Angiotensin-converting enzyme D allele does not influence susceptibility to acute hypoxic respiratory failure in children

Objective  The D allele of the I/D polymorphism in the angiotensin-converting enzyme (ACE) gene has been associated with an increased risk of ARDS in critically ill adults and severity of bronchopulmonary dysplasia in pre-term infants. We hypothesised that the presence of the hypoxia-associated ACE D allele would increase susceptibility to acute hypoxic respiratory failure (AHRF) in a cohort of critically ill children. Design and setting  Single-centre prospective observational cohort study. Patients  Children under 16 years of age requiring admission to a tertiary general PICU. Measurements and results  A total of 216 Caucasian patients were enrolled. Thirty (13.9%) children developed AHRF and 13 were diagnosed with ARDS (6.0%). There was no significant difference in ACE D allele frequency between patient groups with or without AHRF (0.53 vs. 0.54). Conclusions  Variation in ACE activity does not influence the development of paediatric AHRF. This may reflect a different pathogenesis from adult ARDS.     

Small airway remodeling in acute respiratory distress syndrome: a study in autopsy lung tissue

Introduction  

Airway dysfunction in patients with the Acute Respiratory Distress Syndrome (ARDS) is evidenced by expiratory flow limitation and dynamic hyperinflation. These functional alterations have been attributed to closure/obstruction of small airways. Airway morphological changes have been reported in experimental models of acute lung injury, characterized by epithelial necrosis and denudation in distal airways. To date, however, no study has focused on the morphological airway changes in lungs from human subjects with ARDS. The aim of this study is to evaluate structural and inflammatory changes in distal airways in ARDS patients.     

The relationship between ACE insertion/deletion polymorphism and coronary artery disease with or without myocardial infarction

OBJECTIVES: Presence of the D allele or homozygosity for the deletion (D) allele of the angiotensicen-converting enzyme (ACE) insertion/deletion (I/D) polymorphism has been discussed as potent risk factor for coronary artery disease (CAD) and myocardial infarction (MI). The D allele is associated with higher levels of circulating ACE and therefore may predispose one to cardiovascular damage. DESIGN AND METHODS: The study presented here was performed to investigate the association between the ACE genotype and ACE levels. The study group was comprised of 118 angiographically verified CAD patients. 65 patients were MI (+) and 53 patients were MI (-) in this group. A total of 70 healthy individuals were taken as controls. Genomic DNA of 188 subjects was extracted from whole blood. The polymerase chain reaction was used for ACE genotyping, and ACE levels were measured by ELISA. RESULTS: The D allele was found to be significantly more frequent in patients with MI (+) compared with controls (P = 0.024). ACE levels were significantly higher in both MI (-) and MI (+) groups with CAD patients than in controls (P < 0.005). Plasma ACE level was higher in all three groups in the DD genotype compared to II genotype. In groups I and III, this was statistically significant (P < 0.0001, P < 0.01). CONCLUSIONS: It was shown that the I/D polymorphism in the gene for ACE is a genetic risk factor for CAD patients who have a history of MI. ACE insertion/deletion gene polymorphism is also associated with plasma ACE levels in CAD patients with a history of MI.     

A polymorphic locus in the intron 16 of the human angiotensin-converting enzyme (ACE) gene is not correlated with complex regional pain syndrome I (CRPS I).

Exaggerated neurogenic inflammation has been recognized to be one reason for many CRPS symptoms. Since angiotensin-converting enzyme (ACE) is a key enzyme for the termination of neurogenic inflammation, it has been selected as a candidate gene for CRPS predisposition. A previous report of an insertion/deletion (I/D) polymorphism in intron 16 within the ACE gene implicated an increased risk to develop CRPS I associated with the D allele. However, in the present study the D allele frequency was not increased in CRPS I cases (0.51 for D allele, 0.49 for I allele). Furthermore, there was no co-segregation of any genotype (DD, ID, II) with the CRPS phenotype in 12 selected familial CRPS I cases from six CRPS I families. In conclusion, the results presented herein render this particular ACE gene polymorphism unlikely to be a predisposing factor for CRPS I.     

