Genetic variants in the angiopoietin-2 gene are associated with increased risk of ARDS

Objective  Angiopoietin-2 (Ang-2) is a potent regulator of vascular permeability and inflammation in acute lung injury and acute respiratory distress syndrome (ARDS). Genetic variants in the Ang-2 gene may lead to altered activities of Ang-2 (or ANGPT2) gene. The aim of this study was to assess if genetic variants of Ang-2 are associated with the risk of ARDS. Design  Unmatched, case-control study nested within a prospectively enrolled cohort. Setting  Intensive care units (ICU) of an academic medical center. Patients  About 1,529 critically ill patients with risk factors for ARDS consecutively admitted to the ICUs from 1999 to 2006. Cases were 449 patients who developed ARDS and controls were 1,080 subjects who did not developed ARDS. Intervention  None. Measurements and results  Nine tagging SNPs (tSNPs) spanning the entire Ang-2 gene were genotyped in all patients. The results were analyzed using logistic regression models, adjusting for covariates. The variant T allele of one tSNP (rs2515475) was significantly associated with increased risk of ARDS (OR_adjusted = 1.28; P = 0.042). This association was stronger in subjects with extrapulmonary injuries (OR_adjusted = 1.79; P = 0.004). Haplotype TT in block 2 containing the T allele of the rs2515475 was also significantly associated with higher risk of ARDS (OR_adjusted = 1.42; P = 0.009), particularly in subjects with extrapulmonary injuries (OR_adjusted = 1.90; P = 0.004). Conclusion  Common genetic variation in the Ang-2 gene may be associated with increased risk of ARDS, especially among patients with extrapulmonary injuries. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. L. Su and R. Zhai contributed equally to this work.     

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.     

Pilot safety study of low-dose vasopressin in non-septic critically ill children

Objective  To assess the safety of low-dose vasopressin infusion in critically ill children requiring prolonged mechanical ventilation (MV) at risk of developing sedation/analgesia-related hypotension. Method  Randomized pilot safety study in children expected to require MV for at least 3 days. Children received either vasopressin (0.0005 U/kg/min) or sodium chloride (0.9%) infusion for a period of 48 h. Haemodynamic variables, urine output and serum electrolytes were closely monitored and analyzed. Results  Twelve children in each group had similar baseline characteristics. Vasopressin infusion was associated with an 8 mmol/L fall in serum sodium concentration (p < 0.01) and with higher incidence of hyponatraemia (8 vs. 66%, p < 0.01). In normotensive children, low-dose vasopressin also induced a reversible decrease in urine output, and acutely increased blood pressure (p < 0.01). After stopping the vasopressin there was rebound hypotension (p < 0.01). Conclusion  Low-dose vasopressin infusion in haemodynamically stable, but critically ill, children is associated with reduction in urine output and decreased serum sodium level, yielding a high incidence of hyponatraemia. We conclude that these effects limit further study of prophylactic vasopressin for sedation-related hypotension in a randomized controlled trial.     

The influence of infection sites on development and mortality of ARDS

Objective  

Infection is the most frequent cause of acute respiratory distress syndrome (ARDS). However, little is known about the influence of infection sites on ARDS. This study aimed to assess the associations of infection sites with ARDS development and mortality in critically ill infected patients.     

Quality improvement intervention to stimulate early mobilisation of critically ill children

Background

Immobility during hospital stay is associated with muscle weakness, delirium, and delayed neurocognitive recovery. Early mobilisation of critically ill adults improves their physical functioning and shortens the duration of mechanical ventilation. However, comparable research in children is lacking.

Aims

To determine the effects of the implementation of an early mobilisation (EM) program on mobility activities for critically ill children and to explore barriers and facilitators and clinical outcomes before and after implementation.

Study design

A prospective single-centre before-and-after study. This study was conducted in a PICU of a large tertiary hospital. Children aged from 3 months to 18 years, with an expected stay of ≥3 days were eligible to participate. In the “before” phase, participants received usual care; in the “after” phase we implemented a multicomponent, multidisciplinary EM protocol. The primary outcome was a change in the process outcome “mobilisation activities”. Secondary outcomes were PICU staff opinions on mobilisation (survey), safety, process measures, involvement of parents and physical therapist, and clinical outcomes (sedative use and prevalence of delirium).

