Stephan Ehrmann

Respiratory pulse pressure variation fails to predict fluid responsiveness in acute respiratory distress syndrome

IntroductionFluid responsiveness prediction is of utmost interest during acute respiratory distress syndrome (ARDS), but the performance of respiratory pulse pressure variation (ΔRESPPP) has scarcely been reported. In patients with ARDS, the pathophysiology of ΔRESPPP may differ from that of healthy lungs because of low tidal volume (Vt), high respiratory rate, decreased lung and sometimes chest wall compliance, which increase alveolar and/or pleural pressure. We aimed to assess ΔRESPPP in a large ARDS population.MethodsOur study population of nonarrhythmic ARDS patients without inspiratory effort were considered responders if their cardiac output increased by >10% after 500-ml volume expansion.ResultsAmong the 65 included patients (26 responders), the area under the receiver-operating curve (AUC) for ΔRESPPP was 0.75 (95% confidence interval (CI95): 0.62 to 0.85), and a best cutoff of 5% yielded positive and negative likelihood ratios of 4.8 (CI95: 3.6 to 6.2) and 0.32 (CI95: 0.1 to 0.8), respectively. Adjusting ΔRESPPP for Vt, airway driving pressure or respiratory variations in pulmonary artery occlusion pressure (ΔPAOP), a surrogate for pleural pressure variations, in 33 Swan-Ganz catheter carriers did not markedly improve its predictive performance. In patients with ΔPAOP above its median value (4 mmHg), AUC for ΔRESPPP was 1 (CI95: 0.73 to 1) as compared with 0.79 (CI95: 0.52 to 0.94) otherwise (P = 0.07). A 300-ml volume expansion induced a ≥2 mmHg increase of central venous pressure, suggesting a change in cardiac preload, in 40 patients, but none of the 28 of 40 nonresponders responded to an additional 200-ml volume expansion.ConclusionsDuring protective mechanical ventilation for early ARDS, partly because of insufficient changes in pleural pressure, ΔRESPPP performance was poor. Careful fluid challenges may be a safe alternative.

Clinical relevance of pulse pressure variations for predicting fluid responsiveness in mechanically ventilated intensive care unit patients: the grey zone approach

IntroductionPulse pressure variation (PPV) has been shown to predict fluid responsiveness in ventilated intensive care unit (ICU) patients. The present study was aimed at assessing the diagnostic accuracy of PPV for prediction of fluid responsiveness by using the grey zone approach in a large population.MethodsThe study pooled data of 556 patients from nine French ICUs. Hemodynamic (PPV, central venous pressure (CVP) and cardiac output) and ventilator variables were recorded. Responders were defined as patients increasing their stroke volume more than or equal to 15% after fluid challenge. The receiver operating characteristic (ROC) curve and grey zone were defined for PPV. The grey zone was evaluated according to the risk of fluid infusion in hypoxemic patients.ResultsFluid challenge led to increased stroke volume more than or equal to 15% in 267 patients (48%). The areas under the ROC curve of PPV and CVP were 0.73 (95% confidence interval (CI): 0.68 to 0.77) and 0.64 (95% CI 0.59 to 0.70), respectively (P <0.001). A grey zone of 4 to 17% (62% of patients) was found for PPV. A tidal volume more than or equal to 8 ml.kg-1 and a driving pressure (plateau pressure - PEEP) more than 20 cmH2O significantly improved the area under the ROC curve for PPV. When taking into account the risk of fluid infusion, the grey zone for PPV was 2 to 13%.ConclusionsIn ventilated ICU patients, PPV values between 4 and 17%, encountered in 62% patients exhibiting validity prerequisites, did not predict fluid responsiveness.

Noninvasive monitoring of blood pressure in the critically ill: reliability according to the cuff site (arm, thigh, or ankle).

