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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Catecholamines and acute renal failure

, M.D.

Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, U.S.A.

Introduction

Catecholamines are commonly used for hemodynamic support during surgery and in the post-operative management of critically ill patients. These agents increase mean arterial pressure through their effects on inotropy, vasoconstriction or both. Although primary inotropic therapy may be appropriate in certain settings, it is rare that these agents alone will be sufficient to support blood pressure in post-operative patients. Thus, vasoconstrictors are routinely used. However, because these agents increase mean arterial pressure by decreasing blood flow to certain tissues, concern exists about their potential to injury certain organs, most notably the kidneys and the gut. For this reason there is reluctance among some clinicians to use these vasoconstrictors for fear of renal or mesenteric injury. Furthermore, many clinicians attempt to vasodilate the renal vasculature with dopaminergic agents either to preserve flow during concomitant use of vasoconstrictors or in an effort to provide renal protection in a wide variety of clinical conditions. The purpose of this chapter is to review the available evidence in support of these practices with regard to the development of acute renal failure (ARF).

Definitions, pathophysiology and epidemiology

Acute renal failure (ARF) is defined as an abrupt and sustained decline in the glomerular filtration rate (GFR). The reduction in GFR leads to azotemia and uremia (accumulation of nitrogenous waste products and of uremic toxins). There is no clear consensus for the definition of ARF based on biochemical indices. Generally, ARF can be defined as either a serum creatinine of > 2.0 mg/dL (~ 180 μmol/L), or an increase of more than 0.5 mg/dL (45 μmol/L) over baseline. ARF is one of the most common clinical problems facing hospitalized patients. ARF affects nearly 5% of all hospitalized patients and as many as 15% of critically ill patients depending on the definitions used (1).

In critically ill patients, ARF is most frequently the consequence of functional, “pre-renal” disease (40–80%). In pre-renal ARF there is a decrease in GFR secondary to renal hypoperfusion either from intravascular volume depletion, decreased cardiac output, renal vasoconstriction, or rarely, vascular obstruction of the major renal arteries. This form of reversible ARF may lead to renal injury, particularly if sustained. This injury takes the form of acute tubular necrosis (ATN) which may also result from an ischemic or nephrotoxic injury, or both. “Intra-renal” ARF also includes interstitial nephritis, athero-embolic disease, glomerulonephritis, vasculitis and small vessel obstruction. However ATN is by far the most common cause of intra-renal ARF. Finally, post-renal ARF (< 10%), due to an obstruction to urinary flow, either of the lower or upper urinary tract is the least common type of ARF. Note that pre-renal ARF and ATN are two extremes of the same spectrum and that a prolonged pre-renal state may well lead to ATN; therefore, the distinction between the two patterns is not always obvious.

Several risk factors for ARF have been identified which are consistent across multiple etiologies. The most important of these include hypovolemia, hypotension, sepsis, preexisting renal, hepatic or cardiac dysfunction, diabetes melitus and exposure to nephrotoxins. Isolated ARF is rare in the ICU where most ARF occurs as part of the multiple organ dysfunction syndrome (MODS). In the perioperative setting, the risk of ARF is also influenced by factors such as the duration of the aortic clamping, and elective vs. emergent basis of surgery. While the mortality rates for isolated ARF are approximately 10 to 15%, ARF in ICU, generally in association with MODS, carries a mortality rate of 50 to 90%. Therefore, despite the available renal replacement therapies, the outcome of ARF in the ICU remains unfortunately poor around the world. In a recent study (2), the mortality rate among 253 cases of ARF treated in the ICU was 71.5% whereas it was 31.5% among the 495 cases of ARF treated in a non-ICU setting (p = 0.001).

Dopamine and related agents

Dopaminergic agents are usually considered in the prevention or treatment of acute tubular necrosis (ATN). The basic rationale is that ischemic ATN should be improved by increasing renal blood flow and that tubular obstruction should be decreased by maintaining urine flow. However, it is important to appreciate that increased urine output or increased renal blood flow are not important clinical endpoints in themselves. Evidence of clinical effectiveness needs to include outcome measures of clinical significance (e.g. mortality, need for hemodialysis) or biochemical evidence of organ function (serum creatinine or creatinine clearance) which are sustained following the maneuver.

