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1.
PLoS One ; 17(5): e0265720, 2022.
Article in English | MEDLINE | ID: mdl-35503768

ABSTRACT

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, registered 10 January 2011, NCT01293071.


Subject(s)
Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Carbapenems/pharmacology , Cephalosporins/pharmacology , Cross-Over Studies , Gram-Negative Bacteria , Humans , Intensive Care Units , Piperacillin/pharmacology , Prospective Studies , Pseudomonas aeruginosa , Tazobactam/pharmacology
2.
Exp Lung Res ; 46(10): 363-375, 2020 12.
Article in English | MEDLINE | ID: mdl-32945215

ABSTRACT

PURPOSE: 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. MATERIALS AND METHODS: 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 (FiO2 0.21) as well as hypoxic (FiO2 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. RESULTS: 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). CONCLUSIONS: 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.


Subject(s)
Endotoxemia , Potassium Channels, Voltage-Gated , Animals , Humans , Hypoxia , Lipopolysaccharides/pharmacology , Lung , Mice , Pulmonary Artery , Pulmonary Circulation , Vasoconstriction
3.
Ann Intensive Care ; 8(1): 27, 2018 Feb 17.
Article in English | MEDLINE | ID: mdl-29455308

ABSTRACT

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.

4.
Lancet Infect Dis ; 18(4): 401-409, 2018 04.
Article in English | MEDLINE | ID: mdl-29396000

ABSTRACT

BACKGROUND: 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). METHODS: 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 ß-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. FINDINGS: 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. INTERPRETATION: Antibiotic cycling does not reduce the prevalence of carriage of antibiotic-resistant, Gram-negative bacteria in patients admitted to the ICU. FUNDING: European Union Seventh Framework Programme.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Carrier State/microbiology , Drug Resistance, Bacterial , Drug Therapy/methods , Gram-Negative Bacteria/drug effects , Gram-Negative Bacterial Infections/drug therapy , Intensive Care Units , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/pharmacology , Carrier State/epidemiology , Cross-Over Studies , Europe/epidemiology , Female , Gram-Negative Bacteria/isolation & purification , Gram-Negative Bacterial Infections/epidemiology , Gram-Negative Bacterial Infections/microbiology , Humans , Male , Middle Aged , Prevalence
5.
Article in German | MEDLINE | ID: mdl-21560102

ABSTRACT

At present, besides well-known financial problems, German hospitals are facing a serious lack of qualified medical staff. Given these facts, it is of great importance, especially in work load burdened disciplines, such as cardiovascular anaesthesiology, to retain highly qualified medical staff. Here, human resource development measures offer valuable tools for efficient retention management. Moreover, most of these are applicable to almost any clinical specialty. Surprisingly, financial aspects play a minor role in such concepts, in contrast to human resource development tools, such as mentoring, interviews, training and motivational activities. Especially, with regard to "Generation Y", an efficient retention management will play a key role to keep these physicians as hospital employees of long duration in the future.


Subject(s)
Anesthesiology , Cardiology , Health Workforce/organization & administration , Personnel Staffing and Scheduling/organization & administration , Germany
6.
Article in German | MEDLINE | ID: mdl-21243555

ABSTRACT

Recently, human resource development concepts have become more important in intensive care medicine. Motivationally oriented leadership is an essential part of this strategy. Of particular significance, leadership first of all means not to demotivate the personnel. Furthermore, a motivationally oriented leadership concept creates a framework in which the physicians' own motivation may thrive. Intensive care supervisory staff today should be familiar with mechanisms and potential of established motivational concepts and should be able to transfer them consequently into clinical practice.


Subject(s)
Critical Care/organization & administration , Health Workforce/organization & administration , Leadership , Medical Staff/organization & administration , Staff Development/organization & administration , Humans
7.
Eur J Anaesthesiol ; 27(1): 61-6, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19923994

ABSTRACT

BACKGROUND AND OBJECTIVE: During 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. METHODS: Therefore, isolated lungs of mice were perfused with ketamine (0, 0.1, 1.0, and 10 mg kg(-1) 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 (FiO(2) = 0.21) and hypoxic (FiO(2) = 0.01) ventilation were obtained. RESULTS: HPV was reduced in endotoxaemic animals when compared with controls (means +/- SD; DeltaPAP control 103 +/- 28% vs. LPS 23 +/- 25%, P < 0.05). Ketamine caused a dose-dependent reduction of HPV in the lungs of control (DeltaPAP 0 mg kg(-1) min(-1) ketamine 103 +/- 28% vs. 10 mg kg(-1) min(-1) ketamine 28 +/- 21%, P < 0.05) and septic animals (DeltaPAP 0 mg kg(-1) min(-1) ketamine 23 +/- 25% vs. 10 mg kg(-1) min(-1) 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. CONCLUSION: Ketamine 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.