Results

A total of 113 children were included; 55 before and 58 after, with a median age of 31 months (IQR: 10–103) and 35 months (IQR: 7–152), respectively. The number of mobilisation activities (per patient per day) had significantly increased from 5 (IQR: 2–7) to 6 (IQR: 4–8) (U = 272185.0; p < .001). PT consultations for mobilisation had significantly increased from 23.6% (13/55) to 46.5% (27/58) (X² = 6.48; p = .011). In both phases, no mobilisation-related adverse events were documented. The survey showed that PICU staff found EM of critically ill children useful and feasible. In the after phase, PICU staff rated the perceived benefit of the support of the physical therapist during mobilisation activities significantly higher than in the before phase (X² = 34.80; p < .001).

Conclusions

Implementation of a structured EM program for critically ill children is feasible and safe.

Relevance to clinical practice

It is suggested to start the implementation of a structed EM program with the idendentification of local barriers and facilitators by an interdisciplinary PICU team. Further, an increased presence of physiotherapists on the PICU would improve mobilisation levels, and facilitate mobilisation in critically ill children. Also, they can support and advice PICU nurses and parents in mobilising children.     

Differences in tocopherol-lipid ratios in ARDS and non-ARDS patients

Plasma tocopherol, plasma total lipid levels and tocopherol-lipid ratio were measured every 6 h during 48 h in 12 critically ill patients and compared with those of a control group. The patients were divided into two groups. Group I comprised 6 critically ill patients with ARDS and group II comprised 6 severely ill patients without ARDS. The means for all observations of plasma tocopherol, total lipid levels and tocopherol-lipid ratio in groups I and II were significantly depressed relative to a control group (p<0.0001). The difference in the average tocopherol-lipid ratio between the three groups (p<0.0001) and between the groups I and II was statistically significant (p<0.0001). Our results indicated: (1) a decrease of vitamin E concentrations in the critically ill patients, particularly in ARDS patients; (2) the importance of the relationship between plasma tocopherol and plasma lipids levels in evaluating the deficiency in vitamin E which was evident in ARDS patients.     

Immunonutrition in critically ill patients: a systematic review and analysis of the literature

Background  The role of immuno-modulating diets (IMDs) in critically ill patients is controversial. Objective  The goal of this meta-analysis was to determine the impact of IMD’s on hospital mortality, nosocomial infections and length of stay (LOS) in critically ill patients. Outcome was stratified according to type of IMD and patient setting. Data sources  MEDLINE, Embase, Cochrane Register of Controlled Trials. Study selection  RCT’s that compared the outcome of critically ill patients randomized to an IMD or a control diet. Data synthesis  Twenty-four studies (with a total of 3013 patients) were included in the meta-analysis; 12 studies included ICU patients, 5 burn patients and 7 trauma patients. Four of the studies used formulas supplemented with arginine, two with arginine and glutamine, nine with arginine and fish oil (FO), two with arginine, glutamine and FO, six with glutamine alone and three studies used a formula supplemented with FO alone. Overall IMD’s had no effect on mortality or LOS, but reduced the number of infections (OR 0.63; 95% CI 0.47–0.86, P = 0.004, I ² = 49%). Mortality, infections and LOS were significantly lower only in the ICU patients receiving the FO IMD (OR 0.42, 95% CI 0.26–0.68; OR 0.45, 95% CI 0.25–0.79 and WMD -6.28 days, 95% CI −9.92 to −2.64, respectively). Conclusions  An IMD supplemented with FO improved the outcome of medical ICU patients (with SIRS/sepsis/ARDS). IMDs supplemented with arginine with/without additional glutamine or FO do not appear to offer an advantage over standard enteral formulas in ICU, trauma and burn patients.     

Non-invasive ventilation for acute hypoxemic respiratory failure: intubation rate and risk factors

Introduction

We assessed rates and predictive factors of non-invasive ventilation (NIV) failure in patients admitted to the intensive care unit (ICU) for non-hypercapnic acute hypoxemic respiratory failure (AHRF).

Methods

This is an observational cohort study using data prospectively collected over a three-year period in a medical ICU of a university hospital.

