Acute Kidney Injury in Children after Cardiac Surgery

Introduction Acute kidney injury (AKI) occurs in up to 30% of patients who undergo cardiac surgery (CS), while 1% of patients have AKI severe enough to require some form of renal replacement therapy.[1,2] The mechanism of AKI is probably multifactorial (hemodynamic insult, inflammatory mediators, cardiopulmonary bypass and nephrotoxins). AKI after CS is associated with adverse outcomes, including prolonged intensive care and hospital stays, diminished quality of life and increased long-term mortality.[3] Even mild degrees of post-operative AKI can cause a significant increase in mortality and morbidity.[3,4,5] Mortality in children developing AKI after CS remains high, inspite of advances 111 surgical techniques, intensive care management and increased use of renal replacement therapies.[6] Factors leading to AKI-associated mortality include fluid overload, acidosis, hyperkalemia and abnormal cross-talk between organs resulting in decreased end organ function. Patients who survive have an increased rate of chronic renal disease secondary to the AKI sustained in post-operative period. Early diagnosis of AKI as well as appropriate management in the peri-operative period should help to decrease the mortality, morbidity and chronic residual renal damage. Incidence The incidence of AKI following CS has been difficult to determine. AKI was found to be more common children undergoing complex CS for congenital heart disease. Depending on the patient’s age, RACHS (Risk Adjusted classification for Congenital Heart Surgery) score, time on cardiopulmonary bypass (CPB), need for extracorporeal life support (ECLS) and definition of AKI, the incidence of AKI can be as high as 42%, 1-17% needing dialysis and with a 20%? 100% mortality rate.[7,8,9,10] Risk factors of AKI in Post op CS The kidneys receive 20% of cardiac output and are very sensitive to hypo perfusion and hypo perfusion related injuries.[11] The etiology of AKI after CPB is multifactorial and incompletely understood. CS incurs risk for AKI through hypotension, inflammation and the use of nephrotoxic medications. Prematurity, single ventricle physiology, longer cardiopulmonary bypass time, peak postoperative lactic acid concentration, higher postoperative lactate levels and a history of heart surgery are few of the predictors of AKI development in post-operative period.[12,13] Pathophysiology of AKI following CS The clinical phases of AKI after cardiopulmonary bypass (CPB) are characterized by pathologic changes occurring in the clinical course and are determined by preoperative, intraoperative, and postoperative events.[14] (Figure 1) The characteristics of the neonatal-infant kidney represent an additional risk factor for the development of AKI under these conditions.Figure 1: Acute kidney injury after cardiopulmonary bypass (CPB): an overview of the pathophysiologic features and management strategies. ANP - atrial natriuretic peptide; ARB-_ angiotensin receptor blocker; CH- congestive heart failure; IABP-intraaortic balloon pump; MAP- mean arterial pressure; SIRSsystemic inflammatory response syndrome; VAD - ventricularassist device.[15]Diagnosis Acute kidney injury (AKI), formerly known as acute renal failure is characterized by an abrupt (<48 hours) and sustained decline in glomerular filtration rate and an inability of kidneys to appropriately regulate fluid, electrolytes and acid-base homeostasis. The pRIFLE and AKIN criteria (Table 1) were developed by panels of experts to provide a uniform definition of AKI and facilitate recommendations for patients suffering from renal failure.[16,17]Table 1: pRIFLE, AKIN, KDIGO CriteriaThese definitions rely upon serum creatinine levels and urine output to define and categorize the severity of kidney injury. Although new concepts such as RIFLE and AKIN have helped standardize the definition of AKI, the criteria involved in making the diagnosis can take hours to days, leading to delayed recognition ofrenal dysfunction. Creatinine Serum creatinine, the traditional marker of renal function, only rises appreciably after a 50% loss in GFR. In addition, it does not peak till 1 to 3 days after CS, has a low sensitivity and specificity and is affected by several non renal factors such as age, gender, muscle mass, vigorous exercise, and medications.