Repeated rotation of empiric antibiotic treatment strategies is hypothesized to reduce antibiotic resistance. Clinical rotation studies failed to change unit-wide prevalence of antibiotic resistant ...bacteria (ARB) carriage, including an international cluster-randomized crossover study. Unit-wide effects may differ from individual effects due to "ecological fallacy". This post-hoc analysis of a cluster-randomized crossover study assesses differences between cycling and mixing rotation strategies in acquisition of carriage with Gram-negative ARB in individual patients.
This was a controlled cluster-randomized crossover study in 7 ICUs in 5 European countries. Clinical cultures taken as routine care were used for endpoint assessment. Patients with a first negative culture and at least one culture collected in total were included. Community acquisitions (2 days of admission or less) were excluded. Primary outcome was ICU-acquisition of Enterobacterales species with reduced susceptibility to: third- or fourth generation cephalosporins or piperacillin-tazobactam, and Acinetobacter species and Pseudomonas aeruginosa with reduced susceptibility for piperacillin-tazobactam or carbapenems. Cycling (altering first-line empiric therapy for Gram-negative bacteria, every other 6-weeks), to mixing (changing antibiotic type every empiric antibiotic course). Rotated antibiotics were third- or fourth generation cephalosporins, piperacillin-tazobactam and carbapenems.
For this analysis 1,613 admissions were eligible (855 and 758 during cycling and mixing, respectively), with 16,437 microbiological cultures obtained. Incidences of acquisition with ARB during ICU-stay were 7.3% (n = 62) and 5.1% (n = 39) during cycling and mixing, respectively (p-value 0.13), after a mean of 17.7 (median 15) and 20.8 (median 13) days. Adjusted odds ratio for acquisition of ARB carriage during mixing was 0.62 (95% CI 0.38 to 1.00). Acquired carriage with ARB were Enterobacterales species (n = 61), Pseudomonas aeruginosa (n = 38) and Acinetobacter species (n = 20), with no statistically significant differences between interventions.
There was no statistically significant difference in individual patients' risk of acquiring carriage with Gram-negative ARB during cycling and mixing. These findings substantiate the absence of difference between cycling and mixing on the epidemiology of Gram-negative ARB in ICU.
This trial is registered with ClinicalTrials.gov, registered 10 January 2011, NCT01293071.
Hypoxic pulmonary vasoconstriction (HPV) regulates regional pulmonary blood flow in order to match regional ventilation to preserve arterial oxygenation. HPV is impaired in patients with sepsis or ...acute respiratory distress syndrome (ARDS). Endotoxemic mice show reduced HPV and recent evidence suggests a central role of voltage gated potassium channel 7 (Kv7) in regulating HPV. Therefore, we tested the hypothesis if Kv7 is induced and inhibition of Kv7 increases HPV in endotoxemia.
Isolated lungs of LPS-pretreated and untreated animals were perfused with and without specific inhibitors of Kv7 (linopirdine (LI) 0, 0.1, 1 and 10 µM) or Kv7.1 (HMR1556 100 nM). Pulmonary artery pressure (PAP) during normoxic (FiO
2
0.21) as well as hypoxic (FiO
2
0.01) ventilation were obtained. Expressions of Kv7 composing (KCNQ1-5) as well as auxiliary subunits (KCNE1-5) were measured in mouse lungs with and without endotoxemia.
HPV was impaired in lungs from LPS mice (16 ± 7% vs 105 ± 13% control, p < 0.05). Perfusion of control lungs with 10 µM LI or 100 nM HMR1556 did not affect HPV (LI 105 ± 12% vs 105 ± 13% vehicle, HMR1556 100 ± 6% vs 98 ± 26%, P = NS). In LPS mice perfusion with 10 µM LI (74.2 ± 7% vs. 16 ± 7% vehicle, P < 0.05) or HMR1556 100 nM augmented HPV (74 ± 28% vs. 15 ± 17% vehicle, P < 0.05). KCNQ1, 4 and 5 gene- and protein expressions as well as KCNE1, 2 and 4 gene expressions were unaltered in endotoxemic lungs. KCNE3 gene and protein expressions were increased in lungs of LPS treated mice (3.1 ± 1.3-fold and 1.8 ± 0.3-fold, respectively, P < 0.05 for both).
