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Recombinant human activated protein C ameliorates oleic acid-induced lung injury in awake sheep
IntroductionAcute lung injury (ALI) may arise both after sepsis and non-septic inflammatory conditions and is often associated with release of fatty acids, including oleic acid (OA). Infusion of OA has been extensively used to mimic ALI. Recent research has revealed that intravenously administered recombinant human activated protein C (rhAPC) is able to counteract ALI. Our aim was to find out whether rhAPC dampens oleic acid-induced ALI in sheep.
Methods:
Twenty-two yearling sheep underwent instrumentation. After two days of recovery, animals were randomized to three groups: 1) an OA+rhAPC group (n=8) receiving oleic acid 0.06 ml/kg infused over 30 min in parallel with an intravenous infusion of rhAPC 24 mg/kg per hour over 2 hours; 2) an OA group (n = 8) receiving oleic acid as above; 3) a sham-operated group (n = 6). After 2 hours, sheep were sacrificed. Hemodynamics was assessed by catheters in the pulmonary artery and the aorta, and extravascular lung water index (EVLWI) was determined with the single transpulmonary thermodilution technique. Gas exchange was evaluated at baseline and at cessation of the experiment. Data were analyzed by ANOVA; p< 0.05 was regarded statistically significant.
Results:
OA induced profound hypoxemia, increased right atrial - and pulmonary artery pressures and EVLWI markedly, and decreased cardiac index. rhAPC counteracted the OA-induced changes in EVLWI and arterial oxygenation, and reduced the OA-induced increments in right atrial and pulmonary artery pressures.
Conclusions:
In ovine OA-induced lung injury, rhAPC dampens the increase in pulmonary artery pressure and counteracts the evolvement of lung edema and the derangement of arterial oxygenation.
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End-expiratory lung volume during mechanical ventilation: a comparison to reference values and the effect of PEEP in ICU patients with different lung conditions
IntroductionFunctional residual capacity (FRC) reference values are obtained from spontaneous breathing patients, measured in the sitting or standing position. During mechanical ventilation, FRC is determined by the level of PEEP and therefore it is better to speak of end-expiratory lung volume. Application of higher levels of PEEP leads to increased end-expiratory lung volume values as a result of recruitment or further distention of already ventilated alveoli. The aim of this study was to measure end-expiratory lung volume in mechanically ventilated ICU patients with different types of lung pathology at different PEEP levels and compare them to predicted sitting FRC values, arterial oxygenation and compliance values.
Methods:
End-expiratory lung volume measurements were performed at three stepwise reductions in PEEP levels (15-10-5 cm H2O) in 45 mechanically ventilated patients divided into three groups related to pulmonary condition: normal lungs (group N), primary lung disorder (group P), or secondary lung disorder (group S).
Results:
In all three groups end-expiratory lung volume, decreased significantly (p<0.001) while decreasing PEEP from 15 to 5 cm H2O, whereas the PaO2/FiO2 ratio did not change. At 5 cm H2O of PEEP, end-expiratory lung volume was 31, 20, 17 ml/kg predicted body weight in groups N, P, and S, respectively. These measured values were only 66%, 42%, 34 % of the predicted sitting FRC. A correlation between the change in end-expiratory lung volume and change in dynamic compliance was found in group S (p<0.001, R2 0.52), whereas not in both other groups.
Conclusion:
End-expiratory lung volume measured at 5 cm H2O of PEEP was markedly lower compared to predicted sitting functional residual capacity values in all groups. Only in patients with secondary lung disorders, PEEP induced end-expiratory lung volume changes were the result of derecruitment. In combination with compliance, end-expiratory lung volume can provide additional information to optimize the ventilator settings.
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Correlation between the AKI classification and outcome
IntroductionThe Acute Kidney Injury Network proposed a new classification for acute kidney injury (AKI) distinguishing between 3 stages. We applied the criteria to a large intensive care unit (ICU) population and evaluated the impact of AKI in the context of other risk factors.
Methods:
Using the Riyadh Intensive Care Program database, we applied the AKI classification to 22,303 adult patients admitted to 22 ICUs in United Kingdom and Germany between 1989-1999, who stayed in the ICU for more than or equal to 24 hours and did not have end-stage dialysis dependent renal failure.