Results

Among 113 patients receiving NIV for AHRF, 82 had acute respiratory distress syndrome (ARDS) and 31 had non-ARDS. Intubation rates significantly differed between ARDS and non-ARDS patients (61% versus 35%, P = 0.015) and according to clinical severity of ARDS: 31% in mild, 62% in moderate, and 84% in severe ARDS (P = 0.0016). In-ICU mortality rates were 13% in non-ARDS, and, respectively, 19%, 32% and 32% in mild, moderate and severe ARDS (P = 0.22). Among patients with moderate ARDS, NIV failure was lower among those having a PaO₂/FiO₂ >150 mmHg (45% vs. 74%, p = 0.04). NIV failure was associated with active cancer, shock, moderate/severe ARDS, lower Glasgow coma score and lower positive end-expiratory pressure level at NIV initiation. Among intubated patients, ICU mortality rate was 46% overall and did not differ according to the time to intubation.

Conclusions

With intubation rates below 35% in non-ARDS and mild ARDS, NIV stands as the first-line approach; NIV may be attempted in ARDS patients with a PaO₂/FiO₂ > 150. By contrast, 84% of severe ARDS required intubation and NIV did not appear beneficial in this subset of patients. However, the time to intubation had no influence on mortality.     

Timing of recovery of lung function after severe hypoxemic respiratory failure in children

Objective: To describe the timing of recovery of lung function after severe acute hypoxemic respiratory failure (AHRF) in children. Design: A serial observational follow-up study of clinical and lung function measurements up to 53 months after acute illness. Setting: University pediatric intensive care unit in a national children's hospital. Patients: Five critically ill children aged 5–14 years. Interventions: None Results: Clinical recovery: each patient required a 3–5 month convalescence before being able to attend full-time school because of lethargy and dyspnea. All patients developed wheeze 3–12 months after illness and four received long-term bronchodilator therapy. Lung function recovery: for both the forced vital capacity (FVC) and forced vital capacity in the first second (FEV₁) four patients had abnormally low values, regaining only 60–70 % of predicted values for their height and sex, and all of this improvement had occurred by 6–12 months after illness. Beyond this interval, patients remained on their same FVC and FEV₁ centile. FEV₁/FVC ratios were consistently within the normal range, indicating a predominantly restrictive defect. Changes in peak expiratory flow exhibited a time course of improvement similar to the other lung function tests. Conclusion: In children, pulmonary recovery after severe AHRF may occur for 6–12 months. A 1-year follow-up could offer a rational single point for assessment of outcome and long-term counselling of child and parents. Received: 10 November 1997 Accepted: 20 January 1998     

Insertion/deletion polymorphism in the promoter of <Emphasis Type="Italic">NFKB1</Emphasis> influences severity but not mortality of acute respiratory distress syndrome

Objective This study investigated whether the insertion/deletion polymorphism in the promoter of NFKB1 is associated with severity and/or mortality in ARDS. Design and setting Prospective study in a mixed anesthesiological ICU of the University Hospital Essen. Patients and participants 103 adult patients with ARDS (white Germans). Measurements and results Patients with ARDS were genotyped for the insertion/deletion polymorphism in the promoter of NFKB1 (−94ins/delATTG). In ARDS patients genotypes differed significantly between those with severe ARDS [Lung Injury Score (LIS) ≥ 3; 23 homozygote deletion (DD), heterozygote (ID) 31, and homozygote insertion wildtype (II) 23], and those with LIS below 3 (1 DD, 9 ID, 16 II). Likewise, the frequency of the D allele was significantly less in patients with higher LIS (50% D) than lower LIS (21% D). Using these values produces a significantly higher OR of 16.0 (95% CI 1.96–130.9) for DD than for II, while the OR for ID vs. II was 2.4 (95% CI 0.9–6.4). Genotypes of the NFKB1 promoter polymorphism were associated neither with 30-day survival nor with duration of ICU stay. Conclusions The insertion/deletion polymorphism in the promoter of NFKB1 influences the severity but not the mortality of ARDS.     

