Presence Of Critical Illness Research Articles

INHIBITION OF INTEGRIN VLA-3 AND TETRASPANIN CD151 PROTECTS AGAINST NEUTROPHIL-MEDIATED ENDOTHELIAL DAMAGE.

Background: The recruitment of neutrophils to sites of localized injury or infection is initiated by changes on the surface of endothelial cells located in proximity to tissue damage. Inflammatory mediators, such as TNF-α, increase surface expression of adhesive ligands and receptors on the endothelial surface to which neutrophils tether and adhere. Neutrophils then transit through the activated endothelium to reach sites of tissue injury with little lasting vascular injury. However, in cases of sepsis, the interaction of endothelial cells with highly activated neutrophils can cause damage vascular damage. The identification of molecules that are essential for neutrophil diapedesis may reveal targets of therapeutic opportunity for preservation of endothelial function in the presence of critical illness. We tested the hypothesis that inhibition of neutrophil β1 integrin very late antigen-3 (VLA-3; α3β1) and/or inhibition of the tetraspanin (TM4) family member CD151 would protect against neutrophil-mediated loss of endothelial function. Methods: Blood was obtained from septic patients or healthy donors. Neutrophils were purified, and aliquots were treated with/without proinflammatory molecules. Confluent human umbilical vascular endothelial cells were activated with TNF-α. Electric cell impedance sensing was used to determine monolayer resistance over time after the addition of neutrophils that were treated with blocking antibodies against VLA-3 and/or CD151 or isotype controls. Groups (depending on relevancy) were analyzed by Mann-Whitney U test, Wilcoxon test, or repeated-measures one-way ANOVA. Results: Neutrophils from septic patients and neutrophils activated ex vivo reduced endothelial monolayer resistance to a greater extent than neutrophils from healthy donors. Antibody blockade of VLA-3 and/or CD151 significantly reduced activation-associated endothelial damage. Similar findings were demonstrated on fibronectin, collagen I, collagen IV, and laminin, suggesting that neutrophil surface VLA-3 and CD151 are responsible for endothelial damage regardless of substrata and are likely to be operative in all bodily tissues. Conclusion: This report identifies VLA-3 and CD151 on the activated human neutrophil, which are responsible for damage to endothelial function. Targeting these molecules in vivo may demonstrate preservation of organ function during critical illness.

Non-thyroidal illness syndrome and SARS-CoV-2-associated multisystem inflammatory syndrome in children

PurposeCOVID-19 disease may result in a severe multisystem inflammatory syndrome in children (MIS-C), which in turn may alter thyroid function (TF). We assessed TF in MIS-C, evaluating its impact on disease severity.MethodsWe retrospectively considered children admitted with MIS-C to a single pediatric hospital in Milan (November 2019–January 2021). Non-thyroidal illness syndrome (NTIS) was defined as any abnormality in TF tests (FT3, FT4, TSH) in the presence of critical illness and absence of a pre-existing hormonal abnormality. We devised a disease severity score by combining severity scores for each organ involved. Glucose and lipid profiles were also considered. A principal component analysis (PCA) was performed, to characterize the mutual association patterns between TF and disease severity.ResultsOf 26 (19 M/7F) patients, median age 10.7 (IQR 5.8–13.3) years, 23 (88.4%) presented with NTIS. A low FT3 level was noted in 15/23 (65.3%), while the other subjects had varying combinations of hormone abnormalities (8/23, 34.7%). Mutually correlated variables related to organ damage and inflammation were represented in the first dimension (PC1) of the PCA. FT3, FT4 and total cholesterol were positively correlated and characterized the second axis (PC2). The third axis (PC3) was characterized by the association of triglycerides, TyG index and HDL cholesterol. TF appeared to be related to lipemic and peripheral insulin resistance profiles. A possible association between catabolic components and severity score was also noted.ConclusionsA low FT3 level is common among MIS-C. TF may be useful to define the impact of MIS-C on children’s health and help delineate long term follow-up management and prognosis.

Influence of sarcopenia focused on critically ill patients.

