Perioperative Renoprotection: Clinical Implications

Khaschayar Saadat-Gilani, MD; Alexander Zarbock, MD; Melanie Meersch, MD

Disclosures

Anesth Analg. 2020;131(6):1667-1678. 

In This Article

Why Bundled Strategies are Useful

Considering the different measures recommended by the KDIGO guidelines, it is conceivable that the adherence to a bundled approach may be effective in terms of preventing AKI.

Hemodynamic Control

One component of the proposed KDIGO bundle is hemodynamic monitoring and optimization. Intraoperative hypotension due to a change of perfusion pressure or the presence of hypovolemia can be responsible for AKI and represents a preventable risk factor.[81,82]

Common treatment thresholds in clinical practice are systolic blood pressure <80 mm Hg,[83,84] MAP <60 mm Hg,[85] or a reduction of 30% to 50% from baseline.[84] The relationship between MAP and risk for AKI seems to be proportional. A recent meta-analysis revealed that a MAP <60 mm Hg for >1 minute was associated with increased risk for AKI.[86,87] The Effect of individualized vs standard blood pressure management on postoperative organ dysfunction among high-risk patients undergoing major surgery (INPRESS) study group demonstrated that an individualized blood pressure target (within 10% of each patients resting value) was superior to the above-mentioned standard values and resulted in significant lower rates of organ dysfunction (38.1% individualized vs 51.7% standard blood pressure management; P = .02).[88] A recent study in noncardiac surgical patients focused on blood pressure variability and suggested that this is the value of interest.[82] They demonstrated that a higher blood pressure variability independent of hypotension was associated with higher risk of postoperative AKI.

The call for individualized goal-directed therapy raises the question of how to monitor individualized pressure goals through fluid administration. Early studies in the 1980s started with looking at goal-directed therapies utilizing pulmonary artery catheters.[89,90] These were followed by esophageal Doppler sonography[91] and more recently by calibrated pulse contour analysis.[92] The use of functional parameter for guidance of fluid management has been under some criticism, because of the increased risk of hypervolemia. A recent meta-analysis looked at uncalibrated pulse contour analysis for monitoring and demonstrated that goal-directed therapy resulted in more colloid administration but less crystalloid solutions without a change in total fluid amount.[93]

In terms of fluid administration, multiple studies noted the large variability of intraoperative application of fluid volume.[94,95] Evidence suggests that a treatment of hypovolemia should not result in fluid overload because fluid overload is associated with the occurrence of AKI and less recovery from AKI.[96–98] Based on data from patients undergoing major abdominal surgery, some studies advocated a more restrictive fluid management and demonstrated that this approach led to a reduced postoperative complication rate and shorter length of hospital stay.[99,100] These findings resulted in international consensus statements supporting restrictive fluid management to facilitate enhanced recovery after surgery.[101,102] However, on the other hand, a growing body of evidence suggests that this strategy not only worsens respiratory function but also increases the risk for wound healing and sepsis.[103] Of special concern is the impact of hypovolemia on AKI due to impaired renal autoregulatory abilities, facilitating further renal injury and worsening AKI.[104,105]

Apart from the amount of fluid, the type of fluid that is given remains a matter of ongoing debate. Current evidence suggests the use of balanced crystalloid instead of chloride-rich solutions. The rationale behind this is that chloride-rich solutions cause renal vasoconstriction and have been shown to deteriorate kidney function.[106,107] Two large trials were recently published: the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) and Saline Against Lactated Ringer's or Plasma-Lyte in the Emergency Department (SALT-ED) trial, 2 cluster-randomized, cluster-crossover trial comparing balanced crystalloid with 0.9% sodium chloride for patients in the ICU and emergency department.[108–110] Both trials demonstrated that especially patients at high risk are at risk for the development of major adverse kidney events consisting of persistent renal dysfunction, need for RRT, or mortality after 30 days: SMART: 14.3% vs 15.4%; odds ratio (OR), 0.90; 95% CI, 0.82–0.999; P = .04) and SALT-ED: 4.7% balanced crystalloid vs 5.7% saline group; OR, 0.82; 95% CI, 0.70–0.95; P = .01). Two trials, the Plasma-Lyte 148 vs Saline (PLUS) and Balanced Solution versus Saline in Intensive Care Study (BaSICS) trials, are ongoing which may provide more insights into the effects of saline solutions on outcomes in critically ill adults. However, high doses of saline solutions should not be used in the critical care setting.

This also applies to the administration of hydroxyethyl starch because there is overwhelming evidence that starch solution may foster the occurrence of AKI in vulnerable patients[111,112] as well as mortality in critically ill patients with sepsis.[113–115] There are currently recommendations against the use of starch in septic and burned patients as well as a boxed warning by the Food and Drug Administration.[116] However, new preparations of hydroxyethyl starch solutions (130/0.4) are currently being investigated in 2 international prospective, multicenter, randomized controlled trials (Safety and efficacy of 6% hydroxyethyl starch solution vs an electrolyte solution in patients undergoing elective abdominal surgery [PHOENICS], NCT03278548, and Safety and efficacy of 6% hydroxyethyl starch solution vs an electrolyte solution in trauma patients [TETHYS], NCT03338218). Whether the results revoke some of the apprehension around hydroxyethyl starch remains to be awaited.

