Laura R. A. Schouten

Surgical glue for repair of the aortic root as a possible explanation for increased F-18 FDG uptake

A 40-year-old man with Marfan syndrome (an autosomal dominant connective tissue disease) had undergone a valve-sparing aortic root replacement (David procedure) because of a dilation of the ascending aorta. His recovery was uncomplicated. On a routine outpatient visit 4 months after surgery, there were no abnormalities except for an asymptomatic third-degree atrioventricular (AV) block. Transesophageal echocardiography showed a large vegetation on the aortic valve, thereby supporting the diagnosis of endocarditis (Figure 1A). Although blood cultures remained negative, the patient was intravenously treated with antibiotics (vancomycin and gentamicin). Shortly after treatment, the vegetation resolved and the AV block disappeared. Five months after this episode and nine months after surgery, a recurrent AV block was noted. However, this time, echocardiography showed no significant abnormalities except for a small cavity dorsal to the aortic root prosthesis (Figure 1B). To exclude a recurrence of endocarditis, Fluorine 18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET)– computed tomography (CT) was performed. The images showed increased and circumferential uptake of F-18 FDG around the proximal part of the aortic root, suggestive of inflammation (Figures 1C, 1D, and 1E). On the basis of these findings, recurrent endocarditis was suspected, but no final decision with regard to the treatment could be made. Fortunately, we were able to compare the scintigraphic findings with those of an another male patient with Marfan syndrome who also underwent a David procedure in the same period, without any signs of endocarditis. In this patient a similar pattern of increased uptake of F-18 FDG was seen around the proximal part of the aorta prosthesis (Figures 1F, 1G, and 1H). The common denominator in both patients was the David procedure. In this procedure glue is used to seal the aortic root prosthesis (BioGlue surgical adhesive; CryoLife, Kennesaw, Ga). BioGlue surgical adhesive is a topically applied mixture of bovine serum albumin and glutaraldehyde. It is supplied in a prefilled cartridge and stored below 25°C. The components of the product are mixed within a double-helix applicator attached to a syringe. Polymerization with tissues occurs immediately on application, and bonding strength is reached within 2 minutes, resulting in a strong scaffold. However, polymerized BioGlue releases amounts of glutaraldehyde that are capable of inducing cytotoxic effects both in vitro and in vivo. Severe active inflammation surrounding the glue remnant with multiple granulocytes and histiocytes and a massive foreign-body reaction with numerous multinucleated giant cells has been described. This type of inflammation could explain the finding of increased F-18 FDG uptake in both our patients. The explanation for the recurrent AV block in the patient with the previous endocarditis is uncertain. It is possible that fibrosis and edema in the AV node—as a result of the BioGlue surgical adhesive or previous endocarditis (or both)—might explain the recurrent AV block. A wide range of reactions have been described in different tissues, and the aortic wall seems to be less sensitive to the toxic effects of BioGlue. Whether the altered tissue composition of the aortic wall of patients with Marfan syndrome makes the tissue more sensitive to the glue remains to be determined. F-18 FDG-PET is increasingly used for the diagnosis of endocarditis and endarteritis. However, in patients with an aortic root prosthesis, positive findings should be interpreted with caution.

Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study

BACKGROUND Host responses during sepsis are highly heterogeneous, which hampers the identification of patients at high risk of mortality and their selection for targeted therapies. In this study, we aimed to identify biologically relevant molecular endotypes in patients with sepsis. METHODS This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units (ICUs) in the Netherlands between Jan 1, 2011, and July 20, 2012 (discovery and first validation cohorts) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK (second validation cohort). We generated genome-wide blood gene expression profiles from admission samples and analysed them by unsupervised consensus clustering and machine learning. The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. We also established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice. FINDINGS The discovery cohort had 306 patients, the first validation cohort had 216, and the second validation cohort had 265 patients. Four molecular endotypes for sepsis, designated Mars1-4, were identified in the discovery cohort, and were associated with 28-day mortality (log-rank p=0·022). In the discovery cohort, the worst outcome was found for patients classified as having a Mars1 endotype, and at 28 days, 35 (39%) of 90 people with a Mars1 endotype had died (hazard ratio [HR] vs all other endotypes 1·86 [95% CI 1·21-2·86]; p=0·0045), compared with 23 (22%) of 105 people with a Mars2 endotype (HR 0·64 [0·40-1·04]; p=0·061), 16 (23%) of 71 people with a Mars3 endotype (HR 0·71 [0·41-1·22]; p=0·19), and 13 (33%) of 40 patients with a Mars4 endotype (HR 1·13 [0·63-2·04]; p=0·69). Analysis of the net reclassification improvement using a combined clinical and endotype model significantly improved risk prediction to 0·33 (0·09-0·58; p=0·008). A 140-gene expression signature reliably stratified patients with sepsis to the four endotypes in both the first and second validation cohorts. Only Mars1 was consistently significantly associated with 28-day mortality across the cohorts. To facilitate possible clinical use, a biomarker was derived for each endotype; BPGM and TAP2 reliably identified patients with a Mars1 endotype. INTERPRETATION This study provides a method for the molecular classification of patients with sepsis to four different endotypes upon ICU admission. Detection of sepsis endotypes might assist in providing personalised patient management and in selection for trials. FUNDING Center for Translational Molecular Medicine, Netherlands.

