Remote ischaemic preconditioning does not modulate the systemic inflammatory response or renal tubular stress biomarkers after endotoxaemia in healthy human volunteers: a single-centre, mechanistic, randomised controlled trial.

BACKGROUND: Remote ischaemic preconditioning (RIPC) consists of repeated cycles of limb ischaemia and reperfusion, which may reduce perioperative myocardial ischaemic damage and kidney injury. We hypothesised that RIPC may be beneficial by attenuating the systemic inflammatory response. We investigated whether RIPC affects the response in humans to bacterial endotoxin (lipopolysaccharide [LPS]) by measuring plasma cytokines and renal cell-cycle arrest mediators, which reflect renal tubular stress. METHODS: Healthy male volunteers were randomised to receive either daily RIPC for 6 consecutive days (RIPCmultiple, n=10) plus RIPC during the 40 min preceding i.v. LPS (2 ng kg-1), RIPC only during the 40 min before LPS (RIPCsingle, n=10), or no RIPC preceding LPS (control, n=10). As a surrogate marker of renal tubular stress, the product of urinary concentrations of two cell-cycle arrest markers was calculated (tissue inhibitor of metalloproteinases-2 [TIMP2]*insulin-like growth factor binding protein-7 [IGFBP7]). Data are presented as median (inter-quartile range). RESULTS: In both RIPC groups, RIPC alone increased [TIMP2]*[IGFBP7]. LPS administration resulted in fever, flu-like symptoms, and haemodynamic alterations. Plasma cytokine concentrations increased profoundly during endotoxaemia (control group: tumor necrosis factor alpha [TNF-α] from 14 [9-16] pg ml-1 at baseline to 480 [284-709] pg ml-1 at 1.5 h after LPS; interleukin-6 [IL-6] from 4 [4-4] pg ml-1 at baseline to 659 [505-1018] pg ml-1 at 2 h after LPS). LPS administration also increased urinary [TIMP2[*[IGFBP7]. RIPC had no effect on LPS-induced cytokine release or [TIMP2]*[IGFBP7]. CONCLUSIONS: RIPC neither modulated systemic cytokine release nor attenuated inflammation-induced tubular stress after LPS. However, RIPC alone induced renal markers of cell-cycle arrest. CLINICAL TRIAL REGISTRATION: NCT02602977.

Predictive value of cell cycle arrest biomarkers for cardiac surgery-associated acute kidney injury: a meta-analysis.

BACKGROUND: A biomarker test based on a combination of urine tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) has been used as a potential biomarker of acute kidney injury (AKI). This meta-analysis aimed to evaluate the predictive value of this biomarker for cardiac surgery-associated acute kidney injury (CSA-AKI). METHODS: We searched MEDLINE, PubMed, Cochrane, and EMBASE for studies. We evaluated the methodological quality of each included study using the Quality Assessment of Diagnostic Accuracy Studies 2 criteria. Meta-DiSc and STATA were used for statistical analyses. RESULTS: A total of 10 studies (747 patients) were included in this meta-analysis. Pooled sensitivity and specificity with corresponding 95% confidence intervals (CI) were 0.77 (95% CI: 0.70-0.83, I2=40.7%) and 0.76 (95% CI: 0.72-0.79, I2=69.1%), respectively. Pooled positive likelihood ratio (LR), negative LR, and diagnostic odds ratio were 3.26 (95% CI: 2.51-4.23, I2=50.7%), 0.32 (95% CI: 0.24-0.41, I2=6.7%), and 10.08 (95% CI: 6.85-14.84, I2=6.7%), respectively. The area under the curve estimated by summary receiver operating characteristics was 0.83 [standard error (SE) 0.023] with a Q* value of 0.759 (se 0.021). There was no heterogeneity amongst the 10 studies from both threshold and non-threshold effects. Subgroup analysis showed that the diagnostic value was related to the severity of AKI and time measurement. CONCLUSIONS: Urinary [TIMP-2]·[IGFBP7] is an effective predictive test for cardiac surgery associated acute kidney injury with good diagnostic accuracy within 24 h. Studies examining use of biomarker-guided care bundles are indicated.

Acute kidney injury following orthotopic liver transplantation: incidence, risk factors, and effects on patient and graft outcomes.

