation, and disease severity in critically ill infected and noninfected adults early after intensive care unit admission

BACKGROUND Zinc deficiency is a cause of immune dysfunction and infection. Previous human studies have shown that the activation of the acute phase response alters zinc metabolism. Whether the alteration in zinc metabolism is predictive of disease severity in the setting of critical illness is unclear. OBJECTIVE We sought to determine whether differences occur in zinc metabolism at the onset of critical illness between infected (septic) and noninfected subjects. DESIGN We conducted this prospective study in an adult medical intensive care unit (MICU) at a tertiary care hospital. Subjects were enrolled within 24 h of intensive care unit admission. Subjects who did not meet sepsis criteria were considered for the critically ill control (CIC) arm. After patient consent, blood was immediately collected to measure plasma zinc and cytokine concentrations and zinc transporter gene expression in peripheral blood monocytes. Clinical data during the MICU stay were also recorded. RESULTS A total of 56 patients were evaluated (22 septic, 22 CIC, and 12 healthy subjects). Plasma zinc concentrations were below normal in CIC patients and further reduced in the septic cohort (57.2 ± 18.2 compared with 45.5 ± 18.1 μg/dL). Cytokine concentrations increased with decreasing plasma zinc concentrations (P = 0.05). SLC39A8 gene expression was highest in patients with the lowest plasma zinc concentrations and the highest severity of illness. CONCLUSIONS The alteration of zinc metabolism was more pronounced in septic patients than in noninfected critically ill patients. Specifically, sepsis was associated with lower plasma zinc concentrations and higher SLC39A8 mRNA expression, which correlated with an increased severity of illness, including cardiovascular dysfunction.

Inflammasome mRNA expression in human monocytes during early septic shock.

RATIONALE Monocytes are central to the initiation of the inflammatory response in sepsis, with caspase-1 activation playing a key role. Monocyte deactivation during sepsis has been linked to poor outcomes. OBJECTIVES Given the importance of caspase-1 in the immune response, we investigated whether monocytes from patients early in septic shock demonstrate alterations in mRNAs for caspase-1-related molecules. METHODS Patients with septic shock (n = 26; age >18 years), critically ill intensive care unit patients (n = 20), and healthy volunteers (n = 22) were enrolled in a prospective cohort study in a university intensive care unit. Demographic, biological, physiologic, and plasma cytokine measurements were obtained. Monocytes were assayed for ex vivo tumor necrosis factor-alpha production, and fresh monocyte mRNA was analyzed by quantitative reverse-transcription polymerase chain reaction for Toll-like receptors, NOD-LRR proteins, cytokines, and nuclear factor-kappaB-related genes. MEASUREMENTS AND MAIN RESULTS Relative copy numbers for the inflammasome mRNAs for ASC, caspase-1, NALP1, and Pypaf-7 were significantly lower in patients with septic shock compared with critically ill control subjects. NALP1 mRNA levels were linked to survival in patients with sepsis (P = 0.0068) and correlated with SAPS II scores (r = -0.63). CONCLUSIONS These data suggest that monocyte deactivation occurs during the earliest stages of the systemic inflammatory response and that changes in inflammasome mRNA expression are part of this process.

Beyond the bundle - journey of a tertiary care medical intensive care unit to zero central line-associated bloodstream infections

IntroductionWe set a goal to reduce the incidence rate of catheter-related bloodstreaminfections to rate of <1 per 1,000 central line days in a two-year period.MethodsThis is an observational cohort study with historical controls in a 25-bedintensive care unit at a tertiary academic hospital. All patients admitted to theunit from January 2008 to December 2011 (31,931 patient days) were included. Amultidisciplinary team consisting of hospital epidemiologist/infectious diseasesphysician, infection preventionist, unit physician and nursing leadership wasconvened. Interventions included: central line insertion checklist, demonstrationof competencies for line maintenance and access, daily line necessity checklist,and quality rounds by nursing leadership, heightened staff accountability,follow-up surveillance by epidemiology with timely unit feedback and case reviews,and identification of noncompliance with evidence-based guidelines. Molecularepidemiologic investigation of a cluster of vancomycin-resistant Enterococcusfaecium (VRE) was undertaken resulting in staff education forproper acquisition of blood cultures, environmental decontamination and dailychlorhexidine gluconate (CHG) bathing for patients.ResultsCenter for Disease Control/National Health Safety Network (CDC/NHSN) definitionwas used to measure central line-associated bloodstream infection (CLA-BSI) ratesduring the following time periods: baseline (January 2008 to December 2009),intervention year (IY) 1 (January to December 2010), and IY 2 (January to December2011). Infection rates were as follows: baseline: 2.65 infections per 1,000catheter days; IY1: 1.97 per 1,000 catheter days; the incidence rate ratio (IRR)was 0.74 (95% CI = 0.37 to 1.65, P = 0.398); residual seven CLA-BSIsduring IY1 were VRE faecium blood cultures positive from central linealone in the setting of findings explicable by noninfectious conditions. Followingstaff education, environmental decontamination and CHG bathing (IY2): 0.53 per1,000 catheter days; the IRR was 0.20 (95% CI = 0.06 to 0.65, P = 0.008)with 80% reduction compared to the baseline. Over the two-year interventionperiod, the overall rate decreased by 53% to 1.24 per 1,000 catheter-days (IRR of0.47 (95% CI = 0.25 to 0.88, P = 0.019) with zero CLA-BSI for a total of15 months.ConclusionsResidual CLA-BSIs, despite strict adherence to central line bundle, may be relatedto blood culture contamination categorized as CLA-BSIs per CDC/NHSN definition.Efforts to reduce residual CLA-BSIs require a strategic multidisciplinary teamapproach focused on epidemiologic investigations of practitioner- or unit-specificetiologies.