Association between Maturation and Aging and Pulmonary Responses in Animal Models of Lung Injury: A Systematic Review.

Background:Advanced age is associated with an increased susceptibility and mortality of the acute respiratory distress syndrome. This may be due to the progressive changes in innate immune responses and intrinsic properties of the lung that occur during the process of aging. Therefore, this study assesses the association between maturation and aging and pulmonary responses to injury in animal models of lung injury. Methods:A systematic search was conducted in PubMed, EMBASE (up to June 2014) and in the references of relevant articles to identify the studies using in vivo models of lung injury caused by an acute pulmonary insult, in which at least two age groups were compared. Because methodological diversity precluded combining these studies in a quantitative meta-analysis, data are presented based on the qualitative comparison with the adult group. Results:Of the 2,840 identified studies, 51 were included in this review. Most studies showed that, in response to a pulmonary insult, increasing age is associated with more pulmonary inflammation, edema, alveolar damage, and higher mortality. In addition, results indicate the existence of age-dependent changes in key components of the intracellular signaling pathways involved in the inflammatory response. Conclusions:Increasing age seems to be correlated with exaggerated pulmonary responses to injury, ultimately leading to more severe lung injury. Pulmonary inflammation seems relatively suppressed in infants/juveniles, whereas in the middle aged/elderly, the inflammatory response seems delayed but aggravated. This implies that investigators and clinicians need to use caution about extrapolating results from adolescent or youngadult animals to pediatric or elderly patients in clinical practice.

Age-Dependent Changes in the Pulmonary Renin-Angiotensin System Are Associated With Severity of Lung Injury in a Model of Acute Lung Injury in Rats

Objectives:A growing body of evidence suggests that age affects the main pathophysiologic mechanisms of the acute respiratory distress syndrome. This may imply the need for developing age-tailored therapies for acute respiratory distress syndrome. However, underlying molecular mechanisms governing age-related susceptibility first need to be unraveled. In a rat model of acute lung injury, we investigated whether age affects the balance between the two key enzymes of the pulmonary renin-angiotensin system, angiotensin-converting enzyme, and angiotensin-converting enzyme 2. We hypothesized that aging shifts the balance toward the lung injury–promoting angiotensin-converting enzyme, which may form an explanation for the differences in severity of lung injury between different age groups. Design:Prospective, randomized controlled animal study. Setting:University medical research laboratory. Subjects:Infant (15 ± 2 d), juvenile (37 ± 2 d), adult (4 ± 0.2 mo), and elderly (19.5 ± 0.5 mo) male RCCHan Wistar rats. Interventions:Lung injury was induced by intratracheal administration of lipopolysaccharide (5 mg/kg) and 4 hours of mechanical ventilation (15 mL/kg). Measurements and Main Results:In lipopolysaccharide-exposed and mechanical ventilated rats, angiotensin-converting enzyme activity in bronchoalveolar lavage fluid increased 3.2-fold in elderly when compared with infants. No changes in bronchoalveolar lavage fluid angiotensin-converting enzyme 2 activity were found. In addition, membrane-bound angiotensin-converting enzyme activity decreased. Together with the presence of angiotensin-converting enzyme-sheddase ADAM9 (a disintegrin and metalloproteinase domain–containing protein 9) and an age-dependent increase in tumor necrosis factor-&agr;, an activator of ADAM9, these results indicate increased shedding of angiotensin-converting enzyme in the alveolar compartment, thereby shifting the balance toward the injurious pathway. This imbalance was associated with an increased inflammatory mediator response and more lung injury (wet-to-dry ratio and histology) in elderly rats. Conclusions:Increasing age is associated with an imbalance of the pulmonary renin-angiotensin system, which correlates with aggravated inflammation and more lung injury. These changes might form the ground for new therapeutic strategies in terms of dosing and effectiveness of renin-angiotensin system–modulating agents for treatment of acute respiratory distress syndrome.

Promising but still uncertain steps towards better prediction of functional outcome in ICU patients

In a recent publication on their ‘Towards RECOVER’ study, an ongoing multicenter project evaluating patient and caregiver outcomes after prolonged mechanical ventilation, Herridge et al . report on functional outcome up to one year after discharge in patients who needed support in an intensive care unit (ICU) for more than one week (1). For this, the ‘Towards RECOVER’—investigators used the Functional Independence Measure (FIM), the Short-Form 36, a 6-minute walking test and Medical Research Counsel score-muscle strength testing. The main findings were that young patients (aged 66 years) who needed longer ICU–care (LOS >2 weeks) had the worst functional outcome. Young patients with a LOS >2 weeks, older patients with a LOS 2 weeks had a functional status in between the first two groups. Based on these results, the ‘Towards RECOVER’—researchers suggest that these age—and LOS cutoffs could be useful in resource planning and informing patients and their families about expected functional outcomes.