vasoactive drugs and the kidney

4

Vasoactive drugs and the kidney

Raymond Wai Chuen Lee MD

Visiting Clinical Fellow

David Di Giantomasso MD

Research Fellow

Clive May PhD

Senior Investigator

Florey Research Institute, Melbourne, Australia

Rinaldo Bellomo* MD

Professor

Department of Intensive Care and Department of Medicine, Austin Hospital and Florey

Institute of Physiology, Melbourne, Vic., Australia

Protection of renal function and prevention of acute renal failure (ARF) are important goals ofresuscitation in critically ill patients. Beyond fluid resuscitation and avoidance of nephrotoxins,little is known about how such prevention can be achieved. Vasoactive drugs are oftenadministered to improve either cardiac output or mean arterial pressure in the hope that renalblood flow will also be improved and, thereby, renal protection achieved. Some of these drugs(especially low-dose dopamine) have even been proposed to have a specific beneficial effect onrenal blood flow. However, when all studies dealing with vasoactive drugs and their effects on thekidney are reviewed, it is clear that none have been demonstrated to achieve clinically importantbenefits in terms of renal protection. It is also clear that, with the exception of low-dosedopamine, there have been no randomized controlled trials of sufficient statistical power todetect differences in clinically meaningful outcomes. In the absence of such data, all that is availableis based on limited physiological gains (changes in renal blood flow or urine output) with one oranother drug in one or another subpopulation of patients. Furthermore, given our lack ofunderstanding of the pathogenesis of ARF, it is unclear whether haemodynamic manipulation is anappropriate avenue to achieve renal protection. There is a great need for large randomizedcontrolled trials to test the clinical, instead of physiological, effects of vasoactive drugs in criticalillness.

Key words: dopamine; vasopressin; epinephrine (adrenalin); norepinephrine (noradrenalin);dopexamine; milrinone; terlipressin; levosimendan; vasopressors; kidney; acute renal failure.

1521-6896/$ - see front matter Q 2003 Elsevier Ltd. All rights reserved.

Best Practice & Research Clinical AnaesthesiologyVol. 18, No. 1, pp. 53–74, 2004doi:10.1016/S1521-6896(03)00073-9, available online at http://www.sciencedirect.com

* Corresponding author. Tel.: þ61-3-9496-5992; Fax: þ61-3-9496-3932.E-mail address: [email protected] (R. Bellomo).

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Vasoactive drugs are commonly used in critical care for different indications. Allvasoactive drugs affect renal function either through their systemic effects or throughtheir direct effects on the renal circulation.1 In this chapter, we briefly discuss the effectsof the vasoactive drugs, with particular emphasis on their impact on the renalcirculation.

THE RATIONALE FOR VASOACTIVE DRUGS IN ICU

In patients with cardiogenic shock and vasodilatory shock maintenance of an adequatemean arterial pressure and cardiac output is fundamental to ensure adequate vital organperfusion and function. In many ICU patients, plasma volume expansion is sufficient toachieve these goals. In many others it is not. In these patients, vasoactive drugs (many ofwhich have both inotropic and vasopressor properties) are used to augment eithercardiac output or perfusion pressure, or both. A large body of data supports theirphysiological efficacy, although positive long-term effects and clinical outcomes have notyet been proven. However, many aspects of their use remain controversial. Oneparticular area of controversy relates to their renal effects. In order to understand suchcontroversy, it is important to consider several aspects of renal physiology.

The regulation of renal blood flow (RBF)

In the normal physiological state, RBF and glomerular filtration rate (GFR) are regulatedby both extrinsic and intrinsic mechanisms.

Extrinsic mechanisms

Extrinsic mechanisms (sympathetic–adrenal axis, the renin–angiotensin–aldosteronesystem, arginine vasopressin) are vasoconstrictor systems which protect againsthypovolaemia and hypotension. These vasoconstrictor responses typically modulatethe intra-renal vascular tone and stimulate the contraction of glomerular mesangialcells, which results in a reduction of glomerular surface area and GFR.2 Sympathetic–adrenal effects regulate the glomerular filtration pressure by preferential efferentarteriolar constriction through alpha and dopaminergic receptors.2 However, intensesympathetic system–adrenal gland activation also constricts the afferent arteriole,decreases the filtration fraction, and worsens GFR.3 This effect can be teleologicallyexplained by the need to minimize any fluid loss during shock. Evolutionarily, thisresponse would have ensured survival from limited injury and death in major injury,which would have been advantageous to the species.

The specialized endothelial cells of afferent arterioles also release renin inhypotensive states, which leads to an increase in angiotensin II. At low levels,angiotensin causes preferential efferent arteriolar constriction, increases the filtrationfraction, and preserves the GFR, whereas high levels of angiotensin constrict theafferent arteriole and the mesangial cells.2 Arginine vasopressin, at its usual plasma level,stimulates V2-receptors in the collecting ducts and causes water re-absorption and adecrease in urine output. However, high plasma levels of vasopressin in severehypotension act predominantly on the V1-receptor to preferentially constrict theefferent arteriole. This effect might preserve glomerular filtration pressure and GFR.2

54 R. W. C. Lee et al

Intrinsic mechanism

The intrinsic mechanism of RBF regulation, so-called renal autoregulation, refers to thechanges in resistance of the pre-glomerular afferent arteriole in response to a widerange of renal arterial perfusion pressure changes. This response is aimed at maintaininga constant level of RBF and GFR within physiological variations in arterial bloodpressure and cardiac output. One of the mechanisms of autoregulation is explained byBayliss’ myogenic theory, which states that afferent arteriolar tone and vascular walltension decrease as perfusion pressure decreases.2 This reflex myogenic response ismediated by vascular smooth muscle cells and is operative at the interlobular artery andat the afferent arteriole only.

The other major mechanism for the autoregulation of RBF relies on the tubulo-glomerular feedback controlled by the juxta-glomerular apparatus. A decrease in MAP,RBF and GFR decreases the tubular fluid chloride concentration bathing the maculadensa. This change, in turn, inhibits angiotensin activation and restores RBF and GFR byreduction of afferent arteriolar resistance.2 According to recent evidence the afferentarteriolar resistance changes induced by the TGF rely on adenosine via the adenosine-1receptor. The magnitude of this effect depends on the ambient level of angiotensin II.4

The intra-renal generation of vasodilator prostaglandins also causes vasodilatation,and preserved RBF and GFR5 and may be important in the maintenance of GFR,especially in states of chronic diminished perfusion (e.g. cardiac failure) where it isknown that prostaglandin inhibition can trigger the development of acute renal failure.5

Why maintaining an adequate renal perfusion pressure might be usefulin early acute renal failure

The major determinants of renal perfusion in the clinical situation are: (a) cardiacoutput, (b) arterial blood pressure, and (c) intra-vascular volume state. Because, givenan adequate cardiac output and intra-vascular volume state, RBF is dependent on renalperfusion pressure, systemic hypotension should logically be promptly and aggressivelycorrected to avoid the development of acute renal failure.

In the normal mammalian kidney, loss of autoregulation of RBF generally occurs at aMAP of 75–80 mmHg.6 Maintaining a mean arterial pressure (MAP) at about 65 mmHgin septic shock may be inadequate for renal resuscitation in elderly patients, patientswith known hypertension and patients with diabetes. It may be adequate in relativelyyoung patients without any co-morbidites. A blood pressure of ,60 mmHg is likely tobe inadequate in any patient.

According to classical physiology, mammalian GFR is autoregulated at lowerperfusion pressure than RBF due to efferent vasoconstriction increasing glomerularperfusion pressure. Such regulation is lost in the setting of experimental acute renalfailure.7

Animal models of septic shock show that increasing MAP with norepinephrine(noradrenalin) increases RBF.8 Other animal studies have also shown increments in RBFwhen MAP was increased from 52 to 65 mmHg but not further.9 In patients with septicshock, LeDoux et al10 recently reported that increasing MAP from 65 to 85 mmHg didnot alter urine output. So, it has been recommended not to increase MAP above 65–70 mmHg.11 Such recommendations should be viewed with great caution as they arebased on small, short-lived physiological studies with little power to detect anything butvery large differences and do not take into account the effects of co-morbidities.Nonetheless, from an evidence-based analysis point of view, the issue of whether one

Vasoactive drugs and the kidney 55

can achieve an improvement in renal function with augmentation of perfusion pressurehas not been investigated by prospective, randomized, controlled trials.