Endotoxemia does not alter KCNQ1, 4 and 5 gene and protein expressions but increases pulmonary KCNE3 gene and protein expression. In isolated perfused endotoxemic mouse lungs, perfusion with 10 µM LI or 100 nM HMR1556 augments HPV.
Background
Outcome data on fluid therapy in critically ill patients from randomised controlled trials may be different from data obtained by observational studies under “real-life” conditions. We ...conducted this prospective, observational study to investigate current practice of fluid therapy (crystalloids and colloids) and associated outcomes in 65 German intensive care units (ICUs). In total, 4545 adult patients who underwent intravenous fluid therapy were included. The main outcome measures were 90-day mortality, ICU mortality and acute kidney injury (AKI). Data were analysed using logistic and Cox regression models, as appropriate.
Results
In the predominantly post-operative overall cohort, unadjusted 90-day mortality was 20.1%. Patients who
also
received colloids (54.6%) had a higher median Simplified Acute Physiology Score II 25 (interquartile range 11; 41) vs. 17 (7; 31) and incidence of severe sepsis (10.2 vs. 7.4%) on admission compared to patients who received
exclusively
crystalloids (45.4%). 6% hydroxyethyl starch (HES 130/0.4) was the most common colloid (57.0%). Crude rates of 90-day mortality were higher for patients who received colloids (OR 1.845 1.560; 2.181). After adjustment for baseline variables, the HR was 1.666 1.405; 1.976 and further decreased to indicate no associated risk (HR 1.003 0.980; 1.027) when it was adjusted for vasopressor use, severity of disease and transfusions. Similarly, the crude risk of AKI was higher in the colloid group (crude OR 3.056 2.528; 3.694), after adjustment for baseline variables OR 1.941 1.573; 2.397, and after full adjustment OR 0.696 0.629; 0.770), the risk of AKI turned out to be reduced. The same was true for the subgroup of patients treated with 6% HES 130/0.4 (crude OR 1.931 1.541; 2.419, adjusted for baseline variables OR 2.260 1.730; 2.953 and fully adjusted OR 0.800 0.704; 0.910) as compared to crystalloids only.
Conclusions
The present analysis of mostly post-operative patients in routine clinical care did not reveal an independent negative effect of colloids (mostly 6% HES 130/0.4) on renal function or survival after multivariable adjustment. Signals towards a reduced risk in subgroup analyses deserve further study.
Trial registration
ClinicalTrials.gov Identifier: NCT01122277, registered May 11th, 2010
Whether antibiotic rotation strategies reduce prevalence of antibiotic-resistant, Gram-negative bacteria in intensive care units (ICUs) has not been accurately established. We aimed to assess whether ...cycling of antibiotics compared with a mixing strategy (changing antibiotic to an alternative class for each consecutive patient) would reduce the prevalence of antibiotic-resistant, Gram-negative bacteria in European intensive care units (ICUs).
In a cluster-randomised crossover study, we randomly assigned ICUs to use one of three antibiotic groups (third-generation or fourth-generation cephalosporins, piperacillin–tazobactam, and carbapenems) as preferred empirical treatment during 6-week periods (cycling) or to change preference after every consecutively treated patient (mixing). Computer-based randomisation of intervention and rotated antibiotic sequence was done centrally. Cycling or mixing was applied for 9 months; then, following a washout period, the alternative strategy was implemented. We defined antibiotic-resistant, Gram-negative bacteria as Enterobacteriaceae with extended-spectrum β-lactamase production or piperacillin–tazobactam resistance, and Acinetobacter spp and Pseudomonas aeruginosa with piperacillin–tazobactam or carbapenem resistance. Data were collected for all admissions during the study. The primary endpoint was average, unit-wide, monthly point prevalence of antibiotic-resistant, Gram-negative bacteria in respiratory and perineal swabs with adjustment for potential confounders. This trial is registered with ClinicalTrials.gov, number NCT01293071.
