Max Bell

Findings of the First Consensus Conference on Medical Emergency Teams

Background:Studies have established that physiologic instability and services mismatching precede adverse events in hospitalized patients. In response to these considerations, the concept of a Rapid Response System (RRS) has emerged. The responding team is commonly known as a medical emergency team (MET), rapid response team (RRT), or critical care outreach (CCO). Studies show that an RRS may improve outcome, but questions remain regarding the benefit, design elements, and advisability of implementing a MET system. Methods:In June 2005 an International Conference on Medical Emergency Teams (ICMET) included experts in patient safety, hospital medicine, critical care medicine, and METs. Seven of 25 had no experience with an RRS, and the remainder had experience with one of the three major forms of RRS. After preconference telephone and e-mail conversations by the panelists in which questions to be discussed were characterized, literature reviewed, and preliminary answers created, the panelists convened for 2 days to create a consensus document. Four major content areas were addressed: What is a MET response? Is there a MET syndrome? What are barriers to METS? How should outcome be measured? Panelists considered whether all hospitals should implement an RRS. Results:Patients needing an RRS intervention are suddenly critically ill and have a mismatch of resources to needs. Hospitals should implement an RRS, which consists of four elements: an afferent, “crisis detection” and “response triggering” mechanism; an efferent, predetermined rapid response team; a governance/administrative structure to supply and organize resources; and a mechanism to evaluate crisis antecedents and promote hospital process improvement to prevent future events.

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.

Quantification of Postprandial Triglyceride-Rich Lipoproteins in Healthy Men by Retinyl Ester Labeling and Simultaneous Measurement of Apolipoproteins B-48 and B-100

The metabolism of chylomicrons, very-low-density lipoprotein (VLDL), and their remnants in the postprandial state was studied in normolipidemic healthy men by measuring apoB-48 and apoB-100 and retinyl palmitate (RP) in fractions of triglyceride-rich lipoproteins after a mixed meal type of oral fat load supplemented with vitamin A. ApoB-48 was present at low concentrations in the fasting plasma samples in most subjects and increased in response to the test meal in Svedbergs flotation rate (Sf) > 20 lipoprotein fractions. Concomitantly, the level of Sf 60 to 400 apoB-100 (large VLDL) had doubled at 3 hours and returned to baseline at 9 hours. The number of apoB-48-containing lipoprotein particles did not exceed 20% of the total number of apoB-containing lipoproteins contained in Sf 12 to 400 fractions at any time point after fat intake. The peak plasma level of RP was delayed compared with the peak plasma concentration of apoB-48, suggesting that retinyl ester labeling of chylomicrons is questionable as a means of quantifying postprandial triglyceride-rich lipoproteins of intestinal origin. Approximately 2000 and 4000 RP molecules were carried in each chylomicron particle in the 3- and 6-hour samples, respectively, in contrast to the remnant fractions in which 100 to 600 RP molecules were found for each lipoprotein particle. The limited RP exchange between lipoprotein particles indicates that the smaller intestinal lipoproteins do not originate primarily from larger Sf > 400 chylomicron particles but instead are secreted directly into the Sf 20 to 400 fraction and subsequently converted to smaller chylomicron remnants.(ABSTRACT TRUNCATED AT 250 WORDS)

Coeliac disease and risk of sepsis

Objective: To examine the risk of subsequent sepsis in individuals with coeliac disease. Design: We used Swedish national health registers to identify 15 325 individuals with a diagnosis of coeliac disease (1964–2003) and 14 494 inpatient reference individuals. Cox regression estimated the hazard ratios (HRs) for subsequent sepsis. Results: Compared with inpatient reference individuals, individuals with coeliac disease were at increased risk of sepsis (HR  = 1.6, 95% confidence interval (95% CI)  = 1.2 to 1.9, p<0.001). The highest risk estimates were seen for pneumococcal sepsis (HR  = 2.5, 95% CI  = 1.2 to 5.1, p = 0.014). Individuals with coeliac disease diagnosed in childhood were not at increased risk of subsequent sepsis (HR  = 1.0, 95% CI  = 0.6 to 1.9, p = 0.908). When individuals with coeliac disease were compared with reference individuals from the general population, coeliac disease was associated with an increased risk of sepsis (HR  = 2.6, 95% CI  = 2.1 to 3.0, p<0.001). The HR for pneumococcal sepsis was 3.9 (95% CI  = 2.2 to 7.0, p<0.001). In this comparison, children with coeliac disease were also at an increased risk of sepsis (HR  = 1.8, 95% CI  = 1.2 to 2.7, p = 0.003). Conclusion: This study showed a modestly increased risk of sepsis in patients with coeliac disease with the highest risk for pneumococcal sepsis. This risk increase was limited to those with coeliac disease diagnosed in adulthood. Potential explanations include hyposplenism, increased mucosal permeability and an altered composition of the intestinal glycocalyx in individuals with coeliac disease.

