Congress report Schweiz Med Wochenschr 2000;130:19427Peer reviewed article

1942

A. Meier-Hellmann, S. G. Sakka, K. Reinhart

Department of Anaesthesiology and Intensive Care Medicine,Friedrich-Schiller-University, Jena (D)

Catecholamines and splanchnic perfusion1

Summary

Correspondence:Andreas Meier-HellmannDepartment of Anaesthesiology and Intensive Care MedicineFriedrich-Schiller-UniversityBachstrasse 18D-07743 Jenae-mail: meier-hellmann@med.uni-jena.de

1 Main lecture at the Annual meeting of the Swiss Society of Intensive Care, the Swiss Society of Pulmology and the Swiss Society of Infectiology(Lausanne, June 1516, 2000)

For supportive therapy in sepsis adequate vol-ume loading is probably the first, and possiblythe most important step in the treatment of pa-tients with septic shock. An elevated global O2-supply (DO2) may be necessary and beneficialin most of these patients, but the increase inDO2 should be guided by measurement of pa-rameters assessing global and regional oxy-genation. Routine strategies for elevating DO2by the use of very high dosages of cate-cholamines cannot be recommended.Vasopressors should be used to achieve ade-quate perfusion pressure. With noradrenaline,no negative effects on regional perfusion havebeen demonstrated when the patient is ade-quately volume-resuscitated and the DO2 isnormal or even slightly elevated. In contrast,adrenaline should be avoided because it ap-pears to redistribute blood flow away from thesplanchnic region. There is controversy as towhether dopamine should still be used as afirst-line drug in patients with septic shock,since some clinical and experimental data in-dicate unfavourable effects on mucosal per-fusion of the gut.

To date there are no convincing data to sup-port the routine use of low-dose dopamine ordopexamine in patients with sepsis. Neitherlow-dose dopamine nor dopexamine have beenproved to prevent renal failure in septic pa-tients. Furthermore, there is evidence that low-dose dopamine may reduce mucosal perfusionin the gut in some patients. Dopexamine hasbeen suggested for improvement of splanchnicperfusion, but since these effects remain some-what controversial there are no currentgrounds for a general recommendation infavour of dopexamine in septic patients.These recommendations are currently limitedby the lack of sufficient outcome studies andstudies evaluating regional perfusion. Until the various catecholamine regimes are more fully examined, recommendations for cate-cholamine support in sepsis must be consideredconditional.Keywords: sepsis; treatment; catecholamines;dobutamine; adrenaline; noradrenaline; dopa-mine; dopexamine

Zusammenfassung

Evidenz-basierte Vorschlge fr eine rationaleKatecholamintherapie bei kritisch kranken Pa-tienten, insbesondere im Hinblick auf regio-nale Effekte, zu geben ist durch das Fehlengrosser, prospektiver und randomisierter Stu-dien, die sich mit den Effekten von Katechol-

aminen beschftigt haben, limitiert. Fernermuss betont werden, dass eine adquateVolumentherapie unbedingte Voraussetzungeiner rationalen Katecholamintherapie ist.Das Konzept der Maximierung des DO2 mit-tels hochdosierter Katecholamine ist abzuleh-

1943

Congress reportSchweiz Med Wochenschr 2000;130: Nr 50

nen. Zur Therapie der eingeschrnkten Pump-funktion ist Dobutamin Katecholamin derWahl. Zur Entscheidung, ob ein weiterer DO2-Anstieg sinnvoll ist, mssen die Marker derperipheren Perfusion und Organfunktion (z.B.Diurese, Laktat, rCO2) beachtet werden. Ein inadquater Perfusionsdruck sollte nichtwegen potentieller ungnstiger Effekte vonVasopressoren toleriert werden. Auch der Per-fusionsdruck muss unter Beachtung von Para-metern der peripheren Perfusion und Organ-funktion titriert werden. Noradrenalin ist Ka-techolamin der Wahl, da es keine Hinweise frungnstige regionale Effekte gibt. Darber hin-aus haben sowohl Adrenalin als auch Dopamin