A systemic review was performed to evaluate the epidemiological, pathophysiological, and clinical features of sarcopenia, the relationship of sarcopenia with critical illness and its impact on mortality, and diagnostic methods and treatment modalities. Generally, in the presence of critical illness, sarcopenia is not included in the treatment approach strategies. An intensivist should be aware that sarcopenia may be present in critically ill patients. Although the main modalities against sarcopenia are early mobilization and nutritional support, they can only prevent its development and may have positive effects on prognosis rather than treating the existing sarcopenia.

Antibiotic Distribution into Cerebrospinal Fluid: Can Dosing Safely Account for Drug and Disease Factors in the Treatment of Ventriculostomy-Associated Infections?

Ventriculostomy-associated infections, or ventriculitis, in critically ill patients are associated with considerable morbidity. Efficacious antibiotic dosing for the treatment of these infections may be complicated by altered antibiotic concentrations in the cerebrospinal fluid due to variable meningeal inflammation and antibiotic properties. Therefore, doses used to treat infections with a higher degree of meningeal inflammation (such as meningitis) may often fail to achieve equivalent exposures in patients with ventriculostomy-associated infections such as ventriculitis. This paper aims to review the disease burden, infection rates, and common pathogens associated with ventriculostomy-associated infections. This review also seeks to describe the disease- and drug-related factors that influence antibiotic distribution into cerebrospinal fluid and provide a critical appraisal of current dosing of antibiotics commonly used to treat these types of infections. A Medline search of relevant articles was conducted and used to support a review of cerebrospinal fluid penetration of vancomycin, including critical appraisal of the recent paper by Beach et al. recently published in this journal. We found that in the intensive care unit, ventriculostomy-associated infections are the most common and serious complication of external ventricular drain insertion and often result in prolonged patient stay and increased healthcare costs. Reported infection rates are extremely variable (between 0 and 45%), hindered by the inherent diagnostic difficulty. Both Gram-positive and Gram-negative organisms are associated with such infections and the rise of multi-drug-resistant pathogens means that effective treatment is an ongoing challenge. Disease factors that may need to be considered are reduced meningeal inflammation and the presence of critical illness; drug factors include physiochemical properties, degree of plasma-protein binding, and affinity to active transporter proteins present in the blood-cerebrospinal fluid barrier. The relationship between cerebrospinal fluid antibiotic exposures in the setting of ventriculostomy-associated infection and clinical response has not been fully elucidated for many of the antibiotics commonly used in its treatment. More thorough and clinically relevant investigations are needed to better define blood pharmacokinetic/pharmacodynamics targets and optimal therapeutic exposures for treatment of ventriculostomy-associated infections. It is hoped that this future research will be able to provide clearer recommendations for clinicians frequently faced with dosing-related dilemmas when treating patients with these challenging infections.

Risk factors for the failure to achieve normal albumin serum levels after albumin transfusion in neonates

Background Albumin transfusion for the treatment of neonatal hypoalbuminemia may reduce morbidity. In conditions with disrupted endothelial integrity (e.g., sepsis and critical illness), the administered albumin may leak into the interstitial space, hence, serum albumin levels may fall below expected levels after transfusion. To date, few studies have been done to evaluate the risk factors for failure to achieve normal neonatal albumin levels after transfusion.Objectives To determine the risk factors for failure to achieve normal neonatal albumin levels after transfusion.Methods We performed a case-control study in the Neonatal Ward of Dr. Sardjito Hospital from 2007 to 2012. Normal albumin level was defined as above 3 g/dL. The case group included neonates with post-transfusion albumin levels <3 g/dL and the control group included those with post-transfusion albumin ≥3 g/dL. Subjects received intravenous transfusions of 25% or 20% albumin according to the clinical standard of the Neonatal Ward of Dr. Sardjito Hospital. Neonates with very low birth weight, severe birth trauma, burn injuries, severe bleeding, or incomplete medical records were excluded. The data were analyzed with logistic regression test.Results From January 2007 to December 2012, 124 neonates were enrolled in the study. Multivariate analysis showed that low albumin levels before transfusion (OR 12.27; 95%CI 2.17 to 69.30), presence of critical illness (OR 4.01; 95%CI 1.49 to 10.79), diagnosis of sepsis (OR 3.56; 95%CI 1.36 to 9.32), and the >24-hour interval between albumin examination and transfusion (OR 0.06; 95%CI 0.01 to 0.37) were significant risk factors affecting the failure to achieve normal albumin levels.Conclusions Failure to achieve normal albumin levels after transfusion in neonates was significantly associated with low albumin level prior to transfusion, critical illness, sepsis, and >24-hour interval between transfusion and post-transfusion albumin examination.[Paediatr Indones. 2016;56:129-33.].