BACKGROUND: Liver transplant recipients frequently develop acute kidney injury (AKI), but the predisposing factors and long-term consequences of AKI are not well understood. The aims of this study were to identify predisposing factors for early post-transplant AKI and the impact of AKI on patient and graft survival and to construct a model to predict AKI using clinical variables. METHODS: In this 5-year retrospective study, we analysed clinical and laboratory data from 424 liver transplant recipients from our centre. RESULTS: By 72 h post-transplant, 221 patients (52%) had developed AKI [according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria]. Predisposing factors for development of AKI were female sex, weight (>100 kg), severity of liver disease (Child-Pugh score), pre-existing diabetes mellitus, number of units of blood or fresh frozen plasma transfused during surgery, and non-alcoholic steatohepatitis as the aetiology of end-stage liver disease (P≤0.05). Notably, preoperative serum creatinine (SCr) was not a significant predisposing factor. After fitting a forward stepwise regression model, female sex, weight >100 kg, high Child-Pugh score, and diabetes remained significantly associated with the development of AKI within 72 h (P≤0.05). The area under the receiver operator characteristic curve for the final model was 0.71. The incidence of new chronic kidney disease and requirement for dialysis at 3 months and 1 yr post-transplant were significantly higher among patients who developed AKI. CONCLUSIONS: Development of AKI within the first 72 h after transplant impacted short-term and long-term graft survival.

Four phases of intravenous fluid therapy: a conceptual model.

I.V. fluid therapy plays a fundamental role in the management of hospitalized patients. While the correct use of i.v. fluids can be lifesaving, recent literature demonstrates that fluid therapy is not without risks. Indeed, the use of certain types and volumes of fluid can increase the risk of harm, and even death, in some patient groups. Data from a recent audit show us that the inappropriate use of fluids may occur in up to 20% of patients receiving fluid therapy. The delegates of the 12th Acute Dialysis Quality Initiative (ADQI) Conference sought to obtain consensus on the use of i.v. fluids with the aim of producing guidance for their use. In this article, we review a recently proposed model for fluid therapy in severe sepsis and propose a framework by which it could be adopted for use in most situations where fluid management is required. Considering the dose-effect relationship and side-effects of fluids, fluid therapy should be regarded similar to other drug therapy with specific indications and tailored recommendations for the type and dose of fluid. By emphasizing the necessity to individualize fluid therapy, we hope to reduce the risk to our patients and improve their outcome.

Choice of fluid in acute illness: what should be given? An international consensus.

Fluid management during critical illness is a dynamic process that may be conceptualized as occurring in four phases: rescue, optimization, stabilization, and de-escalation (mobilization). The selection and administration of resuscitation fluids is one component of this complex physiological sequence directed at restoring depleted intravascular volume. Presently, the selection of i.v. fluid is usually dictated more by local practice patterns than by evidence. The debate on fluid choice has primarily focused on evaluating outcome differences between 'crystalloids vs colloids'. More recently, however, there is interest in examining outcome differences based on the chloride content of crystalloid solutions. New insights into the conventional Starling model of microvascular fluid exchange may explain that the efficacy of colloids in restoring and maintaining depleted intravascular volume is only moderately better than crystalloids. A number of investigator-initiated, high-quality, randomized controlled trials have demonstrated that modest improvements in short-term physiological endpoints with colloids have not translated into better patient-centred outcomes. In addition, there is substantial evidence that certain types of fluids may independently worsen patient-centred outcomes. These include hydroxyethyl starch and albumin solutions in selected patient populations. There is no evidence to support the use of other colloids. The use of balanced salt solutions in preference to 0.9% saline is supported by the absence of harm in large observational studies. However, there is no compelling randomized trial-based evidence demonstrating improved clinical outcomes with the use of balanced salt solutions compared with 0.9% saline at this time.

Vascular content, tone, integrity, and haemodynamics for guiding fluid therapy: a conceptual approach.

BACKGROUND: Despite many clinical trials and investigative efforts to determine appropriate therapeutic intervention(s) for shock, this topic remains controversial. The use of i.v. fluid has represented the cornerstone for the treatment of hypoperfusion for two centuries. METHODS: As a part of International Acute Dialysis Quality Initiative XII Fluids Workgroup meeting, we sought to incorporate recent advances in our understanding of vascular biology into a more comprehensive yet accessible approach to the patient with hypoperfusion. In this workgroup, we attempted to develop a framework that incorporates key aspects of the vasculature into a diagnostic approach. RESULTS: The four main components of our proposal involve the assessment of the blood flow (BF), vascular content (vC), the vascular barrier (vB), and vascular tone (vT). Any significant perturbation in any of these domains can lead to hypoperfusion at both the macro- and micro-circulatory level. We have termed the BF, vC, vB, and vT diagnostic approach the vascular component (VC) approach. CONCLUSIONS: The VC approach to hypoperfusion has potential advantages to the current diagnostic system. This approach also has the distinct advantage that it can be used to assess the systemic, regional, and micro-vasculature, thereby harmonizing the approach to clinical vascular diagnostics across these levels. The VC approach will need to be tested prospectively to determine if this system can in fact improve outcomes in patients who suffer from hypoperfusion.