Results:
7,898 patients (35.4%) fulfilled the criteria for AKI (AKI I 19.1%, AKI II 3.8%, AKI III 12.5%). ICU mortality was 10.7% in patients without AKI, 20.1% in AKI I, 25.9% in AKI II and 49.6% in AKI III. Multivariate analysis confirmed that AKI stage III but not AKI I and AKI II were independently associated with ICU mortality [odds ratio (OR) 2.27). Other independent risk factors for ICU mortality were age (OR 1.03), sequential organ failure assessment (SOFA) score on admission to ICU (OR 1.11), pre-existing end-stage chronic health (OR 1.65), emergency surgery (OR 2.33), mechanical ventilation (OR 2.83), maximum number of failed organ systems (OR 2.80) and non-surgical admission (OR 3.57). Cardiac surgery, AKI I and renal replacement therapy were associated with a reduced risk of dying in ICU. AKI II was not an independent risk factor for ICU mortality. Without renal replacement therapy as a criterion, 21% of patients classified as AKI III would have been classified as AKI II or AKI I. Renal replacement therapy as a criterion for AKI III may inadvertently diminish the predictive power of the classification.
Conclusions:
The proposed AKI classification correlated with ICU outcome but only AKI III was an independent risk factor for ICU mortality. The use of renal replacement therapy as a criterion for AKI III may have a confounding effect on the predictive power of the classification system as a whole.
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Phenylephrine versus norepinephrine for initial hemodynamic support of patients with septic shock: a randomized, controlled trial
IntroductionPrevious findings suggest that a delayed administration of phenylephrine replacing norepinephrine in septic shock patients causes a more pronounced hepatosplanchnic vasoconstriction as compared with norepinephrine. Nevertheless, a direct comparison between the two study drugs has not yet been performed. The aim of the present study was, therefore, to investigate the effects of a first-line therapy with either phenylephrine or norepinephrine on systemic and regional hemodynamics in patients with septic shock.
Methods:
We performed a prospective, randomized, controlled trial in a multidisciplinary intensive care unit in a university hospital. We enrolled septic shock patients (n = 32) with a mean arterial pressure below 65 mmHg despite adequate volume resuscitation. Patients were randomly allocated to treatment with either norepinephrine or phenylephrine infusion (n = 16 each) titrated to achieve a mean arterial pressure between 65 and 75 mmHg. Data from right heart catheterization, thermo-dye dilution catheter, gastric tonometry, acid-base homeostasis as well as creatinine clearance and cardiac troponin were obtained at baseline and after 12 hours. Differences within and between groups were analyzed using a two-way ANOVA for repeated measurements with group and time as factors. Time-independent variables were compared with one-way ANOVA.
Results:
No differences were found in any of the investigated parameters.
Conclusions:
The present study suggests that there are no differences in terms of cardiopulmonary performance, global oxygen transport, and regional hemodynamics when phenylephrine was administered instead of norepinephrine in the initial hemodynamic support of septic shock.
TRIAL REGISTRATION: ClinicalTrial.gov NCT00639015
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Determinants and impact of multidrug antibiotic resistance in pathogens causing ventilator-associated-pneumonia
IntroductionIt is still debated whether multidrug antibiotic resistance (MDR) in pathogens causing ventilator-associated pneumonia (VAP) is an independent risk factor for adverse outcome. We aimed to identify the determinants of multidrug antibiotic resistance (MDR) versus non-MDR microbial etiology in VAP and assessed whether MDR versus non-MDR VAP was independently associated with increased 30 days mortality.
Methods:
We performed a retrospective analysis of a prospectively registered cohort of adult patients with microbiologically confirmed VAP, diagnosed at a university hospital intensive care unit during a three-year period. Determinants of MDR as compared to non-MDR microbial etiology and impact of MDR versus non-MDR etiology on mortality were investigated using multivariate logistic and competing risk regression analysis.
Results:
MDR pathogens were involved in 52 of 192 episodes of VAP (27%): methicillin-resistant Staphylococcus aureus in 12 (6%), extended-spectrum beta-lactamase producing Enterobacteriaceae in 28 (15%), MDR Pseudomonas aeruginosa and other non-fermenting pathogens in 12 (6%). Multivariable logistic regression identified the Charlson index of comorbidity (OR 1.38, 95% CI 1.08-1.75, p=0.01) and previous exposure to more than two different antibiotic classes (OR 5.11, 95% CI 1.38-18.89, p=0.01) as predictors of MDR etiology. 30 days mortality following VAP caused by MDR versus non-MDR was 37% and 20% (p=0.02) respectively. A multivariate competing risk regression analysis showed that renal replacement therapy prior to VAP (Standardized Hazard Ratio (SHR) 2.69, 95% CI 1.47-4.94, p=0.01), the Charlson index of comorbidity (SHR 1.21, 95% CI 1.03 -1.41, p=0.03) and septic shock upon ICU admission (SHR 1.86, 95% CI 1.03 - 3.35, p=0.03), but not MDR etiology of VAP, were independent predictors of mortality.