The epidemiology of acute respiratory distress syndrome in pediatric intensive care units in China

Objective  To assess the incidence of, predisposing factors for, and the rates and relative risks of mortality from acute respiratory distress syndrome (ARDS) in pediatric patients. Design  A prospective study in 12 consecutive months from 2004 to 2005 in 25 pediatric intensive care units (PICUs). Patients and setting  ARDS was diagnosed according to the 1994 American–European Consensus Conference definitions, applied to all severely ill admissions between 1 month and 14 years of age. The PICUs were in major municipalities and provincial cities, and half were university affiliated. Measurements and results  From a total of 12,018 admissions, 7,269 were severely ill. One hundred and five (1.44%) patients developed ARDS and 64 (61.0%) died, which accounts for 13.2%, of the total ICU death (n = 485, 6.7%) or a nine times relative risk of dying. The median age at onset of ARDS was 24 months and 40% were less than 12 month old. Median time from PICU admission to the onset of ARDS was 16 h, and in 63% <24 h. Pneumonia (55.2%) and sepsis (22.9%) were the major predisposing factors for ARDS. These were respectively 14 and 5 times as high a death rate as those of the severely ill patients without ARDS. Conclusions  ARDS has a high mortality in these Chinese PICUs, especially in those with pneumonia and sepsis, and adequate management including lung protective ventilation strategy is required. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Association between vitamin D deficiency and mortality in critically ill adult patients: a meta-analysis of cohort studies

Introduction

Vitamin D deficiency is common in critically ill patients, and was reported to be associated with adverse outcomes. However, the effect of vitamin D deficiency on mortality in critically ill patients remains unclear.

Methods

We searched PubMed and EMBASE from the inception to July 2014 for cohort studies to assess the effect of vitamin D deficiency on the incidence of mortality in critically ill patients. Mortality-specific odds ratio (OR) with 95% confidence interval (CI) were pooled with a random- or fixed-effect models when appropriate.

Results

Seven cohort studies with a total of 4,204 participants including 1,679 cases of vitamin D deficiency were included in this meta-analysis. Vitamin D deficiency was significantly associated with an increased hospital mortality (OR 1.76; 95% CI, 1.38 to 2.24; P <0.001), with very low heterogeneity (I² = 2.3%; P = 0.402). The finding of increased hospital mortality in critically ill adult patients was consistently found in every stratum of our subgroup analyses.

Conclusions

This meta-analysis suggests that vitamin D deficiency is associated with increased incidence of hospital mortality in critically ill adult patients.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0684-9) contains supplementary material, which is available to authorized users.     

Hemodynamic response of restoring sinus rhythm in critically ill patients with atrial fibrillation

BackgroundElectrical cardioversion (ECV) is the recommended treatment for atrial fibrillation (AFib) in critically ill patients, despite lacking data showing hemodynamic benefits of restoring sinus rhythm in this setting. The aim of this study was to assess the hemodynamic effect of successful ECV in a cohort of hemodynamically unstable critically ill patients.Methods and resultsThis study included 66 successful ECV performed in hemodynamically unstable critically ill patients with new-onset AFib. The primary outcome was the requirement of norepinephrine and inotropes 6 h after successful ECV in relation to baseline. Baseline norepinephrine dose was 0.19 ± 0.02 μg/kg/min, and 67% of patients were treated with positive inotropic drugs. Six hours after ECV, 33 patients (50%) were considered hemodynamic non-responders. Overall, the mean norepinephrine dose at 6 h was 0.17 ± 0.02 μg/kg/min (P = 0.051 compared to baseline) and 61% of patients were on inotropes (P = 0.13 compared to baseline). During the 6-hour period after ECV the mean norepinephrine dose temporary increased to 0.20 ± 0.02 μg/kg/min (P = 0.033 compared to baseline).ConclusionsECV is associated with a large proportion of hemodynamic non-responders and a numerically modest, non-significant hemodynamic improvement in critically ill patients with new-onset AFib.     

小儿急性低氧性呼吸衰竭呼吸支持相关预后差异及影响因素

目的 探讨26家医院小儿重症监护室(PICU)患者呼吸支持相关的预后之差异及影响因素.方法 多中心前瞻性临床协作研究,研究时间为2005年12月至2006年11月连续12个月,研究对象为29 d至15周岁的PICU患儿.患儿纳入后记录其基本情况、疾病诊断、治疗及预后等数据,汇总后分析不同PICU其患者预后及呼吸治疗的差异.结果 在研究期间,26家PICU共收治危重病例11521例,占PICU收治患者总数的70%,不同单位该比例从14%到98%.26家单位共纳入小儿低氧性呼吸衰竭(AHRF)病例461例,患病率4%,各单位AHRF患病率中位值4.7%(Qr:2.4%～7.1%).AHRF总病死率41.6%,26家PICU病死率中位值39.8%(四分位数间距22%～57%).AHRF病死率在大学附属医院低于非大学附属医院(37%vs.46%,x~2=4.16,P:0.04),经济发达地区低于欠发达地区医院(38%vs.46%,x~2=3.1,P=0.08).结论 我国不同地区及不同类别医院PICU危重病例及AHRF呼吸支持相关的预后存在较大差异.PICU所在医院的学术背景及地区经济发展水平是影响患者预后的两个重要原因.在开展提高PICU的呼吸支持治疗水平和AHRF生存率的干预性研究设计中应予考虑.     