Subject(s)
Anesthetics, Dissociative/therapeutic use , Endotoxemia/drug therapy , Hypoxia/pathology , Ketamine/therapeutic use , Pulmonary Artery/drug effects , Pulmonary Circulation/drug effects , Vasoconstriction/drug effects , Animals , Blood Pressure , Disease Models, Animal , Lipopolysaccharides/metabolism , Mice , Oxygen/metabolism , Time Factors
8.
Resuscitation ; 80(8): 940-5, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19487065

ABSTRACT

BACKGROUND: The clinical symptoms and pathophysiologic mechanisms during and after ischaemia-reperfusion following cardiac arrest (CA) and successful cardiopulmonary resuscitation (CPR) closely resemble those observed in patients with severe sepsis. Impairment of microcirculation and endothelial leakage seem to play key roles in the underlying pathophysiology. Recombinant human activated protein C (rhAPC) is the first drug being licensed for the treatment of severe sepsis in patients. Therefore, for the first time, we investigated effects of rhAPC on microhaemodynamic changes and endothelial leakage applying in vivo microscopy of postcapillary mesenteric venules after CA and CPR in rats. METHODS: After 6 min of CA, male Wistar rats were randomised into two groups (n=10) to receive rhAPC or placebo (0.9% NaCl). Sham-operated animals (n=10) served as non-ischaemic controls. At 360, 420, and 480 min after CA in vivo microscopy was performed to assess wall shear rate (WSR) and plasma extravasation (PE). RESULTS: Both treatment groups showed typical signs of impaired microcirculation and a severe endothelial leakage after CA at all time points studied when compared to the sham group. However, no significant differences between the treatment groups were observed with regard to WSR and PE. CONCLUSION: Our results show that CA with consecutive successful CPR leads to a microcirculatory impairment closely resembling experimentally induced sepsis. Intriguingly, despite these similarities, rhAPC had no significant effects on WSR and PE. Our results strongly suggest that further mechanisms such as mast cell activation might play an important role and have therefore to be studied to elucidate the pathophysiology of "postresuscitation disease".


Subject(s)
Heart Arrest/physiopathology , Mesentery/blood supply , Microcirculation/drug effects , Protein C/administration & dosage , Sepsis/drug therapy , Animals , Anti-Infective Agents/administration & dosage , Cardiopulmonary Resuscitation/methods , Disease Models, Animal , Dose-Response Relationship, Drug , Fibrinolytic Agents , Follow-Up Studies , Heart Arrest/drug therapy , Heart Arrest/etiology , Male , Microcirculation/physiology , Rats , Rats, Wistar , Recombinant Proteins/administration & dosage , Sepsis/complications , Sepsis/physiopathology , Treatment Outcome
9.
Resuscitation ; 80(4): 478-83, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19231060

ABSTRACT

SUBJECT: Recent data demonstrated potent neuroprotective effects of growth hormones such as granulocyte colony-stimulating factor (G-CSF) after focal cerebral ischaemia. In order to assess possible effects of intracerebroventricular application of G-CSF on cerebral recovery after cardiac arrest (CA) in rats, neurological testing and histological analyses were performed. INTERVENTIONS: After 6 min of electrically induced CA, rats were resuscitated (CPR) and divided into two groups (G-CSF vs. placebo) with two different reperfusion times (7 and 14 days). G-CSF (3.84 microg) or placebo was applied 30 min after restoration of spontaneous circulation (ROSC). At 24h, 3, 7, 10 and 14 days, behavioural neurological testing was done (tape removal test, TRT). Neuronal degeneration of the hippocampal CA-1 sector was analyzed by TUNEL- and Nissl-staining. RESULTS: Before CA all animals passed the TRT (G-CSF 7 [4-12] s, placebo 9 [6-10] s). After ROSC both groups showed a clear neurological deficit (24h: G-CSF and placebo 180 [180-180] s), that improved with ongoing reperfusion times, without reaching baseline values (14 days: G-CSF 25 [21-59] s, placebo 34 [14-175] s). Survival rates did not differ between the groups. All animals showed massive neurodegeneration histologically without any differences between the groups 7 days after CA (TUNEL-positive: G-CSF 63.2 [53.8-72.1], placebo 72.6 [66.6-82.7]; Nissl-positive: G-CSF 2.5 [1.8-3.4], placebo 2.8 [2.0-5.1]). At 14 days, TUNEL-staining revealed no differences (G-CSF 45.2 [35.0-60.0], placebo 56.0 [37.6-63.4]), while G-CSF treatment led to fewer Nissl-positive neurons (G-CSF 1.5 [1.2-2.2], placebo 3.1 [2.1-4.2]; p=0.011). CONCLUSIONS: Despite promising experimental data concerning focal cerebral ischaemia, in this model of 6 min of normothermic CA no beneficial effects of G-CSF application could be demonstrated by behavioural testing and histological analyses of the hippocampal CA-1 sector.