ACE inhibitor use was associated with lower serum dehydroepiandrosterone concentrations in older men

ContextAngiotensin converting enzyme (ACE) activity may influence the production of adrenal androgen precursors and testosterone. Use of ACE inhibitors may therefore have an influence on serum sex hormone concentrations in older men.Design and Methods1486 out of 2,000 community-dwelling Chinese men aged 65 years who participated in a cohort study were randomly selected to have archived fasting morning serum analyzed for androgen precursors and sex hormones. DNA was extracted from whole blood and analyzed for ACE gene I/D polymorphism.ResultsSubjects with the ACE gene D allele (higher ACE activity) had higher serum dehydroepiandrosterone (DHEA) sulphate and DHEA than those with I/I genotype (P = 0.014 and 0.018 respectively, Mann Whitney test). These differences were not significant after Bonferroni correction. Among those with history of hypertension, but without diabetes mellitus or cardiac failure, users of ACE inhibitors had significantly lower serum DHEA (median 1.78 versus 1.49 ng/ml in non-users, P = 0.0074, Mann Whitney test) and also tended to have lower serum androstenedione and androst-5-ene-3β,17β-diol (0.68 versus 0.72 ng/ml in non-users; 552.4 versus 624.1 pg/ml respectively, both P values < 0.05). Serum testosterone and estradiol were not significantly changed.ConclusionsACE inhibitor use was associated with lower serum DHEA in older men.     

Transesophageal echocardiography in prone position during severe acute respiratory distress syndrome

Objective  

Patients with severe acute respiratory distress syndrome (ARDS) often require prolonged sessions of prone position (PP) because of refractory hypoxemia. Because of frequent hemodynamic impairment, use of transesophageal echocardiography (TEE) is also advocated during ARDS, but its implementation during PP has not been described yet. Our objective is to report the feasibility, tolerance, and therapeutic implications of TEE during PP for severe ARDS, and to compare it with TEE performed supine.     

Respiratory pulse pressure variation fails to predict fluid responsiveness in acute respiratory distress syndrome

Introduction  

Fluid responsiveness prediction is of utmost interest during acute respiratory distress syndrome (ARDS), but the performance of respiratory pulse pressure variation (Δ_RESPPP) has scarcely been reported. In patients with ARDS, the pathophysiology of Δ_RESPPP may differ from that of healthy lungs because of low tidal volume (Vt), high respiratory rate, decreased lung and sometimes chest wall compliance, which increase alveolar and/or pleural pressure. We aimed to assess Δ_RESPPP in a large ARDS population.     

Impact of therapy with statins,beta-blockers and angiotensin-converting enzyme inhibitors on plasma myeloperoxidase in patients with coronary artery disease

Purpose  

The present study investigated whether therapy with statins, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors on admission affects the plasma level of myeloperoxidase (MPO) in patients with coronary artery disease (CAD).     

Risk factors for acute respiratory distress syndrome during neutropenia recovery in patients with hematologic malignancies

Introduction

Neutropenia recovery may be associated with deterioration in oxygenation and exacerbation of pre-existing pulmonary disease. However, risk factors for acute respiratory distress syndrome (ARDS) during neutropenia recovery in patients with hematologic malignancies have not been studied.

Methods

We studied critically ill patients with hematologic malignancies with the dual objectives of describing patients with ARDS during neutropenia recovery and identifying risk factors for ARDS during neutropenia recovery. A cohort of consecutive neutropenic patients with hematologic malignancies who were admitted to the intensive care unit (ICU) was studied. During a 6-year period, 71 patients recovered from neutropenia, of whom 38 (53.5%) developed ARDS during recovery.

Results

Compared with non-ARDS patients, patients who experienced ARDS during neutropenia recovery were more likely to have pneumonia, be admitted to the ICU for respiratory failure, and receive mechanical ventilator therapy. The in-ICU mortality was significantly different between the two groups (86.8% versus 51.5%, respectively, for patients who developed ARDS during neutropenia recovery versus those who did not during neutropenia recovery). In multivariate analysis, only occurrence of pneumonia during the neutropenic episode was associated with a marked increase in the risk of ARDS (odds ratio, 4.76).