Clinical evidence

A systematic review using the effectiveness criteria outlined above was published in 1997 (3). At this time, a total of 30 clinical trials had been published both for prevention and treatment of ATN. Of these, however, only 20 used outcomes other than surrogate markers (e.g. urine output, renal blood flow) and of these only three were positive. The remaining 17 studies, collectively enrolling over 700 patients, were all negative (3). Furthermore, each of the positive studies was methodologically inferior. In one study examining the effects of dopamine on the development of radiocontrast-induced ATN the control group received mannitol, an agent associated with a increased incidence of ARF compared to saline (4). The other two studies were both low level, one level IV study enrolling patients following liver transplant and one level V study of patients with IL-2 induced ATN. In addition, neither of these studies has been supported by subsequent level II studies using patients with the same clinical settings. Since 1996, another 22 studies have been published adding further support to the assertion that dopamine does not provide any renal protection in any subpopulation of patients.

Experimental evidence and scientific rationale

Dopamine is frequently used by clinicians to increase urine output in ARF in the hope that this might attenuate renal injury or improve survival. Much of the enthusiasm for this agent comes from the assumptions that dopamine increases renal blood flow and that such an outcome is, in fact, desirable. In addition, clinicians often interpret an increase in urine output as proof that these two assumptions are valid. Indeed, dopamine may increase urine output through four separate mechanisms (table I). However, the most important mechanism for the increase in urine output secondary to dopamine is the inhibition of sodium-potassium ATPase at the tubular epithelial cell level. The effect is to increase sodium excretion and thereby diuresis. Thus, apart from its direct and indirect effects on the renal vasculature, dopamine increases urine output because it is a diuretic. The naturetic/diuretic effects of dopamine are of importance not only because they may lull clinicians into believing that they are improving renal function when they observe an increase in urine output with the drug, but also because this increase in urine output may come with unexpected effects. First, the presence of urine output may mask hypovolemia and continued diuresis may produce renal injury rather than prevent it. Second, the renal outer medulla normally lives on the edge of dysoxia. Oxygen diffuses from the descending to the ascending vasa recta within vascular bundles limiting oxygen delivery to the renal medulla. In addition the medulla suffers from unusually high oxygen demand related to tubular transport activity. Thus, the renal medulla is constantly on the brink of dysoxia owing to high demand and low delivery of oxygen. Increasing renal blood flow would presumably improve medullary oxygen delivery, but unfortunately it appears that it does not. In a recent study, dopamine increased outer medullary blood flow in hypo-volemic rats, but failed to improve outer medullary dysoxia (5). In fact the increased solute delivery to the distal tubular cells produced by the naturetic effects of dopamine (via inhibition of proximal tubular reabsorption) might actually increase their oxygen consumption and therefore increase the risk of ischemia rather decrease it. Similar concerns exist regarding the newer dopaminergic agents and as of this writing, there is no evidence that they are beneficial.

Table I. Pharmacologic mechanisms of dopamine induced diuresis.

Table I

Pharmacologic mechanisms of dopamine induced diuresis.

Although renal blood flow (but not GFR) has been shown to decrease in normotensive healthy volunteers given norepinephrine and reversed with dopamine (6), these authors correctly point out that the effects of these drugs in patients with shock may be quite different. Thus, there is no evidence that dopamine provides any benefit to patients with impending or existing ARF or in the setting of vasconstrictor therapy.

Other catecholamines

The failure of dopamine to reduce the risk of ARF in no way diminishes the concerns about vasoconstrictors and their potential to produce renal injury. In healthy humans and animals high doses of potent vasoconstrictors such as norepinephrine may produce renal vasoconstriction. However, there is no evidence that these agents are harmful to the kidney when used in standard doses to treat hypotention. Furthermore, the finding of intensive vasoconstriction has only been seen to occur with the infusion of norepinephrine directly into the renal artery, not via the systemic route, and the doses of drug used in such models of norepinephrine-induced ARF were well beyond the doses typically administered in clinical practice. In a more clinically relevant study of norepinephrine (7) it was found that although renal vascular resistance increased from baseline, total renal blood flow progressively increased with increasing intravenous doses up to 1.6 mcg/kg/min. However, this study used healthy animals with a baseline mean arterial blood pressure of > 150 mmHg and norepinephrine infusion was associated with an increase in pressure of approximately 30% to 200 mmHg. Interestingly, animal studies of experimental sepsis have found that renal blood flow increased and renal vascular resistance decreased in response to norepinephrine infusions. One recent study using endotoxin-induced shock in the dog distinguished the effects of norepinephrine on renal blood flow due to increased perfusion pressure from those due to other effects of the drug (such as inducing blood flow redistribution) (8). These authors found that norepinephrine increased renal blood flow by both mechanisms.