Noninvasive pressure-support ventilation in immunocompromised children with ARDS: a feasibility study

Objective  To verify the feasibility of non-invasive ventilation (NIV) in immunocompromised children affected by ARDS. Setting  University Hospital PICU. Patients  Twenty-three consecutive immunocompromised children treated with NIV for ARDS. Interventions  All consecutive patients received NIV through a face-mask or a helmet. Results  No differences were found regarding admission data and severity scores between NIV responders and non-responders. Early and sustained improvement in PaO₂/FiO₂ ratio were observed in 82 and 74% of cases, respectively. 13 out of 23 patients (54.5%) avoided intubation and were discharged from the PICU; ten patients required intubation: two of them survived and eight patients died (two refractory hypoxemia, three septic shock, three multi-organ failure). PICU and intra-hospital mortality was significantly higher for NIV-nonresponders (P < 0.001). PICU stay was significantly shorter for NIV responders (P = 0.03). NIV responders had significantly lower heart and respiratory rate at the end of treatment (P < 0.001 and P = 0.048, respectively). Conclusions  NIV administration is feasible and well tolerated in immunocompromised children with ARDS. A short NIV trial can be used to verify the usefulness of the technique. A randomized controlled trial is needed to confirm the efficacy of NIV in immunocompromised children requiring ventilatory support for ARDS. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Partial results from this study were presented at the 9th European Pediatric and Neonatal Ventilation Conference (EPNV 2008), held in Montreux (Switzerland), April 2008.     

Lung sonography and recruitment in patients with early acute respiratory distress syndrome: A pilot study

Introduction  

Bedside lung sonography is a useful imaging tool to assess lung aeration in critically ill patients. The purpose of this study was to evaluate the role of lung sonography in estimating the nonaerated area changes in the dependent lung regions during a positive end-expiratory pressure (PEEP) trial of patients with early acute respiratory distress syndrome (ARDS).     

The use of propofol for medium and long-term sedation in critically ill adult patients: a meta-analysis

Objective  To investigate the effects of using propofol for medium and long-term sedation on mortality and length of intensive care unit (ICU) stay of critically ill adult patients. Design  Randomised controlled studies comparing propofol with an alternative sedative agent in critically ill adult patients were included without language restriction from the Cochrane Controlled Trial Register (2007 issue 3), EMBASE, and MEDLINE databases (1966 to 1 December 2007). Two reviewers reviewed the quality of the studies and performed data extraction independently. Measurements and results  Sixteen randomised controlled studies with a total of 1,386 critically ill adult patients were considered. Nine of the pooled studies (56%) limited the doses of propofol infusion to <6 mg/kg h⁻¹. Mortality was not significantly different between patients sedated with propofol, or an alternative sedative agent (odds ratio [OR] 1.05, 95% confidence interval [CI] 0.80–1.38, P = 0.74; I ²  = 0%). Using propofol for medium and long-term sedation was associated with a significant reduction in length of ICU stay (overall weighted-mean-difference [WMD] in days −0.99, 95%CI −1.51 to −0.47, P = 0.0002; I ² = 82.26%) when compared to an alternative sedative agent; however, this benefit became insignificant (overall WMD in days −0.98, 95%CI −2.86 to 0.89, P = 0.30; I ² = 78.8%) when the comparison was limited to between propofol and midazolam. Conclusions  Using propofol for prolonged sedation in critically ill patients appears to be safe and may reduce duration of mechanical ventilation. It reduces the length of ICU stay when compared to long acting benzodiazepines, but not when compared to midazolam.     