in vasopressorischer Dosierung negative Ef-fekte auf die Perfusion des Gastrointestinal-traktes. Es gibt zurzeit keine hinreichend gesicherteTherapieoption, die ber die Stabilisierung derglobalen Hmodynamik hinaus, eine gezielteBeeinflussung der regionalen Zirkulation er-mglicht. Dopamin (auch in sogenannter Nie-rendosis) scheint die Perfusion der intestinalenMukosa zu verschlechtern. Auch fr Dopex-amin liegen zurzeit keine Daten vor, die denklinischen Einsatz rechtfertigen.Keywords: Sepsis; Therapie; Katecholamine;Dobutamin; Adrenalin; Noradrenalin; Dopa-min; Dopexamin

Introduction

To restore and maintain the oxygen transportand tissue oxygenation is the most importantstep in the supportive treatment of patientswith sepsis. Therefore, the supportive treat-ment should be focused on an adequate volumeresuscitation and appropriate use of vasoactivedrugs. Tissue hypoxia, especially in the splanchnicarea, is still considered to be an important co-factor in the pathogenesis of multiple organfailure (MOF) [1]. Therefore, the specific ef-fects of the various therapeutic interventionson splanchnic perfusion and oxygenation areof particular interest.

Since the effects of the various vasoactive drugson global and regional haemodynamics arewell studied, one would assume that an ap-propriate use of vasoactive drugs in the treat-ment of sepsis should easily be established. Un-fortunately, there is evidence that the effects ofvasoactive drugs on global and regional per-fusion in patients with sepsis or septic shockmay well differ from patients studied withoutsepsis [2]. Especially important are studiesmeasuring the effects of various fluids andcatecholamines on splanchnic perfusion andoxygenation under the specific conditions ofsepsis.

Dobutamine

Under the conditions of an adequate volumereplacement, dobutamine increases cardiacoutput (CO) and DO2 to a greater extent thandopamine [3]. Hannemann et al. [4] demon-strated in septic patients that a combination ofdobutamine with noradrenaline when com-pared with dopamine alone, titrated to a simi-lar mean arterial pressure, is associated with alower heart rate, lower filling pressures, andlower intrapulmonary shunt. A higher DO2with dopamine alone was not associated witha higher oxygen consumption. Therefore, theauthors concluded that dopamine did not im-prove tissue oxygenation but induced a greatermyocardial stress and impaired pulmonary gasexchange.Hayes et al. [5] found no difference in globaloxygen consumption (VO2) between 50 pa-tients treated with dobutamine up to 200 g/kg/min to achieve three goals (cardiac indexabove 4.5 l/min/m2, DO2 above 600 ml/min/m2, VO2 above 170 ml/min/m2) and 50 otherpatients who were only treated with an ade-

quate volume therapy. Surprisingly, survival inthe patients with the dobutamine treatmentwas lower than in the control group. The au-thors speculated that the aggressive dobuta-mine treatment as an attempt to increase VO2may have been detrimental in some patients.That dobutamine improves splanchnic perfu-sion and oxygenation has been supported bystudies demonstrating an increased pHi (intra-mucosal pH) under dobutamine infusion [6, 7].Nevertheless, these effects paralleled an in-crease in whole body blood flow. Thus, furtherselective effects of dobutamine on splanchniccirculation, beyond the global haemodynamiceffects, seem to be very unlikely [8].In conclusion, when dobutamine is used to in-crease DO2, there is some evidence of im-provement in tissue oxygenation. Neverthe-less, there is no clear recommendation to whatextent DO2 should be increased, and it isdoubtful that there is an optimal DO2 appro-priate for all septic patients. Therefore, theincrease in DO2 by dobutamine should be

1944

Congress report Schweiz Med Wochenschr 2000;130: Nr 50

carefully monitored by using methods whichindicate changes in tissue oxygenation such as

lactate levels, regional CO2 production (pHi),or changes in VO2.