The effects on renal blood flow of other potent α-agonists such as epinephrine and phenylephrine have not been as extensively studied. In healthy sheep, after a short-lived (minutes) decrease in renal blood flow at the highest doses tested (0.4 to 0.8 g/kg/min), epinephrine has been associated with a progressive increase in renal blood flow. A similar increase in renal blood flow was seen in septic sheep. This increase in renal blood flow occurred in association with a non-significant trend toward greater renovascular resistance that was offset by greater renal perfusion pressure. Complementary data are not available for phenylephrine and concern remains about the effects of this agent when infused for more than several hours. Studies that directly measure renal blood flow and renovascular resistance in man in response to α-agonists are not available. However, many clinical reports now support the notion that the continuous infusion of norepinephrine may increase urine output and improve creatinine clearance in patients with hyperdynamic septic shock (9). The effects of epinephrine are less clear. A recent study in patients with septic shock demonstrated a decrease in mesenteric blood flow (measured by tonometry) with the epinephrine but not with norepinephrine/dobutamine (10). The clinical significance of these findings is uncertain but concern remains about the potentially deleterious effects of epinephrine and phenylephrine on the mesenteric and renal vasculature. These concerns may give way with further study and do not appear to extend to norepinephrine.

Conclusions and recommendations

ARF is a common sequella of critical illness and its clinical consequences are grave. The assurance of adequate circulating blood volume and the avoidance of hypotension or nephrotoxins are the only known ways to reduce the incidence of ARF in the post-operative period. There is no evidence that, so called “renal-dose” dopamine is beneficial and there is evidence that it may be harmful in certain settings. Therefore the routine use of dopamine for renal protection should be avoided.

The use of catecholamines to support blood pressure in patients with distributive shock is not without hazard. Adequate fluid resuscitation should always be a priority. However, there is no evidence that α-adrenergic agents are harmful to the kidneys when used in standard doses to support blood pressure in patients with distributive shock who have been adequately fluid-resuscitated. In particular, norepinephrine has been shown to be associated with improved renal hemodynamics in animal models of sepsis and with sustained renal function in patients with hyperdynamic septic shock. Accordingly, the available evidence at the present time does not support the use of dopamine for renal protection, nor does it suggest that norepinephrine is harmful to the kidney when used to support blood pressure in patients with distributive shock after adequate fluid resuscitation.

References

1.
Brivet F G, Kleinknecht D J, Loirat P, Landais P J M. on behalf of the French Study Group on Acute Renal Failure. Acute renal failure in intensive care units – causes, outcomes and prognostic factors of hospital mortality: a prospective multicenter study. Crit Care Med. (1996);24:192–198. [PubMed: 8605788]
2.
Liano F, Junco E, Pascual J, Verde E. and the Madrid Acute Renal Failure Study Group. The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. Kidney Int. (1998);53 (suppl 66):S16–S24. [PubMed: 9580541]
3.
Kellum J A. The use of diuretics and dopamine in acute renal failure: a systematic review of the evidence. Crit Care. (1997);1:53–59. [PMC free article: PMC3386653] [PubMed: 11094464]
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Solomon R, Werner C, Mann D, D'Elia J, Silva P. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med. (1994);331:1416–1420. [PubMed: 7969280]
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Heyman S N, Kaminski N, Brezis M. Dopamine increases renal medullary blood flow without improving regional hypoxia. Exp Nephrol. (1995);3:331–337. [PubMed: 8528677]
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Hoogenberg K, Smit A J, Girbes A R J. Effects of low-dose dopamine on renal and systemic hemodynamics during incremental nor-epinephrine infusion in healthy volunteers. Crit Care Med. (1998);26:260–265. [PubMed: 9468162]
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Schaer G L, Fink M P, Parrillo J E. Norepinepherine alone versus norepinepherine plus low-dose dopamine: enhanced renal blood flow with combination pressor therapy. Crit Care Med. (1985);3:492–496. [PubMed: 3996002]
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Bellomo R, Kellum J A, Wisniewski S, Pinsky M R. Differential Effects of Norepinephrine on Renal Vascular Resistance and Renal Blood Flow in Normal and Endotoxemic Dogs. Am J Resp Crit Care Med. (1999);55:86–92.
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Martin C, Papazian L, Perrin G. et al. Norepinephrine or dopamine for the treatment of hyperdynamic septic shock? Chest. (1993);103:1826–1831. [PubMed: 8404107]
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Levy B, Bollaert P -E, Charpentier C. et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective randomized study. Intensive Care Med. (1997);23:282–287. [PubMed: 9083230]
Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK6930

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