The effect of microgravity on the human venous system and blood coagulation: a systematic review.

NEW FINDINGS: What is the central question of this study? Recently, an internal jugular venous thrombus was identified during spaceflight: does microgravity induce venous and/or coagulation pathophysiology, and thus an increased risk of venous thromboembolism (VTE)? What is the main finding and its importance? Whilst data are limited, this systematic review suggests that microgravity and its analogues may induce an enhanced coagulation state due to venous changes most prominent in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability in microgravity and its analogues. However, whether such changes precipitate an increased VTE risk in spaceflight remains to be determined. ABSTRACT: Recently, an internal jugular venous thrombus was identified during spaceflight, but whether microgravity induces venous and/or coagulation pathophysiology, and thus, an increased risk of venous thromboembolism (VTE) is unclear. Therefore, a systematic (Cochrane compliant) review was performed of venous system or coagulation parameters in actual spaceflight (microgravity) or ground-based analogues in PubMed, MEDLINE, Ovid EMBASE, Cochrane Library, European Space Agency, National Aeronautics and Space Administration, and Deutsches Zentrum für Luft-und Raumfahrt databases. Seven-hundred and eight articles were retrieved, of which 26 were included for evaluation with 21 evaluating venous, and five coagulation parameters. Nine articles contained spaceflight data, whereas the rest reported ground-based analogue data. There is substantial variability in study design, objectives and outcomes. Yet, data suggested cephalad venous system dilatation, increased venous pressures and decreased/reversed flow in microgravity. Increased fibrinogen levels, presence of thrombin generation markers and endothelial damage were also reported. Limited human venous and coagulation system data exist in spaceflight, or its analogues. Nevertheless, data suggest spaceflight may induce an enhanced coagulation state in the cephalad venous system, as a consequence of changes in venous flow, distension, pressures, endothelial damage and possibly hypercoagulability. Whether such changes precipitate an increased VTE risk in spaceflight remains to be determined.

Volume Infusion Markedly Increases Femoral dP/dtmax in Fluid-Responsive Patients Only.

OBJECTIVES: To evaluate the preload dependence of femoral maximal change in pressure over time (dP/dtmax) during volume expansion in preload dependent and independent critically ill patients. DESIGN: Retrospective database analysis. SETTING: Two adult polyvalent ICUs. PATIENTS: Twenty-five critically ill patients with acute circulatory failure. INTERVENTIONS: Thirty-five fluid infusions of 500 mL normal saline. MEASUREMENTS AND MAIN RESULTS: Changes in femoral dP/dtmax, systolic, diastolic, and pulse femoral arterial pressure were obtained from the pressure waveform analysis using the PiCCO2 system (Pulsion Medical Systems, Feldkirchen, Germany). Stroke volume index was obtained by transpulmonary thermodilution. Statistical analysis was performed comparing results before and after volume expansion and according to the presence or absence of preload dependence (increases in stroke volume index ≥ 15%). Femoral dP/dtmax increased by 46% after fluid infusion in preload-dependent cases (mean change = 510.6 mm Hg·s; p = 0.005) and remained stable in preload-independent ones (mean change = 49.2 mm Hg·s; p = 0.114). Fluid-induced changes in femoral dP/dtmax correlated with fluid-induced changes in stroke volume index in preload-dependent cases (r = 0.618; p = 0.032), but not in preload-independent ones. Femoral dP/dtmax strongly correlated with pulse and systolic arterial pressures and with total arterial stiffness, regardless of the preload dependence status (r > 0.9 and p < 0.001 in all cases). CONCLUSIONS: Femoral dP/dtmax increased with volume expansion in case of preload dependence but not in case of preload independence and was strongly related to pulse pressure and total arterial stiffness regardless of preload dependence status. Therefore, femoral dP/dtmax is not a load-independent marker of left ventricular contractility and should be not used to track contractility in critically ill patients.

Influence of changes in ventricular systolic function and loading conditions on pulse contour analysis-derived femoral dP/dtmax.