Noradrenaline

In experimental models, noradrenaline in-creased splanchnic vascular resistance and de-creased splanchnic blood flow [9]. As a conse-quence, noradrenaline is most commonly usedas a last resort when haemodynamic stabili-sation cannot be achieved with other cate-cholamines [10].It has been demonstrated that treatment withnoradrenaline in septic shock restored renalfunction [11, 12]. However, it should be em-phasised that these patients had markedly de-creased blood pressures prior to the adminis-tration. Therefore, the potential unfavourableeffects of vasopressors must be weighed againstthe known danger of inadequate perfusionpressure.In fact, findings on the effects of noradrenalineon splanchnic perfusion in sepsis are inconsis-tent. Bersten et al. [2] compared the effects ofseveral catecholamines on regional blood flowin septic and non-septic sheep. They found a redistribution of blood flow to the heart and away from the brain, kidneys, liver andpancreas with noradrenaline, dobutamine,

dopamine, dopexamine or salbutamol treat-ment in the non-septic animals. In contrast,such a redistribution of regional blood flowwas not observed in the septic animals.A beneficial effect of noradrenaline on splanch-nic oxygenation in septic patients was shownby Marik and Mohedin [13] who comparednoradrenaline and dopamine as vasopressors.Patients who were treated with noradrenalinehad an increase in pHi whereas dopamine ledto a decrease in pHi.We measured splanchnic blood flow in 10 pa-tients with septic shock using the indocyanine-dye dilution technique [14]. After changing thecatecholamine treatment from a combinationof dobutamine with noradreanline to nor-adrenaline alone, we observed a parallel de-crease in splanchnic perfusion and cardiac output, while splanchnic VO2 remained un-changed.In conclusion, as long as an adequate DO2is maintained, treatment with noradrenalinealone seems to be without negative effects ontissue oxygenation.

Adrenaline

The rationale for using adrenaline in the treat-ment of septic shock is its beta-receptor medi-ated increase in cardiac output and alpha-re-ceptor mediated increase in systemic perfusionpressure [1517].We [18] measured splanchnic perfusion, DO2and VO2 in 8 patients with septic shock whowere treated with a combination of dobuta-mine and noradrenaline. After a change toadrenaline alone, titrated to achieve the samemean arterial pressure (MAP) as before, DO2and VO2 remained unchanged. However,splanchnic perfusion decreased despite un-changed cardiac output. The decrease in

splanchnic DO2 was associated with a decreasein splanchnic VO2. Furthermore, the deterio-ration of tissue oxygenation following the ad-ministration of adrenaline was evident by anincrease in lactate levels and a decrease in pHi.Similar findings were reported by Levy et al.[19] who also found an increase in lactate anda decrease in pHi from adrenaline when com-pared with a combination of dobutamine andnoradrenaline. These findings point to a verylimited role for adrenaline in septic patients,and in our opinion, noradrenaline should bethe vasopressor of first choice.

Dopamine

Vincent and Preiser [20] suggested dopamineas the primary drug of choice in the manage-ment of decreased MAP in patients in septicshock. However, other authors have suggestedthat the alpha-mimetic effects of dopaminecould further compromise an already disturbedmicrocirculation [3, 21]. In 437 critically illpatients, Shoemaker et al. [10] were able toinduce an increase in DO2 and VO2 more

frequently with dobutamine than dopamine.Lherm et al. [22] demonstrated in a group ofseptic patients that low-dose dopamine in-creased urine output and creatinine clearancein patients with severe sepsis, whereas no ef-fects in patients with septic shock were found.Nevertheless, the beneficial effects in patientswith severe sepsis were only seen for 48 hours.Giraud and MacCannell [23] administered

