Vasoactive Drugs, Renal Function, and Acute Kidney Injury

Sepsis is the most common cause of acute kidney injury (AKI), accounting for nearly 50% of cases of renal failure in intensive care units (ICUs). AKI is also an independent risk factor for death in patients with sepsis, with a mortality rate of up to 50% to 60% depending on its severity. Recent epidemiologic studies indicate that patients who survive AKI are at a greater risk of developing chronic and end-stage kidney disease in later stages of life. These studies demonstrate that all severities of AKI predispose individuals to short- and long-term organ dysfunction, morbidity, and mortality.

Conventionally, sepsis-induced AKI was considered a disease of the renal macrocirculation resulting from global renal ischemia, cellular damage, and acute tubular necrosis. However, accumulating evidence from human and experimental animal models of hyperdynamic sepsis recently has challenged this paradigm by suggesting that AKI can develop despite maintained or even increased renal blood flow. Furthermore, histologic assessment of postmortem kidneys from patients with septic AKI reported heterogeneous tubular injury with apical vacuolization, but with an absence of tubular necrosis or even extensive apoptosis. It is obvious that an understanding of the mechanisms causing reductions in renal function in the face of renal hyperperfusion is vital if we are to develop new therapeutic interventions and improve management of patients.

Renal tissue hypoxia is emerging as a critical mediatory factor in the pathogenesis of multiple forms of AKI arising because of stressors such as cardiothoracic surgery requiring cardiopulmonary bypass, radiocontrast administration, and sepsis. An increase in global renal blood flow during sepsis does not preclude the possibility of redistribution of intrarenal blood flow, with some portions of the kidney receiving a more than adequate perfusion at the expense of others experiencing local tissue ischemia and hypoxia. Increased heterogeneity of perfusion in the sublingual circulation in humans, resulting from microcirculatory dysfunction, is a hallmark of sepsis and is associated with a high mortality. However, whether heterogeneity of perfusion contributes to the development of septic AKI has received little attention. Recent experimental evidence in conscious sheep with hyperdynamic sepsis and AKI, which closely mimics the human septic phenotype, demonstrated an early onset of tissue ischemia and hypoxia selective to the renal medulla ( Fig. 225.1 ), despite an increase in total renal blood flow and oxygen delivery. In turn, hypoxia can lead to inflammation and oxidative stress, which can initiate a vicious cycle leading to cellular injury, further kidney injury, and reduced function. Thus the development and implementation of therapeutic strategies for patients with sepsis should include consideration of their effects on intrarenal oxygenation.

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Time course of changes in medullary tissue oxygen tension and urine flow during the development of septic acute kidney injury in conscious sheep. Each point is the between-animal mean ± SEM of 60-minute averages (n = 13).

(Figure modified from Lankadeva et al. Kidney Int. 2016;90[1]:100–108.)

Central hemodynamic support with the use of intravenous fluids and vasopressors remains the mainstay of therapy in patients with septic shock. In critically ill patients, with or at risk of developing AKI, the main therapeutic goals for the use of vasopressors are to improve arterial pressure and maintain renal function. The most commonly used vasopressor drugs in patients with septic shock are norepinephrine, epinephrine, vasopressin or its longer-acting analogue terlipressin, dopamine, and phenylephrine. There is also an increasing level of interest in the potential of angiotensin II as an effective adjunctive therapy for patients with catecholamine-refractory septic shock. Now that we appreciate the harmful effects of renal tissue hypoxia in the pathogenesis of septic AKI, it is imperative to understand how restoring renal function with vasopressors affects regional kidney perfusion and oxygenation.

Vasopressor Drugs

Norepinephrine

Norepinephrine is the first-choice vasopressor used clinically to restore blood pressure and renal function in patients with septic shock. Norepinephrine is a potent α-adrenergic receptor agonist with low affinity for β-adrenergic receptors. Norepinephrine increases arterial pressure by α-adrenergic receptor-mediated vasoconstriction, with a small β-adrenergic receptor-mediated increase in stroke volume, and thus cardiac output. The use of norepinephrine in the treatment of septic AKI has been the subject of ongoing debates resulting from the fear of it causing further deterioration in renal function due to renal ischemia. Nevertheless, in patients with sepsis norepinephrine therapy has been shown to consistently reverse hypotension and transiently improve renal function, as assessed through estimated glomerular filtration rate, with fewer adverse effects than dopamine, vasopressin, epinephrine, and phenylephrine. These findings, among others, have provided the clinical basis for the administration of norepinephrine as the first line of therapy for patients with septic shock.

It is now becoming increasingly evident from clinically relevant animal models of sepsis that a preservation of global kidney blood flow and oxygen delivery does not preclude the possibility of localized tissue ischemia and hypoxia. Indeed, restoration of arterial blood pressure with a clinically relevant dose of norepinephrine (0.4–0.8 µg/kg/min) was shown to exacerbate the underlying renal medullary ischemia and hypoxia in conscious sheep with established septic AKI ( Fig. 225.2 ). Importantly, these effects of norepinephrine occurred in face of preserved global kidney blood flow and oxygen delivery and without measurable changes in whole-kidney oxygen consumption. These findings are not surprising considering the evidence that restoration of systemic hemodynamics with norepinephrine does not improve microcirculatory flow abnormalities in patients with septic shock. Experimental evidence in a porcine model of septic shock further demonstrated that resuscitation with norepinephrine has the potential to worsen microcirculatory flow abnormalities in the mesenteric circulation.

The long-term consequences for kidney health of this exaggerated renal medullary ischemia and hypoxia induced by norepinephrine in sepsis are unknown and merit further investigation. However, there is evidence from a meta-analysis that most survivors of septic AKI are predisposed to a greater risk of developing chronic kidney disease in later stages of life. This provides the impetus for using caution when using vasopressors that have the potential to worsen the underlying pathologic and reparative processes that occur during septic AKI. It is also critical to determine if other vasopressors commonly used in the ICU in the treatment of septic AKI have similar effects on regional kidney oxygenation or if these effects are specific to norepinephrine. Such studies may lead to the development of therapies that restore blood pressure while preserving regional kidney oxygenation and thus renal function, which may hold the key to the better management of patients with septic AKI.

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