BACKGROUND: Femoral dP/dtmax (maximum rate of the arterial pressure increase during systole) measured by pulse contour analysis has been proposed as a surrogate of left ventricular (LV) dP/dtmax and as an estimator of LV systolic function. However, femoral dP/dtmax may be influenced by LV loading conditions. In this study, we evaluated the impact of variations of LV systolic function, preload and afterload on femoral dP/dtmax in critically ill patients with cardiovascular failure to ascertain its reliability as a marker of LV systolic function. RESULTS: We performed a prospective observational study to evaluate changes in femoral dP/dtmax, thermodilution-derived variables (PiCCO2-Pulsion Medical Systems, Feldkirchen, Germany) and LV ejection fraction (LVEF) measured by transthoracic echocardiography during variations in dobutamine and norepinephrine doses and during volume expansion (VE) and passive leg raising (PLR). Correlations with arterial pulse and systolic pressure, effective arterial elastance, total arterial compliance and LVEF were also evaluated. In absolute values, femoral dP/dtmax deviated from baseline by 21% (201 ± 297 mmHg/s; p = 0.013) following variations in dobutamine dose (n = 17) and by 15% (177 ± 135 mmHg/s; p < 0.001) following norepinephrine dose changes (n = 29). Femoral dP/dtmax remained unchanged after VE and PLR (n = 24). Changes in femoral dP/dtmax were strongly correlated with changes in pulse pressure and systolic arterial pressure during dobutamine dose changes (R = 0.942 and 0.897, respectively), norepinephrine changes (R = 0.977 and 0.941, respectively) and VE or PLR (R = 0.924 and 0.897, respectively) (p < 0.05 in all cases). Changes in femoral dP/dtmax were correlated with changes in LVEF (R = 0.527) during dobutamine dose variations but also with effective arterial elastance and total arterial compliance in the norepinephrine group (R = 0.638 and R = - 0.689) (p < 0.05 in all cases). CONCLUSIONS: Pulse contour analysis-derived femoral dP/dtmax was not only influenced by LV systolic function but also and prominently by LV afterload and arterial waveform characteristics in patients with acute cardiovascular failure. These results suggest that femoral dP/dtmax calculated by pulse contour analysis is an unreliable estimate of LV systolic function during changes in LV afterload and arterial load by norepinephrine and directly linked to arterial waveform determinants.

Systematic review and meta-analysis of complications and mortality of veno-venous extracorporeal membrane oxygenation for refractory acute respiratory distress syndrome.

Veno-venous extracorporeal membrane oxygenation (ECMO) for refractory acute respiratory distress syndrome (ARDS) is a rapidly expanding technique. We performed a systematic review and meta-analysis of the most recent literature to analyse complications and hospital mortality associated with this technique. Using the PRISMA guidelines for systematic reviews and meta-analysis, MEDLINE and EMBASE were systematically searched for studies reporting complications and hospital mortality of adult patients receiving veno-venous ECMO for severe and refractory ARDS. Studies were screened for low bias risk and assessed for study size effect. Meta-analytic pooled estimation of study variables was performed using a weighted random effects model for study size. Models with potential moderators were explored using random effects meta-regression. Twelve studies fulfilled inclusion criteria, representing a population of 1042 patients with refractory ARDS. Pooled mortality at hospital discharge was 37.7% (CI 95% = 31.8-44.1; I 2 = 74.2%). Adjusted mortality including one imputable missing study was 39.3% (CI 95% = 33.1-45.9). Meta-regression model combining patient age, year of study realization, mechanical ventilation (MV) days and prone positioning before veno-venous ECMO was associated with hospital mortality (p < 0.001; R 2 = 0.80). Patient age (b = 0.053; p = 0.01) and maximum cannula size during treatment (b = -0.075; p = 0.008) were also independently associated with mortality. Studies reporting H1N1 patients presented inferior hospital mortality (24.8 vs 40.6%; p = 0.027). Complication rate was 40.2% (CI 95% = 25.8-56.5), being bleeding the most frequent 29.3% (CI 95% = 20.8-39.6). Mortality due to complications was 6.9% (CI 95% = 4.1-11.2). Mechanical complications were present in 10.9% of cases (CI 95% = 4.7-23.5), being oxygenator failure the most prevalent (12.8%; CI 95% = 7.1-21.7). Despite initial severity, significant portion of patients treated with veno-venous ECMO survive hospital discharge. Patient age, H1N1-ARDS and cannula size are independently associated with hospital mortality. Combined effect of patient age, year of study realization, MV days and prone positioning before veno-venous ECMO influence patient outcome, and although medical complications are frequent, their impact on mortality is limited.