Eight ICUs (from Belgium, France, Germany, Portugal, and Slovenia) were randomly assigned and patients enrolled from June 27, 2011, to Feb 16, 2014. 4069 patients were admitted during the cycling periods in total and 4707 were admitted during the mixing periods. Of these, 745 patients during cycling and 853 patients during mixing were present during the monthly point-prevalence surveys, and were included in the main analysis. Mean prevalence of the composite primary endpoint was 23% (168/745) during cycling and 22% (184/853) during mixing (p=0·64), yielding an adjusted incidence rate ratio during mixing of 1·039 (95% CI 0·837–1·291; p=0·73). There was no difference in all-cause in-ICU mortality between intervention periods.
Antibiotic cycling does not reduce the prevalence of carriage of antibiotic-resistant, Gram-negative bacteria in patients admitted to the ICU.
European Union Seventh Framework Programme.
To the Editor:
Gueugniaud et al. (July 3 issue)
1
report that administering the combination of vasopressin and epinephrine, as compared with epinephrine alone, during advanced cardiac life support ...for out-of-hospital cardiac arrest does not improve outcome. The results of this study, however, are not surprising, considering that the average time from collapse to the arrival of advanced cardiac life support (downtime) was 16.3 minutes in each group and that only 9% of the patients in each group had ventricular fibrillation and thus a greater chance of survival than the patients with pulseless electrical activity or asystole. Studies have shown that . . .
Summary Background Global cerebral ischaemia after cardiac arrest (CA) leads to programmed cell death (PCD) with characteristic signs of apoptosis in selectively vulnerable areas of the brain. The ...activation of caspase-3, an executioner caspase, plays a key role in the apoptotic cascade. We, therefore, studied the effects of the application of the specific caspase-3 inhibitor zDEVD-FMK on neurological outcome and neuronal cell death after experimental CA in rats. Methods A 6-min CA was induced in anaesthetised and mechanically ventilated male Wistar rats. After cardiopulmonary resuscitation (CPR) and restoration of spontaneous circulation (ROSC) the animals were randomised to two groups to receive a continuous intracerebroventricular (i.c.v.) infusion for 7 days of zDEVD-FMK or placebo (artificial cerebrospinal fluid, CSF). At 24 h, 3 and 7 days after ROSC, animals were tested according to a neurological deficit score (NDS). Seven days after ROSC, coronal sections of the brain were taken at the dorsal hippocampal level and analysed with cresyl-violet staining, the TUNEL technique and a caspase activity assay. Viable and TUNEL-positive neurons were counted in the hippocampal CA-1 sector. Results The NDS demonstrated severe deficits 1 and 3 days after ROSC, which resolved by 7 days with no difference between the two groups. At 7 days after ROSC neuronal death could be detected using cresyl-violet and TUNEL staining with no difference between the groups. Conclusion We conclude that zDEVD-FMK administration has no effect on neurological outcome and PCD after global cerebral ischaemia following CA in rats. Other mechanisms or pathways must be identified in the pathophysiology of PCD after CA.
BACKGROUND AND OBJECTIVEDuring sepsis and endotoxaemia, hypoxic pulmonary vasoconstriction (HPV) is impaired. Sedation of septic patients in ICUs is performed with various anaesthetics, most of which ...have pulmonary dilatory properties. Ketamine is a sympathetic nervous system-activating anaesthetic that preserves cardiovascular stability. The effects of ketamine on the pulmonary vasculature and HPV during sepsis have not been characterized yet.