[18,19] Urine output The most readily available surrogate marker of renal function is urine output. Compared to creatinine, it is more sensitive to changes in renal hemodynamics. Unfortunately, variations in urine output are considerably less specific, except when severely diminished or absent. Oliguria is defined as urine output of less than 0.5mg/kg/hour. The presence of an oliguric state gives physicians a sign that kidney function is at risk or already perturbed, however, the presence of normal urine outputcannot provide assurance that renal function is unperturbed. Urinalysis In patients with decreased urine output or suspected acute kidney injury, urinalysis is an important tool that can differentiate prerenal from renal failure. Consequently, it can be very useful in guiding treatment. Table 2 describes select variables and their association with the aetiology of acute kidney injury.Table 2: Lab investigations to differentiate Pre renal and renal injury.Early detection of AKI: The emerging role of biomarkers in following CS At present, there are no specific markers of AKI which can be used in the early post-operative period. Research to develop such a biomarker is of utmost importance as AKI develops early after CS, mostly within 72hrs. Non-availability of such a reliable test is partly responsible for the limited progress that has been made in preventing and treating post-operative renal failure.[20] Plasma biomarkers that have been recently found to be useful in early diagnosis and prognostication are neutrophil gelatinase-associated lipocalin and cystatin C, while useful urinary biomarkers include neutrophil gelatinase-associated lipocalin, interleukin 18 (IL-18), and kidney injury molecule.[21,22,23] Currently, these biomarkers are being evaluated and are not available for routine bedside use. General measures to prevent AKI after CS As a general rule, hemodynamics and cardiac function optimization are a priority in patients with a congenital heart defect. Low cardiac output state (LCOS) consistsof an inadequate systemic oxygen delivery to meet the metabolic demands of the organ systems associated with low cardiac output.[23] LCOS plays an importantrole after pediatric open-heart surgery, affecting up to 25% of infants between 6 and 18 hours after surgery, and results in longer intensive care unit stay and increased mortality.[24] Features of LCOS include tachycardia, poor systemic perfusion, decreased urine output, increased lactate, and reduced mixed venous oxygen saturation. Infants suffering from LCOS with decreased kidney perfusion usually benefit from inotropes (dopamine, milrinone), vasopressors (high-dose dopamine, epinephrine), vasodilators (milrinone, fenoldopam), and diuretics (furosemide) that must be optimized to achieve the best equilibrium between cardiac function (contractility), blood oxygenation (pulmonary flow), and systemic perfusion (kidney, hepatic, gastrointestinal function). Strict clinical observation and constant modification of drug infusion when signs of pulmonary overflow/systemic hypoperfusion occur are the main determinants for successful management of these patients. Medical interventions to prevent AKI after CS Pharmacologic interventions have been attempted with inconsistent results, and at this time, there are no known drugs that have conclusively demonstrated renal protection. Hydration There is little argument that adequate hydration is a prerequisite to maintaining healthy kidney function. A randomized trial compared a regimen of pre-operative intravenous hydration to standard pre-operative fluid restriction in patients with known renal dysfunction, defined as glomerular filtration rate <45mL/min.[25] Patients in the hydration group were significantly less likely to develop postoperative renal failure and no patients required renal replacement therapy (RRT), compared to 27% ofpatients in the control group. Much effort has been put into identifying the ideal fluid, or ideal combination of fluids, to maintain perioperative circulating volume. A recent randomized pilot study by Magder et al compared the use of colloids to crystalloids in a postoperative CS population.[26] The colloid based resuscitation protocol was associated with less catecholamine use, a lower incidence of pneumonia and mediastinal infection, and less need for cardiac pacing. There was no difference in the daily creatinine, development of RIFLE risk criteria during hospital stay, packed red blood cells transfusion or new dialysis between the 2 groups. It is likely that either colloids or crystalloids are suitable solutions for fluid resuscitation and that a balanced resuscitation avoiding high doses of colloids or crystalloids alone would lead to optimal patient outcome. Glycemic control In 2001, van den Berghe published a seminal randomized trial establishing the benefit of intensive insulin therapy to maintain tight glycemic control (maintenance ofblood glucose at a level between 80 and 110 mg per decilitre in postoperative critically ill patients.[27] More than 60% of patients studied had undergone CS. In addition to a significant mortality benefit, intensive insulin therapy was associated with a 41% reduction in patients requiring dialysis or hemofiltration. Dopamine Dopamine is the commonly used agent in infants after CS, at doses ranging from less than 5 mcg/kg/ min (stimulation of DA1 receptors), 5 to 10 mcg/kg/ min (stimulation of β1 receptors), up to 20 mcg/kg/ min (stimulation of α receptors). Dopamine is titrated after the surgical procedure to achieve adequate mean arterial pressure and systemic perfusion. Dopaminergic receptors (DA1 and DA2) are present in the renal, mesenteric, and coronary vascular beds, but their clinical relevance has been the object of a long-lasting debate. DA receptors appear gradually after birth.