Abstract 4362788: Brash Syndrome Requiring Permanent Pacemaker: A Case Report

Multiple Coronary Artery Bypass Grafting for Kawasaki Disease–Associated Coronary Artery Disease

Case Scenario: Hemodynamic Management of Postoperative Acute Kidney Injury

The term acute kidney injury has replaced acute renal failure and represents a spectrum of clinically meaningful kidney damage.After completing this article, readers should be able to:Acute kidney injury (AKI), formerly called acute renal failure, is characterized by multiple abnormalities, including increases in serum creatinine and blood urea nitrogen, electrolyte abnormalities, acidosis, and difficulties with fluid management. We have come to realize that what was previously thought to be relatively minor damage to the kidney can have significant short-term effects on morbidity and mortality and potential long-term implications for the development of chronic kidney disease. Thus, the term acute kidney injury has replaced acute renal failure, suggesting the spectrum of kidney damage that can occur.AKI is classically defined as an acute decrease in glomerular filtration rate, which results in an increase in serum creatinine. It is important to recognize the limitations of creatinine as a marker of AKI because an increase in creatinine can be delayed by as much as 48 hours after damage to the kidney has occurred. Despite this limitation, change in creatinine remains the gold standard for the diagnosis of AKI. An evolution in the definition of AKI to better understand, characterize, and study the disease spectrum, has occurred, which has sought to capture the clinical importance of even small variations in kidney function. In addition, previous definitions used in the literature were widely disparate; this lack of standardization made the understanding of AKI challenging. These circumstances have led to the development of 2 systems to define pediatric AKI that rely on changes in creatinine, estimated creatinine clearance, or urine output. The first of these definitions is the pediatric Risk, Injury, Failure, Loss, and End-stage (RIFLE) criteria, (1) which are modified from similar adult criteria. (2) The second is the Acute Kidney Injury Network (AKIN) definition, which relies on an increase in creatinine from a previous trough level. (3) The Kidney Disease: Improving Global Outcomes (KDIGO) consortium has put forth modifications to reconcile subtle differences in the adult AKIN and RIFLE criteria. (4) KDIGO is an international initiative composed of experts who, based on systematic review of evidence, develop and standardize clinical practice guidelines for children and adults with a variety of kidney diseases (including AKI). At this time, in practice and research, the pediatric RIFLE and modified AKIN criteria are most frequently used to define AKI in children (Table 1).A basic knowledge of renal development and normal renal physiology is necessary to better understand the pathophysiologic mechanisms of AKI. The kidney is immature at birth and continues to develop early in life. Term neonates are born with a full complement of nephrons but have only approximately 25% of their adult glomerular filtration rates. The renal function of a healthy child progressively increases, reaching a mature glomerular filtration rate by age 2 years. Neonates have immature compensatory mechanisms to handle changes in renal blood flow and are not able to fully concentrate their urine.Renal blood flow helps to drive a number of physiologic processes, including glomerular filtration, oxygen delivery to the kidneys, and solute or water reabsorption. Renal blood flow is under intricate control by a combination of hormones and reflex mechanisms. The afferent and efferent arterioles control renal blood flow to and from the glomerulus, respectively. The stretch of these arterioles (myogenic feedback) and delivery of sodium chloride sensed by the juxtaglomerular apparatus (tubuloglomerular feedback) drive a number of local and systemic hormone responses to low renal blood flow. In decreased renal perfusion, afferent arteriolar vasodilation occurs in response to prostaglandins (progtaglandins E and I), nitric oxide, and bradykinins to maintain glomerular filtration and renal blood flow. At the same time, the efferent arteriole is reflexively constricted by sympathetic nerve activation, endothelin, and activation of the renin-angiotensin system, leading to the production of angiotensin II. These mechanisms work in concert to maintain glomerular filtration and renal blood flow. Disease states and certain medical interventions may interfere with these mechanisms, leading to negative effects on glomerular filtration. Further, some of these compensatory mechanisms, when stressed beyond normal parameters, may themselves lead to diminished urinary output and clinical findings one would associate with AKI.With decreased renal perfusion, a number of these compensatory mechanisms also drive sodium and water reabsorption to increase extracellular volume. Increased activity of the renin-angiotensin system and production of angiotensin II (active in the proximal tubule) leads to increased secretion of aldosterone (active in the distal tubule), resulting in increased sodium reabsorption. Increased sympathetic nerve activity also drives sodium reabsorption. The reabsorption of urea and water is driven by antidiuretic hormone. The activity of these reflex mechanisms explains a number of the changes in urine electrolyte concentrations and clinical findings that help to differentiate the causes of AKI. The immaturity of these mechanisms in the neonate also explains why the diagnosis and evaluation of the cause of AKI in the neonate differs from that in older children.The epidemiology of AKI has evolved over the years and reflects the patient population under study. In developing countries the most common causes of AKI continue to be volume depletion, infection, and primary renal diseases (hemolytic uremic syndrome, glomerulonephritis). In developed countries, volume depletion and primary renal disease remain common causes of AKI in previously healthy children. In hospitalized children in developed countries, particularly in tertiary care centers, there has been a shift in the etiology of AKI from primary renal disease to secondary causes of AKI that are often multifactorial in nature and often complicate another diagnosis or its treatment (eg, heart disease, sepsis, and nephrotoxic drug exposure). (5) Despite this shift in epidemiology, an ordered approach to the