Objective:In the critically ill, blood pressure measurements mostly rely on automated oscillometric devices pending the intra-arterial catheter insertion or after its removal. If the arms are inaccessible, the cuff is placed at the ankle or the thigh, but this common practice has never been assessed. We evaluated the reliability of noninvasive blood pressure readings at these anatomic sites. Design:Prospective observational study. Setting:Medical–surgical intensive care unit. Patients:Patients carrying an arterial line with no severe occlusive arterial disease. Intervention:Each patient underwent a set of three pairs of noninvasive and intra-arterial measurements at each site (arm, ankle, thigh [if Ramsay sedation scale >4]) and, in case of circulatory failure, a second set of measurements after a cardiovascular intervention (volume expansion, change in catecholamine dosage). Measurements and Main Results:In 150 patients, whatever the cuff site, the agreement between invasive and noninvasive readings was markedly higher for mean arterial pressure than for systolic or diastolic pressure. For mean arterial pressure measurement, arm noninvasive blood pressure was reliable (mean bias of 3.4 ± 5.0 mm Hg, lower/upper limit of agreement of –6.3/13.1 mm Hg) contrary to ankle or thigh noninvasive blood pressure (mean bias of 3.1 ± 7.7 mm Hg and 5.7 ± 6.8 mm Hg and lower/upper limits of agreement of –12.1/18.3 mm Hg and –7.7/19.2 mm Hg, respectively). During acute circulatory failure (n = 83), arm noninvasive blood pressure but also ankle and thigh noninvasive blood pressure allowed a reliable detection of 1) invasive mean arterial pressure <65 mm Hg (area under the receiver operating characteristic curve of 0.98 [0.92–1], 0.93 [0.85–0.97], and 0.93 [0.85–0.98] for arm, ankle, and thigh noninvasive blood pressure, respectively); and 2) a significant (>10%) increase in invasive mean arterial pressure after a cardiovascular intervention (area under the receiver operating characteristic curve of 0.99 [0.92–1], 0.90 [0.80–0.97], and 0.96 [0.87–0.99], respectively). Conclusion:In our population, arm noninvasive mean arterial pressure readings were accurate. Either the ankle or the thigh may be reliable alternatives, only to detect hypotensive and therapy-responding patients. (Crit Care Med 2012; 40:–1213)

Tracking Hypotension and Dynamic Changes in Arterial Blood Pressure with Brachial Cuff Measurements

BACKGROUND: Arterial cannulation is strongly recommended during shock. Nevertheless, this procedure is associated with significant risks and may delay other emergent procedures. We assessed the discriminative power of brachial cuff oscillometric noninvasive blood pressure (NIBP) for identifying patients with an invasive mean arterial blood pressure (MAP) below 65 mm Hg or increasing their invasive MAP after cardiovascular interventions. METHODS: This prospective study, conducted in three intensive care units, included adults in circulatory failure who underwent 45° passive leg raising, 300 mL fluid loading, and additional 200 mL fluid loading. The collected data were four invasive and noninvasive MAP measurements at each study phase. RESULTS: Among 111 patients (50 septic, 15 cardiogenic, and 46 other source of shock), when averaging measurements of each study phase, NIBP measurements accurately predicted an invasive MAP lower than 65 mm Hg: area under the receiver operating characteristic curve 0.90 (95% CI: 0.71–1), positive and negative likelihood ratios 7.7 (95% CI: 5.4–11) and 0.31 (95% CI: 0.22–0.44) (cutoff 65 mm Hg). For identifying patients increasing their invasive MAP by more than 10%, the area under the receiver operating characteristic curve was 0.95 (95% CI: 0.92–0.96); positive and negative likelihood ratios (cutoff 10%) were 25.7 (95% CI: 10.8–61.4) and 0.26 (95% CI: 0.2–0.34). CONCLUSIONS: NIBP measurements have a good discriminative power for identifying hypotensive patients and performed even better in tracking MAP changes, provided that one averages four NIBP measurements.