Indications and management of mechanical fluid removal in critical illness.

BACKGROUND: The Acute Dialysis Quality Initiative (ADQI) dedicated its Twelfth Consensus Conference (2013) to all aspects of fluid therapy, including the management of fluid overload (FO). The aim of the working subgroup 'Mechanical fluid removal' was to review the indications, prescription, and management of mechanical fluid removal within the broad context of fluid management of critically ill patients. METHODS: The working group developed a list of preliminary questions and objectives and performed a modified Delphi analysis of the existing literature. Relevant studies were identified through a literature search using the MEDLINE database and bibliographies of relevant research and review articles. RESULTS: After review of the existing literature, the group agreed the following consensus statements: (i) in critically ill patients with FO and with failure of or inadequate response to pharmacological therapy, mechanical fluid removal should be considered as a therapy to optimize fluid balance. (ii) When using mechanical fluid removal or management, targets for rate of fluid removal and net fluid removal should be based upon the overall fluid balance of the patient and also physiological variables, individualized, and reassessed frequently. (iii) More research on the role and practice of mechanical fluid removal in critically ill patients not meeting fluid balance goals (including in children) is necessary. CONCLUSION: Mechanical fluid removal should be considered as a therapy for FO, but more research is necessary to determine its exact role and clinical application.

Effect of a single small volume fluid bolus with balanced or un-balanced fluids on chloride and acid-base status: a prospective randomized pilot study (the FLURES-trial).

OBJECTIVE: To compare the short-term effects on acid base, electrolyte status and urine output of a single fluid bolus of saline to that of the balanced solution Plasmalyte® in critically ill patients. METHODS: Prospective, randomized, controlled trial. Adult patients (≥ 18 years) admitted to the ICU receiving a fluid bolus were randomized to receive 1 L of saline (NaCl 0.9%, Baxter) or a balanced fluid [Plasmalyte® (Baxter)]. Blood samples and urine output were collected just before (T0), just after (T1), 2 h after (T2) (only for urinary output) and three hours after termination of the fluid bolus (T4). The effect of fluid boluses on serum chloride, apparent strong ion difference, base excess, urinary output and blood pressure or vasopressor need were analyzed. MAIN RESULTS: Patients who received a 1 L saline fluid bolus had a significant increase in serum chloride (1.60; 95% CI 1.10 to 2.10; P < 0.001) and short-term decrease in apparent strong ion difference (- 1.85; 95% CI - 2.71 to - 0.99; P < 0.001) and base excess (- 0.90; 95% CI - 1.31 to - 0.50; P < 0.001). We observed a 17% increase in patients developing hyperchloremia in the saline group (0.17; 95% CI 0.05 to 0.29; P = 0.005). No significant difference in urinary output, blood pressure or vasopressor need was observed in either group. CONCLUSION: Even a single, small bolus of saline, administered to critically ill patients, causes a significant increase in chloride concentration and a decrease in apparent strong ion difference and base excess, and an increase in the number of patients developing hyperchloremia. No difference in effect on urinary output, blood pressure or vasopressor need was observed between the two groups. EUDRACT NUMBER: 2014-001005-41; date of registration: 28/10/2014. LOCAL EC APPROVAL: EC project number 2014/038.

The role of early and sufficient isolated venovenous ultrafiltration in heart failure patients with pulmonary and systemic congestion.

Hypervolemia, present in at least 70% of patients with decompensated heart failure, results in renal dysfunction due to increased renal venous pressure, impaired renal autoregulation, and decreased renal blood flow that are associated with increased morbidity and mortality. Loop diuretics, widely used in congested patients, result in the production of hypotonic urine and neurohormonal activation. In contrast, ultrafiltration (UF) removes isotonic fluid without increasing renin secretion by the macula densa. Simplified devices that permit us to perform UF with peripheral venous access, adjustable blood flows, and small extracorporeal blood volumes make this therapy feasible at most hospitals and in less acute care settings. Conflicting results on the effects of UF in heart failure patients underscore the challenges of patient selection and choice of fluid removal rates. Unfavorable outcomes in patients undergoing UF in the midst of cardiorenal syndrome type 1 are in contrast with the sustained benefits of UF initiated before unsuccessful use of high-dose intravenous (IV) diuretics. UF rates should be based on a precise knowledge of the degree of hypervolemia and careful assessment of blood volume changes, so that extracellular fluid gradually refills the intravascular space and volume depletion is avoided. Poor outcomes are likely to occur if fluid removal rates are not tailored to individual patients' clinical characteristics. A large trial is ongoing to determine if a strategy of early UF, initiated before renal function is worsened by other therapies, is superior to IV diuretics in reducing 90-day heart-failure-related hospitalizations in patients with pulmonary and systemic congestion.