diagnosis of AKI divides the potential origins into prerenal, intrinsic, and postrenal causes.Prerenal AKI results from a decrease in renal blood flow, leading to hypoperfusion (Table 2). The underlying pathophysiologic states may be due to a decrease in effective circulating volume, loss of vascular tone, or decreased cardiac output or blood delivery to the kidneys. Renal losses, gastrointestinal tract losses, or hemorrhage can lead to direct reduction in volume and decreased renal perfusion. Alternatively, a redistribution of fluid may occur from either reduced oncotic pressure within the blood (low albumin from liver disease, nephrotic syndrome, or protein losing enteropathy) or increased leak from vessels (systemic inflammatory response syndrome or sepsis), leading to suboptimal renal perfusion. Systemic vasodilation or poor vascular tone complicates a number of illnesses in critically ill children and may result in hypoperfusion of the kidneys. Finally, there may be a decrease in the delivery of blood to the kidneys because of an overall decrease in cardiac output (underlying heart disease or myocarditis) or increased resistance to flow (abdominal compartment syndrome or renal artery stenosis). In practice, previously healthy children frequently present with a decreased effective circulating volume from a single cause, whereas chronically ill or hospitalized children may have multifactorial processes.As noted above, low renal blood flow stimulates compensatory mechanisms, including increased sympathetic tone, activation of the renin-angiotensin system, release of antidiuretic hormone, and local paracrine activities (prostaglandin release). In the prerenal state, the afferent arterioles vasodilate in response to the local effects of prostaglandins in an effort to maintain renal blood flow and glomerular filtration. Consequently, nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, in volume-depleted children may worsen AKI by preventing this compensatory afferent arteriolar vasodilation. At the same time, angiotensin II causes efferent arteriolar constriction. Interruption of this compensatory mechanism by angiotensin-converting enzyme (ACE) inhibitors predisposes patients to prerenal AKI. The effects of renin-angiotensin system activation and antidiuretic hormone release result in increased sodium and urea reabsorption, respectively. The reabsorption of sodium, urea, and water leads to oliguria and the characteristic urine findings in prerenal AKI (Table 3).Neonates are a special group when considering prerenal AKI. Neonates have increased insensible losses because of a high body surface area to mass ratio, which can be exacerbated by the use of radiant warmers for critically ill newborns. Neonates are further at risk for prerenal AKI due to immature compensatory mechanisms, including poor urine concentrating abilities. This inability to concentrate urine explains why AKI in neonates is often nonoliguric, making its recognition more difficult.Patients with sickle cell disease are predisposed to prerenal AKI because of a number of pathophysiologic mechanisms inherent to the disease that may affect the kidney. The renal medulla represents an area of the kidney at risk in sickle cell disease because of a low oxygen concentration and high tonicity; this predisposes patients to sickling. Repeated episodes of sickling in the renal medulla result in vascular congestion and the loss of vasa recta of the juxtaglomerular nephrons, which can lead to chronic interstitial fibrosis and urine concentrating defects. In early childhood, the urinary concentrating defects frequently are reversible with treatment of the sickle cell disease but can progress to chronic concentrating defects over time.Intrinsic AKI refers to direct renal parenchymal damage or dysfunction. Categories include AKI associated with tubular, interstitial, glomerular, or vascular damage and nephrotoxin exposure (Table 4).The most common cause of intrinsic AKI in tertiary care centers is transformation of prerenal AKI to acute tubular necrosis (ATN) after prolonged hypoperfusion. The areas of the kidney that are most susceptible to damage with prolonged renal hypoperfusion include the third segment of the proximal tubule (high energy requirement) and the region of the thick ascending limb of the loop of Henle located within the medulla (low oxygen tension in the medulla). The damage seen from prolonged hypoperfusion can range from mild tubular injury to cell death. As cellular necrosis occurs, debris may build up in the tubules and further block tubular flow. Tubular dysfunction, a frequent hallmark of ATN, will not be evident during periods of oliguria but may become apparent during the recovery phase.In previously healthy children, glomerular and vascular causes of intrinsic AKI are more common. Where there is concern for glomerulonephritis, the clinical presentation and timing often suggest the origin, including isolated glomerulonephritides (eg, postinfectious glomerulonephritis) and multisystem immune complex–mediated processes that involve the kidney (eg, systemic lupus erythematosus). Vascular causes of intrinsic AKI include microangiopathic processes (hemolytic uremic syndrome and thrombotic thrombocytopenic purpura) and systemic vasculitides that involve larger vessels.Acute interstitial nephritis occurs after exposure to an offending agent, such as certain medications, including antibiotics, proton pump inhibitors, NSAIDs, and diuretics. Signs and symptoms may develop 3 to 5 days after a second exposure to as long as weeks to months after an initial exposure. Drugs can cause AKI in ways other than acute interstitial nephritis. Nephrotoxin exposure is an increasingly common cause of intrinsic AKI, particularly in hospitalized patients. As previously mentioned, drugs such as NSAIDs and ACE inhibitors can contribute to AKI by inhibiting renal vascular autoregulation. Other common drugs implicated in AKI include aminoglycosides, amphotericin, chemotherapeutic agents (cisplatin, ifosfamide, and methotrexate), and calcineurin inhibitors (cyclosporine and tacrolimus). Radiocontrast agents are a significant cause of nephrotoxin-related AKI; newer iso-osmolar agents are somewhat less nephrotoxic, but the risk remains. In instances of massive hemolysis or rhabdomyolysis, endogenous elements, such as myoglobin and hemoglobin, can obstruct tubules and/or cause direct toxic effects to the kidney.Postrenal AKI results from obstructive processes that block urine flow. Acquired causes of urinary tract obstruction