What is not generally understood, furthermore, is that urinary flow rate is not fullyautoregulated but is subject to perfusion pressure. The hydrostatic pressure inthe peritubular capillaries influences tubular water re-absorption, which is a majordeterminant of urinary flow rate. Oliguria associated with hypotension usually isreversed when the arterial blood pressure is restored toward normal (phenomenon ofpressure diuresis). The effect on GFR, however, is less predictable.

VASOACTIVE DRUGS

Catecholamines are by far the most common vasoactive drugs used in the ICU. Theycan reverse cardiogenic shock through their inotropic effects (b-adrenergic receptors),and distributive shock through their vasoconstrictive effects (a-adrenergic receptorsand b-adrenergic receptor-mediated renin and then angiotensin II generation) or both.

Dopamine

Cardiovascular effects

Dopamine has cardiac b1-adrenergic effects (threshold ,3.0 and maximal dose,10 mg/kg/minute) and peripheral a1-adrenergic receptor agonist activity (threshold,5.0 and maximal ,20 mg/kg/minute), which increase myocardial contractility, heartrate and systemic vascular resistance (SVR) and, in turn, blood pressure. Dopamine isalso well known to have non-selective dopaminergic effects at lower doses(1–2 mg/kg/minute). Stimulation of peripheral dopamine-1 receptors is believed toproduce renal, coronary, and mesenteric arterial vasodilation.12 Low-dose dopamine orso-called renal-dose dopamine has therefore been proposed as an ideal treatment toimprove renal perfusion, and perhaps function, in states of suspected underperfusion.

Renal effects of dopamine

Natriuresis. Dopamine exerts its natriuretic effect by inhibition of baso-lateral Na–K-ATPase activity in the proximal tubule, medullary thick ascending limb of the loop ofHenle and cortical collecting duct epithelial cells through engagement of DA-1 andprobably DA-2 receptors. This dopaminergic receptor activation leads to theattenuation of tubular re-absorption of sodium. Dopamine also promotes renalexcretion of free water, probably by inhibiting central antidiuretic hormone (ADH)release and antagonizing the actions of ADH (vide infra) on collecting duct cells.

Blood flow. Dopamine at low dose also induces a dose-dependent (threshold ,0.5and maximal ,3.0 mg/kg/minute) increase in the renal plasma flow in animals andhealthy humans13,14 and to a lesser extent in disease states. It also induces intra-renalvasodilatation in the absence of detectable systemic haemodynamic effects.15 Thisresponse is mediated predominantly through the DA-1 subclass of dopamine receptorslocated on the renal vasculature, DA-2 receptors on presynaptic sympathetic nerveterminals and possibly post-synaptic DA-2 receptors.12

In a recent animal study done by Berstenm and Rutten, dopamine did indeeddecrease renal vascular resistance and increase RBF but not creatinine clearance inhealthy animals. However, these effects were lost once an experimental septic state wasinduced.16 Furthermore, recent experiments from our groups show that RBF is more


markedly increased by medium-dose 0.4 mg/kg/minute norepinephrine (noradrenalin)than by low-dose dopamine (Figure 1). What remains unclear, however, is the clinicalsignificance of these effects, demonstrated in normal mammals, once the drug is givento critically ill patients.

Preventive role of low-dose dopamine

In view of its renal vasodilatatory effect and natriuretic effect, many studies have beenconducted on the use of dopamine as a prophylactic agent to protect the kidney indifferent clinical scenarios in which patients are deemed to be at risk of developing acuterenal failure. Unfortunately, all such studies are at most of level II– III evidence, anddefinite conclusions on the prophylactic role of low-dose dopamine cannot be drawn.

Critically ill patients. Five studies evaluated the effectiveness of low-dose dopamine onat-risk critically ill patients, including sepsis and burn patients. Three of them were levelII17–19, one was level III20 and the other was level V.21 All of them were small in terms ofsample size. The results on urine output and renal perfusion were contradictory and nostudy showed an improvement in creatinine clearance.17–21 Therefore, the improvedurine output, if any, may only reflect the diuretic effect of dopamine rather thanprotection in renal function. Whether inducing a diuresis in patients at risk of renalfailure is beneficial remains controversial.22

Liver and kidney transplantation. In patients undergoing orthotopic liver transplan-tation, Swygert et al23 demonstrated no significant difference in urine output, GFRs andthe need for dialysis. Gray et al24 also showed no significant difference in renalimpairment, peri-operative urine output, urine/plasma osmolality ratio or creatineclearance when comparing dopexamine and dopamine infusion. However, Polson et al25

found that prophylactic use of dopamine resulted in significantly less acute renal failure,higher urine output and higher creatinine clearance. This study, however, was not arandomized study. Thus, dopamine infusion with the goal of achieving renal protectionin liver transplant patients does not appear justified.

Two level II studies and one level III study also evaluated the influence of dopamine onthe incidence of acute renal failure after renal transplantation. The results argue stronglyagainst the use of prophylactic ‘renal-dose’ dopamine after renal transplantation.26,27

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Figure 1. Graph illustrating the differential effect of norepinephrine (NE) ( ¼ noradrenalin) and low-dosedopamine on renal blood flow (RBF) in the normal sheep. NE at 0.4 mg/kg/minute was superior to low-dosedopamine in increasing renal blood flow.


Cardiovascular surgery. In patients with pre-operative normal or impaired renal functionundergoing cardiopulmonary bypass (CPB), low-dose dopamine showed no improve-ment in urine output28, serum electrolytes and urea29, creatinine clearance28,30,31,fractional sodium excretion30, osmolarity and free water clearance28–31, incidence oftransient renal impairment28, and post-operative renal dysfunction.29 Furthermore,Baldwin et al32 reported no advantage of low-dose dopamine in elective abdominal aorticaneurysm repair. Although the serum urea level decreased and the mean 24-hourcreatinine clearance, and urine volumes increased non-significantly, plasma creatininelevels remained unchanged in the dopamine group. In patients who underwent infra-renalaortic surgery, dopamine alone33 or in combination with mannitol34 also showed noattenuation of the renal dysfunction associated with aortic cross-clamping.

Critically ill patients at risk of renal failure. A few early small and uncontrolled studies inthe 1980s and early 1990s showed beneficial effects of low-dose dopamine on oliguricrenal failure. In patients with oliguria and/or acute renal failure or hepatorenalsyndrome despite normal intra-vascular volume, low-dose dopamine with/withoutfurosemide infusion produced a diuresis35,36, higher osmolar clearance36, better sodiumand creatinine clearance, higher fractional excretion of sodium, reduced serumcreatinine levels, and reduction of plasma renin activity.36 Lumlertgul et al37 showedthat dopamine increased creatinine clearance and arrested the progress of renal failurewhen the serum creatinine was less than 400 mmol/l. However, most of these studiesare level V and cannot be used to guide clinical practice.

Other level II and level III studies done later on septic patients contradicted theseresults.38,39 In oliguric septic patients with or without shock, dopamine failed to reverseoliguria and hypotension and did not significantly affect the incidence of acute renalfailure. Low-dose dopamine also failed to improve survival or obviate the need fordialysis39, it was inferior to norepinephrine (noradrenalin) in terms of improvements inurine output and, in the presence of high-dose noradrenalin (norepinephrine),dopamine increased urine output but not creatinine clearance.

