Eric Hoste

Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

IntroductionAcute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI.MethodsWe performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection.ResultsModerate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P <0.002), none of which achieved an AUC >0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method.ConclusionsTwo novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI.Trial registrationClinicalTrials.gov number NCT01209169.

Variation in critical care services across North America and Western Europe

Objective:Critical care represents a large percentage of healthcare spending in developed countries. Yet, little is known regarding international variation in critical care services. We sought to understand differences in critical care delivery by comparing data on the distribution of services in eight countries. Design:Retrospective review of existing national administrative data. We identified sources of data in each country to provide information on acute care hospitals and beds, intensive care units and beds, intensive care admissions, and definitions of intensive care beds. Data were all referenced and from as close to 2005 as possible. Setting:United States, France, United Kingdom, Canada, Belgium, Germany, The Netherlands, and Spain. Patients:Not available. Interventions:None. Measurements and Main Results:No standard definition existed for acute care hospital or intensive care unit beds across countries. Hospital beds varied three-fold from 221/100,000 population in the United States to 593/100,000 in Germany. Adult intensive care unit beds also ranged seven-fold from 3.3/100,000 population in the United Kingdom to 24.0/100,000 in Germany. Volume of intensive care unit admissions per year varied ten-fold from 216/100,000 population in the United Kingdom to 2353/100,000 in Germany. The ratio of intensive care unit beds to hospital beds was highly correlated across all countries except the United States (r = .90). There was minimal correlation between the number of intensive care unit beds per capita and health care spending per capita (r = .45), but high inverse correlation between intensive care unit beds and hospital mortality for intensive care unit patients across countries (r = −.82). Conclusions:Absolute critical care services vary dramatically between countries with wide differences in both numbers of beds and volume of admissions. The number of intensive care unit beds per capita is not strongly correlated with overall health expenditure, but does correlate strongly with mortality. These findings demonstrate the need for critical care data from all countries, as they are essential for interpretation of studies, and policy decisions regarding critical care services.

Epidemiology of acute kidney injury: how big is the problem?

Objective:Acute kidney injury (AKI) is a complication that occurs frequently in hospitalized patients. In this article, we provide an overview of the literature on the epidemiology of AKI in hospitalized patients. Patients and Setting:The overview is restricted to hospitalized patients, and most emphasis is put on intensive care unit patients. Measurements and Main Results:The population incidence of less severe AKI and AKI treated with renal replacement therapy is approximately 2,000–3,000 and 200–300 per million population per year, respectively. These numbers are comparable with the estimates for severe sepsis and acute lung injury. Approximately 4–5% of general intensive care unit patients will be treated with renal replacement therapy, and up to two thirds of intensive care unit patients will develop AKI defined by the RIFLE classification. The incidence of AKI is increasing. Intensive care unit patients with AKI have a longer length of stay and therefore generate greater costs. In addition, AKI is associated with increased mortality, even after correction for covariates. Increasing RIFLE class is associated with increasing risk of in-hospital death. Patients with AKI who are treated with renal replacement therapy still have a mortality rate of 50–60%. Of surviving patients, 5–20% remain dialysis dependent at hospital discharge. Conclusion:AKI has a high incidence, comparable with acute lung injury and severe sepsis, and is associated with higher hospital mortality.

Acute Renal Failure in Patients with Sepsis in a Surgical ICU: Predictive Factors, Incidence, Comorbidity, and Outcome

Acute renal failure (ARF) is a common complication in intensive care unit (ICU) patients. Although there are several reports on outcome of septic patients with ARF, there are no data regarding predisposing factors for ARF. Therefore, the incidence of ARF was investigated in 185 sepsis patients admitted in a surgical ICU during a 16-mo period. Variables predisposing to ARF on day 1 of sepsis were evaluated with univariate and multivariable analyses. APACHE II and SOFA scores were compared during a 14-d period. Additionally, the impact of organ failure on mortality was evaluated. ARF developed in 16.2% of the patients, and 70.0% of these needed renal replacement therapy (RRT). Patients with ARF were more severely ill and had a higher mortality. Remarkably, serum creatinine was already increased on day 1. Creatinine > 1 mg/dl and pH < 7.30, both on day 1 of sepsis, were independently associated with ARF. Age, need for vasoactive therapy, mechanical ventilation, and RRT, but not ARF itself, were associated with mortality. In conclusion, ARF was a frequent complication in sepsis. Sepsis patients with ARF were more severely ill and had a higher mortality. Need for RRT was independently associated with mortality. A simple risk model for ARF, on basis of two readily available parameters on day 1 of sepsis, was developed. This model allows initiating specific therapeutic measures earlier in the course of sepsis, hopefully resulting in a lower incidence of ARF and needi for RRT, thereby lowering mortality.

