Leo Anthony Celi

Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial).

We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.

The eICU: it's not just telemedicine.

Intensive care units (ICUs) are major sites for medical errors and adverse events. Suboptimal outcomes reflect a widespread failure to implement care delivery systems that successfully address the complexity of modern ICUs. Whereas other industries have used information technologies to fundamentally improve operating efficiency and enhance safety, medicine has been slow to implement such strategies. Most ICUs do not even track performance; fewer still have the capability to examine clinical data and use this information to guide quality improvement initiatives. This article describes a technology-enabled care model (electronic ICU, or eICU) that represents a new paradigm for delivery of critical care services. A major component of the model is the use of telemedicine to leverage clinical expertise and facilitate a round-the-clock proactive care by intensivist-led teams of ICU caregivers. Novel data presentation formats, computerized decision support, and smart alarms are used to enhance efficiency, increase effectiveness, and standardize clinical and operating processes. In addition, the technology infrastructure facilitates performance improvement by providing an automated means to measure outcomes, track performance, and monitor resource utilization. The program is designed to support the multidisciplinary intensivist-led team model and incorporates comprehensive ICU re-engineering efforts to change practice behavior. Although this model can transform ICUs into centers of excellence, success will hinge on hospitals accepting the underlying value proposition and physicians being willing to change established practices.

Proton-pump inhibitor use is associated with low serum magnesium concentrations.

Although case reports link proton-pump inhibitor (PPI) use and hypomagnesemia, no large-scale studies have been conducted. Here we examined the serum magnesium concentration and the likelihood of hypomagnesemia (<1.6 mg/dl) with a history of PPI or histamine-2 receptor antagonist used to reduce gastric acid, or use of neither among 11,490 consecutive adult admissions to an intensive care unit of a tertiary medical center. Of these, 2632 patients reported PPI use prior to admission, while 657 patients were using a histamine-2 receptor antagonist. PPI use was associated with 0.012 mg/dl lower adjusted serum magnesium concentration compared to users of no acid-suppressive medications, but this effect was restricted to those patients taking diuretics. Among the 3286 patients concurrently on diuretics, PPI use was associated with a significant increase of hypomagnesemia (odds ratio 1.54) and 0.028 mg/dl lower serum magnesium concentration. Among those not using diuretics, PPI use was not associated with serum magnesium levels. Histamine-2 receptor antagonist use was not significantly associated with magnesium concentration without or with diuretic use. The use of PPI was not associated with serum phosphate concentration regardless of diuretic use. Thus, we verify case reports of the association between PPI use and hypomagnesemia in those concurrently taking diuretics. Hence, serum magnesium concentrations should be followed in susceptible individuals on chronic PPI therapy.

Human cerebrovascular and ventilatory CO2 reactivity to end-tidal, arterial and internal jugular vein PCO2

This study examined cerebrovascular reactivity and ventilation during step changes in CO2 in humans. We hypothesized that: (1) end‐tidal P  CO 2 (P  ET,CO 2 ) would overestimate arterial P  CO 2 (P  a,CO 2 ) during step variations in P  ET,CO 2 and thus underestimate cerebrovascular CO2 reactivity; and (2) since P  CO 2 from the internal jugular vein (P  jv,CO 2 ) better represents brain tissue P  CO 2, cerebrovascular CO2 reactivity would be higher when expressed against P  jv,CO 2 than with P  a,CO 2, and would be related to the degree of ventilatory change during hypercapnia. Incremental hypercapnia was achieved through 4 min administrations of 4% and 8% CO2. Incremental hypocapnia involved two 4 min steps of hyperventilation to change P  ET,CO 2, in an equal and opposite direction, to that incurred during hypercapnia. Arterial and internal jugular venous blood was sampled simultaneously at baseline and during each CO2 step. Cerebrovascular reactivity to CO2 was expressed as the percentage change in blood flow velocity in the middle cerebral artery (MCAv) per mmHg change in P  a,CO 2 and P  jv,CO 2. During hypercapnia, but not hypocapnia, P  ET,CO 2 overestimated P  a,CO 2 by +2.4 ± 3.4 mmHg and underestimated MCAv‐CO2 reactivity (P < 0.05). The hypercapnic and hypocapnic MCAv‐CO2 reactivity was higher (∼97% and ∼24%, respectively) when expressed with P  jv,CO 2 than P  a,CO 2 (P < 0.05). The hypercapnic MCAv–P  jv,CO 2 reactivity was inversely related to the increase in ventilatory change (R2= 0.43; P < 0.05), indicating that a reduced reactivity results in less central CO2 washout and greater ventilatory stimulus. Differences in the P  ET,CO 2, P  a,CO 2 and P  jv,CO 2 –MCAv relationships have implications for the true representation and physiological interpretation of cerebrovascular CO2 reactivity.