Lherm et al40 conducted a study on septic patients with or without shock andtreated with exogenous catecholamines. Although low-dose dopamine increaseddiuresis and significantly improved creatinine clearance, these responses decreasedsignificantly after 48 hours, which suggested a desensitization of renal dopaminergicreceptors. Similarly, Ichai et al41 found that, in patients with mild non-oliguric renalimpairment, low-dose dopamine significantly increased urine flow, creatinine clearanceand fractional excretion of sodium in the first 4 hours but that the effect wanedprogressively after 24 hours and disappeared after 48 hours.

Given the importance of this issue and the absence of sufficiently poweredrandomized controlled studies, a larger level I multicentre randomized placebo-controlled investigation was needed. Such a study was recently done by the Australianand New Zealand Intensive Care Society Clinical Trials Group42 in 324 critically illpatients with systemic inflammatory syndrome and early renal dysfunction. The resultshowed that there was no difference between the dopamine and placebo groups in peakserum creatinine concentration during treatment, in the increase from baseline tohighest value during treatment, in the number of patients whose serum creatinineconcentration exceeded 300 mmol/l or who required renal replacement therapy.However, although this study was sufficiently powered to detect small changes in serumcreatinine concentration, it did not have enough statistical power to detect smallchanges in other clinical outcomes, such as death or length of hospital stay.43

Importantly, however, there was a small trend against dopamine in the number ofdeaths and concerns remain about the endocrine side-effects of the drug.44


Physiological concerns about nephroprotection with dopamine

Because of the diuretic properties of dopamine, an increase in urine output bydopamine may only reflect diuresis but not really improved renal perfusion.Furthermore, this diuretic effect wanes by 48 hours after initiation of infusion.40,41

Moreover, the natriuretic effect of dopamine increases solute delivery to the distaltubular cells, which may increase medullary oxygen consumption and exacerbate theischaemia during hypotension. This effect could partly explain why increases in RBF bydopamine are not protective.

It should also be noticed that, although an increase in RBF with dopamine wasdemonstrated in animal studies and human volunteers, this effect in septic and critical illpatients with incipient or established acute renal failure might be different from that inthe normal state.44 The renal haemodynamic effects of low-dose dopamine in septicshock are uncertain. The sensitivity of tubular epithelial cells and vessels to the drugmay be only partial or even absent when renal lesions are established. This is supportedby the observation that, in a number of trials, some agents were effective only in the lesssevere cases.44 Even if RBF could be increased by low-dose dopamine, it is not clear thatincreased blood flow at the pre-glomerular level per se is useful or even desirable toachieve meaningful clinical end points.44 Finally, there is uncertainty whether acute renalfailure of critical illness is predominantly due to a decrease in renal blood supply or anincreased oxygen demand or a toxic effect of sepsis on tubular cells, or a combination ofthese, and whether hypoperfusion is present in septic renal failure at all.

Conclusions

Despite years of clinical use, no compelling evidence exists for the routine or evenselective administration of so-called ‘low-dose dopamine’ to humans. Whether, if givenat higher doses (3–8 mg/kg/minute), dopamine would prove to be beneficial to kidneyfunction remains unknown. At such doses, dopamine increases cardiac output (and attimes, mean arterial blood pressure) through a beta-adrenergic agonist effect much thesame way as dobutamine or adrenalin (epinephrine) would. Thus, such an effect wouldnot be unique to dopamine. The scientific question would then become whetheraugmenting cardiac output with beta-agonist drugs is beneficial to kidney function.Although this is likely to be true in patients with a low cardiac output state, there is noinformation on whether it would be true in a broader group of critically ill patients or inpatients with septic renal dysfunction. Given the disappointing results of systemiccalculated oxygen delivery augmentation in critically ill patients or in post-operativepatients in general45, this question may not be worth pursuing.

Fenoldopam

Fenoldopam is a selective dopamine receptor-1 (DA-1) agonist that causes DA-1receptor-mediated vasodilatation and does not stimulate DA-2 or adrenergic a- or b-receptors, even at high doses. The peripheral vasodilatatory effect of fenoldopam causesreduction of mean arterial pressure while its renal vasodilatatory effect, being more thansix times as potent as dopamine, appears preferentially directed at efferent arterioles.46

Fenoldopam also induces a natriuresis. Fenoldopam reduced renal vascularresistance, increased RBF, fractional excretion of sodium and free water clearance inall studies in normal volunteers and hypertensive patients.47 As with dopamine, therehas been some expectation that fenoldopam might protect the kidney owing to its renalvasodilatatory and natriuretic effect. Although animal studies and studies in normal or


hypertensive subjects are encouraging, studies with both congestive heart failure and

cirrhosis have been disappointing.46 Studies related to critically ill conditions are scantyand mainly confined to drug or contrast-induced nephropathy.

Contrast-induced nephropathy. Human studies have shown encouraging results.Fenoldopam was associated with improved renal plasma flow48, lower peak serumcreatinine level48 and more rapid recovery in contrast-induced renal impairment. Inwell-hydrated patients with renal impairment, some studies showed reduction in theincidence of contrast-induced nephropathy49,50 but one study showed no difference.48

These studies suggest a potential of fenoldopam as a renoprotective agent in contrast-induced nephropathy. However, these are all level IV or V studies except one. The roleof fenoldopam in the management of contrast-induced nephropathy requires a largerandomized controlled trial.

Cardiovascular surgery

As with dopamine, fenoldopam was tried perioperatively in high-risk patientsundergoing cardiovascular surgery. When used perioperatively in cardiac surgery,fenoldopam appeared to reduce the incidence of renal failure51 and attenuate thereduction in mean creatinine clearance after CPB.52

For patients undergoing aortic surgery, prophylactic use of fenoldopam prevented

the reduction in creatinine clearance52,53, rapidly returning renal function back tobaseline values53 and was also associated with reductions in mortality, dialysisrequirements and length of stay in the hospital and intensive care unit.53 These data onthe use of fenoldopam in the protection of renal function during cardiovascular surgeryappear encouraging. However, they are from small level II, level III or level V studiesonly. It is difficult to evaluate the role of fenoldopam without a large-scale randomizedcontrolled trial.

Conclusion

The results of studies on the prophylactic use of fenoldopam in contrast-inducednephropathy and cardiovascular surgery seem promising but are not conclusive.54

Results in other areas are either equivocal or discouraging. More studies are necessaryto define its role in different clinical situations. In many ways the data available forfenoldopam is similar to those available for low-dose dopamine 15 years ago.

Norepinephrine (noradrenalin)


Norepinephrine (NE) (noradrenalin) has a moderate b1- and b2-adrenergic effect butstrong alpha-adrenergic effects, which causes vasoconstriction in all vascular beds,including the renal circulation. As a result, it increases blood pressure, pre-load andafterload and causes variable changes in cardiac output and DO2.

Renal effects

Due to its potential vasoconstrictive effect on the renal vascular bed, the use of NEcarries a potential adverse effect on urine output and renal perfusion. Indeed, NE hasbeen used in animal studies to induce renal failure by infusion into the renal artery.55

Furthermore, two studies done on healthy volunteers with NE infusion at mean of


0.1 mg/kg/minute with and without dopamine showed that NE increased renal vascularresistance56 and decreased effective RBF.56,57 However, GFR was increased modestly56

or remained unchanged.56 Fractional sodium excretion and urine output remainedunaltered. Importantly, the results of previous animal models in which NE was used toinduce acute renal failure may not be applicable to humans because of the massive doseused and intra-arterial injection. Furthermore, a recent animal study by DiGiantomasso et al58 with NE infusion at 0.4 mg/kg/minute in the normal mammaliancirculation showed that NE increased all haemodynamic parameters as well as RBF,urine output and creatinine clearance, an effect which was associated with mild renalvasodilatation. Thus, even though NE may be a mild renal vasoconstrictor when givenintravenously (Figure 2), its effect on blood pressure/perfusion pressure would be suchthat overall RBF should be at least preserved (Figure 3).