METHODSTherefore, isolated lungs of mice were perfused with ketamine (0, 0.1, 1.0, and 10 mg kg body weight min) 18 h following intraperitoneal injection of lipopolysaccharide (LPS); untreated mouse groups served as controls (n = 7 per group, respectively). Pulmonary artery pressure (PAP) and pressure–flow curves during normoxic (FiO2 = 0.21) and hypoxic (FiO2 = 0.01) ventilation were obtained.
RESULTSHPV was reduced in endotoxaemic animals when compared with controls (means ± SD; ΔPAP control 103 ± 28% vs. LPS 23 ± 25%, P < 0.05). Ketamine caused a dose-dependent reduction of HPV in the lungs of control (ΔPAP 0 mg kg min ketamine 103 ± 28% vs. 10 mg kg min ketamine 28 ± 21%, P < 0.05) and septic animals (ΔPAP 0 mg kg min ketamine 23 ± 25% vs. 10 mg kg min ketamine 0 ± 4%, P < 0.05). Analysis of pressure–flow curves revealed that ketamine partly reversed the endotoxin-induced changes in basal pulmonary vascular wall properties rather than interfering with the HPV response itself.
CONCLUSIONKetamine modified baseline pulmonary vascular properties, resulting in a reduced HPV responsiveness in untreated mice. Further, ketamine counteracted the LPS-induced changes in pulmonary vascular pressure–flow relationships, but did not affect impaired HPV in this murine endotoxaemia model.
In acute lung injury (ALI) pulmonary hyporesponsiveness to inhaled nitric oxide (iNO) still represents an unresolved clinical challenge. In septic ALI-patients the incidence of hyporesponsiveness to ...iNO is increased; therefore, endotoxemia appears to play a major role. Experimental data suggest that endotoxemia, e.g., induced by lipopolysaccharides (LPS), contribute to the hyporesponsiveness to iNO. Guanosine 3′,5′-cyclic monophosphate (cGMP) is metabolized by phosphodiesterases (PDE). The role of PDE in reduced pulmonary vascular response in experimental endotoxemia is still not known. Here, we hypothesized that PDE activity modulates initial pulmonary responsiveness to iNO in ALI following systemic endotoxin exposure. Rats were treated with LPS or used as controls. Lungs were isolated-perfused 0–36 h after LPS injection and the synthetic thromboxane analogue U46619 was added to increase pulmonary artery pressure by 6–8 mmHg ( n = 47). Then, the pulmonary vasodilatory response to 3 doses of iNO (0.4, 4 and 40 ppm) was measured. Furthermore, lungs were prepared as described previously, and 2, 10, and 18 h after LPS the change in pulmonary artery pressure in response to two different inhibitors of PDE, one of which is PDE sensitive (8-Br-cGMP) and one is PDE stable (8-pCPT-cGMP), was determined ( n = 43). Serum nitrite/nitrate levels started to increase 4 h after LPS, with a maximum at 18 h. In contrast, decreased pulmonary vasoreactivity in response to iNO developed as early as 2 h later and remained depressed up to 18 h. The pulmonary vasoreactivity to the PDE-sensitive 8-Br-cGMP after LPS-stimulation was lower than that in lungs treated with the PDE-stable 8-pCPT-cGMP. In rats pretreated with LPS, hyporesponsiveness of pulmonary vessels to iNO is time-limited and associated with increased serum nitrite/nitrate levels, and appears to be attributed in part to increased pulmonary PDE activity.
Massive postoperative pulmonary embolism (PE) is associated with a poor prognosis in patients presenting with haemodynamic instability. Since recent surgery is a commonly accepted contraindication ...for thrombolytic therapy, pulmonary embolectomy is an appropriate therapeutic approach in these patients. If life-threatening symptoms of PE persist after pulmonary embolectomy, however, very few other therapeutic options are available. We report the successful use of locally administered low-dose thrombolysis 2 days after pulmonary embolectomy in a patient with postoperative PE and persistent severe hypoxaemia and pulmonary hypertension. During and after thrombolysis, no bleeding complications occurred. We conclude that low-dose thrombolysis for PE may be considered even in patients who have recently undergone major thoracic and abdominal surgery if embolectomy and continued intravenous heparin have failed to be successful and life-threatening symptoms of PE persist.
