Martin Frossard

Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock.

ObjectiveCurrent guidelines for adjusting antimicrobial therapy regimens commonly are based on drug concentrations measured in plasma. In septic patients, however, the interstitial space of soft tissues in addition to the central compartment represents the target site of infection. We thus hypothesized that one explanation for therapeutic failure during antibiotic treatment might be the inability to achieve effective antimicrobial concentrations in the interstitial space fluid of soft tissues. This is corroborated by the fact that piperacillin, a frequently administered &bgr;-lactam antibiotic, often fails to be effective despite documented susceptibility of the causative pathogen in vitro. DesignProspective comparative study of two groups. SettingThe intensive care unit and research ward of an university hospital. SubjectsSix patients with septic shock and a control group of six gender- and age-matched healthy volunteers. InterventionsTo measure piperacillin penetration into the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue, we employed microdialysis after a single intravenous administration of 4.0 g of piperacillin to patients and healthy volunteers. Piperacillin concentrations were assayed by using reversed-phase high-pressure liquid chromatography. Measurements and Main Results In septic shock patients, interstitial piperacillin concentrations in skeletal muscle and subcutaneous adipose tissue were five- to ten-fold lower than corresponding free plasma concentrations (p < .03). Mean piperacillin concentrations in subcutaneous adipose tissue never exceeded 11 &mgr;g/mL, which is below the minimal inhibitory concentration for a range of relevant pathogens in patients with septic shock. ConclusionThe results of the present study demonstrate that in septic shock patients, piperacillin concentrations in the interstitial space may be subinhibitory, even though effective concentrations are attained in plasma. The lack of success of antimicrobial therapy in these patients thus might be attributable to inadequate target site penetration of antibiotics.

Platelet Function Predicts Myocardial Damage in Patients With Acute Myocardial Infarction

Background—Platelet activation is a hallmark of acute coronary syndromes. Numerous lines of evidence suggest a mechanistic link between von Willebrand factor or platelet hyperfunction and myocardial damage in patients with acute coronary syndromes. Thus, we assessed whether platelet function under high shear rates (collagen adenosine diphosphate closure times [CADP-CTs]) measured with the platelet function analyzer (PFA-100) may be enhanced in patients with myocardial infarction (MI) and whether it may predict the extent of myocardial damage as measured by creatine kinase (CK-MB) or troponin T (TnT) levels. Methods and Results—Patients with acute chest pain or symptoms suggestive of acute coronary syndromes (n=216) were prospectively examined at an emergency department. CADP-CT was significantly shorter in patients with MI, particularly in those with an ST-segment-elevation MI (STEMI) compared with the other patient groups (unstable angina, stable coronary artery disease, or controls). Furthermore, CADP-CT and collagen epinephrine–CT at presentation were independent predictors of myocardial damage as measured by CK-MB or TnT. Patients with MI whose CADP-CT values fell in the first quartile had 3-fold higher CK-MB and TnT levels than those in the fourth quartile. Conclusions—Patients with STEMI have significantly enhanced platelet function when measured under high shear rates. CADP-CT is an independent predictor of the severity of MI, as measured by markers of cardiac necrosis. Measurement of platelet function with the PFA-100 may help in the risk stratification of patients presenting with MI.

Time Course of Serum Neuron-Specific Enolase A Predictor of Neurological Outcome in Patients Resuscitated From Cardiac Arrest

BACKGROUND AND PURPOSE The prediction of neurological outcome in comatose cardiac arrest survivors has enormous ethical and socioeconomic implications. The purpose of the present study was to investigate the prognostic relevance of the time course of serum neuron-specific enolase (NSE) as a biochemical marker of hypoxic brain damage. METHODS Serial analysis of serum NSE levels was performed in 56 patients resuscitated from witnessed, nontraumatic, normothermic, in- or out-of-hospital cardiac arrest. The neurological outcome was evaluated with the use of the cerebral performance category (CPC) within 6 months after restoration of spontaneous circulation (ROSC). The Mann-Whitney U test was used to compare patients with good (CPC 1 to 2) and bad (CPC 3 to 4) neurological outcome. The diagnostic performance at different time points after ROSC was described in terms of areas under receiver operating characteristic curves according to standard methods. RESULTS Patients with a bad neurological outcome (CPC 3 to 4) had significantly higher NSE levels than those with a good neurological outcome at 12 (P=0.004), 24 (P=0.04), 48 (P<0.001), and 72 hours (P<0.001) after ROSC. The maximum NSE level measured within 72 hours after ROSC was also significantly higher in patients with a bad neurological outcome (P<0.001). The NSE value at 72 hours after ROSC was the best predictor of neurological outcome (area under the curve=0.92+/-0.04). In addition, we also found a significant difference in the time course of NSE concentrations during the first 3 days after ROSC. CONCLUSIONS Serum NSE levels are valuable adjunctive parameters for assessing neurological outcome after cardiac arrest.

