Fabio Silvio Taccone

Intra-Arrest Transnasal Evaporative Cooling A Randomized, Prehospital, Multicenter Study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness)

Background— Transnasal evaporative cooling has sufficient heat transfer capacity for effective intra-arrest cooling and improves survival in swine. The aim of this study was to determine the safety, feasibility, and cooling efficacy of prehospital transnasal cooling in humans and to explore its effects on neurologically intact survival to hospital discharge. Methods and Results— Witnessed cardiac arrest patients with a treatment interval ≤20 minutes were randomized to intra-arrest cooling with a RhinoChill device (treatment group, n=96) versus standard care (control group, n=104). The final analysis included 93 versus 101 patients, respectively. Both groups were cooled after hospital arrival. The patients had similar demographics, initial rhythms, rates of bystander cardiopulmonary resuscitation, and intervals to cardiopulmonary resuscitation and arrival of advanced life support personnel. Eighteen device-related adverse events (1 periorbital emphysema, 3 epistaxis, 1 perioral bleed, and 13 nasal discolorations) were reported. Time to target temperature of 34°C was shorter in the treatment group for both tympanic (102 versus 282 minutes, P=0.03) and core (155 versus 284 minutes, P=0.13) temperature. There were no significant differences in rates of return of spontaneous circulation between the groups (38% in treated subjects versus 43% in control subjects, P=0.48), in overall survival of those admitted alive (44% versus 31%, respectively, P=0.26), or in neurologically intact survival to discharge (Pittsburgh cerebral performance category scale 1 to 2, 34% versus 21%, P=0.21), although the study was not adequately powered to detect changes in these outcomes. Conclusions— Prehospital intra-arrest transnasal cooling is safe and feasible and is associated with a significant improvement in the time intervals required to cool patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00808236.

Characteristics and outcomes of cancer patients in European ICUs

IntroductionIncreasing numbers of cancer patients are being admitted to the intensive care unit (ICU), either for cancer-related complications or treatment-associated side effects, yet there are relatively few data concerning the epidemiology and prognosis of cancer patients admitted to general ICUs. The aim of this study was to assess the characteristics of critically ill cancer patients, and to evaluate their prognosis.MethodsThis was a substudy of the Sepsis Occurrence in Acutely Ill Patients (SOAP) study, a cohort, multicentre, observational study that included data from all adult patients admitted to one of 198 participating ICUs from 24 European countries during the study period. Patients were followed up until death, hospital discharge or for 60 days.ResultsOf the 3147 patients enrolled in the SOAP study, 473 (15%) had a malignancy, 404 (85%) had solid tumours and 69 (15%) had haematological cancer. Patients with solid cancers had the same severity of illness as the non-cancer population, but were older, more likely to be a surgical admission and had a higher frequency of sepsis. Patients with haematological cancer were more severely ill and more commonly had sepsis, acute lung injury/acute respiratory distress syndrome, and renal failure than patients with other malignancies; these patients also had the highest hospital mortality rate (58%). The outcome of all cancer patients was comparable with that in the non-cancer population, with a 27% hospital mortality rate. However, in the subset of patients with more than three failing organs, more than 75% of patients with cancer died compared with about 50% of patients without cancer (p = 0.01).ConclusionsIn this large European study, patients with cancer were more often admitted to the ICU for sepsis and respiratory complications than other ICU patients. Overall, the outcome of patients with solid cancer was similar to that of ICU patients without cancer, whereas patients with haematological cancer had a worse outcome.

Insufficient β-lactam concentrations in the early phase of severe sepsis and septic shock

IntroductionAltered pharmacokinetics (PK) in critically ill patients can result in insufficient serum β-lactam concentrations when standard dosages are administered. Previous studies on β-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock.MethodsOpen, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration.Results80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 μg/mL), 45% for ceftazidime (MIC = 32 μg/mL), 34% for cefepime (MIC = 32 μg/mL), and 33% for piperacillin-tazobactam (MIC = 64 μg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam.ConclusionsSerum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.

Influence of respiratory rate on stroke volume variation in mechanically ventilated patients.