Conclusions

Patients with hematologic malignancies complicated by pneumonia during neutropenia are at increased risk for ARDS during neutropenia recovery.     

Increased deformability of red blood cells is associated with a deletion polymorphism of the angiotensin-converting enzyme gene

Angiotensin-converting enzyme (ACE) plays important roles in the renin-angiotensin system. ACE converts angiotensin I to angiotensin II and also inactivates bradykinin, thereby modulating the vascular tone. A polymorphism of the ACE gene, located on chromosome 17, has been found in intron 16, and is characterized by the presence (insertion [I]) or absence (deletion [D]) of a 287-base-pair Alu repeat. Individuals with the D allele of the ACE gene have higher ACE levels and are at higher risk of cardiovascular events. We aimed to investigate the possible relationship between the I/D polymorphism of the ACE gene and hemorheological parameters, including red blood cell (RBC) deformability. The study was performed on 28 healthy young volunteers (13 women and 15 men, mean age 24 +/- 2). The prevalence of the I and D alleles was 30.4% and 69.6%, respectively. The I/I genotype (II) was found in 21.4%, I/D genotype (ID) in 17.9%, and D/D genotype (DD) in 60.7% of the subjects tested. No significant relationship between ACE I/D polymorphism and RBC aggregation or whole blood and plasma viscosity was observed. In contrast, RBC deformability was significantly increased in the subjects with the DD genotype compared with the II (p < 0.05) or the ID (p < 0.01) genotype, and in the subjects with the D allele compared with the I allele (p < 0.01). We suggest that RBC deformability of individuals with the D allele, who have higher risk for cardiovascular pathologies, may have been increased by a compensatory mechanism.     

Do hypooncotic fluids for shock increase the risk of late-onset acute respiratory distress syndrome?

Objective  

In patients with shock, late-onset acute respiratory distress syndrome (ARDS) carries poor prognosis. Hypooncotic fluids may improve kidney function preservation, whereas hyperoncotic fluids may in theory decrease the risk of late-onset ARDS. Our objective was to determine whether predominant or exclusive use of crystalloids and/or hypooncotic colloids for shock resuscitation influenced the risk of late-onset ARDS.     

Angiotensin converting enzyme gene polymorphism and glomerular filtration rate changes in type 2 diabetic patients

It has been suggested that an insertion/deletion (I/D) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene may be associated with diabetic nephropathy The aim of this study was to investigate whether an association exists between ACE I/D polymorphism and glomerular filtration rate (GFR) in type 2 diabetes mellitus. A total of 128 type 2 diabetic patients were included in the study with the following ACE genotype distribution: DD 40, ID 58,11 30. I/D polymorphism was determined by polymerase chain reaction (PCR). Mean GFR was not statistically different according to ACE genotype (DD: 89.9 +/- 28.1 ml/min, ID: 99.5 +/- 25.1 ml/min, II: 96.6 +/- 19.6 ml/min). There was no significant difference in genotype distribution in normo-, micro- and macroalbuminuric patients (DD:ID:II [%], normo- 35:46:19, micro-28:55:17, macro- 31:55:14). ACE I/D polymorphism does not seem to be associated with GFR in type 2 diabetic patients.     

Low plasma citrulline levels are associated with acute respiratory distress syndrome in patients with severe sepsis

Introduction

The role of nitric oxide synthase (NOS) in the pathophysiology of acute respiratory distress syndrome (ARDS) is not well understood. Inducible NOS is upregulated during physiologic stress; however, if NOS substrate is insufficient then NOS can uncouple and switch from NO generation to production of damaging peroxynitrites. We hypothesized that NOS substrate levels are low in patients with severe sepsis and that low levels of the NOS substrate citrulline would be associated with end organ damage including ARDS in severe sepsis.

Methods

Plasma citrulline, arginine and ornithine levels and nitrate/nitrite were measured at baseline in 135 patients with severe sepsis. ARDS was diagnosed by consensus definitions.