Does Critical Illness Change Levofloxacin Pharmacokinetics?

Levofloxacin is commonly used in critically ill patients for which existing data suggest nonstandard dosing regimens should be used. The objective of this study was to compare the population pharmacokinetics of levofloxacin in critically ill and in non-critically ill patients. Adult patients with a clinical indication for levofloxacin were eligible for participation in this prospective pharmacokinetic study. Patients were given 500 mg or 750 mg daily by intravenous administration with up to 11 blood samples taken on day 1 or 2 of therapy. Plasma samples were analyzed and population pharmacokinetic analysis was undertaken using Pmetrics. Thirty-five patients (18 critically ill) were included. The mean (standard deviation [SD]) age, weight, and Cockcroft-Gault creatinine clearance for the critically ill and for the non-critically ill patients were 60.3 (16.4) and 72.0 (11.6) years, 78.5 (14.8) and 70.9 (15.8) kg, and 71.9 (65.8) and 68.2 (30.1) ml/min, respectively. A two-compartment linear model best described the data. Increasing creatinine clearance was the only covariate associated with increasing drug clearance. The presence of critical illness did not significantly affect any pharmacokinetic parameter. The mean (SD) parameter estimates were as follows: clearance, 8.66 (3.85) liters/h; volume of the central compartment (Vc), 41.5 (24.5) liters; intercompartmental clearance constants from central to peripheral, 2.58 (3.51) liters/h; and peripheral to central compartments, 0.90 (0.58) liters/h. Monte Carlo dosing simulations demonstrated that achievement of therapeutic exposures was dependent on renal function, pathogen, and MIC. Critical illness appears to have no independent effect on levofloxacin pharmacokinetics that cannot be explained by altered renal function.

Physical Function and Disability After Acute Care and Critical Illness Hospitalizations in a Prospective Cohort of Older Adults.

To investigate associations between acute care and critical illness hospitalizations and performance on physical functional measures and activities of daily living (ADLs). Prospective cohort study. Large health maintenance organization. Two thousand nine hundred twenty-six participants in Adult Changes in Thought, a study of aging enrolling dementia-free individuals aged 65 and older not living in a nursing home from 1994 to September 30, 2008 (N = 2,926). The exposure of interest was hospitalization during study participation, subdivided by presence of critical illness. Outcomes included gait speed, grip strength, chair stand speed, and difficulty and dependence in performing ADLs measured at biennial visits. Median time between hospital discharge and the next study visit was 311 days (interquartile range (IQR) 151-501 days) after acute care hospitalization and 359 days (IQR 181-420 days) after critical illness hospitalization. Gait speed was slower after acute care (-0.05 m/s, 95% confidence interval (CI) = 0.01-0.04 m/s slower, P < .001) and critical illness (-0.16 m/s, 95% CI = -0.22 to -0.10, P < .001). Grip was weaker after acute care hospitalization (-0.8 kg, 95% CI = -1.0 to -0.6, P < .001) but not significantly different after critical illness hospitalization. Chair-stand speed was slower after acute care hospitalization (-0.04 stands/s, 95% CVI = -0.05 to -0.04, P < .001) and critical illness hospitalization (-0.09, 95% CI = -0.15 to -0.03, P = .003). The odds of difficulty with (odds ratio (OR) = 1.4, 95% CI = 1.2-1.6, P < .001) or dependence in (OR = 2.0, 95% CI = 1.2-3.2, P = .006) one or more ADLs was higher after acute care hospitalization, as were the odds of difficulty with (OR = 1.9, 95% CI = 1.1-3.6, P = .03) or dependence in (OR = 7.9, 95% CI = 2.5-25.7, P = .001) one or more ADLs after critical illness. In older adults, hospitalization, especially for critical illness, was associated with clinically relevant decline in gait and chair stand speed and strongly associated with difficulty with and dependence in ADLs.