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Figure 2. Graph illustrating the differential effect of norepinephrine (NE) ( ¼ noradrenalin) and placebo onrenal conductance (inverse of resistance) in the septic sheep. NE at 0.4 mg/kg/minute was a mild renalvasoconstrictor compared to placebo.

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Figure 3. Graph illustrating the differential effect of norepinephrine (NE) ( ¼ noradrenalin) and placebo onrenal blood flow (RBF) in the septic sheep. Although NE at 0.4 mg/kg/minute is a mild renal vasoconstrictorcompared to placebo, renal blood flow is preserved because perfusion pressure is increased.


Septic shock

Because one of the most important indications of NE is septic shock, the majority ofstudies have been done in this condition.

There are no controlled human data to define the effects of NE on the septic kidney,but many patient series show a positive effect on urine output.58–63 Creatinineclearance was also found to be increased significantly during NE infusion in twostudies.58,61 These results cannot lead to any definite conclusion on the renal effect ofNE in septic shock. Most of the studies are either level III and level Vor, at most, level IIwith small sample size.61,62 None of them examine more important clinically outcomessuch as incidence of acute renal failure or requirement for renal replacement therapy.The interpretation is also confounded by the concurrent use of other vasoactive drugs.However, at least, these studies showed no deterioration or adverse effect of NE onrenal function. More recently the effect of NE on renal function has been explored inpatients with post-bypass hypotensive vasodilatation. In these patients, once again, NEwas shown to be safe from the renal point of view.64

Conclusion

There are insufficient data to define the effect of NE on the kidney, either in normalsubjects or under septic condition. The data available suggest that restoration of anadequate blood pressure by means of NE infusion in patients with septic shock isassociated with increased diuresis, but whether this could be achieved or even betteredwith any other drug that also improved blood pressure to a similar degree is unknown.The same is probably true for NE’s effects on RBF and GFR. Importantly, however, thereappears to be no reason to avoid NE administration because of concerns that it wouldhave a specific adverse effect on renal function. Given its greater efficacy in restoringMAP compared to high-dose dopamine, NE is the vasopressor of choice in vasodilatedhypotensive states with preserved or increased cardiac output.

Epinephrine (adrenalin)


As with norepinephrine (noradrenalin), epinephrine (Epi) (adrenalin) exerts combineda- and b-adrenergic effects. In low dose, it has predominantly b-adrenergic effects,which lead to an increase in cardiac output. In higher dose, its a-adrenergic effectcauses vasoconstriction, particularly in the splanchnic and renal vascular bed, andresults in elevated SVR and blood pressure. Epi also increases left ventricular strokework index, DO2 and cardiac index in both the healthy and septic condition.

Renal effects

Different dose-dependent changes of renal vascular resistance were reported in ananimal study by Bersten et al65 Epinephrine (adrenalin) infusion at a rate of 5 and 10 mg/minute failed to alter renal vascular resistance but when the infusion rate increased to20 and 40 mg/minute, renal vascular resistance increased in the first 10 minutes, butthen fell back to baseline by 120 minutes. RBF also showed a time-dependent behaviour,with an early dose-dependent decrease in RBF which increased back to, or above,baseline at all studied infusion rates.


Septic shock

One of the most important uses of Epi (adrenalin) is in septic shock. However, studiesconcerning the renal effect of epinephrine in septic shock are extremely scanty. Dayet al21 showed that epinephrine (adrenalin) infusion was associated with a significantincrease in renal vascular resistance and a decrease in RBF as a fraction of cardiacoutput. Absolute RBF index and renal oxygen consumption, creatinine clearance andurine output remained constant. The presence or absence of renal failure did notsignificantly influence the effects of epinephrine. Thus, the effect of epinephrine(adrenalin) on the kidney remains largely unknown.

Cardiopulmonary resuscitation

Besides septic shock, another important indication of epinephrine (adrenalin) would becardiopulmonary resuscitation. Only two animal studies have reported the renal effect ofepinephrine during or after resuscitation. Prengel et al66 showed in an animal model ofinduced ventricular fibrillation that, after resuscitation and restoration of spontaneouscirculation, RBF was significantly lower in the vasopressin group as compared with theepinephrine group. However, in a similar animal study, Voelckel et al67 showed that RBF,urine output and GFR after restoration of spontaneous circulation were comparable inboth the vasopressin and epinephrine (adrenalin) groups.

Others

In 10 patients following open heart surgery, epinephrine (adrenalin) at rates of 0.02–0.08 mg/kg/minute showed a marked inotropic action without any significant change inRBF. With 0.04 mg/kg/minute of adrenalin (epinephrine), the RBF to cardiac outputratio declined significantly due to renal vasoconstriction.68

Conclusion

We have very limited knowledge about the renal effects of Epi (adrenalin) compared toeither placebo or other vasoactive drugs. All studies available are level III or IV or areanimal investigations. The data available for Epi (adrenalin) are significantly less than forNE (noradrenalin).

Phenylephrine


Phenylephrine is a predominant a1-adrenergic receptor-mediated agonist. As a result, itincreases blood pressure mainly by increasing SVR. Studies in both cardiac and septicpatients show that blood pressure, central venous pressure and heart rate increasesignificantly while cardiac index and stroke index decrease in cardiac patients butincrease in septic patients.69

Renal effects

Besides increasing SVR, phenylephrine also constricts the renal vasculature anddecreases RBF.70 However, it increases renal perfusion pressure in the presence of alow SVR.70


Septic shock

Phenylephrine is not as commonly used as other drugs in septic shock. Thus, littleevidence is available on its renal effects in this setting. The only human study was aretrospective study done by Gregory et al71 on 13 patients with septic shock. The useof phenylephrine in this setting appeared to have no adverse effect on the kidney, asshown by a stable serum creatinine concentration and increased urine output.

Cardiopulmonary bypass

Phenylephrine has been more commonly used in clinical practice to increase bloodpressure during CPB.69,72 There are two studies reporting its renal effects during CPB.

In a study on patients with pre-operative abnormal renal function undergoing CPB,the result demonstrated no significant difference on GFR, urine output, urinarycreatinine, urinary osmolarity, osmolar clearance and urinary potassium when comparedto dopamine.72

Another prospective randomized trial compared the renal effects of angiotensin andphenylephrine in patients on angiostensin converting enzyme inhibitors (ACEIs)undergoing cardiac surgery requiring CPB. There was no difference in creatinineclearance in the post-operative period compared with baseline values.69

Because only two studies are available, its specific renal effects have not yet been fullyexplored. However, evidence so far has not shown any deleterious effect on renalfunction.

CATECHOLAMINES AS INOTROPES

Dobutamine


The additive effect of the cardiac a1- and b1-agonist activity gives dobutamine a stronginotropic action, which increases myocardial contractility. Although it has opposingperipheral a1- (vasoconstriction) and peripheral b2-(vasodilation) adrenergic effects,the reflex reduction in sympathetic nervous system tone in response to the increasedmyocardial contractility and stroke volume leads to a reduction in total peripheralvascular resistance. In combination to its b2 vasodilatory effects, dobutamine causeshypotension, which may preclude its use as a single agent. It also has a weakchronotropic effect.

Renal effects

The specific renal effects of dobutamine are probably dependent on its ability toaugment cardiac output. In human studies, RBF was increased by dobutamine in somereports but not changed in others. Westman and Jarnberg73 also found a reduction inGFR, urine output, fractional sodium excretion and fractional free water clearance. In ahuman study focusing on the renal effect of dobutamine in stable critically ill patientsincluding sepsis, Duke et al showed that low-dose dobutamine was the only agentcapable of increasing creatinine clearance while urine output remains unchanged.17

However, in a similar group of patients with mild non-oliguric renal impairment, Ichaiet al41 reported that dobutamine infusions did not change urine output, creatinineclearance and fractional excretion of sodium.


On the whole, human studies demonstrate equivocal results. However, due to thelimited number and quality of these studies, it is difficult to assess the effect ofdobutamine on the kidney.