include those that result from local mass effect (bilateral ureteral obstruction by a tumor), renal calculi, or clots within the bladder.An important developing paradigm in the study and treatment of AKI is the idea of renal angina, a term used to describe a high-risk state that occurs before AKI. (6) Earlier recognition of a prerenal state defines a period before significant parenchymal damage (eg, the development of ATN) where AKI can be reversed. Furthermore, patients who are identified as being at risk may have nephrotoxic medications held or dosages adjusted to potentially prevent the development of intrinsic AKI. Research using renal angina scoring systems is an active area that aims to identify patients at risk for AKI. Concurrently, investigation is under way to study novel biomarkers (urine neutrophil gelatinase–associated lipocalin and urine kidney injury molecule 1) that will allow for the earlier identification of kidney injury in critically ill children (often up to 48 hours before an increase in creatinine) to allow prevention and potentially earlier intervention.A detailed history and physical examination are invaluable for children who develop AKI. Quantifying the urine output during the previous several days may provide insight to the cause and severity of the episode of AKI and serves to categorize the event as oliguric (defined as urine output <1 mL/kg/h) or nonoliguric. Systematic evaluation of potential prerenal, intrinsic, and postrenal causes is key to diagnosing the origin of AKI. Frequently, the history will provide insight into causes or risk factors for prerenal AKI, including decreased circulatory volume (gastroenteritis and hemorrhage), redistribution of circulatory volume (edematous states, nephrotic syndrome, and sepsis), decreased cardiac output (heart disease), or increased resistance to blood flow (abdominal compartment syndrome and renal artery stenosis). In previously healthy children, the history and physical examination may offer clues (Table 4) to the underlying intrinsic renal origin, including volume depletion, recent viral illness or sore throat (possibly consistent with acute glomerulonephritis), rashes, swollen joints (suggesting systemic disorders such as lupus), hematuria, or medication exposures. In newborns with a suspected obstruction, a good prenatal history is important. For example, abnormalities on fetal ultrasonogram, including enlarged bladder, hydronephrosis, or decreased amniotic fluid, may suggest posterior urethral valves in a male infant. When evaluating AKI, it is important to remember that an increase in creatinine typically occurs up to 48 hours after renal injury and may reflect events that occurred 2 to 3 days earlier. Therefore, it is important to review episodes of hypotension, hypoxia, sepsis, surgery, contrast exposures, and drug exposures that occur 48 to 72 hours before the episode of AKI becomes apparent.As part of the initial evaluation for AKI, patients should have the following tests performed: basic electrolyte panel, serum creatinine measurement, urinalysis, urine sodium measurement, urine urea measurement, urine creatine measurement, urinalysis, and a renal ultrasound study. Frequently, urine studies will allow differentiation between prerenal AKI and intrinsic AKI (eg, ATN). Typical laboratory findings for prerenal AKI include a normal urinalysis result, concentrated urine (osmolality >500 mOsm/kg [>500 mmol/kg]), fractional excretion of sodium (FENa) less than 1% (<2% in neonates), fractional excretion of urea (FEurea) less than 35%, urine sodium less than 20 mEq/L (<20 mmol/L), and urea nitrogen to creatinine ratio greater than 20 (Table 3). A loss of urine concentrating ability is classically seen in ATN and results in the characteristic urine studies that differentiate it from prerenal AKI (Table 3). Urinalysis with accompanying urine microscopy can be illuminating and point toward particular diagnostic categories. Muddy granular casts on microscopy suggest ATN; red blood cell casts suggest glomerulonephritis. A urinalysis positive for blood on dipstick evaluation without evidence of red blood cells on microscopy should raise concerns for hemoglobinuria (hemolysis) or myoglobinuria (rhabdomyolysis).The presence of hematuria, proteinuria, and/or red blood cell casts in the right clinical scenario should raise concern for possible glomerulonephritis. In the context of a recent upper respiratory tract infection, one should consider the diagnosis of postinfectious glomerulonephritis (classically with pharyngitis 2-3 weeks earlier or skin infections 4-6 weeks earlier) and should evaluate serum complements (low C3 and normal C4). In patients with a more recent upper respiratory tract infection (2-3 days) with gross hematuria on urinalysis, one must consider IgA nephropathy (normal complement levels). A urinalysis consistent with glomerulonephritis in the context of the appropriate systemic symptoms (eg, rash and arthritis) may point toward systemic lupus erythematosus (low C3 and low C4) and may warrant further antibody testing (antinuclear and anti–double-stranded DNA antibodies). If there is involvement of the pulmonary system (cough, infiltrate on radiographs, and hemoptysis) and evidence of active glomerulonephritis, the pulmonary renal syndromes should be considered. These syndromes include granulomatosis with polyangiitis (formerly Wegener granulomatosis and cytoplasmic antineutrophil cytoplasmic antibody [ANCA]), microscopic polyangiitis (perinuclear ANCA), eosinophilic granulomatosis (formerly and ANCA), and syndrome A more detailed of glomerulonephritides is beyond the of this In the of a clinical and laboratory presentation of postinfectious glomerulonephritis, a renal is not but to the diagnosis and treatment of the a is of the glomerulonephritides is of glomerulonephritis, which is defined by blood urea nitrogen and creatine In this a renal and treatment are because renal injury may develop without for interstitial nephritis of and is not often seen in the and is in less than of patients. This is due to a change over in the most common offending In patients with suspected interstitial there is frequently urine that not have red blood cell casts but may have blood cell casts The is urine this is not can be of interstitial nephritis is of nephrotic range A renal is necessary to the a patient has a recent history of low and with AKI, one should consider uremic In the appropriate a blood with is In recent years there has been an increase in the recognition of uremic syndrome by infections (eg, or or abnormalities in complement (eg, or a high of is and is a small in the diagnosis of intrinsic renal disease. Kidney by renal can provide the of the disease. kidneys point toward an acute that active that are particularly small for age may suggest a more chronic the kidneys will increased in the of AKI, which is a A evaluation of the renal is an important initial there are concerns of renal artery but the result of the evaluation is negative and concern of renal artery further studies should be in with a pediatric by renal to is the most important initial in the diagnosis of an obstructive and may provide clues to the of the For example, a more distal If an obstructive is one should the obstruction most important for children with AKI is In the and the this can be by children who are at risk for developing AKI. In it is important to and be of medications children may in the term or long term and ACE that increase the risk of AKI. In hospitalized it is also important to be of volume nephrotoxic medications, or nephrotoxic exposures. For patients at risk for developing AKI, it is important that the potentially nephrotoxic medications, and of medications such as and initial in the treatment of children who present with hypotension, or is to volume. An initial of should be necessary in the of that may be used for short-term volume include normal and red blood The of fluid on the clinical but normal is most This treatment should be to the In children with underlying or suspected cardiac disease, initial fluid may be as for this will appropriate the risk of volume which be in the of heart disease. the fluid is necessary for children to for of fluid or and response and urine fluid early of may be may be for a child who with fluid in adults evaluating low renal have at these low not increase or urine output or the of AKI. should be to renal with the of based on the clinical the patient has been fluid one may consider a of the patient remains The literature results for in patients with The literature the use of is and this medication may be associated with effects serum pulmonary and AKI). The use of to urine output is not children who remain oliguric after volume fluid may be In these children, one may fluid to insensible fluid losses with AKI are to a number of electrolyte including acidosis, and Typical sodium in healthy children are 2 to 3 but should be in children with AKI, with made based on frequent sodium should be to prevent and other of sodium and should be from in these patients to the of and will to be replaced as necessary because low of and can have implications in critically ill children. to maintain or fluid in AKI patients represents an for renal remains one of the most of AKI. The symptoms of are frequently including and even For this and of laboratory results in children with AKI are important. The most of is cardiac abnormalities and changes may be noted when are to mEq/L mmol/L), but there can be significant on the clinical In pathophysiologic states of increased release from cells syndrome and changes may occur at The that result in changes with the underlying pathophysiologic mechanisms, and associated electrolyte abnormalities The changes are first by Other changes may include and prolonged may lead to patients with greater than mEq/L mmol/L), one should an If are to mEq/L and the patient has an appropriate urine output without abnormalities on one may consider treatment with a that in the or a with to and the to a more normal If there are changes on a greater than mEq/L mmol/L), or a in a child with high cell states (eg, and should be as and treatment include which to the cardiac potential and the risk of but not This may be by the of sodium and/or with of which cause of and reduction of blood but these not from the may be there is an associated with the evaluating sodium in adults with have not but this has not been in children. sodium may be as part of treatment for it should not be the by as it is for such as can be This has been to by mEq/L and is but may to be in children with cardiac because is a common effect of with drives into cells by sodium and In with these should be made to from the including loop with fluid and sodium should be in neonates or children with underlying disease. If these renal should be seen in AKI is characterized by an which reflects an inability of the kidneys to or the of the treatment of use of should be for and with of with can lead to a of as are on for which can result in of a suboptimal glomerular filtration rate in the of AKI, can particularly with increased cell syndrome and In most can be by In patients with it is important to and because may occur as a result of to children with AKI drug may be evaluation of patient medication is to drug the kidney function to of most drugs will in episodes of AKI, of kidney function can lead to of the glomerular filtration clinical is should evaluate the of nephrotoxic medications on a consider and drug as able when nephrotoxic medications are When children renal medication must be adjusted further episodes of AKI, it is important to medication in a approach that pediatric and AKI is by a state, particularly in critically ill children. The protein in these children may be as high as 3 of with an accompanying of to that of healthy children and should not protein delivery as a to control blood urea nitrogen to protein one may a blood urea nitrogen of to If and be this may be an for renal is when to AKI have or are to be for renal include volume fluid acidosis, blood urea nitrogen or or an inability to provide in patients with renal dysfunction. In recent years the importance of volume in critically ill children has become and the of fluid at the of renal has been to be associated with increased of renal include and renal The of is a of patient and clinical is in critically ill children and relatively to but not provide the same rate of or ability to volume as other during 3 to hours better but is not as in critically ill children or children with fluid during a can be in these patients. has been a shift toward renal as the of in critically ill children. This for volume and control during include increased of fluid and ability to provide and remain for those patients who renal but are not critically literature has that critically ill children who are after an episode of AKI are at increased risk of chronic kidney disease in life. of these patients is important. The for these children is not In more of AKI that renal should be with In one may consider blood pressure and