In summary, the assurance of an adequate perfusion pressure and volume status is an important mainstay of the KDIGO bundle and has a tremendous effect on the occurrence of AKI. Paying attention to avoid excessive hypovolemia as well as hypervolemia, using preferentially buffered isotonic crystalloid solutions for expansion of intravascular volume assisted by use of vasopressors to an individual blood pressure target are the main tasks of the attending physicians.

Glycemic Control

Different groups have investigated glycemic control in critically ill patients in terms of AKI and suggested a clear relationship between poor glycemic control and worse outcomes (Table 3).[13,31,117–121]

The management of blood glucose levels seems to follow a U-shaped relationship. Van den Berghe et al[122,123] were able to demonstrate a reduction of mortality and lower rates of RRT when using tight glycemic control. However, the Intensive vs conventional glucose control in critically ill patients (NICE-SUGAR) group demonstrated that a too tight glycemic control also increases the risk of hypoglycemia and death.[124] This needs to be kept in mind for the following reason: glycemic hemostasis is impaired in kidney injury patients. The kidneys are responsible for 50% of insulin clearance, and they contribute to around 30% of the overall gluconeogenesis.[125,126] This might be a reason why patients with AKI are more susceptible to the development of hypoglycemia when treated for hyperglycemia.

Nevertheless, the topic of blood sugar control remains a highly debated topic, and the degree of glycemic control might need to be adjusted for the individual patient population.[127] Similar to recent observations of blood pressure variability, some evidence suggests that not the absolute blood sugar level per se results in AKI, but the variability.[128] At this stage, it remains unclear if hyperglycemia, insulin resistance, and the variability are true contributors of poor outcome or if they are just an indicator for general metabolic derangement. Currently, the KDIGO guidelines suggest to adhere blood glucose levels between 110 and 149 mg/dL to prevent the occurrence of AKI.

Nephrotoxic Agents

Diuretics. The question whether to use diuretics for prevention of AKI arises repeatedly. The KDIGO guidelines clearly recommend that the use of diuretics should be reserved for regulation of fluid balance and not as a preventative tool to avoid AKI.

The theoretical mechanism of furosemide for preventing AKI includes decreasing GFR and tubular workload resulting in less renal medullary metabolic demand as well as acting as a vasodilator.[129] However, this remains controversial. Lassnigg et al[130] compared the administration of isotonic sodium chloride, continuous infusion of dopamine (2 μg/kg/min, "renal dose"), or furosemide (0.5 μk/kg/min) in a cohort of elective cardiac surgical patients in terms of reduction of postoperative creatinine levels. They found highest increase in creatinine levels in patients receiving furosemide assuming that furosemide is even detrimental in terms of prevention of AKI. A further trial among high-risk patients undergoing cardiac surgery demonstrated that patients receiving furosemide (4 mg/kg until 12 hours after surgery) had the same incidence of renal dysfunction as compared to those patients receiving saline solution as placebo.[131] In a meta-analysis utilizing the Medical Information Mart for Intensive Care (MIMIC-III) database,[132] furosemide administration was associated with reduced in-hospital mortality (hazard ratio [HR], 0.67; 95% CI, 0.61–0.74; P < .001) and 90-day mortality (HR, 0.69; 95% CI, 0.64–0.75; P < .001).[133] Of note, these findings were only valid for moderate and severe AKI based on urine output and not based on serum creatinine or chronic disease.

In certain situations (contrast medium administration), loop diuretics may act protectively but only if intravascular volume and consequently renal perfusion pressure is maintained.[134] Whether these findings can be verified in large, prospective, randomized controlled trials remains to be seen. Based on current evidence, diuretics for prevention of AKI cannot be recommended.

Contrast Agents. There is a growing body of evidence questioning whether the concerns regarding contrast-induced AKI are justified. Neither a meta-analysis from 2013[135] nor a more recent meta-analysis from 2018 including 28 studies and 107,335 patients receiving contrast-enhanced computed tomography could demonstrate a significant increase in AKI.[136] These findings remained valid even when controlled for type of contrast agent or comorbidities. Furthermore, a secondary analysis from 2020 confirmed similar findings.[137] No association between preoperative contrast administration and AKI within 48 hours after gastrointestinal or hepatobiliary surgery could be demonstrated. There may be 2 possible reasons for these findings: (1) new contrast agents are less nephrotoxic and (2) the dose makes the poison. The KDIGO guidelines recommend to avoid contrast agents if possible and this is what should be considered in daily clinical practice.

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