Westman and Jarnberg73 studied the effects of dobutamine on renal function inpatients after major vascular surgery. The result showed that dobutamine did notaffect RBF, GRF, urine flow, fractional sodium, chloride, osmolar and free waterclearances.

When compared to dopamine, Wenstone et al74 found no clinical or statisticallysignificant difference between the two groups in post-operative urine output, serumconcentration of creatinine, fractional sodium excretion or need for diuretic therapy.When compared to dopexamine, MacGregor et al75 found no significant differences ineither urinary output or net sodium excretion in both groups.

Conclusions

There is little information on any specific effects of dobutamine on RBF or function. Allstudies so far provide level III or IV evidence. It is likely that dobutamine would have abeneficial renal effect in patients with a low cardiac output state by increasing cardiacoutput and overall organ perfusion. Its addition to pressor treatment of septic shockpatients with renal dysfunction in order to further augment an already high cardiacoutput seems unlikely to benefit the kidneys. There is insufficient information torecommend its use for renal protection.

Dopexamine

Cardiovascular effect

This relatively new catecholamine has predominantly b2 and dopaminergic receptoractivity but no a-effect. It has a direct inotropic action in low cardiac output states.76 Itincreases cardiac index and heart rate and decreases SVR.

Renal effects

Its powerful dopaminergic effect is believed to induce splanchnic vasodilatation andincreased gut and renal perfusion. However, RBF was only mildly increased bydopexamine in normal subjects and hypertensive patients.77 GFR and proximal tubularflow were increased, but absolute proximal re-absorption rate and sodium clearanceremained unchanged in normal volunteers. Dopexamine also increased urine output inboth healthy subjects and patients with heart failure.78

Critically ill patients

Ralph et al79 conducted probably the largest prospective, randomized controlledclinical trial on 102 critically ill patients concerning the effect of dopexamine on organfunctions, including the kidney. The result showed no benefit in creatinine clearance orincidence of acute renal failure requiring renal replacement therapy.



There are a few studies examining the effect of dopexamine on renal function in patientsundergoing coronary artery bypass surgery, with or without renal dysfunction.Although Berendes et al80 reported that dopexamine improved creatinine clearanceand an increased urine output, Sherry et al81 found an elevated renal vascular resistanceindex and a reduction in urine output associated with dopexamine. Dehne et al82 alsoshowed no beneficial effects of dopexamine on renal function, and all renal tubulesshowed evidence of damage.

Although a recent randomized controlled trial on high-risk patients undergoingmajor elective surgery showed a significant reduction in hospital mortality andmorbidity associated with pre-operative use of dopexamine83, other findings contradictsuch optimism and only highlight the need for large RCTs to clarify the effect ofdopexamine in this group of patients as its specific renal effects have not yet been fullydefined.

OTHER INOTROPES

Milrinone (amrinone/enoximone)

Milrinone (and other similar drugs such as amrinone and enoximone) is a short-actingphosphodiesterase inhibitor which inhibits the peak III phosphodiesterase and thusincreases cAMP activity resulting in a positive inotropic effect, positive lusitropic effectand systemic vasodilatatory effect.84 Because of its vasodilatatory effect, theconcomitant use of vasopressor agents may be necessary. When cardiac output isincreased and mean arterial blood pressure maintained, milrinone may have beneficialrenal effects. Nonetheless, the specific effects of this drug on the renal circulation arepoorly understood.

One human study also reported some information of the effect of milrinone onkidney. In a group of 13 patients with congestive heart failure, milrinone therapy for 1month did not increase RBF or GFR.85

There has been no clinical human study on critically ill patients focusing on the renaleffect of milrinone or other agents of the same class such as amrinone and enoximone.Although there is no information about the positive renal effect of milrinone, thereare reports of mild elevations in serum creatinine owing to milrinone-inducedhypotension.86

Levosimendan

Levosimendan, a pyridazinone-dinitrile derivative, is a calcium sensitizer of cardiacmuscle that enhances myocardial contractility without increasing cytosolic calciumrelease. It increases myofilament calcium sensitivity by binding to cardiac troponin C ina calcium-dependent manner and stabilizing the calcium-induced conformational changeof troponin C. As a result, the actin–myosin cross-bridge kinetics are changed withoutincreasing the cycling rate of the cross-bridges or myocardial ATP consumption.Moreover, levosimendan also causes vasodilatation, which is due to its blockade ofendothelin-1 release and the activation of adenosine triphosphate (ATP)-regulated orglibenclamide-sensitive potassium channels causing hyperpolarization of myocytes.There are very scanty data about the effect of levosimendan on the kidney under


normal or diseased states. In an anaesthetized dog model, the administration oflevosimendan was shown to increase blood flow to the renal medulla and decreaserenal medullary and cortical vascular resistance.87 The only study on sepsis was done byOldner et al.88 In their study, it was shown that pre-treatment with levosimendan in pigssubjected to endotoxin shock did not affect the RBF.

OTHER VASOPRESSORS

Vasopressin

Vasopressin exerts its vasoconstrictive effect via vascular V1-receptors and its anti-diuretic effect through renal tubular V2-receptors. It also inhibits ATP-sensitive Kchannels and interleukin-1b, effects which probably contribute to its vasoconstriction.However, marked differences in vasoconstrictor reactivity to vasopressin existbetween vascular beds. Stimulation of V1-receptor causes arterial vasoconstriction innon-vital organs, such as skin, skeletal muscle and bowel, in a dose-dependent manner.The main effect is increased SVR and blood pressure. On the other hand, low-dosevasopressin causes vasodilatation in the renal, pulmonary, cerebral and mesentericvasculature, probably due to nitric oxide release by the endothelium89 vasopressindecreases cardiac output in the normal heart or mild heart failure. In addition,vasopressin also modulates the baroreflex response, causing a more prominentreduction in heart rate for a given increase in blood pressure.89

V2-receptor stimulation increases renal free water re-absorption. It also increasesthe medullary concentration gradient by activating a distinct urea transporter, furtherconcentrating the urine. Vasopressin also induces a selective decrease in innermedullary blood flow without altering cortical blood flow, which also contributes tothe maximum concentrating ability of the kidney.90 However, under some conditionssuch as haemorrhage or sepsis, vasopressin increases urine output. The mechanisms ofthis diuretic effect of vasopressin have not been fully explained yet.

Sepsis

The concentration of vasopressin in plasma is inappropriately low in sepsis. Vasopressinis also a very effective pressor agent in patients with septic shock, even in very lowdoses (from 0.01 to 0.05 unit/minute).91 For these reasons, the use of vasopressin ispotentially beneficial in sepsis. However, information about the renal effect ofvasopressin under septic conditions is very limited.

In septic patients, vasopressin infusion at a rate of 0.04–0.06 units/minute wasassociated with a significant increase in urine output91 and creatinine clearance withoutaffecting plasma creatinine level.92 It was suspected that these improved renalparameters are the result of an increase in arterial pressure.92 However, in the study ofPatel et al92 vasopressin infusion was titrated to achieve a given MAP and compared toNE, infused to achieve the same level of blood pressure. There was a greaterimprovement in urine output with VP. Other haemodynamic parameters remainedunchanged.92 Thus, the mechanisms of the diuretic effect of vasopressin could not befully explained by the improvement in cardiovascular performance alone. Vasopressinmay improve other aspects of renal function. It is not known whether this improvementin urine output can be translated into improvement in overall renal function, as it maynot be sustained. Moreover, the dose used in these studies is ‘low-dose’ vasopressin,


ranging from 0.04 to 0.06 units/minute. Higher doses showed no further improvementand may have been associated with adverse effects. In recently completed sheepexperiments we were able to show that low-dose VP might lead to a slight overallincrease in RBF (Figure 4). However, we caution against looking at single-organ flowwith this drug. In the same animals who also had their mesenteric flow monitored bytransit-time flow probes, low-dose VP caused a dramatic reduction in mesentericperfusion (Figure 5).