1945

Congress reportSchweiz Med Wochenschr 2000;130: Nr 50

dopamine in dogs and were able to measure anincrease in superior mesenteric artery bloodflow and in the muscle layer of the gut. How-ever, they found a decreased blood flow to thegut mucosa accompanied by a decrease insplanchnic VO2. In the already mentionedstudy from Marik and Mohedin [13], patientswho were stabilised from septic shock usingdopamine had a lower pHi than patients whoreceived noradrenaline. Moreover, dopaminein a dose of 5 g/kg/min was equally effectivewhen compared with dobutamine but led to adecrease in intestinal mucosa perfusion [24].In 11 patients with septic shock treated withnoradrenaline, we added dopamine in a dosageof 2.8 to 3.0 g/kg/min. In those patients witha fractional splanchnic flow in the normalrange, low-dose dopamine increased splanch-nic perfusion, whereas in patients with an ele-vated fractional splanchnic flow before treat-

ment, no further increase or even decrease insplanchnic flow was observed [25]. This sug-gests that the effect of dopamine depends onthe individual baseline splanchnic flow whichin septic patients could vary from normal tomarkedly increased. Furthermore, it is well known that prolongeddopamine infusion has important effects on theconcentrations of various circulating pituitary-dependent hormones which may influencemetabolic and immunological homoeostasis incritically ill patients [26].In conclusion, it remains questionable whethermanagement of septic shock with higher dosesof dopamine alone is superior to the com-bination of dobutamine and noradrenaline.Whether low-dose dopamine can prevent renalfailure has yet to be proven, and there is evi-dence that low-dose dopamine has deleteriouseffects on splanchnic oxygenation.

Dopexamine

Dopexamine is a relatively new catecholaminewith predominantly beta-2 and dopaminergicreceptor activity. Among animal experiments,Cain and Curtis [27] did not note a differencein mesenteric venous blood flow in septic dogstreated with dopexamine when compared witha control group without catecholamine treat-ment. Since the gut of the dopexamine-treatedanimals released less lactate, the authors con-cluded that dopexamine preferentially in-creased perfusion of the gut mucosa.In another animal model of sepsis, the infusionof dopexamine was associated with less dam-age in hepatic cells than an infusion of dobut-amine [28]. Furthermore, dopexamine in-creased tissue pO2 in various splanchnic organsin animals after the induction of sepsis [29].Also, in a dosage of 2.5 g/kg/min dopexam-ine prevented a hypoperfusion of the intestinalvillus after endotoxin infusion in rats [30].In two clinical studies, dopexamine did in-crease a pathological low gastric mucosal pH[31, 32]. However, it remains unclear whetherdopexamine really had a selective effect onsplanchnic perfusion or if this finding was sim-ply the result of haemodynamic stabilisation.Such an effect, an improved cardiac output butno selective effect on splanchnic perfusion, has

been demonstrated in a recently publishedstudy from Kiefer et al. [33]. Moreover, somestudies have suggested that dopexamine maybe dangerous for the splanchnic perfusion.Uusaro et al. [34] reported an increase in wholebody DO2 and splanchnic DO2 to a similar ex-tent after dopexamine infusion in cardiacsurgery patients. They did not find a specificeffect on splanchnic blood flow by dopex-amine infusion as indicated by an unchangedfractional splanchnic blood flow and reporteda decrease in pHi, which could be a sign of sev-ere splanchnic hypoxia induced by the cardiacsurgery. However, this effect could also be anindicator of a redistribution of splanchnicblood flow and a hypoperfusion of gut mucosasimilar to the effect from low-dose dopamine.In our own studies [35] dopexamine increasedsplanchnic perfusion to the same extent aswhole body blood flow but was also associatedwith a decrease in pHi.Although some investigators recommenddopexamine to improve splanchnic oxygena-tion and renal function, further studies areneeded to more clearly demonstrate the use-fulness of dopexamine in the treatment of sep-tic shock patients and to compare the effectswith those of low-dose dopamine.