A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis

Objective  A lack of published pharmacokinetic data on statins in sepsis has prompted concerns about their safety and toxicity. This study determined single dose pharmacokinetics of Atorvastatin administered orally to acutely ill patients. Design, setting and participants  A prospective open label study conducted in a tertiary referral centre on 5 healthy volunteers, 5 acutely ill patients admitted to the medical ward and a heterogeneous cohort of 25 critically ill patients admitted to an intensive care unit. Intervention  All participants received a single oral dose of 20 mg of atorvastatin. Measurement and results  Plasma pharmacokinetics of atorvastatin as measured by maximal plasma concentration (Cmax) and area under the curve (AUC) _0–24 h. Critically ill patients with sepsis had a significantly higher Cmax and AUC as compared to healthy volunteers [110.5(86.5) vs. 5.9(2.50) ng/ml, p < 0.01 and 1,051(810) vs. 67(48) ng h/ml (p < 0.0001)], respectively. Atorvastatin concentrations in the plasma of critically ill patients with sepsis remained supratherapeutic for up to 20 h after a single dose. The AUC was significantly higher for those patients on concomitant CYP 450 inhibitor therapy as compared to those patients not on inhibitors (1,518 ± 793 vs. 584 ± 540 ng h/ml, p = 0.0260). Conclusions  Very high plasma concentrations were achieved in intensive care patients with sepsis. This can only be partly explained by altered metabolism of atorvastatin. Further investigations are essential to better describe the pharmacokinetics of statins in various groups of critically ill patients. Caution should be exercised prior to adopting high dose regimens in patients with severe sepsis.     

A study of ACE and ADD1 polymorphism in ischemic and hemorrhagic stroke

BackgroundStroke is a common cerebrovascular accident. ACE and ADD1 gene are known to be associated with vascular complications leading to stroke susceptibility. The present study was carried out to evaluate the relative frequency of ACE and ADD1 common polymorphisms in ischemic stroke and intracerebral hemorrhage (ICH).MethodsA total of 386 CT or MRI proven stroke patients were included; 193 each had ischemic stroke and ICH. The locations and type of stroke were noted. ACE- I/D (rs4646994) and ADD1 (rs4961) gene polymorphisms were analyzed by polymerase chain reaction (PCR). The genotype and allele frequencies of ACE and ADD1 polymorphisms were compared between patients and controls as well as between ischemic stroke and ICH.ResultsACE (DD) genotype was significantly higher in ischemic stroke (37.8%) and ICH (33.7%) compared to controls (11.7%). D allele was also more frequent in ischemic stroke (57.3%) and ICH (56.7%) compared to controls (38.3%). ADD1 (WW) genotype and W allele frequencies were not significantly different in ischemic stroke, ICH and controls. In contrast, we found a synergistic role of ACE (DD)*ADD1(GW) interaction showing a positive association in both ischemic and hemorrhagic strokes.ConclusionOur study suggests that ACE (DD) genotype and D allele significantly increase the susceptibility to ischemic and hemorrhagic strokes.     

Using midazolam to monitor changes in hepatic drug metabolism in critically ill patients

Objective  Critical illness and associated sequelae can cause severe metabolic disturbances. The effects these have on hepatic drug metabolism are poorly understood. In vivo, enzyme specific drug probes are used to measure changes in hepatic drug metabolism but they require multiple blood sampling and are time consuming. We suggest that a single measurement, 4 h after intravenous administration of midazolam is a reliable indicator of integral plasma midazolam exposure or area under the curve (AUC) in critically ill patients. We also explore the hypothesis that acute kidney injury (AKI) directly impairs hepatic metabolism of drugs in critically ill patients. Methods  A prospective study in 20 critically ill patients who were not taking specific enzyme inhibitors or inducers or benzodiazepines. Correlation between 4 h midazolam concentration and AUC was calculated. We also assessed the difference in metabolism between the patients with normal renal function and those with AKI. Results  Four hour midazolam concentration correlated with AUC r = 0.956 (p < 0.0001). In addition, the 4 h midazolam concentration was greater in critically ill patients with AKI than those with normal renal function p = 0.023. Conclusion  A single-time-point determination of plasma midazolam concentration is a reliable predictor of integral plasma midazolam exposure in critically ill patients. This tool can now be used to assess the effects of critical illness on hepatic drug metabolism. Using this method, we suggest that AKI reduces the hepatic metabolism of midazolam in critically ill patients.