Simultaneous determination of levofloxacin and ciprofloxacin in microdialysates and plasma by high-performance liquid chromatography

The fluoroquinolones levofloxacin and ciprofloxacin were simultaneously determined in microdialysis and plasma samples by reversed-phase high-performance liquid chromatography (HPLC) and fluorescence detection. After a simple sample preparation step the analytes were separated in the isocratic mode within 12 min. The calibration curve for levofloxacin was linear from 0.0156 to 5 gm l −1 and 0.02–12.5 gm l −1 in microdialysates and plasma samples, respectively. The limits of quantification for levofloxacin and ciprofloxacin were 0.0156 and 0.1 gm l −1 in microdialysis samples, and 0.02 and 0.1 gm l −1 in plasma samples, respectively. Some experimental details concerning microdialysate dilution and plasma protein precipitation were described to ensure accurate quantitation. The assay can be used as a routine method to analyse microdialysis and plasma samples from clinical studies.

Distribution and Antimicrobial Activity of Fosfomycin in the Interstitial Fluid of Human Soft Tissues

ABSTRACT Fosfomycin is a broad-spectrum antibiotic which is established as therapy for uncomplicated lower urinary tract infections. In addition, preliminary data indicate that fosfomycin has a potential role in the treatment of soft tissue infections. However, the use of fosfomycin has not been established for this condition, and it is unclear whether the level of fosfomycin penetration into human soft tissues is high enough to eradicate relevant pathogens. To better characterize the antibiotic potential of fosfomycin, we applied a combined in vivo pharmacokinetic-in vitro pharmacodynamic model to human volunteers. For this purpose fosfomycin concentrations in vivo in the fluid of the interstitial space of human soft tissues were measured by microdialysis following intravenous infusion of 4 or 8 g of fosfomycin (n = 6). Subsequently, bacterial isolates with relevance for soft tissue infections were exposed to concentrations according to the in vivo pharmacokinetic profile in the interstitial space fluid obtained by microdialysis. Our experiments indicated a high degree of soft tissue penetration for fosfomycin, with ratios of the area under the concentration-time curve from 0 to 8 h for muscle (AUC0–8muscle)/AUC0–8serumof 0.48 ± 0.08 and 0.53 ± 0.04 and ratios of AUC0–8adipose tissue/AUC0–8serum of 0.74 ± 0.12 and 0.71 ± 0.11 following administration of 4 and 8 g, respectively. In corresponding in vitro simulation experiments with selected isolates of Staphylococcus aureus,Enterobacter cloacae, and Serratia marcescensfor which MICs were 16 μg/ml, organisms were undetectable after a single dosing interval. Fosfomycin exhibits a strong ability to penetrate into the fluid of the interstitial space of soft tissues and reaches levels sufficient to substantially inhibit the growth of relevant bacteria at the target site. We therefore conclude that fosfomycin might qualify as an alternative candidate for the therapy of soft tissue infections.

Transcapillary insulin transfer in human skeletal muscle

Background Transcapillary insulin transfer is considered a rate‐limiting step in insulin action at supraphysiological insulin concentrations. However, it remains unclear whether this concept also applies for physiological conditions.

