Is There Still a Place for Is There Still a Place for Dopamine in the Modern Dopamine in the Modern

Intensive Care Unit?Intensive Care Unit?

R1 R1 劉志中劉志中

Anesth Analg 2004;98:461-8

What we thought Dopamine Before…What we thought Dopamine Before…

Cardiovascular effectCardiovascular effect 2 to 5 µg · kg-1 · min-1: dopaminergic (82 to 5 µg · kg-1 · min-1: dopaminergic (8

0% to 100%), [beta]-adrenergic effects 0% to 100%), [beta]-adrenergic effects (5% to 20%). (5% to 20%).

5 to 10 µg · kg-1 · min-1: [beta]-adrener5 to 10 µg · kg-1 · min-1: [beta]-adrenergic effects predominate, and [alpha]-adrgic effects predominate, and [alpha]-adrenergic actions gradually become importenergic actions gradually become important. ant.

10 to 20 µg · kg-1 · min-1 : primarily [alp10 to 20 µg · kg-1 · min-1 : primarily [alpha]- and [beta]-adrenergic effects ha]- and [beta]-adrenergic effects

What we thought What we thought Low DoseLow Dose Dopamine Before…Dopamine Before…

Prevention and treatment of Prevention and treatment of acute renal failureacute renal failure

Protection of the gutProtection of the gut Relatively free of side effectRelatively free of side effect

IntroductionIntroduction

Goldberg : a protective effect of loGoldberg : a protective effect of low dose dopamine(<5w dose dopamine(<5µg · kg-1 · min-1µg · kg-1 · min-1) o) on renal functionn renal function

The presumed protective effects oThe presumed protective effects on renal and splachnic perfusion hn renal and splachnic perfusion have been repeatedly questioned.ave been repeatedly questioned.

Renal effectsRenal effects

Augment renal blood flowAugment renal blood flow DA-1 recepter: renal vasodilationDA-1 recepter: renal vasodilation DA-2 recepter on presynaptic nerve endings: DA-2 recepter on presynaptic nerve endings:

inhibition of NE releaseinhibition of NE release Large doses: βeffect to increase C.O.Large doses: βeffect to increase C.O.

Trigger natriuresis and diuresis tTrigger natriuresis and diuresis through a direct effect on the tubhrough a direct effect on the tubular cell function ular cell function

Renal effectsRenal effects

Trigger natriuresis and diuresis tTrigger natriuresis and diuresis through a direct effect on the tubhrough a direct effect on the tubular cell functionular cell function DA-1, DA-2 recepter on proximal tubule, thick asDA-1, DA-2 recepter on proximal tubule, thick as

cending limb of the loop of Henle,cortical collecticending limb of the loop of Henle,cortical collecting tube : inhibit Na/K –ATPase ng tube : inhibit Na/K –ATPase Natriuresis. Natriuresis.

DA-2 recepters in the inner medullary collecting DA-2 recepters in the inner medullary collecting ducts ducts PGE2 production PGE2 production antagonizes ADH antagonizes ADH increase free water clearance increase free water clearance

Renal effectsRenal effects

Regional redistribution of blood Regional redistribution of blood flow within the kidney flow within the kidney (potentially detrimental)(potentially detrimental) Preferentially increasing cortical blood flowPreferentially increasing cortical blood flow PGE2:enhance blood flow in inner medullaPGE2:enhance blood flow in inner medulla

shunting of blood away from the shunting of blood away from the outer medulla which is very susceptible to outer medulla which is very susceptible to ischemic injury in ARFischemic injury in ARF..

Dopamine and the kidney: ten years on. Clin Sci (Lond) 1993; 84: 357–7

5.

Renal effectsRenal effects

Increasing urine outputIncreasing urine output renal hypoperfusion is a leading cause of renal hypoperfusion is a leading cause of

ARF ARF The risk of inducing renal failure in normovThe risk of inducing renal failure in normov

olemic and hypovolemic patients olemic and hypovolemic patients LDD increases urine output by enhancing LDD increases urine output by enhancing

cardiac output and thus not primarily by a cardiac output and thus not primarily by a direct renal effect direct renal effect

……During norepinephrine infusion, During norepinephrine infusion, increasing doses of dopamine frincreasing doses of dopamine from 2 to 6 μg kg‧om 2 to 6 μg kg‧ -1-1 min‧min‧ -1-1,augm,augments CO,diuresis,and sodium exents CO,diuresis,and sodium excretion in p’t treated for septic shcretion in p’t treated for septic shock,ock,without changes in creatininwithout changes in creatinine clearancee clearance……

The renal and neurohumoral effects of the addition of low-dose dopamine in septic critically ill patients.

Intensive Care Med 2000; 26: 1685–9

Controversy of LDD on Renal functionControversy of LDD on Renal function

Beneficial or detrimental ?Beneficial or detrimental ? Increased urine output = Increased urine output =

improved renal function?improved renal function? How strong is the clinical How strong is the clinical

evidence on critically ill evidence on critically ill patient ?patient ?