A embolia pulmonar massiva pós-operatória (PE), com instabilidade hemodinâmica na apresentação, está associada a mau prognóstico. Quando a cirurgia recente é uma contra-indicação para a terapêutica trombólitica, a embolectomia pulmonar é uma abordagem terapêutica apropriada nestes doentes. Contudo se os sintomas ameaçadores para a vida persistirem após embolectomia pulmonar não existem muitas outras opções terapêuticas. Descrevemos o uso com sucesso da trombólise de baixa dose administrada localmente 2 dias após a embolectomia pulmonar num doente com PE pós-operatória e com hipoxemia grave e hipertensão pulmonar persistente. Não ocorreu qualquer complicação hemorrágica quer durante quer após a trombólise. Concluı́mos que a trombólise em baixa dose deve ser considerada, para a PE, mesmo em doentes que foram recentemente submetidos a cirurgia torácica ou abdominal major se a embolectomia e a heparina endovenosa contı́nuas não tiverem sucesso e persiste manifestações a traduzir o risco de vida.
El embolismo pulmonar masivo postoperatorio (PE) está asociado con mal pronóstico en pacientes que se presentan con inestabilidad hemodinámica. Dado que una cirugı́a reciente es una contraindicación comúnmente aceptada para la terapia trombolı́tica, la embolectomı́a pulmonar es una aproximación terapéutica apropiada en estos pacientes. Si los sı́ntomas que amenazan la vida de PE persisten después de la embolectomı́a pulmonar, sin embargo, hay muy pocas otras opciones terapéuticas disponibles. Reportamos el uso exitoso de una trombolisis de baja dosis realizada 2 dı́as después de la embolectomı́a pulmonar en un paciente con PE postoperatoria con hipoxemia e hipertensión pulmonar severas persistentes. Durante y después de la trombolisis, no ocurrieron complicaciones hemorrágicas. Concluimos que la trombolisis con dosis bajas puede ser considerada para el PE incluso en pacientes que hayan sido sometidos recientemente a cirugı́a mayor torácica y abdominal si han fallado la embolectomı́a y la heparina intravenosa continua y persisten los sı́ntomas de PE que amenazan la vida.
This study evaluated the time course of caspase activation in
selectively vulnerable brain areas (hippocampus, nucleus reticularis thalami (NRT), cortex and striatum) following cardiopulmonary ...resuscitation (CPR) after
global cerebral ischemia due to cardiac arrest (CA) in rats. Caspases are well known to play a crucial role in the apoptotic cascade and inflammatory syndromes and, therefore, represent potential therapeutic postischemic targets. Given the delayed neurodegeneration following CA, it is highly important to study the time course of caspase activation in regard to therapeutic interventions after CA. To assess caspase activity,
in situ staining was applied to detect general caspase activity at 6
h, 3
d and 7
d and caspase-3 activity at 3
d after return of spontaneous circulation (ROSC). For detection of neuronal apoptosis, TUNEL staining was applied at 7
d after ROSC. Distinct patterns of early caspase activation were observed at 6
h and 3
d in the NRT and striatum and of late activation at 7
d in the hippocampal CA-1 sector. General caspase and caspase-3 activity correlated strongly at 3
d after ROSC in all areas studied. At 7
d, the TUNEL-positive neuron counts in the hippocampal CA-1 sector correlated strongly with caspase activation. In conclusion, general caspase and caspase-3 activity after 6
min of CA and the delayed occurence of TUNEL-positive neurons strongly indicate that neuronal degeneration after CA is at least strongly associated with apoptosis. Therefore, postischemic antiapoptotic interventions might offer potential future therapeutic opportunities
global cerebral ischemia due to CA.
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