Piperacillin population pharmacokinetics in critically ill patients with multiple organ dysfunction syndrome receiving continuous venovenous haemodiafiltration: effect of type of dialysis membrane on dosing requirements.

OBJECTIVES: This multicentre study aimed to describe the pharmacokinetics (PK) of piperacillin in critically ill patients with multiple organ dysfunction syndrome (MODS) receiving continuous venovenous haemodiafiltration (CVVHDF), to identify the sources of PK variability and evaluate different dosing regimens to develop recommendations based on clinical parameters. PATIENTS AND METHODS: Nineteen patients with MODS and CVVHDF receiving piperacillin/tazobactam were enrolled from three tertiary hospitals (95 plasma samples). Population PK modelling and Monte Carlo simulations were performed using NONMEM v7.3(®). RESULTS: Patients' median age was 70 years (range 39-82), median weight was 80 kg (45-129), median APACHE II score at admission was 21 (13-33) and median SOFA score on the day of study was 11 (8-21). The final population PK model was characterized by CL (L/h) = 6.11 * [weight (kg)/80](1.39) * CLMEMB. If membrane = 1.5 m(2) AN69ST, CLMEMB = 1; if membrane = 0.9 m(2) AN69, CLMEMB = 0.51. Monte Carlo simulations showed that: (i) to maintain unbound piperacillin concentrations above the MIC for the bacteria for 100% of dosing interval T (100%fuT>MIC), patients receiving CVVHDF with 1.5 m(2) AN69ST membranes required doses of 4000 mg q8h for the treatment of bacteria with a susceptibility to piperacillin close to the clinical breakpoint (MIC = 8-16 mg/L) (2000 mg q8h was sufficient for patients with CVVHDF using 0.9 m(2) AN69 membranes); and (ii) for the treatment of bacteria with high susceptibility to piperacillin (MIC <4 mg/L) or for the attainment of a more traditional pharmacodynamic target (50%fuT>MIC), 2000 mg q8h sufficed regardless of type of membrane and body weight. CONCLUSIONS: Our results suggest that type of membrane and body weight should be considered for piperacillin dose titration in critically ill patients with MODS and CVVHDF requirement.

Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements.

Meropenem dosing in critically ill patients with septic shock and continuous renal replacement therapy (CRRT) is complex, with the recommended maintenance doses being 500 mg to 1,000 mg every 8 h (q8h) to every 12 h. This multicenter study aimed to describe the pharmacokinetics (PKs) of meropenem in this population to identify the sources of PK variability and to evaluate different dosing regimens to develop recommendations based on clinical parameters. Thirty patients with septic shock and CRRT receiving meropenem were enrolled (153 plasma samples were tested). A population PK model was developed with data from 24 patients and subsequently validated with data from 6 patients using NONMEM software (v.7.3). The final model was characterized by CL = 3.68 + 0.22 · (residual diuresis/100) and V = 33.00 · (weight/73)(2.07), where CL is total body clearance (in liters per hour), residual diuresis is the volume of residual diuresis (in milliliters per 24 h), and V is the apparent volume of distribution (in liters). CRRT intensity was not identified to be a CL modifier. Monte Carlo simulations showed that to maintain concentrations of the unbound fraction (fu ) of drug above the MIC of the bacteria for 40% of dosing interval T (referred to as 40% of the ƒ uT >MIC), a meropenem dose of 500 mg q8h as a bolus over 30 min would be sufficient regardless of the residual diuresis. If 100% of the ƒ uT >MIC was chosen as the target, oligoanuric patients would require 500 mg q8h as a bolus over 30 min for the treatment of susceptible bacteria (MIC < 2 mg/liter), while patients with preserved diuresis would require the same dose given as an infusion over 3 h. If bacteria with MICs close to the resistance breakpoint (2 to 4 mg/liter) were to be treated with meropenem, a dose of 500 mg every 6 h would be necessary: a bolus over 30 min for oligoanuric patients and an infusion over 3 h for patients with preserved diuresis. Our results suggest that residual diuresis may be an easy and inexpensive tool to help with titration of the meropenem dose and infusion time in this challenging population.