Thrombospondin-1 Contributes to Mortality in Murine Sepsis through Effects on Innate Immunity

Background Thrombospondin-1 (TSP-1) is involved in many biological processes, including immune and tissue injury response, but its role in sepsis is unknown. Cell surface expression of TSP-1 on platelets is increased in sepsis and could activate the anti-inflammatory cytokine transforming growth factor beta (TGFβ1) affecting outcome. Because of these observations we sought to determine the importance of TSP-1 in sepsis. Methodology/Principal Findings We performed studies on TSP-1 null and wild type (WT) C57BL/6J mice to determine the importance of TSP-1 in sepsis. We utilized the cecal ligation puncture (CLP) and intraperitoneal E.coli injection (IP E.coli) models of peritoneal sepsis. Additionally, bone-marrow-derived macrophages (BMMs) were used to determine phagocytic activity. TSP-1−/− animals experienced lower mortality than WT mice after CLP. Tissue and peritoneal lavage TGFβ1 levels were unchanged between animals of each genotype. In addition, there is no difference between the levels of major innate cytokines between the two groups of animals. PLF from WT mice contained a greater bacterial load than TSP-1−/− mice after CLP. The survival advantage for TSP-1−/− animals persisted when IP E.coli injections were performed. TSP-1−/− BMMs had increased phagocytic capacity compared to WT. Conclusions TSP-1 deficiency was protective in two murine models of peritoneal sepsis, independent of TGFβ1 activation. Our studies suggest TSP-1 expression is associated with decreased phagocytosis and possibly bacterial clearance, leading to increased peritoneal inflammation and mortality in WT mice. These data support the contention that TSP-1 should be more fully explored in the human condition.

Sepsis: Links between Pathogen Sensing and Organ Damage

The hosts inflammatory response to sepsis can be divided into two phases, the initial detection and response to the pathogen initiated by the innate immune response, and the persistent inflammatory state characterized by multiple organ dysfunction syndrome (MODS). New therapies aimed at pathogen recognition receptors (PRRs) particularly the TLRs and the NOD-like receptors offer hope to suppress the initial inflammatory response in early sepsis and to bolster this response in late sepsis. The persistence of MODS after the initial inflammatory surge can also be a determining factor to host survival. MODS is due to the cellular damage and death induced by sepsis. The mechanism of this cell death depends in part upon mitochondrial dysfunction. Damaged mitochondria have increased membrane permeability prompting their autophagic removal if few mitochondria are involved but apoptotic cell death may occur if the mitochondrial losses are more extensive. In addition. severe loss of mitochondria results in low cell energy stores, necrotic cell death, and increased inflammation driven by the release of cell components such as HMGB1. Therapies, which aim at improving cellular energy reserves such as the promotion of mitochondrial biogenesis by insulin, may have a role in future sepsis therapies. Finally, both the inflammatory responses and the susceptibility to organ failure may be modulated by nutritional status and micronutrients, such as zinc, Therapies aimed at micronutrient repletion may further augment approaches targeting PRR function and mitochondrial viability.

Utilization of Hyperbaric Oxygen Therapy and Induced Hypothermia After Hydrogen Sulfide Exposure

Hydrogen sulfide is a toxic gas produced as a by-product of organic waste and many industrial processes. Hydrogen sulfide exposure symptoms may vary from mild (dizziness, headaches, nausea) to severe lactic acidosis via its inhibition of oxidative phosphorylation, leading to cardiac arrhythmias and death. Treatment is generally supportive. We report the case of a patient presenting with cardiac arrest secondary to hydrogen sulfide exposure treated with both hyperbaric oxygen therapy and therapeutic hypothermia to achieve full neurologic recovery.