Emergency preservation and resuscitation improve survival after 15 minutes of normovolemic cardiac arrest in pigs

Objective: Outcome after prolonged normovolemic cardiac arrest is poor, and new resuscitation strategies have to be found. We hypothesized that the induction of deep hypothermia for emergency preservation and resuscitation (EPR) during prolonged cardiac arrest, before the start of reperfusion, will mitigate the deleterious cascades leading to neuronal death and will thus improve outcome. Design: Prospective experimental study. Setting: University research laboratory. Subjects: Thirteen pigs, Large White breed (27–37 kg). Interventions: After 15 mins of ventricular fibrillation, pigs were subjected to 1) EPR (n = 6), 20 mins of hypothermic stasis induced with a cold saline aortic flush; or 2) 20 mins of conventional resuscitation (n = 7). Then cardiopulmonary bypass was initiated in both groups, followed by defibrillation. Controlled ventilation and mild hypothermia were continued for 20 hrs; survival was for 9 days. For neurologic evaluation, neurologic deficit score (100% = brain dead, 0–10% = normal), overall performance category (1 = normal, 5 = dead or brain dead), and brain histologic damage score were used. Measurements and Main Results: In the EPR group, brain temperature decreased from 38.5°C ± 0.2°C to 16.7°C ± 2.5°C within 235 ± 27 secs. Five animals achieved restoration of spontaneous circulation and survived to 9 days: two pigs with overall performance category 2 and three pigs with overall performance category 3. Their neurologic deficit score was 45% (interquartile range 35, 50) and histologic damage score was 142 (interquartile range 109, 159). In the control group, four pigs achieved restoration of spontaneous circulation: one survived to 9 days with overall performance category 3, neurologic deficit score 45%, and histologic damage score 226 (restoration of spontaneous circulation, p = .6; survival, p = .03; overall performance category, p = .02). Conclusions: EPR is feasible in an experimental pig model and improves survival after prolonged cardiac arrest in pigs. Further experimental studies are needed before this concept can be brought into clinical practice.

IV milrinone for cardiac output increase and maintenance: comparison in nonhyperdynamic SIRS/sepsis and congestive heart failure.

Objective: To characterize the effect of the phosphodiesterase inhibitor (PDEI) milrinone in adult patients with a non-hyperdynamic condition during the course of the systemic inflammatory response syndrome (SIRS) or sepsis when compared with patients with congestive heart failure (CHF). PDEIs are potent inhibitors of cytokine production and expression. We hypothesized that there might be an outstanding beneficial effect of PDEIs in the setting of SIRS/sepsis. Design: Prospective, open labeled, protocol-driven pilot study. Patients: Nine patients with a non-hyperdynamic hemodynamic condition during SIRS/sepsis (group 1) and seven patients with CHF (group 2) requiring inotropic support. All patients were having heart disease. All patients had a combination of various catecholamines at the time of inclusion in the study and had received fluid resuscitation to an extent that left ventricular stroke work index (LVSWI) did not increase further. Intervention: Milrinone infusion at a rate of 0.5 μg/kg per min in addition to preexisting catecholamine therapy. Measurements and results: Measurements of cardiac index (CI; thermodilution) and calculation of vascular resistance and LVSWI was done every 8 h for at least 40 h during milrinone infusion. CI and LVSWI significantly increased in both groups (p < 0.001 and p = 0.006, respectively). There were no significant differences between groups in these parameters (p > 0.11 and p > 0.13, respectively). The LVSWI increase occurred while there was a decrease in pulmonary capillary wedge pressure, suggesting a true and comparable improvement in cardiac function relatively independent of loading conditions. Preexisting catecholamines had to be increased in both groups (NS). Milrinone had to be discontinued in one patient due to hypotension. Conclusion: Milrinone administration is feasible in selected patients with a non-hyperdynamic condition during SIRS/sepsis and with preexisting heart disease. Under the conditions of this study, milrinone was no better in terms of CI and LVSWI maintenance in septic cardiac dysfunction when compared with CHF. These results do not necessarily extend to other cohorts with no preexisting heart disease.