Immunoassays distinguishing between HNL/NGAL released in urine from kidney epithelial cells and neutrophils

BACKGROUND The distinction between monomeric human neutrophil lipocalin/neutrophil gelatinase-associated lipocalin (HNL/NGAL), secreted by injured kidney tubular cells, and dimeric HNL/NGAL, released by activated neutrophils, is important to accurately diagnose acute kidney injury (AKI). METHODS 132 urine samples from 44 intensive care unit (ICU) patients and five urine samples from non-ICU patients with urinary tract infections (UTIs) were analyzed by two monoclonal enzyme-linked immunosorbent assays (ELISA-1 and ELISA-2). The presence of monomeric and/or dimeric HNL/NGAL in each sample was visualized by Western blotting. RESULTS The ELISA-1 detected both monomeric and dimeric HNL/NGAL whereas the ELISA-2 almost exclusively detected dimeric HNL/NGAL with an area under the receiver-operating characteristics curve (AuROC) of 0.90. The ELISA-1/ELISA-2 ratio detected the monomeric form with an AuROC of 0.92. In 32 AKI patients, dimer-specific ELISA-2 levels decreased pre-AKI whereas the monomer-specific ELISA-1/ELISA-2 ratio gradually increased beyond AKI diagnosis. High ELISA-2 levels and/or low ELISA-1/ELISA-2 ratios detected a predominance of dimeric HNL/NGAL in urine from the patients with UTIs. CONCLUSIONS In combination, our two ELISAs distinguish monomeric HNL/NGAL, produced by the kidney epithelium, from dimeric HNL/NGAL, released by neutrophils during AKI development, as well as reduce the confounding effect of neutrophil involvement when bacteriuria is present.

End-stage renal disease patients on renal replacement therapy in the intensive care unit: short- and long-term outcome.

Objective:The number of patients with end-stage renal disease has increased during the last decades. Data shows that 10% of the renal replacement therapy population in the intensive care unit are patients with end-stage renal disease. We aimed to describe the short- and long-term outcome of these patients after renal replacement therapy in the intensive care unit. Design:Nationwide cohort study between the years 1995 and 2004. Follow-up up to 5 years. Setting:Swedish general intensive care units and Swedish hospitals. Patients:Eligible subjects were end-stage renal disease patients treated with renal replacement therapy in 32 Swedish general intensive care units. In total, 245 patients were studied. Interventions:None. Measurements and Main Results:Short- and long-term mortality was studied. Logistic regression was used to analyze short-term mortality. Long-term mortality was compared with the mortality of end-stage renal disease patients outside the intensive care unit and the mortality in the population. Diabetes and heart failure are significant risk factors for 90-day mortality, with an odds ratio of 1.9 and 2.0, respectively. The intensive care unit end-stage renal disease cohort had increased long-term mortality as compared with non-intensive care unit end-stage renal disease patients, relative risk of death 2.32 (confidence interval 1.84–2.92). A comparison with the mortality rate in the general population yielded a standardized mortality ratio of 25 (95% confidence interval: 19.6–31.4). Conclusions:For end-stage renal disease patients in the intensive care unit, age, diabetes mellitus, and heart failure are risk factors for 90-day mortality. Long-term mortality is associated with age and heart failure. The long-term mortality of end-stage renal disease patients surviving the intensive care unit stay is significantly higher compared with end-stage renal disease patients without a known intensive care unit admission.

Acute kidney injury after coronary artery bypass grafting and long-term risk of myocardial infarction and death.

BACKGROUND Acute kidney injury (AKI) after coronary artery bypass grafting (CABG) is associated with early mortality. Its impact on the risk of myocardial infarction (MI) over time and long-term mortality has not been well described. METHODS We performed a nationwide population-based cohort study in 27,929 patients who underwent a first isolated CABG between 2000 and 2008 in Sweden. Acute kidney injury was divided into three categories based on the absolute increase in postoperative serum creatinine (sCr) concentration compared with the preoperative baseline: stage 1, sCr increase of 0.3 to 0.5mg/dL; stage 2, sCr increase of >0.5 to 1.0mg/dL and stage 3, sCr increase of ≥ 1.0mg/dL. RESULTS The overall incidence of postoperative AKI was 13%, 6.3% met the criterion for stage 1, 4.3% for stage 2 and 2.3% for stage 3. During a mean follow-up of 5.0 years, there were 2119 (7.6%) MIs and 4679 (17%) deaths. Multivariable adjusted hazard ratios with 95% confidence intervals for MI were 1.35 (1.15 to 1.57), 1.80 (1.53 to 2.13) and 1.63 (1.29 to 2.07), in AKI stages 1, 2 and 3, respectively. The corresponding hazard ratios for all-cause mortality were 1.30 (1.17 to 1.44), 1.65 (1.48 to 1.83) and 2.68 (2.37 to 3.03), respectively. CONCLUSIONS Our results show that AKI after CABG is associated with an increased long-term risk of MI and death.