Acute Kidney Injury

Relation of Major Depression to Survival After Coronary Artery Bypass Grafting

Acute Renal Failure and Mechanical Ventilation: Reality or Myth?

Surgical collateralization: The hidden mechanism for improving prognosis in chronic coronary syndromes

Perioperative Acute Kidney Injury

This bibliography provides a literature base for residents on medical consultation services and for internists performing consultations in a field that is difficult to research through Index Medicus.

Patient: Male, 76-year-old Final Diagnosis: Cardiogenic shock Symptoms: Lethargy Medication:— Clinical Procedure: N/A Specialty: Cardiology Objective: Rare disease Background:BRASH syndrome is a newly recognized clinical entity characterized by bradycardia, renal failure, atrioventricular blockade, shock, and hyperkalemia. Patients with BRASH syndrome often have severe bradycardia that is refractory to antidotes and chronotropic medications. In these situations, transvenous pacemaker and renal replacement therapy may be necessary. Therefore, rapid diagnosis and correct management of this entity are crucial to reduce mortality. We report a case and the management of BRASH syndrome in the Emergency Department.Case Report:A 76-year-old man with chronic kidney disease stage 3, essential hypertension and psoriasis, and receiving atenolol presented to the Emergency Department with lethargy and weakness that started 3 days ago, with rapid deterioration into shock. His initial laboratory tests revealed hyperkalemia, metabolic acidosis, and acute kidney injury. His initial electrocardiogram was remarkable for sinus bradycardia with junctional escape rhythm with ventricular rate of 26 bpm. A chest X-ray was normal. Transthoracic echocardiogram showed normal systolic and diastolic function. Atenolol was immediately held. He was treated with potassium-lowering agents and vasoactive drugs. Due to the persistence of bradycardia, even after reversal of hyperkalemia, a temporary transvenous pacemaker was placed. Renal replacement therapy was not required. Renal function improved and heart rate stabilized at 80 bpm. The patient was discharged and advised to avoid atrioventricular-blocking agents, with Cardiology follow-up.Conclusions:BRASH syndrome is a serious complication due to a combination of hyperkalemia, hypotension, and bradycardia in the setting of kidney dysfunction and medications that block the atrioventricular node. Hemodynamic support and temporary pacemaker use may be needed to manage this entity.

Transatlantic Editorial: The Use of Multiple Arterial Grafts for Coronary Revascularization in Europe and North America

Cigarette smoking and renal function impairment.

Priorities in coronary artery bypass grafting: Is midterm survival more dependent on completeness of revascularization or multiple arterial grafts?