Pronounced platelet hyperfunction in patients with cardiac arrest achieving restoration of spontaneous circulation

Objective:Markers of platelet activation are increased in patients undergoing cardiopulmonary resuscitation. Hyperfunctional platelets may contribute to impairment of microcirculatory function and overall poor outcome despite restoration of spontaneous circulation (ROSC). Patients with myocardial infarction have hyperfunctional platelets, which predict the degree of myocardial necrosis. Thus, we hypothesized that platelets may be even more activated in patients whose myocardial infarction leads to cardiac arrest and compared them with patients whose cardiac arrest was due to a noncardiac origin. Design:Prospective observational study. Setting:Emergency department of a tertiary care hospital. Patients:One hundred four patients with witnessed cardiac arrest who achieved ROSC. Interventions:Blood sampling. Measurements and Main Results:We assessed collagen adenosine diphosphate closure time with the platelet function analyzer-100, and measured plasma levels of von Willebrand factor: ristocetin cofactor activity levels by turbidometry. Independent physicians diagnosed the origin of cardiac arrest. The majority of cardiac arrests were caused by myocardial ischemia. Invariably, collagen adenosine diphosphate closure time values (55 seconds; 95% confidence interval: 52–58 seconds) were much shorter in these patients compared with patients with other causes of cardiac arrest (110 seconds; 95% confidence interval: 84–135 seconds, p < 0.001). von Willebrand factor: ristocetin cofactor activity plasma levels were more than three-fold above normal values in both groups. Conclusions:Patients with myocardial ischemia-triggered cardiac arrest had the highest degree of platelet hyperfunction under high shear rates, which was not solely due to increased von Willebrand factor. Future trials are necessary to clarify whether rapid, more aggressive antiplatelet therapy improves outcome after cardiac arrest.

Cold aortic flush and chest compressions enable good neurologic outcome after 15 mins of ventricular fibrillation in cardiac arrest in pigs.

Objective:The induction of deep cerebral hypothermia via ice-cold saline aortic flush during prolonged ventricular fibrillation cardiac arrest, followed by hypothermic stasis and delayed resuscitation (emergency preservation and resuscitation), improved neurologic outcome after cardiac arrest in pigs, as compared to conventional resuscitation. We hypothesized that emergency preservation and resuscitation with chest compressions would further improve outcome in the same model. Design:Prospective experimental study. Setting:University research laboratory. Subjects:Twenty-four female, large, white breed pigs (27–37 kg). Interventions:Fifteen minutes of ventricular fibrillation cardiac arrest were followed by 20 mins of resuscitation with chest compressions (control, n = 8), deep cerebral hypothermia via 200 mL/kg 4°C saline aortic flush and hypothermic stasis (emergency preservation and resuscitation, n = 8), and emergency preservation and resuscitation combined with chest compressions (emergency preservation and resuscitation plus chest compressions, n = 8). At 35 mins after cardiac arrest, cardiopulmonary bypass was initiated, followed by defibrillation. Mild hypothermia was continued for 20 hrs. Pigs were evaluated after 9 days using a neurologic deficit (neurologic deficit score: 100% = brain dead; 0%–10% = normal) and an overall performance category score (overall performance category score: 1 = normal; 2 = slightly handicapped; 3 = severely handicapped; 4 = comatose; 5 = dead/brain dead). Measurements and Main Results:Brain temperature decreased from 38.5°C to 15.3°C ± 3.3°C in the emergency preservation and resuscitation group, and to 11.3°C ± 1.2°C in the emergency preservation and resuscitation plus chest compressions group. In the control group, restoration of spontaneous circulation was achieved in four out of eight pigs, and one survived to 9 days. In the emergency preservation and resuscitation group, restoration of spontaneous circulation was achieved in seven out of eight pigs and five survived; in the emergency preservation and resuscitation plus chest compressions group, all had restoration of spontaneous circulation and seven survived (restoration of spontaneous circulation, p = .08). Neurologic outcome for (median and interquartile range) the control group included overall performance category score of 3, neurologic deficit score of 45%; for the emergency preservation and resuscitation group, overall performance category score was 3 (2–5) and neurologic deficit score was 45% (36; 50) and in the emergency preservation and resuscitation plus chest compressions group, overall performance category score was 2 (1–3) and neurologic deficit score was 13% (5; 21) (overall performance category score, p = .04; neurologic deficit score emergency preservation and resuscitation vs. emergency preservation and resuscitation plus chest compressions, p = .003). Conclusions:Emergency preservation and resuscitation by deep cerebral hypothermia combined with chest compressions during prolonged cardiac arrest in pigs are feasible and improve neurologic outcome.