Clinical and Economic Outcomes in Critically Ill Patients with Nosocomial Catheter-Related Bloodstream Infections

BACKGROUND Central venous catheters are universally used during the treatment of critically ill patients. Their use, however, is associated with a substantial infection risk, potentially leading to increased mortality and costs. We evaluate clinical and economic outcomes associated with nosocomial central venous catheter-related bloodstream infection (CR-BSI) in intensive care unit (ICU) patients. METHODS A retrospective (1992-2002), pairwise-matched (ratio of case patients to control subjects, 1:2 or 1:1), risk-adjusted cohort study was performed at a 54-bed general ICU at a university hospital. ICU patients with microbiologically documented CR-BSI (n = 176) were matched with control subjects (n = 315) on the basis of disease severity, diagnostic category, and length of ICU stay (equivalent or longer) before the onset of CR-BSI in the index case patient. Clinical outcome was principally evaluated by in-hospital mortality. Economic outcome was evaluated on the basis of duration of mechanical ventilation, length of ICU and hospital stays, and total hospital costs, as derived from the patients hospital invoices. RESULTS The attributable mortality rate for CR-BSI was estimated to be 1.8% (95% confidence interval, -6.4% to 10.0%); in-hospital mortality rates for patients with CR-BSI and matched control subjects were 27.8% and 26.0%, respectively. CR-BSI was associated with significant excesses in duration of mechanical ventilation, duration of ICU and hospital stays, and a significant increase in total hospital cost. Linear regression analysis with adjustment for duration of hospitalization and clinical covariates, revealed that CR-BSI is independently associated with higher costs. CONCLUSIONS In ICU patients, CR-BSI does not result in increased mortality. It is, however, associated with a significant economic burden, emphasizing the importance of continuous efforts in prevention.

Effects of nosocomial candidemia on outcomes of critically ill patients

PURPOSE To determine whether nosocomial candidemia is associated with increased mortality in intensive care unit (ICU) patients. SUBJECTS AND METHODS We performed a retrospective (1992 to 2000) cohort study of 73 ICU patients with candidemia and 146 matched controls. Controls were matched based on disease severity as measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score (+/- 1 point), diagnostic category, and length of ICU stay before onset of candidemia. RESULTS In comparison with the control group, patients with candidemia developed more acute respiratory failure (97% [n = 71] vs. 88% [n = 129], P = 0.03) during their ICU stay. They were mechanically ventilated for a longer period (29 +/- 26 days vs. 19 +/- 19 days, P<0.01) and had a longer stay in the ICU (36 +/- 33 days vs. 25 +/- 23 days, P = 0.02) as well as in the hospital (77 +/- 81 days vs. 64 +/- 69 days, P = 0.04). There was no difference in in-hospital mortality between the groups (48% [n = 35] vs. 43% [n = 62], P = 0.44), a difference of 5% (95% confidence interval [CI]: -8% to 19%). In a multivariate analysis, older age (hazard ratio [HR] = 1.13 per 10 years; 95% CI: 1.04 to 1.23; P = 0.004), acute renal failure (HR = 1.4; 95% CI: 1.1 to 2.0; P = 0.02), and unfavorable APACHE II scores (HR = 1.10 per 5 points; 95% CI: 1.00 to 1.20; P = 0.05) were independent predictors of mortality. Candidemia was not associated with mortality in a model that adjusted for these factors (HR = 0.9; 95% CI: 0.7 to 1.2; P = 0.53). CONCLUSION Nosocomial candidemia does not adversely affect the outcome in ICU patients in whom mortality is attributable to age, the severity of underlying disease, and acute illness.

Use of continuous bispectral EEG monitoring to assess depth of sedation in ICU patients

Abstract Monitoring the depth of sedation in patients under intensive care is difficult. Clinical assessment by the different scoring systems produces insufficient information, especially once deeply sedated patients become unresponsive to any external stimulation. Recently, the bispectral index (BIS), the result of computerized bispectral electroencephalographic monitoring, was found to be the best predictor of depth of anaesthesia during surgical intervention. This report concerns BIS monitoring in 18 randomly selected, deeply sedated, surgical patients in the intensive care unit, who were unresponsive to standard clinical stimulation (Ramsay sedation score). A wide range of BIS was observed, with 15 of the patients having a BIS below 60, indicating a state of deep sedation (or possibly oversedation). Therefore, further studies using BIS monitoring in patients under intensive care are needed to determine if this method can guide sedation and prevent oversedation in this context and, most importantly, to analyse its final cost – benefit ratio.

