Are Alpha-2 Agonists Effective in Reducing Perioperative Renal Injury?

INTRODUCTION

Despite advances in anesthesia care over the past decades, perioperative organ injury remains the leading precursor to death after surgery. Perioperative renal injury is one of the most common postoperative complications and leads to increased health care expenditure, prolonged hospital stay, and increases in short- and long-term mortality. ^, It is difficult to determine the true incidence of perioperative acute kidney injury (AKI). Because of its heterogenous nature and multifactorial etiology, the reported incidence of AKI varies widely depending on the definition used and population studied. In a retrospective study of over 160,000 U.S. veterans after major surgery, the overall incidence of postoperative AKI was 11.8%, with the highest-risk surgeries being cardiac, general surgery, and thoracic surgery. When looking specifically at a high-risk group such as cardiac surgery, a systematic review of over 300,000 cardiac surgical patients found that the pooled incidence of AKI was 22.3%.

Thinking of AKI as merely a single-organ injury is unfortunately too simplistic. It should instead be understood as a systemic disease process that can provoke remote organ dysfunction, including cardiac, pulmonary, neurologic, hepatic, gastrointestinal, and immunologic dysfunction. Despite the widespread recognition of perioperative AKI and its sequelae, the identification of an efficacious preventative or therapeutic preventative strategy has been elusive.

Alpha-2 agonists are a unique class of drugs that have broad uses in anesthesia, pain, and perioperative medicine. They have numerous useful effects including analgesia, anxiolysis, sedation, and anesthesia sparing effects. They also possess an ability to attenuate perioperative hemodynamic abnormalities and balance organ oxygen supply/demand ratio. ^, More recently, alpha-2 agonists have been investigated for potential organ protective effects attributable to anti-inflammatory and antiapoptotic actions. Because of these novel actions, the use of alpha-2 agonists is now being explored for prevention of perioperative AKI.

Before we address the use of alpha-2 agonists in the prevention of perioperative AKI, it is important to outline the definitions of AKI to appreciate the various endpoints used in the literature. One of the reasons for the poor quality of older evidence is that many studies used different definitions of AKI. The diagnosis of AKI has traditionally been made by assessing increases in serum creatinine concentration, decreases in creatinine clearance or glomerular filtration rate (GFR), and decreases in urine output or the requirement for renal replacement therapy. There have been several attempts to create a uniform definition of AKI to improve accuracy in reporting incidence and outcomes and allow comparability of studies. The first of these was the Risk, Injury, Failure, Loss or End-Stage Kidney disease criteria (RIFLE) in 2004. After recognition that RIFLE underestimates the effect of small acute creatinine changes on mortality, the Acute Kidney Injury Network (AKIN) incorporated changes that accounted for small increases in creatinine over time. The more recently developed Kidney Disease Improving Global Outcomes (KDIGO) criteria attempts to reconcile the differences between the RIFLE and AKIN criteria. These criteria are summarized in Table 15.1 .

TABLE 15.1

Classifications of Acute Kidney Injury

	RIFLE (Risk, Injury, Failure and End-stage)	AKIN (Acute Kidney Injury Network)	KDIGO (Kidney Disease, Improving Global Outcomes)
Grade 1	Increased sCr x1.5 or decrease in GFR > 25% from baseline in 7 days OR UO < 0.5 mL/kg/hr for 6–12 hours	Increases sCr x1.5 or by ≥0.3 mg/dL (≥26.5 mol/L) from baseline in 48 hrs OR UO <0.5 mL/kg/hr for 6–12 hrs	Increased sCr by ≥0.3 mg/dL (≥26.5 mol/L) in 48 hrs OR increased sCr x1.5–1.9 from baseline within 7 days OR UO <0.5 mL/kg/hr for 6–12 hrs
Grade 2	Increased sCr x2-2.9 or GFR decrease >50% from baseline in 7 days OR UO <0.5 mL/kg/hr for >12 hrs	Increased sCr x2-2.9 in 7 days from baseline OR UO <0.5 mL/kg/ hr for >12 hrs	Increased sCr x2-2.9 in 7 days from baseline OR UO <0.5 mL/kg/hr for >12 hrs
Grade 3	Increased sCr >x3 or GFR decreases >75% from baseline in 7 days or sCr >4 mg/dL (with an acute rise of >0.5 mg/dL) OR UO <0.3 mL/kg/hr for 24 hrs or anuria for >12 hrs	Increased sC >x3 from baseline in 7 days or sCr>4 mg/dL (with an acute rise of >0.5 mg/dL) OR UO <0.3 mL/kg/hr for 24 hrs or anuria for >12 hrs or initiation of RRT	Increased sCr >x3 from baseline in 7 days or sCr > 4 mg/dL (with no need for an acute rise of >0.5 mg/dL) or eGFR decreased <35 mL/ min if age <18 years old or initiation of RRT OR UO <0.3 mL/kg/hr for 24 hrs or anuria for >12 hrs