Cardiopulmonary resuscitation

The other most important area of vasopressin use is in cardiopulmonary resuscitation asit is already included in advanced cardiac life support (ACLS) resuscitation protocol.93

However, its renal effect during or after resuscitation is still not clear. Only animal studieshave reported its renal effects.

280

290

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310

320

330

340

350

0 20 40 60 80 100 120 140 160 180

Placebo

Vasopressin

RB

F (

ml/m

inut

e)

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Figure 4. Graph illustrating the differential effect of low-dose vasopressin (VP) and placebo on renal bloodflow (RBF) in the septic sheep. Low-dose VP leads to mild increase in renal blood flow.

0

100

200

300

400

500

600

700

800

0 20 40 60 80 100 120 140 160 180

Placebo

Vasopressin

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F (

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inut

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Figure 5. Graph illustrating the differential effect of low-dose vasopressin (VP) and placebo on mesentericblood flow (MBF) in the septic sheep. Low-dose VP leads to a marked decrease in mesenteric blood flow.


The results of RBF in these animal studies are variable. In pig models of ventricularfibrillation arrest94 or haemorrhagic shock and cardiac arrest comparing vasopressinand epinephrine (adrenalin), the results showed either increased or unchanged94 oreven worsening RBF. Urine output and calculated GFR showed no difference betweenthe two groups.94

Conclusion

Although the pressor effect of VP in septic shock patients may increase renal perfusionpressure sufficiently to improve flow and function, these effects may be achievable withother pressor agents. It remains unclear whether the unique properties of VP offer anyclinically significant advantages over the use of any other pressor agent or whether acombination of low-dose VP infusion and NE (norepinephrine, noradrenalin) infusionrepresents the best pressor combination for the septic kidney.

Terlipressin

Terlipressin is a long-acting analogue of vasopressin. It has a higher affinity thanvasopressin for vascular receptors. In healthy animal, terlipressin significantly increasesSVR index.95 In healthy human subjects, terlipressin mildly increases MAP but decreasescardiac index and hepatic blood flow.

While the vast majority of studies of terlipressin have concentrated on cirrhoticpatients with hepatorenal syndrome and variceal haemorrhage, only one studyconcerning the use of terlipressin in septic patients has been reported. In this study,eight unselected patients with septic shock refractory to fluid loading, high-dosenorepinephrine (noradrenalin) infusion, or dexamethasone and methylene blue rescuetherapy were given an intravenous bolus dose of terlipressin (1–2 mg). Terlipressin wasassociated with a progressive increase in mean arterial pressure. In two patients witholiguria, urine output increased after administration of terlipressin without obviouscomplication.96

Conclusions

As terlipressin is a relatively new drug used in critically ill patients, more studies arenecessary before a clear view emerges of its renal effects outside of the field ofhepatorenal syndrome.

Practice points

† low-dose dopamine does not achieve clinically important renal protection incritically ill patients

† the administration of norepinephrine ( ¼ noradrenalin) by continuousintravenous infusion in patients with hypotensive vasodilatation does notdecrease renal blood flow

† the administration of norepinephrine ( ¼ noradrenalin) by continuousintravenous infusion in patients with hypotensive vasodilatation increasesurine output


SUMMARY

Dopamine is the vasoactive drug whose renal effects have been most extensivelystudied. However, studies so far do not support a prophylactic and therapeutic role forthis agent in the ICU.

For all other vasoactive drugs, the pathophysiological information available iscontradictory and very few conclusions can be made. It appears that maintaining anadequate cardiac output and an adequate mean arterial pressure is an important way ofavoiding renal underperfusion. The way this goal is achieved, including the drugs used toachieve it, may be less important to the kidney than the speed and extent to which it isachieved. It remains unclear whether septic acute renal failure is a haemodynamicdisease, an immunological/toxic disorder or a composite of both. However, given thatthe use of vasoactive drugs is a pervasive practice in ICU, this area of critical caremedicine badly needs suitably powered, multicentre, randomized placebo-controlleddouble-blind studies similar to that of low-dose dopamine to provide a more rationalbasis for clinical practice, including renal protection.

REFERENCES

1. Bellomo R, Cole L & Ronco C. Hemodynamic support and the role of dopamine. Kidney International 1998;66: S71–S74.

2. Sladen RN & Landry D. Renal blood flow regulation, autoregulation, and vasomotor nephropathy.Anesthesiology Clinics of North America 2000; 18: 791–807.

* 3. Schrier RW. Effects of the adrenergic nervous system and catecholamines on systemic and renalhemodynamics, sodium and water excretion, and renin secretion. Kidney International 1974; 6: 291–306.

* 4. Schnermann J. The juxtaglomerular apparatus: from anatomical peculiarity to physiological relevance.Journal of the American Society of Nephrology 2003; 14: 1681–1694.

5. Papaioannides D, Bouropoulos C, Sinapides D et al. Acute renal dysfunction associated with selectiveCOX-2 inhibitor therapy. International Journal of Urology and Nephrology 2001; 33: 609–611.

6. Ronco C & Bellomo R. Prevention of acute renal failure in the critically ill. Nephron Clinical Practice 2003;93: c13–c20.

Research agenda

† we need randomized controlled trials of sufficient statistical power to compareclinically meaningful renal outcomes with one vasoactive drug versus another

† we need randomized controlled trials of sufficient statistical power to compareclinically meaningful renal outcomes with one haemodynamic strategy versusanother

† we need to achieve greater understanding of the pathogenesis of acute renalfailure, which may, in great part, be independent of haemodynamic manipulation

† there is no evidence that optimizing cardiac output and mean arterial bloodpressure with one drug versus another makes any clinically importantdifference to renal blood flow or function

† there is no evidence that maximizing cardiac output is protective to the kidney† the target mean arterial blood pressure for the optimization of renal blood flow

in critically ill patients remains unknown


* 7. Kelleher SP, Robinette JB & Conger JD. Sympathetic nervous system in the loss of autoregulation in acuterenal failure. American Journal of Physiology 1984; 264: F379–F386.

* 8. Bellomo R, Kellum JA, Wisniewski SR et al. Effects of norepinephrine on the renal vasculature in normaland endotoxemic dogs. American Journal of Respiratory and Critical Care Medicine 1999; 159: 1186–1192.

9. Treggiari MM, Romand JA, Burgener D et al. Effect of increasing norepinephrine dosage on regional bloodflow in a porcine model of endotoxin shock. Critical Care Medicine 2002; 30: 1334–1339.

10. LeDoux D, Astiz ME, Carpati CM et al. Effects of perfusion pressure on tissue perfusion in septic shock.Critical Care Medicine 2000; 28: 2729–2732.

11. De Backer D & Vincent JL. Norepinephrine administration in septic shock: how much is enough? CriticalCare Medicine 2002; 30: 1398–1399.

* 12. Rudis MI, Basha MA & Zarowitz BJ. Is it time to reposition vasopressors and inotropes in sepsis? CriticalCare Medicine 1996; 24: 525–537.

13. Mousdale S, Clyburn PA, Mackie AM et al. Comparison of the effects of dopamine, dobutamine, anddopexamine upon renal blood flow: a study in normal healthy volunteers. British Journal of ClinicalPharmacology 1988; 25: 555–560.

14. Goldberg LI. Cardiovascular and renal actions of dopamine. Potential clinical applications. PharmacologicalReview 1972; 24: 1–29.

15. McDonald R, Goldberg L, McNay J et al. Effects of dopamine in man: augmentation of sodiumexcretion, glomerular filtration rate and renal plasma flow. Journal of Clinical Investigation 1964; 43:1116–1124.

16. Bersten AD & Rutten AJ. Renovascular interaction of epinephrine, dopamine, and intraperitoneal sepsis.Critical Care Medicine 1995; 23: 537–544.

17. Duke GJ, Briedis JH & Weaver RA. Renal support in critically ill patients: low dose dopamine or low dosedobutamine. Critical Care Medicine 1994; 22: 1919–1925.