Microvesicular Caspase-1 Mediates Lymphocyte Apoptosis in Sepsis

Objective Immune dysregulation during sepsis is poorly understood, however, lymphocyte apoptosis has been shown to correlate with poor outcomes in septic patients. The inflammasome, a molecular complex which includes caspase-1, is essential to the innate immune response to infection and also important in sepsis induced apoptosis. Our group has recently demonstrated that endotoxin-stimulated monocytes release microvesicles (MVs) containing caspase-1 that are capable of inducing apoptosis. We sought to determine if MVs containing caspase-1 are being released into the blood during human sepsis and induce apoptosis.. Design Single-center cohort study Measurements 50 critically ill patients were screened within 24 hours of admission to the intensive care unit and classified as either a septic or a critically ill control. Circulatory MVs were isolated and analyzed for the presence of caspase-1 and the ability to induce lymphocyte apoptosis. Patients remaining in the ICU for 48 hours had repeated measurement of caspase-1 activity on ICU day 3. Main Results Septic patients had higher microvesicular caspase-1 activity 0.05 (0.04, 0.07) AFU versus 0.0 AFU (0, 0.02) (p<0.001) on day 1 and this persisted on day 3, 0.12 (0.1, 0.2) versus 0.02 (0, 0.1) (p<0.001). MVs isolated from septic patients on day 1 were able to induce apoptosis in healthy donor lymphocytes compared with critically ill control patients (17.8±9.2% versus 4.3±2.6% apoptotic cells, p<0.001) and depletion of MVs greatly diminished this apoptotic signal. Inhibition of caspase-1 or the disruption of MV integrity abolished the ability to induce apoptosis. Conclusion These findings suggest that microvesicular caspase-1 is important in the host response to sepsis, at least in part, via its ability to induce lymphocyte apoptosis. The ability of microvesicles to induce apoptosis requires active caspase-1 and intact microvesicles.

An Assessment of H1N1 Influenza-Associated Acute Respiratory Distress Syndrome Severity after Adjustment for Treatment Characteristics

Pandemic influenza caused significant increases in healthcare utilization across several continents including the use of high-intensity rescue therapies like extracorporeal membrane oxygenation (ECMO) or high-frequency oscillatory ventilation (HFOV). The severity of illness observed with pandemic influenza in 2009 strained healthcare resources. Because lung injury in ARDS can be influenced by daily management and multiple organ failure, we performed a retrospective cohort study to understand the severity of H1N1 associated ARDS after adjustment for treatment. Sixty subjects were identified in our hospital with ARDS from “direct injury” within 24 hours of ICU admission over a three month period. Twenty-three subjects (38.3%) were positive for H1N1 within 72 hours of hospitalization. These cases of H1N1-associated ARDS were compared to non-H1N1 associated ARDS patients. Subjects with H1N1-associated ARDS were younger and more likely to have a higher body mass index (BMI), present more rapidly and have worse oxygenation. Severity of illness (SOFA score) was directly related to worse oxygenation. Management was similar between the two groups on the day of admission and subsequent five days with respect to tidal volumes used, fluid balance and transfusion practices. There was, however, more frequent use of “rescue” therapy like prone ventilation, HFOV or ECMO in H1N1 patients. First morning set tidal volumes and BMI were significantly associated with increased severity of lung injury (Lung injury score, LIS) at presentation and over time while prior prescription of statins was protective. After assessment of the effect of these co-interventions LIS was significantly higher in H1N1 patients. Patients with pandemic influenza-associated ARDS had higher LIS both at presentation and over the course of the first six days of treatment when compared to non-H1N1 associated ARDS controls. The difference in LIS persisted over the duration of observation in patients with H1N1 possibly explaining the increased duration of mechanical ventilation.

Effect of ganciclovir on IL-6 levels among cytomegalovirus-seropositive adults with critical illness: A randomized clinical trial