Subject(s)
Brain/pathology , Brain/physiopathology , Granulocyte Colony-Stimulating Factor/administration & dosage , Heart Arrest/therapy , Animals , Behavior, Animal , Cardiopulmonary Resuscitation , Catheterization , Filgrastim , Heart Arrest/pathology , Heart Arrest/physiopathology , Injections, Intraventricular , Male , Psychomotor Performance , Rats , Reaction Time/physiology , Recombinant Proteins , Recovery of Function
10.
Neurosci Lett ; 448(2): 194-9, 2008 Dec 26.
Article in English | MEDLINE | ID: mdl-18938215

ABSTRACT

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 6h, 3d and 7d and caspase-3 activity at 3d after return of spontaneous circulation (ROSC). For detection of neuronal apoptosis, TUNEL staining was applied at 7d after ROSC. Distinct patterns of early caspase activation were observed at 6h and 3d in the NRT and striatum and of late activation at 7d in the hippocampal CA-1 sector. General caspase and caspase-3 activity correlated strongly at 3d after ROSC in all areas studied. At 7d, 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 occurrence 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.


Subject(s)
Brain Ischemia/enzymology , Brain/enzymology , Caspases/metabolism , Heart Arrest/physiopathology , Animals , Apoptosis , Brain/pathology , Brain/physiopathology , Brain Ischemia/etiology , Brain Ischemia/pathology , Brain Ischemia/physiopathology , Cardiopulmonary Resuscitation , Caspase 3/metabolism , Cell Count , Cerebral Cortex/enzymology , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Corpus Striatum/enzymology , Corpus Striatum/pathology , Corpus Striatum/physiopathology , Enzyme Activation , Heart Arrest, Induced , Hippocampus/enzymology , Hippocampus/pathology , Hippocampus/physiopathology , In Situ Nick-End Labeling , Male , Nerve Degeneration , Neurons/pathology , Rats , Rats, Wistar , Regression Analysis
12.
Resuscitation ; 79(2): 316-24, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18621461

ABSTRACT

BACKGROUND: The response of the human body to cardiac arrest (CA) and cardiopulmonary resuscitation is characterised by excessive coagulation, inadequate endogenous anti-coagulation and fibrinolysis as well as an inflammatory syndrome that closely resembles the immunological profile observed in patients with sepsis. Recombinant human activated protein C (rhAPC) has been found to be protective in severe sepsis and in animal models of stroke and spinal cord injury. In the present study, we evaluated the effects of rhAPC on neurological outcome after CA in rats. METHODS: After 6 min of CA and subsequent cardiopulmonary resuscitation, male Wistar rats were randomized into 3 treatment groups: high dose rhAPC (2 mg/kg bolus and 0.1 mg/(kg h) for 6 h), low dose rhAPC (0.5 mg/kg and 0.025 mg/(kg h) for 6 h), and placebo (n=12 per treatment and reperfusion time). Neurological outcome was determined using a tape removal test and a composite neurological deficit score (NDS). As secondary measurements, we evaluated overall and neuronal survival, hippocampal caspase activity and inflammatory markers. RESULTS: No difference between groups was found with the NDS. The tape removal test showed only a transitory improvement in the low dose group at 3 d after CA (P=0.041). No significant differences were observed for secondary measurements. CONCLUSION: A clear and lasting effect of rhAPC on neurological outcome or inflammation after CA could not be shown in this study but the detailed analysis of the postresuscitation syndrome given here builds a firm basis for further research.