Conclusion

An adequate fluid resuscitation is consideredessential treatment in sepsis, before or with cat-echolamines. Any attempt to correct low car-diac output or MAP due to hypovolaemia by

using catecholamines has to be strictly rejected.Catecholamines may exhibit marked inter-in-dividual variation in septic patients. Variousfactors, such as the fractional flow of the car-

1946

Congress report Schweiz Med Wochenschr 2000;130: Nr 50

diac output to the splanchnic perfusion bed ortherapy with other vasoactive substances, mayinfluence the effects of catecholamines. Whena supranormal value for DO2 has already beenachieved by sufficient fluid resuscitation, anyfurther attempt to increase global O2-supply isquestionable unless signs of inadequate tissueperfusion are still present. The clinical decisionto further increase catecholamine dosages to el-evate DO2 should be guided by parameters thatreflect organ function or tissue oxygenation,e.g. lactate, rCO2, and urine output. Due to thepotentially harmful effects of dopamine andadrenaline, dobutamine seems to be the cate-cholamine of choice to improve compromisedcardiac function. The use of dobutamine inmoderate dosages may further increase globalDO2, and thus also lead to an increase in O2-supply to the splanchnic area and to an im-proved gastric mucosal perfusion.Again, based on the potential negative effectsof dopamine and adrenaline, noradrenalinemay be regarded as first choice catecholaminefor increasing peripheral vascular resistance.The well-documented negative effects of nor-adrenaline on kidney function in non-septicpatients do not seem to be present in sepsispatients with adequate volume resuscitation.

An inadequate perfusion pressure should notbe tolerated just because of concerns over theuse of noradrenaline.There is no good evidence for a routine treat-ment with dopamine in the so-called renaldosage. In septic patients with low fractionalsplanchnic blood flow, dopamine increasedselective and absolute splanchnic blood flow.However, it remains unclear whether tissueoxygenation actually improves, since animalstudies suggest a decrease in intestinal mucosalperfusion during dopamine infusion. In view ofthe lack of evidence of benefits, and due to thepotential adverse side effects (selective impair-ment of mucosal perfusion, no or even nega-tive effects on splanchnic blood flow in patientswith primarily already increased blood flow,and its endocrinological effects) dopamineshould only be used with caution. For dopex-amine a selective effect on splanchnic bloodflow has yet to be documented. Clinical stud-ies that showed a positive effect for dopex-amine on pHi could not be confirmed by otherswho in fact reported a decrease in pHi withdopexamine. Accordingly, dopexamine cancurrently not be recommended in the routinetreatment of patients with sepsis.

Evidence-based assessment

It is now well documented that routine sepsistreatment to supranormal levels of DO2 by us-ing high doses of catecholamines is not benefi-cial (one multicentre, randomised, controlledstudy, n = 762 [36]; one randomised, con-trolled study, n = 109 [5]; one meta-analysis, 7studies with in total n = 1016 [37]). The majorrole of an adequate fluid resuscitation and anadequate arterial blood pressure has beenproved in a large number of smaller trials andcan be considered to have a high degree of ev-idence [38]. It has also been confirmed thatadrenaline is not considered as first choice cat-echolamine and that there is no indication for

the use of low-dose dopamine [38, 39]. How-ever, due to the lack of evidence there is con-troversy concerning the use of high-dosedopamine. For dopexamine only animal ex-periments and smaller clinical trials have beenpublished; thus recommendations by an expertcommission on the use of dopexamine are notyet available.Indeed, these strategies are quite limited due tothe lack of outcome studies and methods ofmeasurement of regional perfusion and oxida-tion. Until these limitations are addressed,other alternative treatments should not neces-sarily be dismissed as inappropriate.

References

1 Deitch EA, Berg R, Specian R. Endotoxin promotes thetranslocation of bacteria from the gut. Arch Surg 1987;122:18590.

2 Bersten AD, Hersch M, Cheung H, Rutledge FS, Sibbald WJ.The effect of various sympathomimetics on the regionalcirculations in hyperdynamic sepsis. Surgery 1992;112:54961.

3 Vincent JL, Van der Linden P, Domb M, Blecic S, Azimi G,Bernard A. Dopamine compared with dobutamine in exper-imental septic shock: relevance to fluid administration.Anesth Analg 1987;66:56571.