Simultaneous liver-kidney transplantation: a survey of US transplant centers.

Consensus recommendations have been published to help better define those patients who would benefit from simultaneous liver-kidney transplantation (SLK). We conducted a survey of transplant centers that perform SLK (n = 88, 65% response rate) to determine practice patterns in the United States. The majority of centers (73%) stated that they use dialysis duration whereas only 30% of centers use acute kidney injury duration as a criterion for determining need for SLK. Dialysis duration >4 weeks was used by 32% of centers, >6 weeks by 37% and >8 weeks by 32% of centers. Glomerular filtration rate (GFR) was estimated using the modified diet in renal disease (MDRD)-4 equation in roughly half of centers whereas the MDRD-6 equation was used by only 6%. In patients with chronic kidney disease, GFR < 40 mL/min was used by 24% of centers as a criterion for SLK transplants instead of the recommended threshold of < 30 mL/min. Regional differences in practices were also observed. This survey demonstrates significant variation in the criteria used for SLK among transplant centers, with few centers following the current published recommendations, and emphasizes the need for evidence-based guidelines and uniformity in studying renal dysfunction in liver transplant candidates.

Simultaneous liver-kidney transplantation summit: current state and future directions.

Although previous consensus recommendations have helped define patients who would benefit from simultaneous liver-kidney transplantation (SLK), there is a current need to reassess published guidelines for SLK because of continuing increase in proportion of liver transplant candidates with renal dysfunction and ongoing donor organ shortage. The purpose of this consensus meeting was to critically evaluate published and registry data regarding patient and renal outcomes following liver transplantation alone or SLK in liver transplant recipients with renal dysfunction. Modifications to the current guidelines for SLK and a research agenda were proposed.

Management of the heartbeating brain-dead organ donor.

The main factor limiting organ donation is the availability of suitable donors and organs. Currently, most transplants follow multiple organ retrieval from heartbeating brain-dead organ donors. However, brain death is often associated with marked physiological instability, which, if not managed, can lead to deterioration in organ function before retrieval. In some cases, this prevents successful donation. There is increasing evidence that moderation of these pathophysiological changes by active management in Intensive Care maintains organ function, thereby increasing the number and functional quality of organs available for transplantation. This strategy of active donor management requires an alteration of philosophy and therapy on the part of the intensive care unit clinicians and has significant resource implications if it is to be delivered reliably and safely. Despite increasing consensus over donor management protocols, many of their components have not yet been subjected to controlled evaluation. Hence the optimal combinations of treatment goals, monitoring, and specific therapies have not yet been fully defined. More research into the component techniques is needed.

Hemorrhagic Transformation Rates following Contrast Media Administration in Patients Hospitalized with Ischemic Stroke.

BACKGROUND AND PURPOSE: Hemorrhagic transformation is a critical complication associated with ischemic stroke and has been associated with contrast media administration. The objective of our study was to use real-world in-hospital data to evaluate the correlation between contrast media type and transformation from ischemic to hemorrhagic stroke. MATERIALS AND METHODS: We obtained data on inpatient admissions with a diagnosis of ischemic stroke and a record of either iso-osmolar or low-osmolar iodinated contrast media for a stroke-related diagnostic test and a treatment procedure (thrombectomy, thrombolysis, or angioplasty). We performed multivariable regression analysis to assess the relationship between contrast media type and the development of hemorrhagic transformation during hospitalization, adjusting for patient characteristics, comorbid conditions, procedure type, a threshold for contrast media volume, and differences across hospitals. RESULTS: Inpatient visits with exclusive use of either low-osmolar (n = 38,130) or iso-osmolar contrast media (n = 4042) were included. We observed an overall risk reduction in hemorrhagic transformation among patients who received iso-osmolar compared with low-osmolar contrast media, with an absolute risk reduction of 1.4% (P = .032), relative risk reduction of 12.5%, and number needed to prevent harm of 70. This outcome was driven primarily by patients undergoing endovascular thrombectomy (n = 9211), in which iso-osmolar contrast media was associated with an absolute risk reduction of 4.6% (P = .028), a relative risk reduction of 20.8%, and number needed to prevent harm of 22, compared with low-osmolar contrast media. CONCLUSIONS: Iso-osmolar contrast media was associated with a lower rate of hemorrhagic transformation compared with low-osmolar contrast media in patients with ischemic stroke.