Subject(s)
Anti-Infective Agents/therapeutic use , Behavior, Animal/drug effects , Brain/pathology , Cardiopulmonary Resuscitation , Heart Arrest/therapy , Protein C/therapeutic use , Animals , Anti-Infective Agents/administration & dosage , Brain/enzymology , Caspases/metabolism , Dose-Response Relationship, Drug , Heart Arrest/enzymology , Heart Arrest/pathology , Male , Protein C/administration & dosage , Rats , Rats, Wistar , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use
13.
Resuscitation ; 78(1): 85-91, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18455860

ABSTRACT

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 24h, 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.


Subject(s)
Amino Acid Chloromethyl Ketones/pharmacology , Brain Ischemia/drug therapy , Brain Ischemia/etiology , Caspase Inhibitors , Heart Arrest/complications , Amino Acid Chloromethyl Ketones/administration & dosage , Animals , Cell Death/drug effects , In Situ Nick-End Labeling , Male , Random Allocation , Rats , Rats, Wistar , Statistics, Nonparametric
14.
Curr Opin Crit Care ; 14(3): 292-8, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18467889

ABSTRACT

PURPOSE OF REVIEW: No specific drug therapy has been shown to improve long-term survival after cardiac arrest, and only few drugs have a proven benefit for short-term survival. This study reviews recent studies on drugs during cardiopulmonary resuscitation. RECENT FINDINGS: Epinephrine is the first-line vasopressor during cardiopulmonary resuscitation. Arginine vasopressin may be more effective than epinephrine in patients presenting with asystole or as a second vasopressor in refractory cardiac arrest. Sodium bicarbonate should not be 'blindly' administered during cardiopulmonary resuscitation unless an arterial blood gas analysis can be obtained or after prolonged unsuccessful cardiopulmonary resuscitation. Amiodarone may improve short-term survival. Thrombolytic therapy during cardiopulmonary resuscitation may be beneficial if a pulmonary embolism or acute myocardial infarction is suggested to be the cause of cardiac arrest. SUMMARY: Epinephrine is the vasopressor of first choice for routine use during cardiopulmonary resuscitation. Arginine vasopressin may be considered in patients presenting with asystole or who are unresponsive to initial treatment with epinephrine. Amiodarone should be used in shock-refractory ventricular fibrillation. Although not recommended for routine use, thrombolytic therapy during cardiopulmonary resuscitation may be considered in patients with suspected pulmonary embolism or after unsuccessful conventional cardiopulmonary resuscitation in patients with a presumably thrombotic cause of cardiac arrest.


Subject(s)
Cardiopulmonary Resuscitation , Fibrinolytic Agents/therapeutic use , Heart Arrest/drug therapy , Vasoconstrictor Agents/therapeutic use , Anti-Arrhythmia Agents/therapeutic use , Arginine Vasopressin/therapeutic use , Atropine/therapeutic use , Epinephrine/therapeutic use , Heart Arrest/etiology , Heart Arrest/therapy , Humans , Sodium Bicarbonate/therapeutic use
15.
J Surg Res ; 150(1): 66-73, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18468638

ABSTRACT

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.


Subject(s)
Cyclic GMP/metabolism , Endotoxemia/metabolism , Lung/drug effects , Nitric Oxide/administration & dosage , 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid/pharmacology , Animals , Cyclic GMP/analogs & derivatives , Cyclic GMP/pharmacology , Dose-Response Relationship, Drug , Endotoxemia/chemically induced , In Vitro Techniques , Lipopolysaccharides/pharmacology , Lung/enzymology , Nitrates/metabolism , Nitrites/metabolism , Phosphoric Diester Hydrolases/metabolism , Pulmonary Circulation/drug effects , Pulmonary Wedge Pressure , Rats , Rats, Sprague-Dawley , Thionucleotides/pharmacology
16.
Anasthesiol Intensivmed Notfallmed Schmerzther ; 43(3): 226-30; quiz 231, 2008 Mar.
Article in German | MEDLINE | ID: mdl-18350476