Results

Plasma citrulline levels were below normal in all patients (median 9.2 uM, IQR 5.2 - 14.4) and were significantly lower in ARDS compared to the no ARDS group (6.0 (3.3 - 10.4) vs. 10.1 (6.2 - 16.6), P = 0.002). The rate of ARDS was 50% in the lowest citrulline quartile compared to 15% in the highest citrulline quartile (P = 0.002). In multivariable analyses, citrulline levels were associated with ARDS even after adjustment for covariates including severity of illness.

Conclusions

In severe sepsis, levels of the NOS substrate citrulline are low and are associated with ARDS. Low NOS substrate levels have been shown in other disease states to lead to NOS uncoupling and oxidative injury suggesting a potential mechanism for the association between low citrulline and ARDS. Further studies are needed to determine whether citrulline supplementation could prevent the development of ARDS in patients with severe sepsis and to determine its role in NOS coupling and function.     

How large is the lung recruitability in early acute respiratory distress syndrome: a prospective case series of patients monitored by computed tomography

Introduction  

The benefits of higher positive end expiratory pressure (PEEP) in patients with acute respiratory distress syndrome (ARDS) have been modest, but few studies have fully tested the "open-lung hypothesis". This hypothesis states that most of the collapsed lung tissue observed in ARDS can be reversed at an acceptable clinical cost, potentially resulting in better lung protection, but requiring more intensive maneuvers. The short-/middle-term efficacy of a maximum recruitment strategy (MRS) was recently described in a small physiological study. The present study extends those results, describing a case-series of non-selected patients with early, severe ARDS submitted to MRS and followed until hospital discharge or death.     

Resolved versus confirmed ARDS after 24 h: insights from the LUNG SAFE study

Purpose

To evaluate patients with resolved versus confirmed ARDS, identify subgroups with substantial mortality risk, and to determine the utility of day 2 ARDS reclassification.

Methods

Our primary objective, in this secondary LUNG SAFE analysis, was to compare outcome in patients with resolved versus confirmed ARDS after 24 h. Secondary objectives included identifying factors associated with ARDS persistence and mortality, and the utility of day 2 ARDS reclassification.

Results

Of 2377 patients fulfilling the ARDS definition on the first day of ARDS (day 1) and receiving invasive mechanical ventilation, 503 (24%) no longer fulfilled the ARDS definition the next day, 52% of whom initially had moderate or severe ARDS. Higher tidal volume on day 1 of ARDS was associated with confirmed ARDS [OR 1.07 (CI 1.01–1.13), P?=?0.035]. Hospital mortality was 38% overall, ranging from 31% in resolved ARDS to 41% in confirmed ARDS, and 57% in confirmed severe ARDS at day 2. In both resolved and confirmed ARDS, age, non-respiratory SOFA score, lower PEEP and P/F ratio, higher peak pressure and respiratory rate were each associated with mortality. In confirmed ARDS, pH and the presence of immunosuppression or neoplasm were also associated with mortality. The increase in area under the receiver operating curve for ARDS reclassification on day 2 was marginal.

Conclusions

ARDS, whether resolved or confirmed at day 2, has a high mortality rate. ARDS reclassification at day 2 has limited predictive value for mortality. The substantial mortality risk in severe confirmed ARDS suggests that complex interventions might best be tested in this population.

Trial Registration

ClinicalTrials.gov NCT02010073.

     

Angiotensin-converting enzyme insertion/deletion polymorphism is not associated with susceptibility and outcome in sepsis and acute respiratory distress syndrome