[28,29] Natriuresis in response to DA agonists also is markedly impaired in the newborn.[30] While dopamine increases cardiac output on one hand, on the other hand it increases myocardial oxygen demand by disproportionately increasing inotropy and chronotropy.[31] In addition, at higher doses it can increase systemic vascular resistance thereby increasing the after load on the failing heart. The neonatal heart is characterized by the presence of immature adrenergic receptors, and has a relatively limited response to catecholamine administration. This is owing to the presence of low receptor density and affinity, an increase in β2/β1 receptor ratio, different coupling with intracellular second messengers, and receptor down-regulation after a few hours of catecholamine administration.[32] For this reason, high doses of dopamine infusion often are required during postoperative LCOS and the potential for peripheral and splanchnic vasoconstriction exists. Nevertheless, in clinical practice the priority usually is given to maintenance of adequate mean arterial pressure to achieve kidney perfusion and possibly preserve renal function. Epinephrine When high doses of dopamine fail to restore adequate perfusion pressure, epinephrine infusion often is required in LCOS. Epinephrine has strong α and β-adrenergic-receptor activation. At lower doses (< 0.05 mcg/kg/min), epinephrine increases ventricular contraction, reduces systemic vascular resistance, and increases renal blood flow. As the dose is increased, more prominent vasoconstriction occurs and decrease in renal blood flow is seen. Controversial debate is ongoing about the role of vasopressors in AKI pathophysiology. The respective roles of epinephrine on kidney function under these conditions are unclear. On one hand, vasopressors improve organ perfusion; on the other hand, they have been considered potentially harmful to renal microcirculation.[32] Milrinone Milrinone is a phosphodiesterase inhibitor that has been shown to increase cardiac output in selected children with LCOS after open heart surgery, most likely as a result of direct myocardial inotropic effect as well as pulmonary and systemic vasodilatory properties.[24] A recent multicenter study showed that milrinone, when administered prophylactically to infants after cardiac surgery, is effective in preventing LCOS.[28] Diuretics Loop diuretics such as furosemide are the most used diuretics in the infant undergoing CS.[33] Dosage and administration modality vary from boluses (1 mg/kg every 8 or 12 h) to continuous infusion (0.1 to 0.3 mg/kg/h). The administration strategy has been re- evaluated in light of the results obtained in infants treated with continuous versus intermittent furosemide after heart surgery. Furosemide continuous infusions may be preferred to bolus administration because it yields comparable urinary output with a much lower dose, fewer hourly fluctuations, and less urinary sodium and chloride wasting.[34,35] A 3-day trial of 13 post-heart surgery infants and children noted that a mean starting dose of 0.093 was insufficient, and required a significant increase to 0.175 mg/kg/h in 10 of 13 patients. These investigators suggest a starting dose of 0.2 mg/kg/hour and eventual tapering.[36] Recently, a great amount of interest in the use of dopamine-receptor agonists in post-heart surgery infants has been raised. In a retrospective series of 25 post-CPB neonates, a significant improvement of diuresis was observed with fenoldopam, a selective DA1-receptor agonist, compared with chlorothiazide and furosemide.[37] Natriuretic peptides Natriuretic peptides are known to oppose the renin- angiotensin-aldosterone and arginine vasopressin systems through multiple mechanisms.[38] They can induce natriuresis and vasodilatation to prevent hypervolemia and oppose the vasoconstrictive response induced by hypovolemia. Synthetic analogues of these proteins have been suggested as therapies to prevent renal failure following CS. Anaritide, the human recombinant form of atrial natriuretic peptide (ANP), is administered intravenously to induce arterial and venous dilatation, thus decreasing cardiac preload and afterload. Nesiritide, a human recombinant form of Brain-type natriuretic peptide (BNP) is used in the treatment of decompensated heart failure. In a randomized controlled trial of heart failure patients, nesiritide improved diuresis and decreased pulmonary congestion and edema.[39] RCTs regarding use of these drugs in children are not available at present. Treatment of complications Dyselectrolytemia In children with AKI, serum potassium should be measured at least daily since hyperkalemia is a life threatening complication of AKI. When potassium levels become high or ECG changes develop, emergency treatment may include intravenous infusion of calcium, sodium bicarbonate, glucose and insulin, or an inhaled beta agonist.