Operational evaluation of the earlobe arterialized blood collector in critically ill patients.

BACKGROUND: The new Earlobe Arterialized Blood Collector (EABC®) is a minimally invasive prototype system able to perform capillary blood collection from the earlobe (EL) with minimal training and risk. This system could improve medical emergency management in extreme environments. Consequently, a prospective validation study was designed to evaluate operational performance of the EABC® in a cohort of critically ill patients. METHODS: Arterialized capillary blood was sampled from the EL of 55 invasively ventilated patients using the EABC® following a validated procedure. Operational characteristics such as the number of cuts and cartridges required, sampling failure/success ratio, bleeding complications, storage requirements and other auxiliary aspects were recorded. Result turnaround laboratory times (TAT) were compared with published references. RESULTS: Blood collection was as easily performed on one earlobe as the other. Twenty-six minutes (mean 25.8; SD = 3.8) were required to obtain results, 15 min for patient preparation (mean 15.3; SD = 2.6) + 11 min for sampling and analysis (mean 11.4; SD = 2.1), which is similar to published hospital reference laboratory TAT. The average number of cartridges required was 1.3 (1-3; mode = 1) with the mean number of cut attempts being 1.2 (1-4; mode = 1). Problems/difficulties occurred in 59% of cases but were mainly attributed to patient's demographic characteristics, with only 10% attributable to the collector (superficial cut, blood leak, collector misalignment and obstructed vision). Haemostasis was quickly achieved with minimum complications. Storage of the complete sampling kit required a 300 × 300 × 300 mm box. Two 9-V batteries were used during the 2-year study period. CONCLUSIONS: The new EABC® system concept is safe, fast and easy to use. Observed problems/difficulties are easily amendable with certain design modifications. Definitive versions of the prototype have the potential for significant benefits for isolated and extreme environments in medicine.

Active transmembrane drug transport in microgravity: a validation study using an ABC transporter model.

Microgravity has been shown to influence the expression of ABC (ATP-Binding Cassette) transporters in bacteria, fungi and mammals, but also to modify the activity of certain cellular components with structural and functional similarities to ABC transporters. Changes in activity of ABC transporters could lead to important metabolic disorders and undesired pharmacological effects during spaceflights. However, no current means exist to study the functionality of these transporters in microgravity. To this end, a Vesicular Transport Assay (®) (Solvo Biotechnology, Hungary) was adapted to evaluate multi-drug resistance-associated protein 2 (MRP2) trans-membrane estradiol-17-ß-glucuronide (E17ßG) transport activity, when activated by adenosine-tri-phosphate (ATP) during parabolic flights. Simple diffusion, ATP-independent transport and benzbromarone inhibition were also evaluated. A high accuracy engineering system was designed to perform, monitor and synchronize all procedures. Samples were analysed using a validated high sensitivity drug detection protocol. Experiments were performed in microgravity during parabolic flights, and compared to 1g on ground results using identical equipment and procedures in all cases. Our results revealed that sufficient equipment accuracy and analytical sensitivity were reached to detect transport activity in both gravitational conditions. Additionally, transport activity levels of on ground samples were within commercial transport standards, proving the validity of the methods and equipment used. MRP2 net transport activity was significantly reduced in microgravity, so was signal detected in simple diffusion samples. Ultra-structural changes induced by gravitational stress upon vesicle membranes or transporters could explain the current results, although alternative explanations are possible. Further research is needed to provide a conclusive answer in this regard. Nevertheless, the present validated technology opens new and interesting research lines in biology and human physiology with the potential for significant benefits for both space and terrestrial medicine.

Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy.

Although early and appropriate antibiotic therapy remains the most important intervention for successful treatment of septic shock, data guiding optimization of beta-lactam prescription in critically ill patients prescribed with continuous renal replacement therapy (CRRT) are still limited. Being small hydrophilic molecules, beta-lactams are likely to be cleared by CRRT to a significant extent. As a result, additional variability may be introduced to the per se variable antibiotic concentrations in critically ill patients. This article aims to describe the current clinical scenario for beta-lactam dosing in critically ill patients with septic shock and CRRT, to highlight the sources of variability among the different studies that reduce extrapolation to clinical practice, and to identify the opportunities for future research and improvement in this field. Three frequently prescribed beta-lactams (meropenem, piperacillin and ceftriaxone) were chosen for review. Our findings showed that present dosing recommendations are based on studies with drawbacks limiting their applicability in the clinical setting. In general, current antibiotic dosing regimens for CRRT follow a one-size-fits-all fashion despite emerging clinical data suggesting that drug clearance is partially dependent on CRRT modality and intensity. Moreover, some studies pool data from heterogeneous populations with CRRT that may exhibit different pharmacokinetics (for example, admission diagnoses different to septic shock, such as trauma), which also limit their extrapolation to critically ill patients with septic shock. Finally, there is still no consensus regarding the %T>MIC (percentage of dosing interval when concentration of the antibiotic is above the minimum inhibitory concentration of the pathogen) value that should be chosen as the pharmacodynamic target for antibiotic therapy in patients with septic shock and CRRT. For empirically optimized dosing, during the first day a loading dose is required to compensate the increased volume of distribution, regardless of impaired organ function. An additional loading dose may be required when CRRT is initiated due to steady-state equilibrium breakage driven by clearance variation. From day 2, dosing must be adjusted to CRRT settings and residual renal function. Therapeutic drug monitoring of beta-lactams may be regarded as a useful tool to daily individualize dosing and to ensure optimal antibiotic exposure.

Earlobe arterialized capillary blood gas analysis in the intensive care unit: a pilot study.

BACKGROUND: Earlobe arterialized capillary blood gas analysis can be used to estimate arterial gas content and may be suitable for diagnosis and management of critically ill patients. However, its utility and applicability in the ICU setting remains unexplored. METHODS: A prospective observational validation study was designed to evaluate this technique in a cohort of mechanically ventilated adult critically ill patients admitted to a polyvalent ICU. Precision and agreement between capillary gas measures and arterial references was examined. Acute Respiratory Distress Syndrome (ARDS) diagnosis capabilities with the proposed technique were also evaluated. Finally, factors associated with sampling failure were explored. RESULTS: Fifty-five patients were included into this study. Precision of capillary samples was high (Coefficient of Variation PO2 = 9.8%, PCO2 = 7.7%, pH = 0.3%). PO2 measures showed insufficient agreement levels (Concordance Correlation Coefficient = 0.45; bias = 12 mmHg; percentage of error = 19.3%), whereas better agreement was observed for PCO2 and pH (Concordance Correlation Coefficient = 0.94 and 0.93 respectively; depreciable bias; percentage of error 11.4% and 0.5% respectively). The sensitivity and specificity for diagnosing ARDS were 100% and 92.3% using capillary gasometric measures. Sampling was unsuccessful in 43.6% of cases due to insufficient blood flow. Age > 65 years was independently associated with failure (odds ratio = 1.6), however hemodynamic failure and norepinephrine treatment were also influencing factors. CONCLUSIONS: Earlobe capillary blood gas analysis is precise and can be useful for detecting extreme gasometrical values. Diagnosis of ARDS can be done accurately using capillary measurements. Although this technique may be insufficient for precise management of patients in the ICU, it has the potential for important benefits in the acute phase of various critical conditions and in other critical care arenas, such as in emergency medicine, advanced medical transport and pre-hospital critical care.