Objective The insertion/deletion (I/D) of a 289 base pair Alu repeat sequence polymorphism in the angiotensin-converting enzyme gene (ACE) has been shown to predict susceptibility and outcome in the acute respiratory distress syndrome (ARDS). We hypothesized that the I/D polymorphism also confers susceptibility to sepsis and is a predisposing factor for morbidity and mortality of patients with severe sepsis. Design and setting Case-control study including 212 consecutive patients fulfilling criteria for severe sepsis admitted to a Spanish network of postsurgical and critical care units, and 364 population-based controls. Susceptibility to severe sepsis was evaluated as primary outcome; mortality in severe sepsis, susceptibility to sepsis-induced ARDS, and mortality in sepsis-induced ARDS were examined as secondary outcomes. An additive model of inheritance in which patients were classified into three genotype groups (II, ID, and DD) was used for association testing. Measurements and results Genotype and allele frequencies of I/D were distributed similarly in all septic, ARDS, and non-ARDS patients and in population-based controls. ACE I/D polymorphism was not associated with severe sepsis susceptibility or mortality. The ACE I/D polymorphism was associated neither with sepsis-induced ARDS susceptibility (p = 0.895) or mortality (p = 0.950). These results remained nonsignificant when adjusted for other covariates using multiple logistic regression analysis or Kaplan–Meier estimates of 28-day survival. Conclusions Our data do not support an association of the ACE gene I/D polymorphism with susceptibility or mortality in severe sepsis or with sepsis-induced ARDS in Spanish patients. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. This research was supported by grants from FUNCIS (53/04) and the Ministerio de Educación y Ciencia, Spain (SAF2004-06833). J.V. is the principal investigator in both grants. The authors named above wrote this article on behalf of the GRECIA and GEN-SEP groups. The members of the GRECIA and GEN-SEP groups are listed under Acknowledgements at the end of the article. J. Villar, C. Flores, and L. Pérez-Méndez contributed equally to this work.     

Management and outcomes of acute respiratory distress syndrome patients with and without comorbid conditions

Rationale

The standard of care for patients with acute respiratory distress syndrome (ARDS) has been developed based on studies that usually excluded patients with major comorbidities.

Objectives

To describe treatments and outcomes according to comorbidities in patients with ARDS admitted to 19 ICUs (1997–2014).

Methods

Patients were grouped based on comorbidities. Determinants of day-28 mortality were identified by multivariable Cox analysis stratified on center.

Measurements and main results

Among 4953 ARDS patients, 2545 (51.4%) had major comorbidities; the proportion with major comorbidities increased after 2008. Hematological malignancy was associated with severe ARDS and rescue therapies for refractory hypoxemia. COPD, HIV infection, and hematological malignancy were associated with a lower likelihood of invasive mechanical ventilation on the admission day. Admission-day SOFA score was higher in patients with major comorbidities, who more often received vasopressors, dialysis, or treatment-limitation decisions. Day-28 mortality was 33.7% overall, 27.2% in patients without major comorbidities, and 31.1% (COPD) to 56% (hematological malignancy) in patients with major comorbidities. By multivariable analysis, mortality was lower in patients with COPD and higher in those with chronic heart failure, solid tumors, or hematological malignancies. Mortality was independently associated with P_aO₂/F_iO₂ and PaCO₂ on day 1, ARDS of pulmonary origin, worse SOFA score, and ICU-acquired events.

Conclusions

Half the patients with ARDS had major comorbidities, which were associated with severe ARDS, multiple organ dysfunction, and day-28 mortality. These findings do not support the exclusion of ARDS patients with severe comorbidities from randomized clinical trials. Trials in ARDS patients with whatever comorbidities are warranted.

     

Active transforming growth factor-β1 activates the procollagen I promoter in patients with acute lung injury

Objective Fibroproliferation markers like procollagen I predict mortality in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). We sought to determine whether bronchoalveolar lavage fluid (BALF) from patients with lung injury contained mediators that would activate procollagen I promoter and if this activation predicted important clinical outcomes.Design Prospective controlled study of ALI/ARDS.Setting Intensive care units and laboratory of a university hospital.Patients and participants Acute lung injury/ARDS, cardiogenic edema (negative controls) and pulmonary fibrosis (positive controls) patients.Interventions Bronchoalveolar lavage fluid was collected within 48 h of intubation from ALI/ARDS patients. BALF was also collected from patients with pulmonary fibrosis and cardiogenic pulmonary edema. Human lung fibroblasts were transfected with a procollagen I promoter-luciferase construct and incubated with BALF; procollagen I promoter activity was then measured. BALF active TGF-1 levels were measured by ELISA.Results Twenty-nine ARDS patients, nine negative and six positive controls were enrolled. BALF from ARDS patients induced 41% greater procollagen I promoter activation than that from negative controls (p<0.05) and a TGF-1 blocking antibody significantly reduced this activation in ARDS patients. There was a trend toward higher TGF-1 levels in the ARDS group compared to negative controls (–1.056 log₁₀±0.1415 vs –1.505 log₁₀±0.1425) (p<0.09). Procollagen I promoter activation was not associated with mortality; however, lower TGF-1 levels were associated with more ventilator-free and ICU-free days.Conclusions Bronchoalveolar lavage fluid from ALI/ARDS patients activates procollagen I promoter, which is due partly to TGF-1. Activated TGF-1 may impact ARDS outcome independent of its effect on procollagen I activation.Electronic Supplementary Material Supplementary material is available in the online version of this article at     

