Norepinephrine

Maintenance of an adequate BP, specifically mean arterial pressure (MAP), is essential for adequate tissue perfusion. When the MAP falls below the autoregulatory range of an organ, blood flow decreases in an almost linear fashion. Decreased blood flow results in tissue ischemia and organ failure. In patients with narrowing of their renal, coronary, or cerebral arteries, and in patients with long-standing hypertension, the fall in organ blood flow will occur at a higher BP. Furthermore, different vascular beds will lose autoregulation at different BP values. The autoregulatory threshold for the mammalian kidney is about 80 mm Hg, while that for the brain is approximately 50 mm Hg. An important goal in the management of critically ill patients is therefore to maintain the MAP above the autoregulatory threshold of the kidney, namely, 80 mm Hg. A higher threshold should be targeted in patients with a history of hypertension and in patients with atherosclerotic vascular disease. In patients who have experienced acute cerebrovascular insults, cerebral autoregulation may be lost, and in such circumstances blood flow is pressure-dependent. (1) In such patients, increasing the MAP beyond the cerebral autoregulatory range may improve tissue perfusion and decrease neuronal loss. (2,3)

Aggressive volume resuscitation is considered to be the best initial therapy for the management of patients with hypotension. Volume resuscitation is initiated with fluid boluses of 500 mL, titrated to BP (ie, MAP), heart rate, urine output, and respiratory status. In patients with the systemic inflammatory response syndrome due to sepsis or other causes, hypotension may persist despite vigorous volume expansion. These patients require treatment with a vasopressor agent. Traditionally, dopamine has been regarded as the pressor of choice as it was believed that this agent would maintain renal, cerebral, coronary, and splanchnic blood flow. Furthermore, it was taught that norepinephrine was to be avoided at all costs as this agent caused severe vasoconstriction. However, some data have suggested that both of these widely held "truths" are incorrect. The "reno-protective" effects of dopamine have been debunked, and this agent may paradoxically impair splanchnic mucosal blood flow. (4-7) At the same time, the deleterious effects of norepinephrine have not been confirmed, and indeed it has been demonstrated that this agent increases organ and tissue blood flow in patients in various disease states.

Although norepinephrine has been used in an animal model of ischemia-induced renal failure, intense vasoconstriction occurs only with infusion of the drug directly into the renal artery, and not via the systemic route at clinically relevant doses. (8-10) The dose of the drug used in animal models of norepinephrine-induced acute renal failure was two to three times that used in appropriate animal studies and was well beyond the mean dose usually administered in clinical practice. Indeed, as demonstrated by Albanese and colleagues in this issue of CHEST (see page 534), at clinically relevant doses (ie, renal dose norepinephrine) norepinephrine may improve renal function in patients with pathologic vasodilatation and maintain renal function in volume-replete patients who have normal systemic vascular resistance. Norepinephrine has been demonstrated to increase the expression of a cyclooxygenase (COX)-2 isoform in the kidney, and increased production of COX-2-derived prostaglandins (PGs) [ie, PG[E.sub.2] and PC[I.sub.2]] attenuates the renal vasoconstriction induced by uorepinephrine. (11-14) Furthermore, COX2-derived PGs may cause greater afferent arteriolar dilatation, thereby maintaining glomerular filtration. (13-15) In addition, an increase in systemic BP may lead to renal vasodilation by decreasing renal sympathetic tone through a baroreceptor feedback mechanism. (10)

Albanese and coworkers demonstrated that norepinephrine at a mean ([+ or -] SD) dose of up to 1.3 [+ or -] 0.3 [micro]g/kg/min restored the MAP and reestablished urine output in oligurie patients with septic shock. This finding has been observed by other investigators, (16-18) and was confirmed in experimental models of endotoxemia in which norepinephrine restored renal blood flow and renal function. (19-21) It should be appreciated that due to decreased adrenergic receptor density and receptor uncoupling in patients with sepsis, doses of up to 2.0 [micro]g/kg/min may be required to achieve an adequate MAP. (22) While the benefit of norepinephrine in patients with septic shock has been established, (23) the safety of this vasopressor in other clinical scenarios has been questioned. However, the study by Albanese and colleagues has demonstrated that in volume-replete patients with head injuries norepinephrine (in a doses of up to 0.5 [micro]g/kg/min) will reliably increase the MAP (and cerebral perfusion pressure) without compromising renal function. This observation has been confirmed by Morimatsu et al, (24) who demonstrated that norepinephrine maintained renal function in hypotensive patients after cardiac surgery.

Volume resuscitation remains the cornerstone of treatment for the hypotensive patient. In the hypovolemic patient, therapy with norepinephrine may seriously compromise renal function and should therefore be avoided. However, in the volume-replete patient, norepinephrine is the vasopressor of choice. Norepinephrine in clinically relevant doses is a friend of the kidney and not a foe! (25)

REFERENCES

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(20) Zhang H, Smail N, Cabral A, et al. Effects of norepinephrine on regional blood flow and oxygen extraction capabilities during endotoxic shock. Am J Respir Crit Care Med 1997; 155:537-544

(21) Treggiari MM, Romand JA, Burgener D, et al. Effect of increasing norepinephrine dosage on regional blood flow in a porcine model of endotoxin shock. Crit Care Med 2002: 30:1334 -1339

(22) Boillot A, Massol J, Maupoil V, et al. Myocardial and vascular adrenergic alterations in a rat model of endotoxin shock: reversal by an anti-tumor necrosis factor-alpha monoclonal antibody. Crit Care Med 1997; 25:504-511

(23) Martin C, Viviand X, Leone M, et al. Effect of norepinephdoe on the outcome of septic shock. Crit Care Med 2000; 28:2758-2765

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(25) Bellomo R, Di Giantomasso D. Noradrenaline and the kidney: friends or foes? Crit Care 2001:5:293-298

Paul E. Marik, MD, MBBCh, FCCP Pittsburgh, PA

Dr. Marik is affiliated with the Department of Critical Care Medicine, University of Pittsburgh Medical Center. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Paul Marik, MD, MBBCh, FCCP, Professor of Critical Care and Medicine, Department of Critical Care, University of Pittsburgh, 640A Scaife Hall, 3550 Terrace St, Pittsburgh, PA, 15261; e-mail: maripe@ccm.upmc.edu

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