Importance The role of cytomegalovirus (CMV) reactivation in mediating adverse clinical outcomes in nonimmunosuppressed adults with critical illness is unknown. Objective To determine whether ganciclovir prophylaxis reduces plasma interleukin 6 (IL-6) levels in CMV-seropositive adults who are critically ill. Design, Setting, and Participants Double-blind, placebo-controlled, randomized clinical trial (conducted March 10, 2011-April 29, 2016) with a follow-up of 180 days (November 10, 2016) that included 160 CMV-seropositive adults with either sepsis or trauma and respiratory failure at 14 university intensive care units (ICUs) across the United States. Interventions Patients were randomized (1:1) to receive either intravenous ganciclovir (5 mg/kg twice daily for 5 days), followed by either intravenous ganciclovir or oral valganciclovir once daily until hospital discharge (n = 84) or to receive matching placebo (n = 76). Main Outcomes and Measures The primary outcome was change in IL-6 level from day 1 to 14. Secondary outcomes were incidence of CMV reactivation in plasma, mechanical ventilation days, incidence of secondary bacteremia or fungemia, ICU length of stay, mortality, and ventilator-free days (VFDs) at 28 days. Results Among 160 randomized patients (mean age, 57 years; women, 43%), 156 patients received 1or more dose(s) of study medication, and 132 patients (85%) completed the study. The mean change in plasma IL-6 levels between groups was −0.79 log10 units (−2.06 to 0.48) in the ganciclovir group and −0.79 log10 units (−2.14 to 0.56) in the placebo group (point estimate of difference, 0 [95% CI, −0.3 to 0.3]; P > .99). Among secondary outcomes, CMV reactivation in plasma was significantly lower in the ganciclovir group (12% [10 of 84 patients] vs 39% [28 of 72 patients]); absolute risk difference, −27 (95% CI, −40 to −14), P < .001. The ganciclovir group had more median VFDs in both the intention-to-treat (ITT) group and in the prespecified sepsis subgroup (ITT group: 23 days in ganciclovir group vs 20 days in the placebo group, P = .05; sepsis subgroup, 23 days in the ganciclovir group vs 20 days in the placebo group, P = .03). There were no significant differences between the ganciclovir and placebo groups in duration of mechanical ventilation (5 days for the ganciclovir group vs 6 days for the placebo group, P = .16), incidence of secondary bacteremia or fungemia (15% for the ganciclovir group vs 15% for the placebo group, P = .67), ICU length of stay (8 days for the ganciclovir group vs 8 days for the placebo group, P = .76), or mortality (12% for the ganciclovir group vs 15% for the placebo group, P = .54). Conclusions and Relevance Among CMV-seropositive adults with critical illness due to sepsis or trauma, ganciclovir did not reduce IL-6 levels and the current study does not support routine clinical use of ganciclovir as a prophylactic agent in patients with sepsis. Additional research is necessary to determine the clinical efficacy and safety of CMV suppression in this setting. Trial Registration clinicaltrials.gov Identifier: NCT01335932

Nonlinear imputation of pa o 2/F io 2 from Sp o 2/F io 2 among mechanically ventilated patients in the ICU: A prospective, observational study

Objectives: In the contemporary ICU, mechanically ventilated patients may not have arterial blood gas measurements available at relevant timepoints. Severity criteria often depend on arterial blood gas results. Retrospective studies suggest that nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 is accurate, but this has not been established prospectively among mechanically ventilated ICU patients. The objective was to validate the superiority of nonlinear imputation of PaO2/FIO2 among mechanically ventilated patients and understand what factors influence the accuracy of imputation. Design: Simultaneous SpO2, oximeter characteristics, receipt of vasopressors, and skin pigmentation were recorded at the time of a clinical arterial blood gas. Acute respiratory distress syndrome criteria were recorded. For each imputation method, we calculated both imputation error and the area under the curve for patients meeting criteria for acute respiratory distress syndrome (PaO2/FIO2 ⩽ 300) and moderate-severe acute respiratory distress syndrome (PaO2/FIO2 ⩽ 150). Setting: Nine hospitals within the Prevention and Early Treatment of Acute Lung Injury network. Patients: We prospectively enrolled 703 mechanically ventilated patients admitted to the emergency departments or ICUs of participating study hospitals. Interventions: None. Measurements and Main Results: We studied 1,034 arterial blood gases from 703 patients; 650 arterial blood gases were associated with SpO2 less than or equal to 96%. Nonlinear imputation had consistently lower error than other techniques. Among all patients, nonlinear had a lower error (p < 0.001) and higher (p < 0.001) area under the curve (0.87; 95% CI, 0.85–0.90) for PaO2/FIO2 less than or equal to 300 than linear/log-linear (0.80; 95% CI, 0.76–0.83) imputation. All imputation methods better identified moderate-severe acute respiratory distress syndrome (PaO2/FIO2 ⩽ 150); nonlinear imputation remained superior (p < 0.001). For PaO2/FIO2 less than or equal to 150, the sensitivity and specificity for nonlinear imputation were 0.87 (95% CI, 0.83–0.90) and 0.91 (95% CI, 0.88–0.93), respectively. Skin pigmentation and receipt of vasopressors were not associated with imputation accuracy. Conclusions: In mechanically ventilated patients, nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 seems accurate, especially for moderate-severe hypoxemia. Linear and log-linear imputations cannot be recommended.