“Big Data” in the Intensive Care Unit. Closing the Data Loop

The data generated in the process of medical care has historically not just been underused, it has been wasted. This was due in part to the difficulty of accessing, organizing, and using data entered on paper charts, but notable variability in clinical documentation methods and quality made the problem even more challenging. In the absence of a practical way to systematically capture, analyze, and integrate the information contained in the massive amount of data generated during patient care, medicine has remained a highly empirical process in which the disconnected application of individual experiences and subjective preferences continues to thwart continuous improvement and consistent delivery of best practices to all patients.

Red cell distribution width improves the simplified acute physiology score for risk prediction in unselected critically ill patients

IntroductionRecently, red cell distribution width (RDW), a measure of erythrocyte size variability, has been shown to be a prognostic marker in critical illness. The aim of this study was to investigate whether adding RDW has the potential to improve the prognostic performance of the simplified acute physiology score (SAPS) to predict short- and long-term mortality in an independent, large, and unselected population of intensive care unit (ICU) patients.MethodsThis observational cohort study includes 17,922 ICU patients with available RDW measurements from different types of ICUs. We modeled the association between RDW and mortality by using multivariable logistic regression, adjusting for demographic factors, comorbidities, hematocrit, and severity of illness by using the SAPS.ResultsICU-, in-hospital-, and 1-year mortality rates in the 17,922 included patients were 7.6% (95% CI, 7.2 to 8.0), 11.2% (95% CI, 10.8 to 11.7), and 25.4% (95% CI, 24.8 to 26.1). RDW was significantly associated with in-hospital mortality (OR per 1% increase in RDW (95%CI)) (1.14 (1.08 to 1.19), P < 0.0001), ICU mortality (1.10 (1.06 to 1.15), P < 0.0001), and 1-year mortality (1.20 (95% CI, 1.14 to 1.26); P < 0.001). Adding RDW to SAPS significantly improved the AUC from 0.746 to 0.774 (P < 0.001) for in-hospital mortality and 0.793 to 0.805 (P < 0.001) for ICU mortality. Significant improvements in classification of SAPS were confirmed in reclassification analyses. Subgroups demonstrated robust results for gender, age categories, SAPS categories, anemia, hematocrit categories, and renal failure.ConclusionsRDW is a promising independent short- and long-term prognostic marker in ICU patients and significantly improves risk stratification of SAPS. Further research is needed the better to understand the pathophysiology underlying these effects.

Human cerebral arteriovenous vasoactive exchange during alterations in arterial blood gases

Cerebral blood flow (CBF) is highly regulated by changes in arterial Pco(2) and arterial Po(2). Evidence from animal studies indicates that various vasoactive factors, including release of norepinephrine, endothelin, adrenomedullin, C-natriuretic peptide (CNP), and nitric oxide (NO), may play a role in arterial blood gas-induced alterations in CBF. For the first time, we directly quantified exchange of these vasoactive factors across the human brain. Using the Fick principle and transcranial Doppler ultrasonography, we measured CBF in 12 healthy humans at rest and during hypercapnia (4 and 8% CO(2)), hypocapnia (voluntary hyperventilation), and hypoxia (12 and 10% O(2)). At each level, blood was sampled simultaneously from the internal jugular vein and radial artery. With the exception of CNP and NO, the simultaneous quantification of norepinephrine, endothelin, or adrenomedullin showed no cerebral uptake or release during changes in arterial blood gases. Hypercapnia, but not hypocapnia, increased CBF and caused a net cerebral release of nitrite (a marker of NO), which was reflected by an increase in the venous-arterial difference for nitrite: 57 +/- 18 and 150 +/- 36 micromol/l at 4% and 8% CO(2), respectively (both P < 0.05). Release of cerebral CNP was also observed during changes in CO(2) (hypercapnia vs. hypocapnia, P < 0.05). During hypoxia, there was a net cerebral uptake of nitrite, which was reflected by a decreased venous-arterial difference for nitrite: -96 +/- 14 micromol/l at 10% O(2) (P < 0.05). These data indicate that there is a differential exchange of NO across the brain during hypercapnia and hypoxia and that CNP may play a complementary role in CO(2)-induced CBF changes.