BRASH SYNDROME: A DOWNWARD SPIRAL

J. Lance Lichtor, M.D., and Joseph F. Antognini, M.D., Editors Atrial fibrillation (AF) occurs in 27-40% of cases after cardiac surgery. AF is associated with increased risk of complications and increased healthcare resource utilization. In ambulatory patients, four single-nucleotide polymorphisms (SNPs) within the 4q25 chromosomal regional were identified, and clinical and genetic predictors of AF have been validated. Their role in postoperative AF is unknown.This multicenter prospective study assessed whether the genetic variants in the 4q25 chromosomal region are independently associated with postoperative AF after coronary artery bypass graft (CABG) surgery using two prospectively collected cohorts of patients undergoing CABG with cardiopulmonary bypass and with or without concurrent valve surgery. Clinical and genomic multivariate predictors of postoperative AF were identified by genotyping 45 SNPs encompassing the 4q25 locus in the discovery cohort (n = 959 patients; 30.1% had postoperative AF). Validation of three SNPs were then assessed in a separately collected cohort (n = 494 patients, 30.6% had postoperative AF).Older patients and patients with prior AF were at higher risk for postoperative AF, whereas postoperative “statin” use reduced the risk. After adjustment for clinical predictors of postoperative AF, and multiple comparisons, seven SNPs independently predicted postoperative AF in the discovery cohort. Additive odds ratios for the seven associated 4q25 SNPs ranged between 1.57 and 2.17 (P = 0.0008.0-0.000034). The rs10033464 SNP associated with AF in ambulatory patients was not observed for postoperative AF. Association with postoperative AF were measured and replicated for rs2200733 and rs13143308 in the validation cohort.Atrial fibrillation remains a significant complication after coronary artery bypass surgery. Patients who have single nucleotide polymorphisms at the chromosome 4q25 region have increased risk for developing atrial fibrillation after bypass surgery. Further research is needed to determine whether preoperative testing for this genetic alteration can lead to early treatment and prevention of atrial fibrillation.Delirium is common after many surgeries, especially CABG, and its presence increases postoperative morbidity and mortality in the short term (3-12 months postoperatively). However, the impact of a transient postoperative delirium episode on long-term outcomes is not well understood and may be underestimated.The primary objective of this prospective observational study was to determine whether patients with delirium after CABG surgery have higher long-term out-of-hospital mortality compared with CABG patients without delirium. Consecutive patients (n = 5,034) undergoing CABG surgery at a single institution over a 10-yr period were assessed, and patients with delirium were followed for 3 yr.Delirium occurred in 6% of all patients. Patients with delirium had increased mortality, (hazard ratio [HR]= 1.65) after adjustment for risk factors.This study shows that delirium can increase morbidity even 10 years after bypass surgery, especially in younger patients and those without prior stroke. These data further underscore the seriousness of postoperative delirium and invite more research on treatment and prevention.Pneumoperitoneum, insufflating the peritoneal cavity with gas, is commonly used during the millions of laparoscopic abdominal procedures performed annually. However, insufflations with carbon dioxide may significantly reduce organ blood flow, resulting in tissue ischemia and postoperative morbidity and mortality. To determine whether adding ethyl nitrate to the insufflation admixture would attenuate pneumoperitoneum-induced decreases in organ blood flow, an in vivo experiment in pigs was conducted.Laser-Doppler flow probes were placed on the liver and right kidney of anesthetized pigs. After a baseline recording period, animals were insufflated to a final intraperitoneal pressure of 15 mmHg with either carbon dioxide (standard practice) or carbon dioxide plus ethyl nitrite (ENO). Insufflation was maintained for 60 min and then the abdomen was manually deflated; monitoring was continued for another 60 min.Inclusion of ENO increased heart rate and decreased pressure in a dose-related manner; however these changes were moderate. Based on these dose finding studies, 100 ppm ENO was used in subsequent experiments. The addition of ENO was found to increase hepatic blood flow. Renal blood flow was not changed.As an increased number of more complex laparoscopic surgeries are being performed, further refinement of the technique is warranted. In this study of a porcine model of laparoscopic surgery, the addition of ENO to carbon dioxide improved splanchnic but not renal blood flow. Further studies are warranted to determine whether the addition of ENO to carbon dioxide reduces adverse events associated with reduced visceral blood flow in humans undergoing laparoscopic surgery.In England, although many healthcare services have been centralized, numerous studies have demonstrated conflicting data on outcomes in high-volume versus low-volume institutions and/or surgeons. To address the differences, this retrospective study was designed to investigate the relation between volume and mortality after adjustment for case mix for radical cystectomy in the English healthcare setting using improved statistical methods, taking into account the institutional and surgeon volume effects and institutional structural and process-of-care factors.Hospital episode statistics were analyzed, with the use of multilevel modeling, for patients with a primary diagnosis of cancer, undergoing an inpatient elective cystectomy in English hospitals between 2001 and 2007. Institutional and surgeon volume were defined by number of cystectomies per year: institutions: low (more than 2 but less than 10), medium (at least 10 but less than 16), or high (16 or more); surgeons: (at least 1 but less than 5), medium (at least 5 but no more than 8), or high (8 or more).Overall, the number of radical cystectomies increased from 1,120 in 2000 to 1,296 in 2006 (P = 0.005), whereas mortality decreased from 3.5% in 2000 to 2.1% in 2005. Compared with low volume institutions, the odds of 30-day in-hospital (odds ratio [OR]= 1.72; P = 0.05) and total mortality (OR = 1.82; P = 0.02) were higher in medium-volume institutions after adjustment for structural and process-of-care factors. The odds of in-hospital mortality were lower in high-volume institutions (OR = 0.67; P = 0.03) after adjustment for patient case mix. High surgeon volume resulted in lower odds of in-hospital mortality (OR = 0.67 and 0.64; P = 0.03 and 0.01 after no adjustment or adjustment for patient case mix, respectively).In this retrospective analysis of cystectomy patients in England, 30-day in-hospital and total mortality were lower in low-volume compared with medium-volume institutions. The findings were surprising and seemed to be related to institutional structure and processes of care.Preoperative fasting may reduce the metabolic preparation needed