Acute Kidney Injury in the Critically Ill: Is Iodinated Contrast Medium Really Harmful?*

Objectives:To assess whether the use of iodinated contrast medium increases the incidence of acute kidney injury in ICU patients, compared with patients not receiving iodinated contrast medium. Design:Prospective observational matched cohort study. Setting:Two ICUs in two tertiary teaching hospitals. Patients:A total of 380 adults were included (20% more than once), before an iodinated contrast medium infusion (contrast inclusions, n = 307) or before an intrahospital transfer without iodinated contrast medium infusion (control inclusions, n = 170). Interventions:None. Measurements and Main Results:Among contrast inclusions, iodinated contrast medium–associated acute kidney injury occurred after 23 administrations (7.5%) according to the Acute Kidney Injury Network definition (stage ≥ 1, over 48 hr). As expected, a broader definition (≥ 25% increase in serum creatinine over 72 hr) yielded a greater incidence (16%). In 146 pairs of contrast and control inclusions, matched on propensity for iodinated contrast medium infusion, the incidence of acute kidney injury was similar (absolute difference in incidence, 0%; 95% confidence interval, –5.2; 5.2%), Acute Kidney Injury Network definition). Hospital mortality was also similar in 71 contrast and 71 control patients included only once and matched the same way. Contrary to iodinated contrast medium infusion (odds ratio, 1.57; 95% confidence interval, 0.69–3.53), the Sequential Organ Failure Assessment score at inclusion (odds ratio, 1.18; 95% confidence interval, 1.07–1.31) and the number of other nephrotoxic agents (odds ratio, 1.38; 95% confidence interval, 1.03–1.85) were independent risk factors for acute kidney injury. Conclusions:The specific toxic effect of monomeric nonionic low-osmolar iodinated contrast medium in ICU patients with multiple renal aggressions seemed minimal. Severity of disease and the global nephrotoxic burden were risk factors for acute kidney injury, regardless of iodinated contrast medium infusion.

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

AIMS To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock. METHODS Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling. RESULTS The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h(-1) (49%), a mean half-life of 9.6 h (range 0.83-28.6 h) and a total volume of distribution of 19.5 l (range 6.48-35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low. CONCLUSIONS Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (>1 mg l(-1)).

Heterogeneity in the Definition of Mechanical Ventilation Duration and Ventilator-Free Days

An estimated one-third of patients admitted to an intensive care unit (ICU) will present with respiratory failure, thus requiring invasive mechanical ventilation (MV) to help or replace spontaneous breathing (1). This therapy is associated with high morbidity (2). Therefore, duration of MV is often used as an outcome. Death, which is frequent (an estimated one-third of patients who require MV die [2]), is a competing event to extubation. During the 1990s, exposure to MV was proposed to be assessed by an index that combines both MV duration and death status: ventilator-free days (VFDs) (3). VFDs are defined as follows: “one point [for] each day during the measurement period that [patients] are both alive and free of mechanical ventilation. A patient who is extubated on Day 2 of the study and remains alive and free of the ventilator for the remainder of the 28-day study period would receive a VFD score of 26, whereas the patient who is ventilated until death on Day 2 would receive a score of zero” (4). VFDs are now widely used as an outcome in randomized controlled trials (RCTs) (5) and are also advised as a potential primary end point (6). However, the definitions of both MV duration and VFDs are not standardized. For instance, to calculate VFDs, a dead patient may receive “a score of 0” or “the number of days between extubation and death” (7). We aimed to review the definitions of MV duration and VFDs in RCTs of adults in ICUs and to illustrate how the definitions affect individual patient values for these outcome variables.