Evolution of chronic renal impairment and long-term mortality after de novo acute kidney injury in the critically ill; a Swedish multi-centre cohort study

IntroductionAcute Kidney Injury (AKI) is common in critical ill populations and its association with high short-term mortality is well established. However, long-term risks of death and renal dysfunction are poorly understood and few studies exclude patients with pre-existing renal disease, meaning outcome for de novo AKI has been difficult to elicit. We aimed to compare the long-term risk of Chronic Kidney Disease (CKD), End Stage Renal Disease (ESRD) and mortality in critically ill patients with and without severe de novo AKI.MethodThis cohort study was conducted between 2005 and 2011 in Swedish intensive care units (ICU). Data from 130134 adult patients listed on the Swedish intensive care register-database was linked with other national registries. Patients with pre-existing CKD (4192) and ESRD (1389) were excluded, as were cases (26771) with incomplete data. Patients were classified according to AKI exposure during ICU admission. Outcome in the de novo AKI group was compared to the non-exposed (no-AKI) intensive care control group. Primary outcome was all-cause mortality. Follow-up ranged from one to seven years (median 2.1 years). Secondary outcomes were incidence of CKD and ESRD and median follow-up was 1.3 years.ResultsOf 97 782 patients, 5273 (5.4%) had de novo AKI. These patients had significantly higher crude mortality at one (48.4% vs. 24.6%) and five years (61.8% vs. 39.1%) compared to the control group. The first 30% of deaths in AKI patients occurred within 11 days of ICU admission whilst the 30-centile in the no-AKI group died by 748 days. CKD was significantly more common in AKI survivors at one year (6.0% vs. 0.44%) than in no-AKI group (adjusted incidence rate ratio (IRR) 7.6). AKI patients also had significantly higher rates of ESRD at one (2.0% vs. 0.08%) and at five years (3.9% vs. 0.3%) than those in the comparison group (adjusted IRR 22.5).ConclusionThis large cohort study demonstrated that de novo AKI is associated with increased short and long-term risk of death. AKI is independently associated with increased risk of CKD and ESRD as compared to an ICU control population. Severe de novo AKI survivors should be routinely followed-up and their renal function monitored.

Acute kidney injury following coronary artery bypass grafting: early mortality and postoperative complications

Abstract Objectives. To investigate the prognostic importance of acute kidney injury on early mortality, postoperative stroke, and mediastinitis in patients undergoing a first isolated coronary artery bypass grafting. Design. 7594 patients undergoing coronary artery bypass grafting with information on pre- and postoperative serum-creatinine values were included. Patients were classified using the Acute Kidney Injury Network classification. Odds ratios (OR) for mortality and postoperative complications within 60 days of surgery were calculated after adjustment for confounders separately for stage 1 and for stages 2 and 3 together. Results. 1047 (14%) patients developed acute kidney injury. There were 132 (1.7%) deaths, 103 (1.4%) strokes and 118 (1.6%) cases of mediastinitis during follow-up. Among patients in stage 1 the adjusted odds ratio for death was 4.36 (95% confidence interval 2.83–6.71) and for stage 2 plus 3; 21.5 (12.0–38.6) compared to patients without acute kidney injury. Corresponding OR for stroke were 2.34 (1.43–3.82) and 6.52 (2.97–14.3) and for mediastinitis 2.88 (1.84–4.50) and 4.68 (2.07–10.6), respectively. Conclusions. Acute kidney injury following coronary artery bypass grafting is related to postoperative mortality, stroke, and mediastinitis. Patients undergoing coronary artery bypass grafting should be assessed for presence of acute kidney injury postoperatively, in order to predict early prognosis.

Impact of sepsis on levels of plasma cystatin C in AKI and non-AKI patients

BACKGROUND Cystatin C is a marker of acute kidney injury (AKI). However, systemic inflammation associated with sepsis, a common AKI-trigger, may affect cystatin C. We studied the impact of sepsis on cystatin C levels in plasma. Furthermore, we investigated whether the presence of sepsis affects the predictive properties of cystatin C. METHODS Three hundred and twenty-seven intensive care unit (ICU) patients were categorized as having: neither AKI nor sepsis (n = 151), sepsis without AKI (n = 80), AKI without sepsis (n = 24) or AKI and sepsis (n = 72) during their first week in the ICU. Changes in cystatin C and creatinine over time in patients with and without sepsis or AKI were analysed using repeated measures analysis of variance. The performance of cystatin C on admission to predict sustained AKI, worsened AKI or death was assessed from the area under the receiver-operating characteristic curve (AUC-ROC) in septic and non-septic patients separately. RESULTS In non-AKI patients, cystatin C increased and creatinine decreased significantly over the first week. The change in cystatin C or creatinine did not differ significantly between septic and non-septic patients without AKI. Even in AKI patients, the cystatin C change did not differ significantly between septic and non-septic patients. The AUC-ROCs for prediction of the composite outcome were 0.80 and 0.78 in patients with and without sepsis, respectively, and did not differ significantly (P = 0.76). CONCLUSION The inflammatory response induced by sepsis has no impact on the levels of cystatin C in plasma during the first week in the ICU.