to attenuate postoperative insulin resistance. Preoperative carbohydrate (CHO) treatment may lead to reduced insulin resistance and improved clinical outcomes.This is the first placebo controlled, double-blind, randomized study to assess the effect of CHO administration on clinical outcome of patients undergoing elective colorectal surgery or liver resection. Patients (n = 142) received either oral CHO or placebo drinks to be taken on the evening before surgery and 2 h before induction of anesthesia.The groups were well matched with respect to surgical procedure, epidural analgesia, laparoscopic procedures, fasting period before induction, and duration of surgery. Postoperative fatigue score were higher than baseline for all patients but did not differ between the groups. However, the CHO-treated group returned to baseline levels faster than the placebo group (by day 6 in CHO group). The median hospital stay length of stay was also similar between groups (7 vs. 8 days in the CHO and placebo groups, respectively). Median time to oral intake and the rate of postoperative infectious complications were also similar between groups (P = 0.968 and P = 0.387, respectively). Preoperative and postoperative discomfort scores were also similar between groups. It is noteworthy that no significant differences were observed in glucose, insulin, or cortisol response protein (CRP) levels between groups on any study day. However, insulin and CRP were attenuated on day 1 in the CHO group.In this study, nondiabetics undergoing major abdominal surgery received oral carbohydrate drinks or placebo both the evening and 2 h before surgery. Patients who received the carbohydrate drinks had more side effects, including nausea, bloating, and headache; there was no benefit on fatigue or length of hospital stay. Insulin and cortisol response were attenuated in the CHO group.Jean Mantz, M.D., Ph.D., Editor An early acute kidney injury (AKI) biomarker may facilitate timely interventions to ameliorate downstream effects of AKI. Several studies have demonstrated the potential utility of serum and urine neutrophil gelatinase-associated lipocalin (NGAL) for early detection of AKI, specifically in children. However, its generalizability to adults is not yet known.To estimate the diagnostic accuracy of plasma NGAL (pNGAL), this prospective observational study of patients admitted consecutively to a general medical-surgical intensive care unit was conducted. Of 301 enrolled patients, the most common reasons for intensive care unit (ICU) admission were neurologic, respiratory, cardiovascular, traumatic, or gastrointestinal illness. Almost half (44%) of all patients had AKI during their ICU stay; 68% of cases occurred within the first 24 h). The median length of ICU stay was 7 days.The first median pNGAL level was significantly higher in study patients than that observed in healthy adults (117.0 vs. 61.2 ng/ml, respectively; P < 0.001). pNGAL values were significantly higher among patients with AKI at the time of first measurement (P < 0.001) and in patients who developed AKI within 48 h (P < 0.001). Plasma NGAL was a good diagnostic marker for AKI development within the next 48 h (area under receiver operating characteristic curve [ROC], 0.78), and for the need for renal replacement therapy (area under ROC 0.82; 95% confidence interval [CI], 0.70-0.95). Peak plasma NGAL concentrations increased with worsening AKI severity (R = 0.554, P < 0.001).This prospective observational study confirms and extends previous findings by showing that pNGAL is a good predictor of acute kidney injury development early after ICU admission and also predicts need for renal replacement therapy. This suggests that there is utility for the use of pNGAL at the bedside in ICU patients as a diagnostic and prognostic biomarker of acute kidney injury.There has been a lack of progress in understanding and treating AKI, a complication of critical illness that may lead to death. Animal models that more closely mimic the human condition are needed to fully understand the mechanisms of AKI.To investigate the short- and medium-term renal hemodynamic and functional responses to both short and sustained hypoperfusion, 11 conscious sheep were monitored in a prospective observational study after unilateral nephrectomy with a vascular occluder and flow probe implanted on the remaining renal artery. In five animals, renal blood flow (RBF) was reduced by 25, 50, and 75%, respectively, with the use of acute vascular occlusion for 30 min at weekly intervals. In another 6 animals, RBF was reduced by 80% for 2 h.Two hours after occlusion (25, 50, or 75% renal hypoperfusion for 30 min), RBF returned to baseline values, urine output was normal after 24 h and remained normal for 3 days. Creatinine clearance was normal 24 h after occlusion. During 2 h of 80% hypoperfusion, urine output decreased from 80 to 17 ml, and creatinine clearance from 32 to 3 ml/min., In addition, plasma creatinine increased from 103 to 132 μm, and fractional excretion of sodium and urea increased. Release of occlusion induced brief hyperemia. Subsequently, all measured variables returned to normal within 8 h and remained normal for the subsequent 3 days. Kidneys were histopathologically normal.Renal ischemia and reperfusion are usually recognized as the main factors leading to AKI and tubular necrosis in hemodynamically unstable patients in the ICU. This experimental study indicates that even a profound and long lasting reduction of renal perfusion is followed by restoration of baseline function and flow. This suggests that severe renal hypoperfusion by itself cannot induce persistent AKI. Rather, AKI likely occurs when additional factors (e.g. , inflammation, toxic factors) are present.Up to 64% of patients with septic shock have sepsis-related acute renal failure. However, the ideal fluid substitution in these patients remains unclear. Crystalloids are preferred in North America, but crystalloid/colloid combinations are used in European intensive care units.The impact of crystalloid and colloid solutions on kidney function was investigated in a rodent model of abdominal sepsis induced by cecal ligation and puncture (CLP). Rats were anesthetized and underwent either the CLP procedure or were sham-operated. Septic animals were treated with 0.9% sodium chloride (NaCl), a balanced crystalloid solution, hydroxyethyl starch (HES), or gelatin solutions, and kidneys were harvested after 24 h for histopathologic studies.Septic animals exhibited a mortality rate of 19% after 24 h; all rats in the sham group survived and had no signs of critical illness. The highest rate of mortality was in rats treated with 0.9% NaCl (50%) compared with HES (25%), gelatin (25%), and balanced crystalloid solution (0%) groups. Total injury scores were higher in rats treated with colloids (HES, 6%; gelatin, 4%) but were not significantly different in the crystalloid groups compared with sham control animals. The histopathologic observations revealed that gelatin- and HES-treated animals showed vesicles within epithelial cells of the renal tubules and overall increased injury. In