Low-dose dopamine in patients with eaLow-dose dopamine in patients with early renal dysfunction: a placebo-controrly renal dysfunction: a placebo-controlled randomised trial—Australian and lled randomised trial—Australian and New Zealand Intensive Care Society (ANew Zealand Intensive Care Society (ANZICS) Clinical Trials Group.NZICS) Clinical Trials Group. Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

BackgroundBackground

Multicentre, rendomised , doublMulticentre, rendomised , double-blind,placebo-controlled study e-blind,placebo-controlled study in ICU patients at the risk of ARin ICU patients at the risk of ARF to assess whether dopamine aF to assess whether dopamine attenuated the rise in serum creatttenuated the rise in serum creatinineinine

Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

Methods (patients)Methods (patients)

Between March,1996 and April, 1999 Between March,1996 and April, 1999 Inclusion criteria:Inclusion criteria: presence of a central venous catheter two or more of the pathophysiological change

s of the SIRS over a 24 h period At least one indicator of early renal dysfunctio

n (urine output averaging <0·5 mL/kg hourly over 4 h or longer; serum creatinine concentration of >80 mol/L in less than 24 h in theabsence of creatine kinase >5000 IU/L or myoglobin in the urine)

Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

Methods (patients)Methods (patients)

Exclusion criteria:Exclusion criteria: age under 18 years an episode of acute renal failure within the

previous 3 months previous renal transplantation use of dopamine at anydose during the cur

rent hospital stay baseline serum creatinine concentration a

bove 300 μmol/L Enrolling physician’s belief that the drug co

uld not be administered for 8 h or longer; unsuitability for use of renal replacement t

herapy.

Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

MethodsMethods

Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

MethodsMethods

Continuous infusion of dopamine at Continuous infusion of dopamine at 2μg kg‧2μg kg‧ -1-1 min‧min‧ -1 -1 ( or equivalent volu( or equivalent volume for placebo) until ..me for placebo) until .. Renal replacement therapyRenal replacement therapy Patient diedPatient died a serious adverse event developed that

was judged to be related to the trial infusion;

the patient’s SIRS and renal dysfunction had resolved for at least 24 h

the patient was discharged from ICU.

Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

ResultsResults

Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

ResultsResults

Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

ResultsResults

There was no difference inThere was no difference in Peak creatinine concentrationPeak creatinine concentration Increase from baseline to highest valIncrease from baseline to highest val

ue during treatmentue during treatment Who required renal replacement therWho required renal replacement ther

apyapy Duration of ICU stayDuration of ICU stay Hospital stayHospital stay DeathDeath

Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

InterpretationInterpretation

Administration of low-dose dopamine by continuous intravenous infusion to critically ill patients at risk of renal failure does not confer clinically significant protection from renal dysfunction.

Lancet 2000; 356: 2139–43Lancet 2000; 356: 2139–43

Controversy of LDD on Renal functionControversy of LDD on Renal function

Beneficial or detrimental ?Beneficial or detrimental ? Increased urine output = Increased urine output =

improved renal function?improved renal function? How strong is the clinical How strong is the clinical

evidence on critically ill evidence on critically ill patient ?patient ?

LDD on renal effectLDD on renal effect

LDD may increase urine output iLDD may increase urine output in critically ill patient,but it neither n critically ill patient,but it neither prevents nor improves ARF.prevents nor improves ARF.

When dopamine does increase When dopamine does increase diuresis, it may actually increase diuresis, it may actually increase the risk of ARF in normovolemic the risk of ARF in normovolemic and hypovolemic patients.and hypovolemic patients.

Effects on Splachnic perfusionEffects on Splachnic perfusion

The gut may be particularly suscThe gut may be particularly susceptible to ischemia in shockeptible to ischemia in shock

Disruption of the gut mucosal baDisruption of the gut mucosal barrier is thought to play a key role rrier is thought to play a key role in the development of multiple orin the development of multiple organ failuregan failure

~~ Am J Respir Crit Care Med 1998; 158: 444–51 Am J Respir Crit Care Med 1998; 158: 444–51

Effects on Splachnic perfusionEffects on Splachnic perfusion

The gut may be particularly susceptiThe gut may be particularly susceptible to ischemia in shockble to ischemia in shock

Disruption of the gut mucosal barrier Disruption of the gut mucosal barrier is thought to play a key role in the deis thought to play a key role in the development of multiple organ failurevelopment of multiple organ failure

~~ Am J Respir Crit Care Med 1998; 158: 444–51 Am J Respir Crit Care Med 1998; 158: 444–51

Theoratically,LDD may increase splaTheoratically,LDD may increase splanchnic blood flow by stimulation of thnchnic blood flow by stimulation of the splachnic dopaminergic receptorse splachnic dopaminergic receptors

Effects on Splachnic perfusionEffects on Splachnic perfusion

Controversial for human dataControversial for human data Increasing splanchnic flow is not necIncreasing splanchnic flow is not nec

essarily accompanied by an improveessarily accompanied by an improvement of mucosal perfusion.ment of mucosal perfusion.

there is there is no evidenceno evidence that LDD has that LDD has bebeneficial neficial effects on the splanchnic funeffects on the splanchnic function or reduces the progression to ction or reduces the progression to multiple organ failure in sepsis. multiple organ failure in sepsis.