ABSTRACT

Patients suffering cardiac arrest still have a poor prognosis. Up to the present, no drug therapy has shown to improve longterm survival after cardiac arrest. Acute myocardial infarction (AMI) or massive pulmonary embolism (PE) are the underlying causes for sudden cardiac arrest in 50-70 % of patients. Thrombolysis is an effective and causal therapy in patients with AMI or PE. Therefore, combining cardiopulmonary resuscitation (CPR) with thrombolysis may be a promising therapeutic approach. Experimental studies have demonstrated that thrombolytic therapy during CPR is not only a causal treatment for coronary or pulmonary arterial thrombi, but may also improve microcirculatory reperfusion after cardiac arrest. Although numerous case series and small clinical studies showed evidence for the success of thrombolytic therapy during CPR, a large randomised study did not confirm these results. Thrombolysis during CPR today can not be recommended as a standard therapy in patients suffering cardiac arrest. However, it should be considered if a massive PE is supposed to be the cause of cardiac arrest or if conventional CPR has not been successful in a patient with presumed thrombotic cause of cardiac arrest. The expected bleeding risk is outweighed by the potential benefit of this therapy in selected patients.


Subject(s)
Cardiopulmonary Resuscitation/statistics & numerical data , Emergency Medical Services/methods , Emergency Medical Services/statistics & numerical data , Myocardial Ischemia/epidemiology , Myocardial Ischemia/therapy , Practice Guidelines as Topic , Thrombolytic Therapy/statistics & numerical data , Cardiopulmonary Resuscitation/methods , Combined Modality Therapy/statistics & numerical data , Humans , Internationality , Practice Patterns, Physicians' , Prognosis , Thrombolytic Therapy/methods , Treatment Outcome
17.
Anesthesiology ; 107(4): 597-604, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17893456

ABSTRACT

BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) is impaired during inflammatory lung processes such as pneumonia or the acute respiratory distress syndrome. Voltage-gated potassium channels play a central role in mediating HPV. The aim of this study was to determine whether 4-aminopyridine (4-AP), a known voltage-gated potassium channel inhibitor, may restore HPV in sepsis. METHODS: The effects of 0.01, 0.1, and 1.0 mm 4-AP on HPV responsiveness were assessed in isolated lungs of untreated mice and of mice 18 h after lipopolysaccharide injection (20 mg/kg intraperitoneal Escherichia coli 0111:B4 lipopolysaccharide). HPV was quantified as the increase in perfusion pressure in response to hypoxic ventilation in percent of baseline perfusion pressure. Intrinsic pulmonary vascular resistance (R0) and pulmonary vascular distensibility (alpha) were determined by nonlinear regression analysis of pulmonary vascular pressure-flow curves generated during normoxic and hypoxic ventilation, respectively. RESULTS: HPV was impaired in lungs isolated from lipopolysaccharide-challenged mice. Addition of 4-AP to the perfusate did not alter HPV responsiveness in untreated mice but dose dependently restored HPV in endotoxemic mice. Analysis of pulmonary vascular pressure-flow curves revealed that 4-AP (1) counteracted the observed lipopolysaccharide-induced changes in alpha and R0 under normoxic conditions and (2) augmented the hypoxia-induced increase in R0 in lungs of endotoxemic mice. CONCLUSIONS: This study demonstrates that lipopolysaccharide-induced pulmonary vascular hyporesponsiveness to hypoxia can be restored by 4-AP in murine endotoxemia and, thus, may be a new therapeutic approach to treat patients with hypoxemia due to impaired HPV.


Subject(s)
4-Aminopyridine/therapeutic use , Endotoxemia/drug therapy , Endotoxemia/physiopathology , Hypoxia/physiopathology , Potassium Channel Blockers/therapeutic use , Pulmonary Circulation/drug effects , Vasoconstriction/drug effects , Algorithms , Angiotensin II/pharmacology , Animals , Body Weight/drug effects , Dose-Response Relationship, Drug , In Vitro Techniques , Lipopolysaccharides/antagonists & inhibitors , Lipopolysaccharides/pharmacology , Male , Mice , Organ Size/drug effects , Perfusion , Potassium Channels/biosynthesis , Pulmonary Artery/drug effects , Pulmonary Artery/physiopathology , RNA, Messenger/biosynthesis
18.
Article in German | MEDLINE | ID: mdl-16972205

ABSTRACT

We report the case of a 30 year old driver of a car who was jammed after a severe traffic accident. In a step-by-step description of the out-of-hospital and early clinical management of the patient, the case report focuses on diagnostic, therapeutic, and strategic issues. Current controversies in the management of patients with combined thoracic and abdominal trauma are discussed in the light of recent literature.