4 Hannemann L, Reinhart K, Grenzer O, Meier-Hellmann A,Bredle DL. Comparison of dopamine to dobutamine andnorepinephrine for oxygen delivery and uptake in septicshock. Crit Care Med 1995;23:196270.

5 Hayes MA, Timmins AC, Yau EH, Palazzo M, Hinds CJ,Watson D. Elevation of systemic oxygen delivery in the treat-ment of critically ill patients. N Engl J Med 1994;330:171722.

6 Silverman HJ, Tuma P. Gastric tonometry in patients withsepsis. Effects of dobutamine infusions and packed red bloodcell transfusions. Chest 1992;102:1848.

1947

Congress reportSchweiz Med Wochenschr 2000;130: Nr 50

7 Gutierrez G, Clark C, Brown SD, Price K, Ortiz L, NelsonC. Effect of dobutamine on oxygen consumption and gastricmucosal pH in septic patients. Am J Respir Crit Care Med1994;150:3249.

8 Reinelt H, Radermacher P, Fischer G, Geisser W, Wachter U,Wiedeck H, et al. Effects of a dobutamine-induced increasein splanchnic blood flow on hepatic metabolic activity in pa-tients with septic shock. Anesthesiology 1997;86:81824.

9 Granger DN, Richardson PD, Kvietys PR, Mortillaro NA.Intestinal blood flow. Gastroenterology 1980;78:83763.

10 Shoemaker WC, Appel PL, Kram HB. Oxygen transportmeasurements to evaluate tissue perfusion and titrate ther-apy: dobutamine and dopamine effects. Crit Care Med1991;19:67288.

11 Hesselvik JF, Brodin B. Low-dose norepinephrine in patientswith septic shock and oliguria: effects on afterload, urineflow, and oxygen transport. Crit Care Med 1989;17:17980.

12 Martin C, Eon B, Saux P, Aknin P, Gouin F. Renal effects ofnorepinephrine used to treat septic shock patients. Crit CareMed 1990;18:2825.

13 Marik PE, Mohedin M. The contrasting effects of dopamineand norepinephrine on systemic and splanchnic oxygen uti-lization in hyperdynamic sepsis. JAMA 1994;272:13547.

14 Meier-Hellmann A, Reinhart K. Cardiovascular support byhemodynamic subset: sepsis. In: Pinsky MR, ed. AppliedCardiovascular Physiology. Berlin: Springer-Verlag; 1997. p. 23045.

15 Bollaert PE, Bauer P, Audibert G, Lambert H, Larcan A. Ef-fects of epinephrine on hemodynamics and oxygen metabo-lism in dopamine-resistant septic shock. Chest 1990;98:94953.

16 Lipman J, Roux A, Kraus P. Vasoconstrictor effects of adren-aline in human septic shock. Anaesth Intensive Care1991;19:615.

17 Mackenzie SJ, Kapadia F, Nimmo GR, Armstrong IR, GrantIS. Adrenaline in treatment of septic shock: effects on haemo-dynamics and oxygen transport. Intensive Care Med 1991;17:369.

18 Meier-Hellmann A, Reinhart K, Bredle DL, Specht M, SpiesCD, Hannemann L. Epinephrine impairs splanchnic perfu-sion in septic shock. Crit Care Med 1997;25:399404.

19 Levy B, Bollaert PE, Charpentier C, Nace L, Audibert G,Bauer P, et al. Comparison of norepinephrine and dobuta-mine to epinephrine for hemodynamics, lactate metabolism,and gastric tonometric variables in septic shock: a prospec-tive, randomized study. Intensive Care Med 1997;23:2827.

20 Vincent JL, Preiser JC. Inotropic agents. New Horiz 1993;1:13744.

21 Shoemaker WC, Appel PL, Kram HB, Duarte D, Harrier HD,Ocampo HA. Comparison of hemodynamic and oxygentransport effects of dopamine and dobutamine in criticallyill surgical patients. Chest 1989;96:1206.