Lower tidal volume at initiation of mechanical ventilation may reduce progression to acute respiratory distress syndrome: a systematic review

Introduction

The most appropriate tidal volume in patients without acute respiratory distress syndrome (ARDS) is controversial and has not been rigorously examined. Our objective was to determine whether a mechanical ventilation strategy using lower tidal volume is associated with a decreased incidence of progression to ARDS when compared with a higher tidal volume strategy.

Methods

A systematic search of MEDLINE, EMBASE, CINAHL, the Cochrane Library, conference proceedings, and clinical trial registration was performed with a comprehensive strategy. Studies providing information on mechanically ventilated patients without ARDS at the time of initiation of mechanical ventilation, and in which tidal volume was independently studied as a predictor variable for outcome, were included. The primary outcome was progression to ARDS.

Results

The search yielded 1,704 studies, of which 13 were included in the final analysis. One randomized controlled trial was found; the remaining 12 studies were observational. The patient cohorts were significantly heterogeneous in composition and baseline risk for developing ARDS; therefore, a meta-analysis of the data was not performed. The majority of the studies (n = 8) showed a decrease in progression to ARDS with a lower tidal volume strategy. ARDS developed early in the course of illness (5 hours to 3.7 days). The development of ARDS was associated with increased mortality, lengths of stay, mechanical ventilation duration, and nonpulmonary organ failure.

Conclusions

In mechanically ventilated patients without ARDS at the time of endotracheal intubation, the majority of data favors lower tidal volume to reduce progression to ARDS. However, due to significant heterogeneity in the data, no definitive recommendations can be made. Further randomized controlled trials examining the role of lower tidal volumes in patients without ARDS, controlling for ARDS risk, are needed.2013 Fuller et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.     

The angiotensin converting enzyme D allele is an independent risk factor for early onset coronary artery disease

ObjectiveThe role of angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in early onset coronary artery disease age < 55 years (ECAD) is controversial. The aim of this study was to further evaluate the role of this ACE(I/D) gene polymorphism on the risk of premature CAD in patients from western Iran.MethodsThe ACE(I/D) genotypes were detected by PCR-RFLP in 323 individuals undergoing their first coronary angiography. Patients were placed into two groups: ECAD and late onset CAD age ≥ 55 years (LCAD).ResultsWe found a statistically significant association of the ACE D allele, as homozygous or ACE ID plus DD genotypes (ID + DD), only in the ECAD subjects OR = 1.35, p = 0.015, OR = 3.27, p = 0.014, and OR = 2.8, p = 0.013, respectively. In addition, there was a significant association after adjustment for the absence of history of diabetes, presence of normolipidemia and absence of history of blood pressure [OR 1.38, p = 0.017 and 2.35, p = 0.02]. Our results indicated that the ACE D allele is a risk factor for early onset of CAD even after correcting for conventional risk factors. The incidence of triple vessel disease was significantly higher in individuals carrying ACE(D/D) genotype in ECAD patients compared to those who carried ACE(I/I) genotype (OR 3.38; p = 0.019; 57.5% vs. 42.5%; p = 0.013).ConclusionThe presence of D allele of ACE can be important independent risk factor in the onset of CAD patients less than 55 years old in a west population of Iran. Larger collaborative studies are needed to confirm these results.