Recent data even suggest a potentiaRecent data even suggest a potentially detrimental effect of LDD on lly detrimental effect of LDD on splansplanchnic oxygen uptakechnic oxygen uptake

~JAMA 1994; 272: 1354–7~JAMA 1994; 272: 1354–7

Effect on Gastrointestinal MotilityEffect on Gastrointestinal Motility

DA-2 :human enteric nervous systemDA-2 :human enteric nervous system In healthy volunteers: short-term DA In healthy volunteers: short-term DA

could interrupt the fed gastrointestinacould interrupt the fed gastrointestinal motility patternl motility pattern

In critically ill pateints: DA (2.5 -5In critically ill pateints: DA (2.5 -5μg k‧μg k‧gg-1-1 min‧min‧ -1-1)was found to be the most sig)was found to be the most significant factor associated with poor gnificant factor associated with poor gastric emptyingastric emptying

DA may aggravate digestive intoleraDA may aggravate digestive intolerance to enteral feeding.nce to enteral feeding.

Respiratory EffectsRespiratory Effects

Impaired the ventilatory drive in respImpaired the ventilatory drive in response to hypoxemia and probably hyponse to hypoxemia and probably hypercapnia by depressing the carotid bercapnia by depressing the carotid body.ody.

DA reduced arterial oxygen saturatioDA reduced arterial oxygen saturation by impairing V/Q matching in the lun by impairing V/Q matching in the lung.ng.

Patients receiving LDD may be easiePatients receiving LDD may be easier to wean, but with the potential dangr to wean, but with the potential danger of precipitating respiratory failure er of precipitating respiratory failure

Endocrine and immunological Endocrine and immunological effectseffects

initial stress response: all anterior pitinitial stress response: all anterior pituitary hormones is stimulateduitary hormones is stimulated

more prolonged critical illness: a unifmore prolonged critical illness: a uniform suppression of the hypothalamiorm suppression of the hypothalamic-pituitary axes ensues while cortisol c-pituitary axes ensues while cortisol secretion remains increased through secretion remains increased through a peripheral drive. a peripheral drive.

hypothalamic hypopituitarism : evoke hypothalamic hypopituitarism : evoke inappropriate & harmful metabolic chinappropriate & harmful metabolic changes anges

DA infusion: 5μg kg‧μg kg‧ -1-1 min‧min‧ -1-1

NS :not significantNS :not significant

** ** : significant: significant

As a vasopressorAs a vasopressor

DA: act largely by increasing carDA: act largely by increasing cardiac outputdiac output

NE: more specifically increases NE: more specifically increases vascular resistance vascular resistance

LethalphedLethalphed :causing end-organ :causing end-organ hypoperfusion and severe ischehypoperfusion and severe ischemia of vital organ.mia of vital organ.

As a vasopressorAs a vasopressor

NE:NE: in effectively volume-resuscitated in effectively volume-resuscitated

septic shock patients, the fear of eseptic shock patients, the fear of end organ ischemia is unwarrant.nd organ ischemia is unwarrant.

Faster restore MAP and lower serFaster restore MAP and lower serum lactate level than DAum lactate level than DA

No deleterios effects on splachnic No deleterios effects on splachnic perfusion ,even can increase PHi.perfusion ,even can increase PHi.

As a vasopressorAs a vasopressor

Dopamine = Dobutamine+ NE ?Dopamine = Dobutamine+ NE ? Don’t forget Its side effects ! Don’t forget Its side effects ! Separate titration Separate titration more target more target

intervention tailored by the patieintervention tailored by the patients conditions.nts conditions.

ConclusionConclusion

There is indeed no evidence that low There is indeed no evidence that low “renal” dose DA has any beneficial ef“renal” dose DA has any beneficial effect on renal function or on the outcofect on renal function or on the outcome of patients with ARF. me of patients with ARF.

There is no evidence that LDD has bThere is no evidence that LDD has beneficial effects on hepatosplanchnic eneficial effects on hepatosplanchnic circulationcirculation

Recent data suggest that DA may evRecent data suggest that DA may even have detrimental effects on splanen have detrimental effects on splanchnic oxygen uptake chnic oxygen uptake

ConclusionConclusion

DA suppresses the secretion and DA suppresses the secretion and function of anterior pituitary hormfunction of anterior pituitary hormones, aggravating the impairmenones, aggravating the impairment of anabolism and cellular immut of anabolism and cellular immune function. ne function.

DA aggravates the digestive tolerDA aggravates the digestive tolerance of enteral feeding ance of enteral feeding

suppresses the ventilatory drive. suppresses the ventilatory drive.

Time to Wake Up !!Time to Wake Up !!