22 Lherm T, Troche G, Rossignol M, Bordes P, Zazzo JF. Renaleffects of low-dose dopamine in patients with sepsis syn-drome or septic shock treated with catecholamines. IntensiveCare Med 1996;22:2139.

23 Giraud GD, MacCannell KL. Decreased nutrient blood flowduring dopamine- and epinephrine-induced intestinal vaso-dilation. J Pharmacol Exp Ther 1984;230:21420.

24 Neviere R, Mathieu D, Chagnon JL, Lebleu N, Wattel F. Thecontrasting effects of dobutamine and dopamine on gastricmucosal perfusion in septic patients. Am J Respir Crit CareMed 1996;154:16848.

25 Meier-Hellmann A, Bredle DL, Specht M, Spies C, Hanne-mann L, Reinhart K. The effects of low-dose dopamine onsplanchnic blood flow and oxygen uptake in patients withseptic shock. Intensive Care Med 1997;23:317.

26 Van den Berghe G, de Zegher F. Anterior pituitary functionduring critical illness and dopamine treatment. Crit CareMed 1996;24:158090.

27 Cain SM, Curtis SE. Experimental models of pathologic oxy-gen supply dependency. Crit Care Med 1991;19:60312.

28 Tighe D, Moss R, Heywood G, al Saady N, Webb A, Ben-nett D. Goal-directed therapy with dopexamine, dobuta-mine, and volume expansion: effects of systemic oxygentransport on hepatic ultrastructure in porcine sepsis. CritCare Med 1995;23:19972007.

29 Lund N, de Asla RJ, Cladis F, Papadakos PJ, Thorborg PA.Dopexamine hydrochloride in septic shock: effects on oxy-gen delivery and oxygenation of gut, liver, and muscle. JTrauma 1995;38:76775.

30 Schmidt H, Secchi A, Wellmann R, Bach A, Bhrer H, Mar-tin E. Dopexamine maintains intestinal villus blood flow dur-ing endotoxemia in rats. Crit Care Med 1996;24:12337.

31 Smithies M, Yee TH, Jackson L, Beale R, Bihari D. Protect-ing the gut and the liver in the critically ill: effects of dopex-amine. Crit Care Med 1994;22:78995.

32 Maynard ND, Bihari DJ, Dalton RN, Smithies MN, MasonRC. Increasing splanchnic blood flow in the critically III.Chest 1995;108:164854.

33 Kiefer P, Tugtekin I, Wiedeck H, Bracht H, Geldner G,Georgieff M, et al. Effect of a dopexamine-induced increasein cardiac index on splanchnic hemodynamics in septicshock. Am J Respir Crit Care Med 2000;161:7759.

34 Uusaro A, Ruokonen E, Takala J. Gastric mucosal pH doesnot reflect changes in splanchnic blood flow after cardiacsurgery. Br J Anaesth 1995;74:14954.

35 Meier-Hellmann A, Bredle DL, Specht M, Hannemann L,Reinhart K. Dopexamine increases splanchnic blood flowbut decreases gastric mucosal pH in severe septic patientstreated with dobutamine. Crit Care Med 1999;27:216671.

36 Gattinoni L, Brazzi L, Pelosi P, Latini R, Tognoni G, PesentiA, et al. A trial of goal-oriented hemodynamic therapy in crit-ically ill patients. SvO2 Collaborative Group. N Engl J Med1995;333:102532.

37 Heyland DK, Cook DJ, King D, Kernerman P, Brun BuissonC. Maximizing oxygen delivery in critically ill patients: amethodologic appraisal of the evidence. Crit Care Med 1996;24:51724.

38 Hollenberg SM, Ahrens TS, Astiz ME, Chalfin DB, Dasta JF,Heard SO, et al. Practice parameters for hemodynamic sup-port of sepsis in adult patients in sepsis. Crit Care Med1999;27:63960.

39 Sibbald WJ, Vincent JL. Round table conference on clinicaltrials for the treatment of sepsis. Crit Care Med 1995;23:3949.