Severe burn injury in europe: a systematic review of the incidence, etiology, morbidity, and mortality

IntroductionBurn injury is a serious pathology, potentially leading to severe morbidity and significant mortality, but it also has a considerable health-economic impact. The aim of this study was to describe the European hospitalized population with severe burn injury, including the incidence, etiology, risk factors, mortality, and causes of death.MethodsThe systematic literature search (1985 to 2009) involved PubMed, the Web of Science, and the search engine Google. The reference lists and the Science Citation Index were used for hand searching (snowballing). Only studies dealing with epidemiologic issues (for example, incidence and outcome) as their major topic, on hospitalized populations with severe burn injury (in secondary and tertiary care) in Europe were included. Language restrictions were set on English, French, and Dutch.ResultsThe search led to 76 eligible studies, including more than 186,500 patients in total. The annual incidence of severe burns was 0.2 to 2.9/10,000 inhabitants with a decreasing trend in time. Almost 50% of patients were younger than 16 years, and ~60% were male patients. Flames, scalds, and contact burns were the most prevalent causes in the total population, but in children, scalds clearly dominated. Mortality was usually between 1.4% and 18% and is decreasing in time. Major risk factors for death were older age and a higher total percentage of burned surface area, as well as chronic diseases. (Multi) organ failure and sepsis were the most frequently reported causes of death. The main causes of early death (<48 hours) were burn shock and inhalation injury.ConclusionsDespite the lack of a large-scale European registration of burn injury, more epidemiologic information is available about the hospitalized population with severe burn injury than is generally presumed. National and international registration systems nevertheless remain necessary to allow better targeting of prevention campaigns and further improvement of cost-effectiveness in total burn care.

Modulation of Portal Graft Inflow: A Necessity in Adult Living-donor Liver Transplantation?

ObjectiveTo evaluate the clinical significance of modulating the recipient portal inflow (rPVF) through perioperative ligation of the splenic artery in adult living-donor liver transplantation (ALDLTx) by focusing on vascular complications, intractable ascites production, and the prevention of small-for-size syndrome (SFSS). Summary Background DataIn ALDLTx, portal graft flow is enhanced to at least twice the donor value, raising the total liver inflow. Recipient hepatic arterial flow (rHAF) is lower than expected. Portal hyperperfusion of small grafts in larger recipients is thought to be one of the main causes of posttransplant graft dysfunction/SFSS. MethodsSeventeen ALDLTx were reviewed for a minimum of 2 months. Patients were divided retrospectively into two groups: G1 (n = 7), without modulation of rPVF, and G2 (n = 10), with splenic artery ligation to decrease rPVF perioperatively. Donor and recipient hepatic hemodynamics were evaluated against graft function and outcome, including correlations between rPVF, graft weight, graft:recipient body weight ratio, and recipient weight. ResultsFollowing portal and arterial reperfusion, mean rPVF and rPVF/graft weight were much higher than in the donors, whereas mean rHAF and rHAF/graft weight were much lower. No differences were found between groups, except for rPVF and rHAF, which were much more higher and lower, respectively, before splenic artery ligation. In G1 patients, SFSS was seen in two patients and vascular complications occurred in two others. In G2 patients, splenic artery ligation permitted a significant decrease in rPVF, an improvement in rHAF, and the resolution of refractory ascites. Neither SFSS nor vascular complications were seen in G2 patients. ConclusionsWhen a suboptimal graft:recipient body weight ratio is accompanied by high rPVF in ALDLTx, the portal flow should be modulated perioperatively; splenic artery ligation is a simple and safe method that is sufficient to allow this modulation in most patients.

Decompressive laparotomy for abdominal compartment syndrome – a critical analysis

IntroductionAbdominal compartment syndrome (ACS) is increasingly recognized in critically ill patients, and the deleterious effects of increased intraabdominal pressure (IAP) are well documented. Surgical decompression through a midline laparotomy or decompressive laparotomy remains the sole definite therapy for ACS, but the effect of decompressive laparotomy has not been studied in large patient series.MethodsWe reviewed English literature from 1972 to 2004 for studies reporting the effects of decompressive laparotomy in patients with ACS. The effect of decompressive laparotomy on IAP, patient outcome and physiology were analysed.ResultsEighteen studies including 250 patients who underwent decompressive laparotomy could be included in the analysis. IAP was significantly lower after decompression (15.5 mmHg versus 34.6 mmHg before, p < 0.001), but intraabdominal hypertension persisted in the majority of the patients. Mortality in the whole group was 49.2% (123/250). The effect of decompressive laparotomy on organ function was not uniform, and in some studies no effect on organ function was found. Increased PaO2/FIO2 ratio (PaO2 = partial pressure of oxygen in arterial blood, FiO2 = fraction of inspired oxygen) and urinary output were the most pronounced effects of decompressive laparotomy.ConclusionThe effects of decompressive laparotomy have been poorly investigated, and only a small number of studies report its effect on parameters of organ function. Although IAP is consistently lower after decompression, mortality remains considerable. Recuperation of organ dysfunction after decompressive laparotomy for ACS is variable.