GFR , Glomerular filtration rate; RRT , renal replacement therapy; sCr , serum creatinine; UO , urine output.

From Gumbert S, Kork F, Jackson M, Vanga N, Ghebremichael S, Wang C, et al. Perioperative acute kidney injury. Anesthesiology 2020; 132 :180–204.

There are several limitations in using these definitions as endpoints when investigating AKI. A rise in serum creatinine does not occur until relatively late after renal injury, often lagging about 24 to 72 hours behind the initial insult. ^, This leads to a “creatinine blind window.” Urine output is also an unreliable marker in the perioperative period because of the release of hormones such as aldosterone and antidiuretic hormone that reduce urine output. These limitations often delay the diagnosis of AKI, so the use of biomarkers has been explored in an attempt to improve early detection. The ideal biomarker would be highly precise, sensitive, and specific to renal injury and be able to resolve the “blind window.” Biomarkers differ in their sensitivity and specificity to AKI and vary in their time courses. The downside is that they often lack sensitivity to early cellular stress, may lack specificity to renal injury, and may be unable to differentiate between AKI and chronic kidney disease (CKD). Potential biomarkers include plasma and urine neutrophil gelatinase-associated lipocalin (NGAL), Kidney Injury Molecule-1 (KIM-1), and cystatin C (CysC). ^, A recent prospective cohort study has also identified several biomarkers that are independently associated with the development of CKD after cardiac surgery. These included basic fibroblast growth factor, KIM-1, N-terminal pro–B-type natriuretic peptide (NT-proBNP), and tumor necrosis factor receptor.

OPTIONS/THERAPIES

Alpha-2 agonists are highly lipid-soluble drugs that easily penetrate the blood-brain barrier and selectively bind to presynaptic alpha-2 adrenergic receptors located in the central nervous system (specifically the brainstem and locus coeruleus) to activate a negative feedback mechanism that inhibits central sympathetic outflow with a resulting decrease in systemic adrenaline and noradrenaline production. This inhibition of central sympathetic outflow attenuates perioperative hemodynamic abnormalities and the sympathetic surgical stress response, mitigating some of the mechanisms that can lead to perioperative renal injury. Alpha-2 agonists also reduce perioperative oxygen consumption, potentially improving the oxygen supply-demand balance. Despite these potential benefits, the use of alpha-2 agonists may be limited by clinically significant hemodynamic adverse effects such as hypotension and bradycardia.

There are many alpha-2 agonists that vary in their alpha-2 selectivity; of these, clonidine and dexmedetomidine are the main alpha-2 agonists that have been studied in this field. Dexmedetomidine is highly selective to the alpha-2 adrenoceptor, with an alpha-2:alpha-1 specificity of 1620:1, compared with 220:1 for clonidine. ^, Dexmedetomidine is also a full agonist at the alpha-2 adrenoceptor, whereas clonidine is only a partial agonist. An advantage of dexmedetomidine over clonidine is a shorter distribution half-life of only 6 minutes, leading to rapid onset and short duration of effect. This allows administration by infusion and may also reduce adverse effects such as hypotension and bradycardia. After initial administration, transient increases in blood pressure may be seen because of loss of selectivity and peripheral stimulation of alpha-1 receptors. This is seen more with clonidine than dexmedetomidine.

Alpha-2 adrenoreceptors are distributed widely within the renal proximal and distal tubules and peritubular vasculature. Local responses to alpha-2 adrenoceptor activation in the kidney are vasodilation, inhibition of antidiuretic hormone (ADH), and renin release leading to increased renal blood flow, increased glomerular filtration rate, and increased secretion of sodium and water. Clinically, alpha-2 adrenoceptor agonists stimulate urine flow and enhance renal function likely through the modulation of vasoreactivity.