Cefepime Therapy for Monomicrobial Enterobacter cloacae Bacteremia: Unfavorable Outcomes in Patients Infected by Cefepime-Susceptible Dose-Dependent Isolates

A new category of cefepime susceptibility, susceptible dose dependent (SDD), for Enterobacteriaceae, has been suggested to maximize its clinical use. However, clinical evidence supporting such a therapeutic strategy is limited. A retrospective study of 305 adults with monomicrobial Enterobacter cloacae bacteremia at a medical center from 2008 to 2012 was conducted. The patients definitively treated with in vitro active cefepime (cases) were compared with those treated with a carbapenem (controls) to assess therapeutic effectiveness. The 30-day crude mortality rate is the primary endpoint, and clinical prognostic factors are assessed. Of 144 patients receiving definitive cefepime or carbapenem therapy, there were no significant differences in terms of age, sex, comorbidity, source of bacteremia, disease severity, or 30-day mortality (26.4% versus 22.2%; P = 0.7) among those treated with cefepime (n = 72) or a carbapenem (n = 72). In the multivariate analysis, the presence of critical illness, rapidly fatal underlying disease, extended-spectrum beta-lactamase (ESBL) producers, and cefepime-SDD (cefepime MIC, 4 to 8 μg/ml) isolates was independently associated with 30-day mortality. Moreover, those infected by cefepime-SDD isolates with definitive cefepime therapy had a higher mortality rate than those treated with a carbapenem (5/7 [71.4%], versus 2/11 [18.2%]; P = 0.045). Cefepime is one of the therapeutic alternatives for cefepime-susceptible E. cloacae bacteremia but is inefficient for cases of cefepime-SDD E. cloacae bacteremia compared with carbapenem therapy.

Retinopathy of Prematurity in the Dominican Republic: Challenges to Screening and Prevention

To determine the incidence of retinopathy of prematurity (ROP) in an intensive care nursery in the Dominican Republic and to identify factors that impact ROP outcomes, screening, and treatment. A database analysis was performed. The database was prospectively created by the pediatric ophthalmologist in a public maternity hospital in Santo Domingo during 2009. From January to December, all infants (n = 234) who received at least one ophthalmologic examination for ROP were included. ROP screening criteria were based upon: (1) American Academy of Pediatrics guidelines and (2) the presence of critical illness in larger, more mature infants at the discretion of the neonatologist. Overall, 22% were diagnosed with ROP and 4.3% had severe disease. Infants with ROP had a mean birth weight of 1452 g and a mean gestational age of 31 weeks, with 35% having a gestational age >32 weeks. In multivariable regression, only gestational age remained significant (0.8, 0.68 to 0.95). Twenty-two percent diagnosed with ROP did not complete all screening procedures. There are many challenges to preventing and treating ROP in the Dominican Republic. Increased awareness of the detrimental effects of hyperoxia, broader screening criteria, and an improved screening program will help to reduce visual impairment from ROP.

A Prospective Evaluation of Propylene Glycol Clearance and Accumulation During Continuous-Infusion Lorazepam in Critically Ill Patients

Propylene glycol is a commonly used diluent in several pharmaceutical preparations, including the sedative lorazepam. Fifty critically ill patients receiving continuous-infusion lorazepam for a minimum of 36 hours were prospectively evaluated to determine the extent of propylene glycol accumulation over time, characterize propylene glycol clearance in the presence of critical illness, and develop a pharmacokinetic model that would predict clearance based on patient-specific clinical, laboratory, and demographic factors. In this cohort, the median lorazepam infusion rate was 2.1 mg/h (0.5-18). Propylene glycol concentration correlated poorly with osmolality, osmol gap, and lactate. In all, 8 patients (16%) had significant propylene glycol accumulation (>25mg/dL). When propylene glycol concentrations were >25 mg/dL, the median lorazepam infusion rate before sample collection was higher, 6.4 (1.9-11.3) versus 2.0 (0.5-7.4) mg/h (P =.0003). A linear first-order model with interoccasion variability on clearance adjusted for total body weight and Acute Physiology and Chronic Health Evaluation II score predicted propylene glycol concentration.