Subject(s)
Critical Care/methods , Emergency Medical Services/methods , Multiple Trauma/diagnosis , Multiple Trauma/therapy , Accidents, Traffic , Humans , Practice Guidelines as Topic , Practice Patterns, Physicians'
19.
Curr Opin Anaesthesiol ; 19(2): 157-65, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16552222

ABSTRACT

PURPOSE OF REVIEW: During cardiopulmonary resuscitation, no specific drug therapy has been shown to improve survival to hospital discharge after cardiac arrest, and only few drugs have a proven benefit for short-term survival. This article reviews recent experimental and clinical data about vasopressor, antiarrhythmic and thrombolytic agents. RECENT FINDINGS: General use of high-dose epinephrine (>1 mg) can not be recommended, whereas it should be considered during prolonged cardiopulmonary resuscitation. No catecholamine superior to epinephrine has been identified. Arginine vasopressin has been shown to be as effective as epinephrine in patients with ventricular fibrillation and pulseless electrical activity, and may be more effective in patients presenting with asystole or as the second vasopressor (after epinephrine) in refractory cardiac arrest. Sodium bicarbonate should not be 'blindly' administered during cardiopulmonary resuscitation unless an arterial blood gas analysis can be obtained, or after prolonged unsuccessful cardiopulmonary resuscitation. Amiodarone should be preferred over lidocaine, since it may improve short-term survival. Thrombolytic therapy during cardiopulmonary resuscitation may be beneficial if a pulmonary embolism or acute myocardial infarction is suggested to be the cause of the cardiac arrest. SUMMARY: Epinephrine still represents the first-line vasopressor during cardiopulmonary resuscitation. Arginine vasopressin may be considered in patients presenting with asystole or who are unresponsive to initial treatment with epinephrine. Amiodarone should be preferred to other antiarrythmic agents in patients with cardiac arrest. Thrombolytic therapy during cardiopulmonary resuscitation is a promising new therapeutic option, but its general use in cardiac arrest cannot be recommended until the results of a large multicentre trial become available.


Subject(s)
Cardiopulmonary Resuscitation , Fibrinolytic Agents/therapeutic use , Humans
20.
Am J Physiol Heart Circ Physiol ; 289(2): H823-31, 2005 Aug.
Article in English | MEDLINE | ID: mdl-15778287

ABSTRACT

Pulmonary vasoconstriction in response to alveolar hypoxia (HPV) is frequently impaired in patients with sepsis or acute respiratory distress syndrome or in animal models of endotoxemia. Pulmonary vasodilation due to overproduction of nitric oxide (NO) by NO synthase 2 (NOS2) may be responsible for this impaired HPV after administration of endotoxin (LPS). We investigated the effects of acute nonspecific (N(G)-nitro-L-arginine methyl ester, L-NAME) and NOS2-specific [L-N6-(1-iminoethyl)lysine, L-NIL] NOS inhibition and congenital deficiency of NOS2 on impaired HPV during endotoxemia. The pulmonary vasoconstrictor response and pulmonary vascular pressure-flow (P-Q) relationship during normoxia and hypoxia were studied in isolated, perfused, and ventilated lungs from LPS-pretreated and untreated wild-type and NOS2-deficient mice with and without L-NAME or L-NIL added to the perfusate. Compared with lungs from untreated mice, lungs from LPS-challenged wild-type mice constricted less in response to hypoxia (69 +/- 17 vs. 3 +/- 7%, respectively, P < 0.001). Perfusion with L-NAME or L-NIL restored this blunted HPV response only in part. In contrast, LPS administration did not impair the vasoconstrictor response to hypoxia in NOS2-deficient mice. Analysis of the pulmonary vascular P-Q relationship suggested that the HPV response may consist of different components that are specifically NOS isoform modulated in untreated and LPS-treated mice. These results demonstrate in a murine model of endotoxemia that NOS2-derived NO production is critical for LPS-mediated development of impaired HPV. Furthermore, impaired HPV during endotoxemia may be at least in part mediated by mechanisms other than simply pulmonary vasodilation by NOS2-derived NO overproduction.


Subject(s)
Endotoxins/pharmacology , Hypoxia/physiopathology , Nitric Oxide/metabolism , Pulmonary Circulation/drug effects , Vasoconstriction/drug effects , Animals , Enzyme Inhibitors/pharmacology , Lipopolysaccharides/pharmacology , Lysine/analogs & derivatives , Lysine/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , NG-Nitroarginine Methyl Ester/antagonists & inhibitors , Nitric Oxide Synthase/antagonists & inhibitors , Nitric Oxide Synthase/deficiency , Nitric Oxide Synthase Type II , Respiration/drug effects
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