Background:Heart-lung interactions are used to evaluate fluid responsiveness in mechanically ventilated patients, but these indices may be influenced by ventilatory conditions. The authors evaluated the impact of respiratory rate (RR) on indices of fluid responsiveness in mechanically ventilated patients, hypothesizing that pulse pressure variation and respiratory variation in aortic flow would decrease at high RRs. Methods:In 17 hypovolemic patients, thermodilution cardiac output and indices of fluid responsiveness were measured at a low RR (14–16 breaths/min) and at the highest RR (30 or 40 breaths/min) achievable without altering tidal volume or inspiratory/expiratory ratio. Results:An increase in RR was accompanied by a decrease in pulse pressure variation from 21% (18–31%) to 4% (0–6%) (P < 0.01) and in respiratory variation in aortic flow from 23% (18–28%) to 6% (5–8%) (P < 0.01), whereas respiratory variations in superior vena cava diameter (caval index) were unaltered, i.e., from 38% (27–43%) to 32% (22–39%), P = not significant. Cardiac index was not affected by the changes in RR but did increase after fluids. Pulse pressure variation became negligible when the ratio between heart rate and RR decreased below 3.6. Conclusions:Respiratory variations in stroke volume and its derivates are affected by RR, but caval index was unaffected. This suggests that right and left indices of ventricular preload variation are dissociated. At high RRs, the ability to predict the response to fluids of stroke volume variations and its derivate may be limited, whereas caval index can still be used.

A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients.

RATIONALE The clinical relevance of Aspergillus-positive endotracheal aspirates in critically ill patients is difficult to assess. OBJECTIVES We externally validate a clinical algorithm to discriminate Aspergillus colonization from putative invasive pulmonary aspergillosis in this patient group. METHODS We performed a multicenter (n = 30) observational study including critically ill patients with one or more Aspergillus-positive endotracheal aspirate cultures (n = 524). The diagnostic accuracy of this algorithm was evaluated using 115 patients with histopathologic data, considered the gold standard. Subsequently, the diagnostic workout of the algorithm was compared on the total cohort (n = 524), with the categorization based on the diagnostic criteria of the European Organization for the Research and Treatment of Cancer/Mycoses Study Group. MEASUREMENTS AND MAIN RESULTS Among 115 histopathology-controlled patients, 79 had proven aspergillosis. The algorithm judged 86 of 115 cases to have putative aspergillosis. This diagnosis was confirmed in 72 and rejected in 14 patients. The algorithm judged 29 patients to have Aspergillus colonization. This was confirmed in 22 and rejected in 7 patients. The algorithm had a specificity of 61% and a sensitivity of 92%. The positive and negative predictive values were 61 and 92%, respectively. In the total cohort (n = 524), 79 patients had proven invasive pulmonary aspergillosis (15.1%). According to the European Organization for the Research and Treatment of Cancer/Mycoses Study Group criteria, 32 patients had probable aspergillosis (6.1%) and 413 patients were not classifiable (78.8%). The algorithm judged 199 patients to have putative aspergillosis (38.0%) and 246 to have Aspergillus colonization (46.9%). CONCLUSIONS The algorithm demonstrated favorable operating characteristics to discriminate Aspergillus respiratory tract colonization from invasive pulmonary aspergillosis in critically ill patients.

Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care: A statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine

Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. The Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine, and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants’ collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data.

Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy.

IntroductionSepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT.MethodsThis open, prospective study enrolled consecutive patients treated with CRRT and receiving either meropenem (MEM), piperacillin-tazobactam (TZP), cefepime (FEP) or ceftazidime (CAZ). Serum concentrations of these antibiotics were determined by high-performance liquid chromatography from samples taken before (t = 0) and 1, 2, 5, and 6 or 12 hours (depending on the β-lactam regimen) after the administration of each antibiotic. Series of measurements were separated into those taken during the early phase (< 48 hours from the first dose) of therapy and those taken later (> 48 hours).ResultsA total of 69 series of serum samples were obtained in 53 patients (MEM, n = 17; TZP, n = 16; FEP, n = 8; CAZ, n = 12). Serum concentrations remained above four times the minimal inhibitory concentration for Pseudomonas spp. for the recommended time in 81% of patients treated with MEM, in 71% with TZP, in 53% with CAZ and in 0% with FEP. Accumulation after 48 hours of treatment was significant only for MEM.ConclusionsIn septic patients receiving CRRT, recommended doses of β-lactams for Pseudomonas aeruginosa are adequate for MEM but not for TZP, FEP and CAZ; for these latter drugs, higher doses and/or extended infusions should be used to optimise serum concentrations.

Revisiting the loading dose of amikacin for patients with severe sepsis and septic shock.