Ventilator-Integrated Jet Nebulization Systems: Tidal Volume Control and Efficiency of Synchronization

BACKGROUND: Jet nebulizers constitute the aerosolization devices most frequently used during mechanical ventilation. Continuous nebulization can influence the delivered tidal volume (VT) and lead to significant medication loss during expiration. Ventilators thus provide integrated jet nebulization systems that are synchronized during inspiration and ostensibly keep VT constant. METHODS: This was a bench study of systems integrated in the Evita XL, Avea, Galileo, and G5 ventilators. The VT delivered with and without nebulization, the inspiratory synchronization of nebulization, and the aerosol deposition were measured with 2 locations of the nebulizer. RESULTS: Changes in VT with the nebulizer were below 20 mL and below 10% of set VT for all ventilators. Synchronization was good at the beginning of insufflation, but prolonged nebulization was observed with all ventilators at the end of insufflation, until up to 1 s during expiration: 5–80% of nebulization occurred during expiration with significant aerosol loss in the expiratory limb. Synchrony could be improved by (1) reducing gas compression/decompression phenomena proximal to the jet nebulizer and (2) increasing inspiratory time, which reduced the amount of nebulization occurring during expiration. Placing the nebulizer upstream in the inspiratory limb did not affect inspiratory synchrony but allowed reduction of the amount of aerosol lost in the expiratory limb. CONCLUSIONS: Jet nebulizer systems integrated in the tested ventilators are reliable in terms of VT control. Gas compression in tubing driving gas to the nebulizer delays synchronization and reduces nebulization yield if the nebulizer is placed close to the Y-piece. Increasing inspiratory time with no end-inspiratory pause reduces the expiratory loss of medication if placement of the nebulizer upstream in the inspiratory limb is not feasible.

Bioequivalence of inhaled drugs: fundamentals, challenges and perspectives

Interest in bioequivalence (BE) of inhaled drugs derives largely from the desire to offer generic substitutes to successful drug products. The complexity of aerosol dosage forms renders them difficult to mimic and raises questions regarding definitions of similarities and those properties that must be controlled to guarantee both the quality and the efficacy of the product. Despite a high level of enthusiasm to identify and control desirable properties there is no clear guidance, regulatory or scientific, for the variety of aerosol dosage forms, on practical measures of BE from which products can be developed. As more data on the pharmaceutical and clinical relevance of various techniques, as described in this review, become available, it is likely that a path to the demonstration of BE will become evident. In the meantime, debate on this topic will continue.

Blood pressure monitoring during arrhythmia: agreement between automated brachial cuff and intra-arterial measurements

BACKGROUND Since arrhythmia induces irregular pulse waves, it is widely considered to cause flawed oscillometric brachial cuff measurements of blood pressure (BP). However, strong data are lacking. We assessed whether the agreement of oscillometric measurements with intra-arterial measurements is worse during arrhythmia than during regular rhythm. METHODS Among patients of three intensive care units (ICUs), a prospective comparison of three pairs of intra-arterial and oscillometric BP readings was performed among patients with arrhythmia and an arterial line already present. After each inclusion in the arrhythmia group, one patient with regular rhythm was included as a control. International Organization for Standardization (ISO) standard validation required a mean bias <5 (sd 8) mm Hg. RESULTS In 135 patients with arrhythmia, the agreement between oscillometric and intra-arterial measurements of systolic, diastolic and mean BP was similar to that observed in 136 patients with regular rhythm: for mean BP, similar mean bias [-0.1 (sd 5.2) and 1.9 (sd 5.9) mm Hg]. In both groups, the ISO standard was satisfied for mean and diastolic BP, but not for systolic BP (sd >10 mm Hg) in our ICU population. The ability of oscillometry to detect hypotension (systolic BP <90 mm Hg or mean BP <65 mm Hg), response to therapy (>10% increase in mean BP after cardiovascular intervention) and hypertension (systolic BP >140 mm Hg) was good and similar during arrhythmia and regular rhythm (respective areas under the receiver operating characteristic curves ranging from 0.89 to 0.96, arrhythmia vs regular rhythm between-group comparisons all associated with P>0.3). CONCLUSIONS Contrary to widespread belief, arrhythmia did not cause flawed automated brachial cuff measurements.