There are several mechanisms that contribute to the development of perioperative AKI, and these often cross the boundaries of the traditional prerenal, renal, and postrenal causes. The main contributing factors in the perioperative period are likely related to hemodynamic changes and initiation of the inflammatory and neuroendocrine stress responses. Hypovolemia, surgical blood loss, reduced systemic vascular resistance, and reduced venous return reduce cardiac output and renal perfusion. Renal autoregulation gives the kidneys the ability to maintain renal blood flow and GFR within a particular range; however, if hypoperfusion persists, activation of the sympathetic nervous system leads to afferent arteriole vasoconstriction and a reduction in renal blood flow. Perioperative stress and surgical trauma also lead to systemic inflammation and cytokine release that can directly induce tubular injury through activation of the sympathetic nervous system, oxidative stress, proapoptotic pathways, and renal microcirculatory dysfunction. The neurohumoral stress response contributes to AKI, and alpha-2 agonists can reduce this.

Cardiac and aortic surgery, in particular, are a major risk factor for the development of AKI. The use of cardiopulmonary bypass, aortic cross-clamping, ischemia-reperfusion injury, periods of hypotension and low cardiac output, combined with the need for vasopressor and inotropic support, all increase the risk for AKI. The use of CPB and exposure of blood to the CPB circuit triggers several pathophysiologic processes that contribute to the development of AKI, through activation of a systemic inflammatory response syndrome, mechanical blood trauma leading to hemolysis and production of oxidative stress, hemodynamic disturbance, ischemia-reperfusion injury, and microemboli formation. ^,

EVIDENCE

Clonidine

Many of the earlier studies focused on clonidine in the context of cardiac surgery. These initial trials were cautiously positive, but their results were not replicated in a large multicenter study of noncardiac patients.

Cardiac Surgery

Two small placebo-controlled randomized controlled trials (RCTs) showed that clonidine reduced the risk for AKI in cardiac surgery. ^, Although both studies used creatinine clearance as the main endpoint, they used different clonidine dosing regimens. Kulka and colleagues conducted an RCT consisting of 48 patients undergoing coronary artery bypass graft (CABG) surgery. They found that the administration of 4 µg/kg intravenous (IV) clonidine before induction of anesthesia prevented the deterioration of renal function after surgery as measured by 12-hour creatinine clearance. Creatinine clearance decreased significantly over the first night from 98 ± 18 mL/min to 68 ± 19 mL/min in the control group, whereas creatinine clearance remained unchanged in clonidine-treated patients. They did not comment on the incidence of bradycardia or hypotension but noted that fluid administration and blood loss during the first 12 postoperative hours was not different between the groups. Myles and colleagues conducted an RCT involving 156 patients undergoing elective CABG surgery. They found that the administration of clonidine (two doses given orally or nasogastrically at a dose of 5 µg/kg preoperatively and again before initiation of cardiopulmonary bypass) significantly improved early postoperative renal function as measured by 4-hour creatinine clearance. Nevertheless, clonidine was also associated with more bradycardia, hypotension, and a greater need for cardiac pacing after CPB.

Noncardiac Surgery

These initial promising results were not replicated in a large study involving noncardiac surgery. A substudy of the Perioperative Ischemic Evaluation (POISE) 2 trial examined the incidence of AKI as defined by KDIGO (an increase in serum creatinine of 0.3 mg/dL or greater [≥ 26.5 µmol/L] within 48 hours of surgery). POISE-2 was a large multicenter trial investigating moderate- to high-risk patients undergoing noncardiac surgery. The clonidine analysis included 6905 patients who were administered either 0.2 mg of oral clonidine or placebo 2 to 4 hours before surgery followed by a transdermal clonidine patch (0.2 mg/day) or placebo patch until 72 hours after surgery. The administration of clonidine did not alter the risk for AKI (13% in clonidine group vs. 12.7% in placebo group). The use of clonidine was actually associated with more clinically important hypotension, bradycardia, and nonfatal cardiac arrest. Notably, in the post hoc analyses, clinically important hypotension was associated with a greater risk for subsequent AKI.

Dexmedetomidine

More recently, the focus has shifted to dexmedetomidine, and there have been several studies published investigating dexmedetomidine and its role in mitigating perioperative renal injury.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here