18. Olson D, Pohlman A & Hall JB. Administration of low-dose dopamine to nonoliguric patients with sepsissyndrome does not raise intramucosal gastric pH nor improve creatinine clearance. American Journal ofRespiratory and Critical Care Medicine 1996; 154: 1664–1670.

19. Strigle TR & Petrinec D. The effect of renal range dopamine and norepinephrine on the renal vasculature.American Surgeon 1990; 56: 494–496.

20. Graves TA, Cioffi WG, Vaughan GM et al. The renal effects of low-dose dopamine in thermally injuredpatients. Journal of Trauma 1993; 35: 97–102.

21. Day NPJ, Phu NH, Mai NTH et al. Effects of dopamine and epinephrine infusions on renal hemodynamicsin severe malaria and severe sepsis. Critical Care Medicine 2000; 28: 1353–1362.

22. Mehta RL, Pascual MT, Soroko S et al. Diuretics, mortality, and nonrecovery of renal function in acuterenal failure. Journal of the American Medical Association 2002; 288: 2547–2553.

23. Swygert TH, Roberts LC, Valek TR et al. Effect of intraoperative low-dose dopamine on renal function inliver transplant recipients. Anesthesiology 1991; 75: 571–576.

24. Gray PA, Bodenham AR, Park GR et al. A comparison of dopexamine and dopamine to preventrenal impairment in patients undergoing orthotopic liver transplantation. Anaesthesia 1991; 46:638–641.

25. Polson RJ, Park GR, Lindop MJ et al. The prevention of renal impairment in patients undergoingorthotopic liver grafting by infusion of low dose dopamine. Anaesthesia 1987; 42: 15–19.

26. Kadieva VS, Friedman L, Margolius LP et al. The effect of dopamine on graft function in patientsundergoing renal transplantation. Anesthesia and Analgesia 1993; 76: 362–365.

27. Delosangeles A, Baquero A & Bannett A. Dopamine and furosemide infusion for prevention of post-transplant oliguric renal failure. Kidney International 1985; 27: 339–343.

28. Myles PS, Buckland MR, Schenk NJ et al. Effect of ‘renal-dose’ dopamine on renal function followingcardiac surgery. Anaesthesia and Intensive Care 1993; 21: 56–61.

29. Lassnigg A, Donner E, Grubhofer G et al. Lack of renoprotective effects of dopamine and furosemideduring cardiac surgery. Journal of the American Society of Nephrology 2000; 11: 97–104.

30. Costa P, Ottino GM, Matani A et al. Low-dose dopamine during cardiopulmonary bypass in patients withrenal dysfunction. Journal of Cardiothoracic Anesthesiology 1990; 4: 469–473.

31. Yavuz S, Ayabakan N, Goncu MTet al. Effect of combined dopamine and diltiazem on renal function aftercardiac surgery. Medical Science Monitor 2002; 8: 145–150.

32. Baldwin L, Henderson A & Hickman P. Effect of postoperative low-dose dopamine on renal function afterelective major vascular surgery. Annals of Internal Medicine 1994; 120: 744–747.

33. de Lasson L, Hansen HE, Juhl B et al. A randomised, clinical study of the effect of low-dose dopamine oncentral and renal haemodynamics in infrarenal aortic surgery. European Journal of Vascular and EndovascularSurgery 1995; 10: 82–90.

34. Paul MD, Mazer CD, Byrick RJ et al. Influence of mannitol and dopamine on renal function during electiveinfrarenal aortic clamping in man. American Journal of Nephrology 1986; 6: 427–434.


35. Henderson IS, Beattie TJ & Kennedy AC. Dopamine hydrochloride in oliguric states. Lancet 1980; ii:827–828.

36. Parker S, Carlon G, Isaacs M et al. Dopamine administration in oliguria and oliguric renal failure. CriticalCare Medicine 1981; 9: 630–632.

37. Lumlertgul D, Keoplung M, Sitprija V et al. Furosemide and dopamine in malarial acute renal failure.Nephron 1989; 52: 40–44.

38. Desjars P, Pinaud M, Potel G et al. A reappraisal of norepinephrine therapy in human septic shock. CriticalCare Medicine 1987; 15: 134–137.

39. Marik PE & Iglesias J. Low-dose dopamine does not prevent acute renal failure in patients with septicshock and oliguria. American Journal of Medicine 1999; 107: 387–390.

40. Lherm T, Troche G, Rossignol M et al. Renal effects of low-dose dopamine in patients withsepsis syndrome or septic shock treated with catecholamines. Intensive Care Medicine 1996; 22:213–219.

41. Ichai C, Passeron C, Carles M et al. Prolonged low-dose dopamine infusion induces a transientimprovement in renal function in hemodynamically stable, critically ill patients: a single-blind, prospective,controlled study. Critical Care Medicine 2000; 28: 1329–1335.

* 42. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Low-dose dopaminein patients with early renal dysfunction: a placebo-controlled randomised trial. Lancet 2000; 356:2139–2143.

43. Delzell Jr. JE. Is low-dose dopamine effective in preventing renal dysfunction in patients in the intensivecare unit (ICU)? Journal of Family Practice 2001; 50: 369.

44. Holmes CL & Walley KR. Bad medicine: low-dose dopamine in the ICU. Chest 2003; 123: 1266–1275.45. Sandham JD, Hull RD, Brant RF et al. A Randomized, controlled trial of the use of pulmonary-artery

catheters in high risk surgical patients. New England Journal of Medicine 2003; 348: 5–14.46. Singer I & Epstein M. Potential of dopamine A1 agonists in the management of acute renal failure. American

Journal of Kidney Diseases 1998; 31: 743–755.47. Mathur VS, Swan SK, Lambrecht LJ et al. The effects of fenoldopam, a selective dopamine receptor

agonist, on systemic and renal hemodynamics in normotensive subjects. Critical Care Medicine 1999; 27:1832–1837.

48. Tumlin JA, Wang A, Murray PT et al. Fenoldopam mesylate blocks reductions in renal plasma flow afterradiocontrast dye infusion: a pilot trial in the prevention of contrast nephropathy. American Heart Journal2002; 143: 894–903.

49. Kini AS, Mitre CA, Kamran M et al. Changing trends in incidence and predictors of radiographic contrastnephropathy after percutaneous coronary intervention with use of fenoldopam. American Journal ofCardiology 2002; 89: 999–1002.

50. Kini AS, Mitre CA, Kim M et al. A protocol for prevention of radiographic contrast nephropathy duringpercutaneous coronary intervention: effect of selective dopamine receptor agonist fenoldopam. Catheterand Cardiovascular Intervention 2002; 55: 169–173.

51. Garwood S, Davis E & Hines RL. Fenoldopam: an effective renal preservation agent in cardiac surgery.Anesthesiology 1999; 91: A154.

52. Halpenny M, Lakshmi S, O’Donnell A et al. Fenoldopam: renal and splanchnic effects in patientsundergoing coronary artery bypass grafting. Anaesthesia 2001; 56: 953–960.

53. Gilbert TB, Hasnain JU, Flinn WR et al. Fenoldopam infusion associated with preserving renal functionafter aortic cross-clamping for aneurysm repair. Journal of Cardiovascular Pharmacology and Therapy 2001; 6:31–36.

54. Sheinbaum R, Ignacio C, Safi HJ et al. Contemporary strategies to preserve renal function during cardiacand vascular surgery. Reviews in Cardiovascular Medicine 2003; 4(supplement 1): S21–S28.

55. Meier-Hellmann A & Reinhart K. Effects of catecholamines on regional perfusion and oxygenation incritically ill patients. Acta Anaesthesiologica Scandinavica 1995; 107(supplement): 239–248.

56. Hoogenberg K, Smit AJ & Girbes ARJ. The effects of dopamine on noradrenaline induced change in bloodpressure and renal haemodyanmics in healthy volunteers: is there a role for routine use of dopamine inseptic shock? European Journal of Clinical Investigation 1997; 27(supplement 1): A17.