Dynamic cerebral autoregulation and baroreflex sensitivity during modest and severe step changes in arterial PCO2

Changes in the partial pressure of arterial CO2 (PaCO2) regulates cerebrovascular tone and dynamic cerebral autoregulation (CA). Elevations in PaCO2 also increases autonomic neural activity and may alter the arterial baroreflex. We hypothesized that hypercapnia would impair, and hypocapnia would improve, dynamic CA and that these changes would occur independently of any change in baroreflex sensitivity (BRS). In 10 healthy male subjects, incremental hypercapnia was achieved through 4-min administrations of 4% and 8% CO2. Incremental hypocapnia involved two 4-min steps of hyperventilation to change end-tidal PCO2, in an equal and opposite direction, to that incurred during hypercapnia. End-tidal, arterial and internal jugular vein PCO2 were sampled simultaneously at baseline and during each CO2 step. Dynamic CA and BRS was assessed at baseline and during each step change in PaCO2 using spectral and transfer-function analysis of beat-by-beat changes in mean arterial blood pressure (MAP), heart rate and flow velocity in the middle cerebral arterial (MCAv). Critical closing pressure (CCP), an estimate of cerebrovascular tone, was estimated from extrapolation of the MAP-MCAv waveforms. Hypercapnia caused a progressive increase in PaCO2 and MCAv whereas hypocapnia caused the opposite effect. Despite marked changes in CPP, there were no evident change in transfer-function gain, coherence, MAP variability or BRS; however, both MCAv variability and phase in the very-low frequency range was reduced during the most severe level of hyper- and hypocapnia (P < 0.05), and were related to elevations in ventilation (R2 = 0.42-0.52, respectively; P < 0.001). It seems that hyperventilation, rather than PaCO2, has an important influence on dynamic CA.

Big data in global health: improving health in low- and middle-income countries

Abstract Over the last decade, a massive increase in data collection and analysis has occurred in many fields. In the health sector, however, there has been relatively little progress in data analysis and application despite a rapid rise in data production. Given adequate governance, improvements in the quality, quantity, storage and analysis of health data could lead to substantial improvements in many health outcomes. In low- and middle-income countries in particular, the creation of an information feedback mechanism can move health-care delivery towards results-based practice and improve the effective use of scarce resources. We review the evolving definition of big data and the possible advantages of – and problems in – using such data to improve health-care delivery in low- and middle-income countries. The collection of big data as mobile-phone based services improve may mean that development phases required elsewhere can be skipped. However, poor infrastructure may prevent interoperability and the safe use of patient data. An appropriate governance framework must be developed and enforced to protect individuals and ensure that health-care delivery is tailored to the characteristics and values of the target communities.

Accessing the public MIMIC-II intensive care relational database for clinical research

BackgroundThe Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC-II) database is a free, public resource for intensive care research. The database was officially released in 2006, and has attracted a growing number of researchers in academia and industry. We present the two major software tools that facilitate accessing the relational database: the web-based QueryBuilder and a downloadable virtual machine (VM) image.ResultsQueryBuilder and the MIMIC-II VM have been developed successfully and are freely available to MIMIC-II users. Simple example SQL queries and the resulting data are presented. Clinical studies pertaining to acute kidney injury and prediction of fluid requirements in the intensive care unit are shown as typical examples of research performed with MIMIC-II. In addition, MIMIC-II has also provided data for annual PhysioNet/Computing in Cardiology Challenges, including the 2012 Challenge “Predicting mortality of ICU Patients”.ConclusionsQueryBuilder is a web-based tool that provides easy access to MIMIC-II. For more computationally intensive queries, one can locally install a complete copy of MIMIC-II in a VM. Both publicly available tools provide the MIMIC-II research community with convenient querying interfaces and complement the value of the MIMIC-II relational database.