IntroductionIt has been proposed that doses of amikacin of >15 mg/kg should be used in conditions associated with an increased volume of distribution (Vd), such as severe sepsis and septic shock. The primary aim of this study was to determine whether 25 mg/kg (total body weight) of amikacin is an adequate loading dose for these patients.MethodsThis was an open, prospective, multicenter study in four Belgian intensive care units (ICUs). All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom amikacin treatment was indicated, were included in the study.ResultsIn 74 patients, serum samples were collected before (t = 0 h) and 1 hour (peak), 1 hour 30 minutes, 4 hours 30 minutes, 8 hours, and 24 hours after the first dose of amikacin. Blood amikacin levels were measured by using a validated fluorescence polarization immunoassay method, and an open two-compartment model with first-order elimination was fitted to concentrations-versus-time data for amikacin (WinNonlin). In 52 (70%) patients, peak serum concentrations were >64 μg/ml, which corresponds to 8 times the clinical minimal inhibitory concentration (MIC) breakpoints defined by EUCAST for Enterobacteriaceae and Pseudomonas aeruginosa (S<8, R>16 μg/ml). Vd was 0.41 (0.29 to 0.51) L/kg; elimination half-life, 4.6 (3.2 to 7.8) hours; and total clearance, 1.98 (1.28 to 3.54) ml/min/kg. No correlation was found between the amikacin peak and any clinical or hemodynamic variable.ConclusionsAs patients with severe sepsis and septic shock have an increased Vd, a first dose of ≥ 25 mg/kg (total body weight) of amikacin is required to reach therapeutic peak concentrations. However, even with this higher amikacin dose, the peak concentration remained below therapeutic target levels in about one third of these patients. Optimizing aminoglycoside therapy should be achieved by tight serum-concentration monitoring because of the wide interindividual variability of pharmacokinetic abnormalities.

Microcirculatory alterations: potential mechanisms and implications for therapy

Multiple experimental and human trials have shown that microcirculatory alterations are frequent in sepsis. In this review, we discuss the characteristics of these alterations, the various mechanisms potentially involved, and the implications for therapy. Sepsis-induced microvascular alterations are characterized by a decrease in capillary density with an increased number of stopped-flow and intermittent-flow capillaries, in close vicinity to well-perfused capillaries. Accordingly, the surface available for exchange is decreased but also is highly heterogeneous. Multiple mechanisms may contribute to these alterations, including endothelial dysfunction, impaired inter-cell communication, altered glycocalyx, adhesion and rolling of white blood cells and platelets, and altered red blood cell deformability. Given the heterogeneous nature of these alterations and the mechanisms potentially involved, classical hemodynamic interventions, such as fluids, red blood cell transfusions, vasopressors, and inotropic agents, have only a limited impact, and the microcirculatory changes often persist after resuscitation. Nevertheless, fluids seem to improve the microcirculation in the early phase of sepsis and dobutamine also can improve the microcirculation, although the magnitude of this effect varies considerably among patients. Finally, maintaining a sufficient perfusion pressure seems to positively influence the microcirculation; however, which mean arterial pressure levels should be targeted remains controversial. Some trials using vasodilating agents, especially nitroglycerin, showed promising initial results but they were challenged in other trials, so it is difficult to recommend the use of these agents in current practice. Other agents can markedly improve the microcirculation, including activated protein C and antithrombin, vitamin C, or steroids. In conclusion, microcirculatory alterations may play an important role in the development of sepsis-related organ dysfunction. At this stage, therapies to target microcirculation specifically are still being investigated.

Vancomycin Dosing in Critically Ill Patients: Robust Methods for Improved Continuous-Infusion Regimens

ABSTRACT Despite the development of novel antibiotics active against Gram-positive bacteria, vancomycin generally remains the first treatment, although rapidly achieving concentrations associated with maximal efficacy provides an unresolved challenge. The objective of this study was to conduct a population pharmacokinetic analysis of vancomycin in a large population of critically ill patients. This was a retrospective data collection of 206 adult septic critically ill patients who were administered vancomycin as a loading dose followed by continuous infusion. The concentration-versus-time data for vancomycin in serum was analyzed by a nonlinear mixed-effects modeling approach using NONMEM. Monte Carlo simulations were performed using the final covariate model. We found that the best population pharmacokinetic model consisted of a one-compartment linear model with combined proportional and additive residual unknown variability. The volume of distribution of vancomycin (1.5 liters/kg) was described by total body weight and clearance (4.6 liters/h) by 24-hour urinary creatinine clearance (CrCl), normalized to body surface area. Simulation data showed that a 35-mg/kg loading dose was necessary to rapidly achieve vancomycin concentrations of 20 mg/liter. Daily vancomycin requirements were dependent on CrCl, such that a patient with a CrCl of 100 ml/min/1.73 m2 would require at least 35 mg/kg per day by continuous infusion to maintain target concentrations. In conclusion, we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations in these patients.