[40] Administration of loop diuretics can be useful to eliminate potassium, however, varied responses to this medication render the effect unreliable. A sodium potassium exchange resin, such as sodium polystyrene sulfonate (Kayexalate), can be effective in removing potassium, although the maximal effect occurs only after 4-6 hours. Other electrolyte disturbances (hypokalemia, hyponatremia, hypochloremia) can be seen secondary to diuretic therapy and should be monitored closely. Metabolic acidosis Acidosis occurs frequently in acute renal failure, often complicating treatment in the critically ill patient due to altered homeostasis, decreased cardiac contractility, and attenuated responses to catecholamines. Management of metabolic acidosis should focus on correction of the underlying cause and concomitant morbidity. If acidosis remains after optimal therapy, hemodialysis is the most effective and proven method of correction. There is significant controversy regarding the use of bicarbonate in management of acidosis in the critically ill patient. Observational and randomized studies have failed to show a mortality or morbidity benefit when sodium bicarbonate is administered to correct acidosis.[41] The proposed rationale for the lack of benefit is that, while bicarbonate may increase extracellular pH, it exacerbates intracellular acidosis by the generation of carbon dioxide. Consequently, the practice of many critical care physicians is to administer sodium bicarbonate only in the presence of profound acidosis (pH <7.1) and associated hemodynamic instability. RRT of post-heart surgery AKI in infants The optimal time to initiate RRT in CSA-AKI remains uncertain. There is no consensus on indications for initiating CRRT. As claimed in the majority of previous studies, accepted indications of RRT include: fluid overload, overt uremia, hyperkalemia, and severe metabolic acidosis. Furthermore, the presence of any other organ failure accompanied by AKI may be a valid criterion for RRT. In 2012, the KDIGO guideline on renal support for AKI suggests initiating RRT emergently when life-threatening changes in fluid, electrolyte, and acid-base balance exist (not graded).[42] The indication for RRT in these patients has changed through the years and the present tendency is that of a wider application of this kind of treatment. Although no clear recommendation is made for the application of RRT in patients without acute renal failure, it is widely accepted that RRT can positively affect the clinical course of multiple organ disease syndrome. Up to 20% of all cases of pediatric multiple organ disease syndrome are represented by children who underwent CS. In addition, prevention of fluid accumulation has been associated recently with an improved survival rate in critically ill children. In post-CPB children with AKI, the application of preventive dialysis proposed years ago, recently has been associated with very low mortality. Depending on the institution’s preference, need for dialysis efficiency, and availability of access, the 2 dialysis modalities most frequently used in infants with post- heart surgery AKI are peritoneal dialysis and CRRT. Intermittent haemodialysis is not a desirable modality in children after CS due to its impact on systemic hemodynamics. Peritoneal dialysis (PD) With regard to complications, PD is generally a safe method. Even though cardiothoracic surgery may constitute a relative contraindication to PD due to the risk of peritoneo-pleural diaphragmatic communication, the technique is widely used with a low rate of complications. In this setting, PD has long been advocated as the preferred technique because of better hemodynamic stability, no requirement for vascular access or heparin, simplicity, and low cost.[43,44] One of the main disadvantages of PD is a relative lack of efficiency in water removal with direct consequences on fluid balance and frequent limitation of parenteral nutrition. Nonetheless, the early application of PD as a therapy for fluid overload prevention is presently accepted.[45] In particular, infants with specific risk factors for AKI should be considered for the preventive use of PD. In children undergoing surgery with the Fontan procedure, postoperative unfavorable hemodynamic conditions (high venous pressure) may lead to a high incidence of renal failure.[46] An extraordinarily high survival rate was observed (80%) in a group of infants with post heart surgery AKI in which PD was started much earlier than in other studies (time to PD application after surgery, 5-40 h).[47] Although a very limited experience, this study suggests that prevention of renal failure and/ or fluid accumulation may affect survival. PD offers limited fluid removal compared to extracorporeal techniques. Moreover, in post- heart surgery infants, high dialysate volumes to increase PD clearance lead to modifications of atrial, mean pulmonary artery, and systemic pressure.