57. Richer M, Robert S & Lebel M. Renal hemodynamics during norepinephrine and low-dose dopamineinfusions in man. Critical Care Medicine 1996; 24: 1150–1156.

* 58. Di Giantomasso D, May CN & Bellomo R. Norepinephrine and vital organ blood flow. Intensive CareMedicine 2002; 28: 1804–1809.

59. Bellomo R & Giantomasso D. Noradrenaline and the kidney: friends or foes? Critical Care 2001; 5: 294–298.60. Desjars P, Pinaud M, Bugnon D et al. Norepinephrine therapy has no deleterious renal effects in human

septic shock. Critical Care Medicine 1989; 17: 426–429.61. Fukuoka T, Nishimura M, Imanaka H et al. Effects of norepinephrine on renal function in septic patients

with normal and elevated serum lactate level. Critical Care Medicine 1989; 17: 1104–1107.


62. Martin C, Viviand X, Arnaud S et al. Effects of norepinephrine plus dobutamine or norepinephrine aloneon left ventricular performance of septic shock patients. Critical Care Medicine 1999; 27: 1708–1713.

63. Redl-Wenzl EM, Armbruster C, Edelmann G et al. The effects of norepinephrine on hemodynamics andrenal function in severe septic shock states. Intensive Care Medicine 1993; 19: 151–154.

64. Morimatsu M, Uchino S, Chung J et al. Norepinephrine for severe vasodilatation after cardiac surgery:impact on renal function. Intensive Care Medicine 2003; 29: 1106–1112.

65. Bersten AD, Rutten AJ, Summersides G et al. Epinephrine infusion in sheep: systemic and renalhemodynamic effects. Critical Care Medicine 1994; 22: 994–1001.

66. Prengel AW, Lindner KH, Wenzel V et al. Splanchnic and renal blood flow after cardiopulmonaryresuscitation with epinephrine and vasopressin in pigs. Resuscitation 1998; 38: 19–24.

67. Voelckel WG, Lindner KH, Wenzel V et al. Effects of vasopressin and epinephrine on splanchnic bloodflow and renal function during and after cardiopulmonary resuscitation in pigs. Critical Care Medicine 2000;28: 1083–1088.

68. Sato Y, Matsuzawa H & Eguchi S. Comparative study of effects of adrenaline, dobutamine and dopamine onsystemic hemodynamics and renal blood flow in patients following open heart surgery. Japan CirculationJournal 1982; 46: 1059–1072.

69. Lema G & Canessa R. Phenylephrine, dopamine, mannitol, and renal protection during cardiopulmonarybypass. Anesthesia and Analgesia 1998; 87: 1459–1463.

70. Bennett S, McKeown J & Griffin S. Effect of angiotensin and phenylephrine on renal function in cardiacsurgical patients. Heart 1998; 79(supplement 1): 28–31.

71. Gregory JS, Bonfiglio MF, Dasta JF et al. Experience with phenylephrine as a component of thepharmacologic support of septic shock. Crit. Care Med. 1991; 19: 1395–1400.

72. Kanbank M. Phenylephrine, dopamine, mannitol and renal protection during cardiopulmonary bypass.Anaesth. Analg. 1998; 87: 1458–1459.

73. Westman L & Jarnberg PO. Effects of dobutamine on renal function in normal man. Acta AnaesthesiologicaScandinavica 1986; 30: 72–75.

74. Wenstone R, Campbell JM, Booker PD et al. Renal function after cardiopulmonary bypass in children:comparison of dopamine with dobutamine. British Journal of Anaesthesia 1991; 67: 591–594.

75. MacGregor DA, Butterworth JF, Zaloga CP et al. Hemodynamic and renal effects of dopexamine anddobutamine in patients with reduced cardiac output following coronary artery bypass grafting. Chest1994; 106: 835–841.

76. Tan LB, Littler WA & Murray RG. Beneficial haemodynamic effects of intravenous dopexamine in patientswith low-output heart failure. Journal of Cardiovascular Pharmacology 1987; 10: 280–286.

77. Magrini F, Foulds R, Roberts N et al. Human renovascular effects of dopexamine hydrochloride: a novelagonist of peripheral dopamine and beta 2-adreno-receptors. European Journal of Clinical Pharmacology1987; 32: 1–4.

78. Baumann G, Felix SB & Filcek SA. Usefulness of dopexamine hydrochloride versus dobutamine in chroniccongestive heart failure and effects on hemodynamics and urine output. American Journal of Cardiology1990; 65: 748–754.

79. Ralph CJ, Tanser SJ, MacNaughton PD et al. A randomised controlled trial investigating the effects ofdopexamine on gastrointestinal function and organ dysfunction in the critically ill. Intensive Care Medicine2002; 28: 884–890.

80. Berendes E, Mollhoff T, Van Aken H et al. Effects of dopexamine on creatinine clearance, systemicinflammation and splanchnic oxygenation in patients undergoing coronary artery bypass grafting.Anesthesia and Analgesia 1997; 84: 950–957.

81. Sherry E, Tooley MA, Bolsin SN et al. Effect of dopexamine hydrochloride on renal vascular resistanceindex and haemodynamic responses following coronary artery bypass graft surgery. European Journal ofAnaesthesiology 1997; 14: 184–189.

82. Dehne MG, Klein TF, Muhling J, Hempelmann G et al. Impairment of renal function after cardiopulmonarybypass is not influenced by dopexamine. Renal Failure 2001; 23: 217–230.

83. Wilson J, Woods I, Fawcett J et al. Reducing the risk of major elective surgery: randomised controlled trialof preoperative optimisation of oxygen delivery. British Medical Journal 1999; 318: 1099–1103.

84. Konstam MA & Cody RJ. Short-term use of intravenous milrinone for heart failure. American JournalCardiology 1995; 75: 822–826.

85. Cody RJ. Renal and hormonal effects of phosphodiesterase III inhibition in congestive heart failure.American Journal of Cardiology 1989; 63: 31A–34A.

86. Saab G, Mindel G, Ewald G et al. Acute renal failure secondary to milrinone in a patient with cardiacamyloidosis. American Journal of Kidney Diseases 2002; 40: E7.

87. Figgitt DP, Gillies PS & Goa KL. Levosimendan. Drugs 2001; 61: 613–627.88. Oldner A, Konrad D, Weitzberg E et al. Effects of levosimendan, a novel inotropic calcium-sensitizing

drug, in experimental septic shock. Critical Care Medicine 2001; 29: 2185–2193.


89. Holmes CL, Patel BM, Russell JA et al. Physiology of vasopressin relevant to management of septic shock.Chest 2001; 120: 989–1002.

90. Landry DW, Levin HR, Gallant EM et al. Vasopressin pressor hypersensitivity in vasodilatory septic shock.Critical Care Medicine 1997; 25: 1279–1282.

* 91. Tsuneyoshi I, Yamada H, Kakihana Y et al. Hemodynamic and metabolic effects of low-dose vasopressininfusions in vasodilatory septic shock. Critical Care Medicine 2001; 29: 487–493.

92. Patel BM, Chittock DR, Russell JA et al. Beneficial effects of short-term vasopressin infusion during severeseptic shock. Anesthesiology 2002; 96: 576–582.

93. Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Internationalconsensus on science. Circulation 2000; 102(supplement): I1–384.

94. Lindner KH, Prengel AW, Pfenninger EG et al. Cardiopulmonary resuscitation: vasopressin improves vitalorgan blood flow during closed-chest cardiopulmonary resuscitation in pigs. Circulation 1995; 91:215–221.

95. Scharte M, Meyer J, van Aken H et al. Hemodynamic effects of terlipressin (a synthetic analog ofvasopressin) in healthy and endotoxemic sheep. Critical Care Medicine 2001; 29: 1756–1760.

96. O’Brien A, Clapp L & Singer M. Terlipressin for norepinephrine-resistant septic shock. Lancet 2002; 359:1209–1210.


vasoactive drugs and the kidney

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