Conclusions:
The risk of MDR pathogens causing VAP was mainly determined by comorbidity and prior exposure to more than two antibiotics. The increased mortality of VAP caused by MDR as compared to non-MDR pathogens was explained by more severe comorbidity and organ failure prior to VAP.
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Prophylactic antibiotic treatment is superior to therapy on-demand in experimental necrotizing pancreatitis
IntroductionHigh morbidity and mortality rates in severe acute pancreatitis are mainly caused by bacterial superinfection of pancreatic necrosis and subsequent sepsis. The benefit of early prophylactic antibiotics remains controversial because clinical studies performed to date were statistically underpowered. Thus, the aim of this study was to evaluate on-demand versus prophylactic antibiotic treatment in a standardized experimental model.
Methods:
Treatment groups received meropenem either therapeutically 24 hours after induction of necrotizing pancreatitis, or prophylactically before development of pancreatic superinfection. At 24 and 72 hours, pancreatic injury was investigated by histology, and translocation by bacterial cultures of pancreatic tissue and mesenteric lymph nodes. Septic complications were evaluated by blood cultures and survival.
Results:
Without antibiotic treatment, pancreatic superinfection was observed in almost all cases after induction of necrotizing pancreatitis. The 72-hour-mortality rate was 42.9%, and bacterial infection of mesenteric lymph nodes and bacteremia was found in 87.5% of the surviving animals. Therapeutic administration of meropenem on-demand reduced bacteremia to 50% and mortality to 27.3%. However, prophylactic antibiotic treatment significantly reduced bacteremia to 25.0% (p = 0.04), and pancreatic superinfection as well as mortality to 0% (p <0.001 and p = 0.05, respectively) compared to controls.
Conclusions:
In the present study both prophylactic and delayed antibiotic treatment on-demand reduced septic complications in a standardized setting of experimental necrotizing pancreatitis. However, pancreatic superinfection, bacteremia, and mortality rate were reduced significantly by early treatment. Thus, in the absence of statistically relevant and well-designed clinical trials, the study demonstrates that prophylactic antibiotic treatment is superior to antibiotic treatment on-demand.
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Duration of salmeterol-induced bronchodilation in mechanically ventilated COPD patients: a prospective clinical study
IntroductionDelivery of bronchodilators with a metered-dose inhaler (MDI) and a spacer device in mechanically ventilated patients has become a widespread practice. However, except for the short-acting beta2-agonist salbutamol, the duration of action of other bronchodilators, including long-acting beta2-agonists, delivered with this technique is not well established. The purpose of this study was to examine the duration of bronchodilation induced by the long-acting beta2-agonist salmeterol administered with a metered-dose inhaler and a spacer in a group of mechanically ventilated patients with exacerbation of chronic obstructive pulmonary disease (COPD).
Methods:
Ten mechanically ventilated patients with acute exacerbation of chronic obstructive pulmonary disease received four puffs of salmeterol (25 microgram/puff). Salmeterol was administered with a metered-dose inhaler adapted to the inspiratory limb of the ventilator circuit using an aerosol cloud enhance spacer. Static and dynamic airway pressures, minimum (Rint) and maximum (Rrs) inspiratory resistance and the difference between Rrs and Rint (DeltaR), were measured before and at 15, 30 and 60 minutes, as well as at 2, 3, 4, 6, 8, 10 and 12 hours after salmeterol. The overall effects of salmeterol on respiratory system mechanics and heart rate (HR) during the 12-hour study period were analyzed by nonparametric Wilcoxon signed rank test.
Results:
Salmeterol caused a significant decrease in dynamic and static airway pressures, Rint and Rrs. These changes were evident at 30 minutes and remained significant for 8 hours after salmeterol administration. The duration of bronchodilation varied significantly among patients, lasting in some patients more than 10 hours, while in others wearing off in less than 6 hours.
Conclusions:
It is concluded that four puffs of salmeterol delivered with a metered-dose inhaler and a spacer device induces significant bronchodilation in mechanically ventilated patients with COPD exacerbation, the duration of which is highly variable, precluding definite conclusions regarding optimum dosing schedules.