[48] For this reason, a PD prescription of 10 mL/kg dwell volume, with continuous 1-hour cycles (5 minute fill, 45-minute dwell, and 10-minute drain), is prescribed commonly[49,50] CRRT (Continuous renal replacement therapy) CRRT is a slower form of hemodialysis that allows for faster removal of fluid and solutes when desired. However, it requires a double lumen vascular access of at least 7 French size, which can sometimes be a limitation in small infants. Its complications include bleeding, hypothermia, thrombocytopenia, electrolytes and acid base imbalance, immune activation, altered drug delivery, nutritional loss, and blood loss as a result of circuit clotting. In small infants, initiation of CRRT can pose a risk of hypotension due to a relatively large circuit volume. PD may not be the optimal modality for patients with severe volume overload who require rapid ultrafiltration, or for patients with severe life-threatening hyperkalemia who require rapid reduction of serum potassium. Moreover, the amount of ultrafiltration often is unpredictable because of the impaired peritoneal perfusion in hemodynamically unstable patients such as post- heart surgery infants. These limitations of PD explain the increased use of extracorporeal dialysis in critically ill pediatric patients[51] and in post- heart surgery infants.[52] These children generally are treated with CRRT, which provides both fluid and solute re-equilibration and proinflammatory mediator removal. Commercially available circuits with reduced priming volume together with monitors providing an extremely accurate fluid balance have rendered CRRT feasible in infants.[53,54] Infants undergoing CPB show 2 unique features with respect to exposure to a proinflammatory state. First, post CS infants are most exposed to the risk of water accumulation, AKI, and inflammation owing to the nature of hemodilutional, hypothermic CPB and to the massive exposure of blood to the artificial surface of CPB.[54,55,56,57] Second, the exact moment of the renal-inflammatory injury (ie, CPB initiation) is known. CS patients receive ultrafiltration during CPB preventively with the filter placed 111 parallel with the CPB circuit to remove inflammatory mediators from the beginning of their generation. This strategy may exert beneficial effects on hemodynamics, metabolism, and inflammation in the postoperative period. A highly specialized patient with respect to this general description is the infant with AKI and an extracorporeal membrane oxygenation treatment (ECMO). In this case, the CRRT circuit is placed in parallel and counter current to the ECMO circuit (Figure 2). The blood into the CRRT circuit runs in the opposite direction with the one 111 the ECMO circuit, with its arterial side connected to the circuit after the pump. The venous side is connected to the bladder, which collects patient venous return. With this set-up the CRRT circuit receives the blood after the ECMO pump, a positive pressure segment, and it retums it to the ECMO bladder where the pressure is close to zero. Although this configuration may cause minimal recirculation, it results in the safest provision in an ECMO circuit.[58] Recent data detail experience with 2 different subgroups of children: one group that required hemofiltration alone and a second group that required hemofiltration and ECMO.[59] Not surprisingly, the investigators identified a higher mortality rate in those patients requiring continuous venovenous hemofiltration and ECMO compared with those patients requiring hemofiltration alone. The investigators promoted the concept that certain therapies should be reserved for experienced teams.Figure 2: CRRT circuit connected to ECMOConclusion AKI is reported with a high incidence in critically ill children and the incidence is even higher in infants after CS secondary to multiple factors. AKI in this patient population is associated with high mortality and morbidity. Early diagnosis of AKI is imperative in management but no definite test is available. Clinicans should have a high index of suspicion and surveillance for AKI in the immediate post-operative period. Development of new biomarkers offers hope in this regard. Management is largely supportive and should focus on pre-operative stabilisation, early diagnosis of AKI, close monitoring of hemodynamic status and renal function, utmost diligence in fluid management, avoidance of nephrotoxins, collection of metabolic disturbances & dyselectrolytemia and early initiation of renal replacement therapies as indicated. Further research in pediatric congenital heart surgery population is required to better delineate the specific population at risk, validate the experimental biomarkers in clinical studies and prospectively study renal replacement therapies in large randomized trials. Large multicentric international trials and registries would be a step ahead in this regard. Conflict of Interest: None Source of Funding: None