contrast, total injury scores in groups treated with crystalloids (0.9% NaCl or balanced crystalloid solution) were not significantly different compared with sham-operated animals.Volume expansion is a pivotal treatment of sepsis in ICU patients. Renal toxicity of colloids remains a matter of debate. This study indicates that gelatin and HES adversely affected kidney function in an experimental sepsis model. It is noteworthy that gelatin was more harmful than HES.Suggested by: Laurent Jacob, M.D., Ph.D. To correct hypotension, dopamine and norepinephrine are the most frequently recommended first-line vasopressor agents in the treatment of shock. Secondary stimulatory effects on α-adrenergic, β-adrenergic, and catecholamine receptors may result in unwanted side effects.Patients were randomized in this blinded multicenter trial to assess whether first-line norepinephrine could reduce the rate of death among patients in shock. Adult patients (n = 1,679) in shock (arterial pressure less than 70 mmHg or systolic blood pressure less than 100 mmHg despite adequate fluid administration, and no signs of tissue hypoperfusion) received either dopamine or norepinephrine as first-line vasopressor therapy to restore and maintain blood pressure.A subgroup analysis showed that, compared with norepinephrine, dopamine was associated with an increased rate of death at 28 days among the 280 patients with cardiogenic shock but not among the 1,044 patients with septic shock or the 263 with hypovolemic shock (P = 0.03 for cardiogenic shock, P = 0.19 for septic shock, and P = 0.84 for hypovolemic shock).No difference in mortality rates at day 28 was observed in patients with septic shock treated with either dopamine or norepinephrine. After subgroup analyses, there was an increased incidence of arrhythmias and greater mortality in patients with cardiogenic shock treated with dopamine. These results suggest that the recommendation of the American College of Cardiology-American Heart Association be revisited to evaluate whether dopamine should be the first vasopressor used in patients who develop hypotension as a result of acute myocardial infarction.Timothy J. Brennan, Ph.D., M.D., Editor Current clinical guidelines focus on prevention of work disability rather than treatment for pain in patients with chronic low back pain. Integrated care programs with patient-directed and workplace-directed focus have been shown to be cost-effective in patients with subacute low back pain.This population-based, randomized controlled trial evaluated the effectiveness of an integrated care program, including prevention of work disability and pain treatment interventions, for patients with chronic low back pain (n = 134) in primary care (10 physiotherapy practices, 1 occupational health service, 1 occupational therapy practice, and 5 secondary care hospitals). Patients with pain for at least 12 weeks were randomly assigned to usual care or integrated care (participatory ergonomics and a graded activity program based on cognitive behavioral principles). Although patients in the integrated group return to work faster, there was no difference between groups in terms of pain.In this integrated multidisciplinary approach for managing low back pain, patients returned to work earlier and had improved functional status. Surprisingly, there was no improvement in pain. These data further reinforce that chronic low back pain is a psychosocial and work-related phenomenon. Studies suggest positive improvement in the adverse effects of low back pain with an integrated care approach.Little is known about the mechanisms underlying central sensitization in complex regional pain syndromes type I (CRPS). Methylprednisolone demonstrated reductions in spinal cord microglia activation and prevention of nerve injury pain in rats and had a pain-reducing result in patients with postherpetic neuralgia.Because central inflammatory responses accompany many chronic pain conditions in experimental animals, a double-blind randomized placebo-controlled parallel-group trial was initiated to investigate the efficacy and safety of a single intrathecal administration of 60 mg methylprednisolone (ITM) in patients with chronic CRPS. Patients had a median of 4.5 yr of severe pain, movement disorders, and other CRPS symptoms at baseline.At the interim analysis, 21 patients were enrolled (10 had received ITM) and the trial was stopped prematurely for failure to reach its primary outcome of change in pain after 6 weeks or any other outcome measure. In some cases there was a worsening of myoclonus. Treatment-emergent adverse events were not different between the ITM and placebo groups.No beneficial effect of ITM was observed in patients with CRPS, and there were no apparent adverse events. The accompanying editorial applauds the attempt, comments on the importance of halting the trial early after interim analysis, and emphasizes the importance of publishing the negative data from the ITM injection trial.Administration of the synthetic μ-opioid receptor antagonist methadone has been shown to reduce illicit drug consumption, decrease risk for human immunodeficiency virus infection and mortality, and increase socioprofessional rehabilitation for opioid-dependent patients. However, methadone is administered as a chiral mixture of (R ,S )-methadone; although the (R )-methadone is attributed with the opioid efficacy, the (S )-methadone has been associated with adverse reactions, such as drug-induced long QT syndrome, leading to potentially lethal ventricular tachyarrhythmias.This prospective study of 39 opioid-dependent patients receiving methadone maintenance treatment was conducted to investigate whether (R )-methadone alone could reduce the corrected QT (QTc) interval. Patients received (R )-methadone (half-dose) for 14 days. Some patients had the option to remain on (R )-methadone alone based on changes in QTc interval values.No differences in the mean daily dose of (R )-methadone were apparent before trial entry compared with on study (53.8 mg before study entry vs. 54.0 week 2). Opioid adverse effects and withdrawal symptoms were either absent or of low intensity and remained unchanged during the study. (S )-methadone was detected but at low levels in 4 of 34 patients at day 14. The QTc interval decreased when (R ,S )-methadone was replaced by a half-dose of (R )-methadone (median values were 423 ms at day 0 vs. 412 ms at day 14; P = 0.06). The QTc value decreased by a mean of −3.9 ms per week (P = 0.04). In a subset of patients (n = 29), when (R,S )-methadone was reintroduced for 14 days, the QTc value increased (P = 0.01) by a mean of 4.7 ms per week (P = 0.006).Methadone is a mainstay of treating opioid-dependent patients. Patients in this study experienced deceased QT intervals with the R -enantiomer compared with the racemic mixture in the absence of changes in opioid withdrawal symptoms. However, further research is needed to determine whether the R -enantiomer leads to decreased risk of cardiovascular complications (such as tachyarrhythmias) and death in patients taking methadone.Suggested by: Joseph Antognini, M.D.