Acute Dialysis Quality Initiative (ADQI): methodology.

The Acute Dialysis Quality Initiative (ADQI) is an ongoing process that seeks to produce evidence-based recommendations for the prevention and management of acute kidney injury (AKI) and on different issues concerning acute dialysis. Our methods involve a combination of both expert panel and evidence appraisal, and this approach was chosen to achieve the best of both options. This approach has led to important practice guidelines with wide acceptance and adoption into clinical practice. We further recognize that additional research will be needed and have proposed specific studies that will help move this field forward.

Prevention of cardiac surgery-associated acute kidney injury.

Numerous strategies have been evaluated to prevent early CSA-AKI. Although correction of hemodynamic problems is paramount, there are no clinical studies that compare different hemodynamic management or monitoring strategies with regard to their effect on kidney function. Pharmacologic strategies including diuretics, different classes of vasodilators and drugs with anti-inflammatory effects such as N-acetyl-cysteine, do not appear to be effective. Most of the studies are underpowered and use physiological rather than clinical endpoints. Further trials are warranted with fenoldopam and nesiritide (rhBNP). Observational and underpowered randomized studies show beneficial renal effects of off-pump technique and avoidance of aortic manipulation. There is very limited evidence for preoperative fluid loading and preemptive RRT. Potentially nephrotoxic agents should be used with caution in patients at risk of CSA-AKI. Tranexamic acid or aminocaproic acid should be preferred over aprotinin. No pharmacologic intervention has been adequately tested in the prevention of late CSA-AKI. A singlecenter study, including a predominance of patients after cardiac surgery, showed a decrease of kidney injury with tight glycemic control.

Fluids for prevention and management of acute kidney injury.

Fluids are the only known method of attenuating renal injury. Furthermore, whether for hydration, resuscitation or renal replacement therapy, fluid prescriptions must be tailored to the fluid and electrolyte, cardiovascular status and residual renal function of the patient. Different fluids have significantly different effects both on volume expansion as well as on the electrolyte and acid-base balance; while controversial, different fluids may even influence renal function differently. This systematic review focuses on fluids for prevention and management of acute kidney injury. We have reviewed the available evidence and have made recommendations for clinical practice and future studies.

On-pump vs. off-pump coronary artery bypass surgery at a non-academic community hospital: have biocompatibility improvements eliminated the superiority of off-pump surgery?

OBJECTIVES: Standard coronary artery bypass grafting (CABG) surgery involves cardiopulmonary bypass (CPB) but given concerns over neurological and inflammatory complications related to CPB, many patients receive so-called off-pump procedures (OPCABG). Our objective is to determine if the recent improvements in the biocompatibility of CPB circuitry have improved post-operative outcomes at the community hospital level, particularly in terms of hospital length of stay (LOS), stroke and post-operative infection. METHODS: We analyzed hospital LOS, incidence of stroke, infection, and mortality along with several clinical variables in 209 patients (38% underwent OPCABG) at a single, non academic community hospital. We constructed a series of forward, stepwise, multiple-variable regression models using mediastinal infection, hospital LOS, and stroke as dependant variables. RESULTS: OPCABG was associated with a shorter median hospital LOS (3 days vs. 4 days; p=0.0001) and a reduced occurrence of stroke (0% vs. 7.6%; p=0.03). However, mediastinal infections occurred more commonly in OPCABG cases (10% vs. 2.2%; p=0.02). CABG and pre-existing renal disease were predictors of increased hospital LOS (p< 0.0001) whereas CABG was the only factor associated with decreased risk of mediastinal infection (OR=0.21 (0.05-0.80); p=0.02). CONCLUSIONS: At the community level, OPCABG appears to be superior in terms of LOS and incidence of stroke. Paradoxically, CABG surgery demonstrates a reduced rate of mediastinal infection.

Improving outcomes from acute kidney injury (AKI): Report on an initiative.

Acute Kidney Injury (AKI) is a complex disorder for which currently there is no accepted definition. We describe an initiative to develop uniform standards for defining and classifying AKI and establish a forum for multidisciplinary interaction to improve care for patients with, or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a 2-day conference in Amsterdam in September 2005 to draft consensus recommendations for diagnosing and staging AKI. This report describes the proposed diagnostic and staging criteria for AKI and the formation of a multidisciplinary collaborative network.