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Clinical review: Drug metabolism and nonrenal clearance in acute kidney injury
Decreased renal drug clearance is an obvious consequence of acute kidney injury (AKI). However, there is growing evidence to suggest that non-renal drug clearance is also affected. Data derived from human and animal studies suggest that hepatic drug metabolism and transporter function are components of non-renal clearance affected by AKI. AKI may also impair the clearance of formed metabolites. The fact that AKI does not solely impact kidney function may have important implications for drug dosing not only of renally eliminated drugs but those that are hepatically cleared as well.
A review of the literature addressing the topic of drug metabolism and clearance alterations in AKI reveals that the changes in non-renal clearance are highly complicated, poorly studied, yet possibly, quite common. At present, our understanding of how AKI affects drug metabolism and clearance is limited. However based on the evidence that is available, clinicians should be cognizant that even hepatically eliminated drugs and formed drug metabolites may accumulate during AKI, and renal replacement therapy may affect non-renal clearance as well as drug metabolite clearance.
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A systematic review on quality indicators for tight glycaemic control in critically ill patients - need for an unambiguous indicator reference subset
IntroductionTo systematically identify and summarize quality indicators of tight glycaemic control in critically ill patients, and inspect the applicability of their definitions.
Methods:
All studies evaluating a tight glycaemic protocol and/or quality of glucose control that reported original data from a clinical trial or observational study on critically ill adult patients were searched in MEDLINE(R).
Results:
49 studies met the inclusion criteria; 30 different indicators were extracted and categorized in 4 non-orthogonal categories: blood glucose zones (e.g., "hypoglycemia"); blood glucose levels (BGL) (e.g., "mean BGL"); time intervals (e.g., "time to the occurrence of an event"); and protocol characteristics (e.g., "BG sampling frequency"). Hypoglycemia-related indicators were used in 43/49 studies -acting as proxy for safety but had many different definitions. Blood glucose level summaries were used in 41/49 studies -reported as means and/or medians during the study period or at a certain time point (e.g., the morning blood glucose level or blood glucose level at starting insulin therapy). Time spent in the predefined blood glucose level range, time needed to reach the defined blood glucose level target, hyperglycemia-related indicators and protocol related indicators were other frequently used indicators. Most indicators differ in their definitions even when they are meant to measure the same underlying concept. More important, many definitions are not crisp, prohibiting their applicability and hence the reproducibility and comparability of research results.
Conclusions:
An unambiguous indicator reference subset is necessary. The result of this systematic review can be used as a starting point to develop a standard list of well-defined indicators, which are associated with clinical outcomes or concur with clinicians' subjective views on the quality of the regulatory process.
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A prospective trial of elective extubation in brain-injured patients meeting extubation criteria for ventilatory support: a feasibility study
IntroductionTo assess the safety and feasibility of recruiting and randomizing mechanically ventilated patients with brain injury who are solely intubated for airway protection into early or delayed extubation, and to obtain estimates to refine sample-size calculations for a larger study. The design is a single-blinded block randomized controlled trial. A single large academic medical center is the setting.
Methods:
Sixteen neurologically stable but severely brain injured patients with a Glasgow Coma Score (GCS) [less than or equal to] 8 were randomized to immediate or delayed extubation until their neurological exam had improved. Eligible patients met standard respiratory criteria for extubation and passed a modified Airway Care Score (ACS) to ensure adequate control of respiratory secretions. The primary outcome measured between groups was the functional status of the patient at hospital discharge as measured by a Modified Rankin Score (MRS) and Functional Independence Measure (FIM). Secondary measurements included the number of nosocomial pneumonias and re-intubations, and ICU and hospital length of stay. Standard statistical assessments were employed for analysis.
Results:
Five female and eleven male patients ranging in age between 30 to 93 years were enrolled. Responsible etiologies for neurological injury included 6 head traumas, 3 brain tumors, 2 intracerebral hemorrhages, 2 subarachnoid hemorrhages, and 3 ischemic strokes. There were no demographic differences between the groups. There were no unexpected deaths and no significant differences in secondary measures. The difference in means between the MRS and FIM were small (0.25 and 5.62, respectively). These results suggest that between 64 and 110 patients are needed in each treatment arm to detect a treatment effect with 80% power.
Conclusions:
Recruitment and randomization of severely brain injured patients appears to be safe and feasible. A large multicenter trial will be needed to determine if stable, severely brain injured patients who meet respiratory and airway control criteria for extubation need to remain intubated.
Trial registration number - NCT00729261
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