Practice parameters for hemodynamic support of sepsis in ...

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Practice parameters for hemodynamic support of sepsis in adultpatients: 2004 update

Steven M. Hollenberg, MD; Tom S. Ahrens, DNS, RN, CCRN, CS; Djillali Annane, MD, PhD;Mark E. Astiz, MD, FCCM; Donald B. Chalfin, MD, MS, FCCM, FCCP; Joseph F. Dasta, MSc, FCCM;Stephen O. Heard, MD, FCCM; Claude Martin, MD, FCCM; Lena M. Napolitano, MD, FCCM;Gregory M. Susla, PharmD, FCCM; Richard Totaro, MB, BS, FRACP, FJFICM;Jean-Louis Vincent, MD, PhD, FCCM; Sergio Zanotti-Cavazzoni, MD

Shock occurs when the circu-latory system fails to main-tain adequate cellular perfu-sion. Shock is a syndrome

that may arise from any of several ini-tiating causes; as this syndromeprogresses, a common pattern compris-ing an array of symptoms, signs, andlaboratory abnormalities that resultfrom hypoperfusion emerges. If shockis not reversed, irreversible cellulardamage may ensue.

Septic shock results when infectiousagents or infection-induced mediatorsin the bloodstream produce hemody-namic decompensation. Septic shock isprimarily a form of distributive shockand is characterized by ineffective tis-sue oxygen delivery and extraction as-sociated with inappropriate peripheralvasodilation despite preserved or in-creased cardiac output (1). In septicshock, a complex interaction betweenpathologic vasodilation, relative and ab-solute hypovolemia, myocardial dys-function, and altered blood flow distri-bution occurs due to the inflammatoryresponse to infection. Even after therestoration of intravascular volume,microcirculatory abnormalities maypersist and lead to maldistribution ofcardiac output (2). About half of thepatients who succumb to septic shockdie of multiple organ system failure (1).Most of the rest have progressive hypo-tension with low systemic vascular re-sistance refractory to vasopressoragents (3). Although myocardial dys-

function is not uncommon, death frommyocardial failure is rare (1).

Cellular dysfunction in sepsis is thefinal outcome of a process with multi-ple stimuli. Prominent mechanisms in-clude cellular ischemia, disruption ofcellular metabolism by the effects ofinflammatory mediators, and toxic ef-fects of free radicals (3). Activation ofcaspases and induction of heat shockproteins may lead to apoptotic celldeath. In early shock, compensatorymechanisms are activated in an attemptto restore pressure and flow to vitalorgans. When these compensatorymechanisms begin to fail, damage tocellular membranes, loss of ion gradi-ents, leakage of lysosomal enzymes,proteolysis due to activation of cellularproteases, and reductions in cellularenergy stores occur and may result incell death (3). Once enough cells fromvital organs have reached this stage,shock can become irreversible, anddeath can occur despite eradication ofthe underlying septic focus.

The American College of Critical Care Medicine(ACCM), which honors individuals for their achieve-ments and contributions to multidisciplinary criticalcare medicine, is the consultative body of the Societyof Critical Care Medicine (SCCM) that possesses rec-ognized expertise in the practice of critical care. TheCollege has developed administrative guidelines andclinical practice parameters for the critical care prac-titioner. New guidelines and practice parameters arecontinually developed, and current ones are system-atically reviewed and revised.

Copyright © 2004 by the Society of Critical CareMedicine and Lippincott Williams & Wilkins

DOI: 10.1097/01.CCM.0000139761.05492.D6

Objective: To provide the American College of Critical CareMedicine with updated guidelines for hemodynamic support ofadult patients with sepsis.

Data Source: Publications relevant to hemodynamic support ofseptic patients were obtained from the medical literature, sup-plemented by the expertise and experience of members of aninternational task force convened from the membership of theSociety of Critical Care Medicine.

Study Selection: Both human studies and relevant animalstudies were considered.

Data Synthesis: The experts articles reviewed the literatureand classified the strength of evidence of human studies accord-ing to study design and scientific value. Recommendations weredrafted and graded levels based on an evidence-based ratingsystem described in the text. The recommendations were de-

bated, and the task force chairman modified the document until<10% of the experts disagreed with the recommendations.

Conclusions: An organized approach to the hemodynamic sup-port of sepsis was formulated. The fundamental principle is thatclinicians using hemodynamic therapies should define specificgoals and end points, titrate therapies to those end points, andevaluate the results of their interventions on an ongoing basisby monitoring a combination of variables of global and regionalperfusion. Using this approach, specific recommendations forfluid resuscitation, vasopressor therapy, and inotropic therapyof septic in adult patients were promulgated. (Crit Care Med2004; 32:1928 –1948)

KEY WORDS: sepsis; hemodynamic support; fluid resuscitation;vasopressor therapy; inotropic therapy

1928 Crit Care Med 2004 Vol. 32, No. 9

Therapy of septic shock may be viewedas having three main components. Theinitial priority in managing septic shockis to maintain a reasonable mean arterialpressure and cardiac output to keep thepatient alive. Then the nidus of infectionmust be identified and eliminated, usingantimicrobial therapy in all cases andsurgical drainage whenever indicated.Another therapeutic goal is to interruptthe pathogenic sequence leading to septicshock. While these latter goals are beingpursued, adequate organ system perfu-sion and function must be maintained,guided by cardiovascular monitoring.The purpose of this practice parameter isto provide guidelines for hemodynamicsupport in sepsis to maintain adequateorgan system and cellular perfusion.

PURPOSE AND STRUCTURE OFPRACTICE PARAMETERS FORHEMODYNAMIC SUPPORT INSEPSIS

These practice parameters were devel-oped by a panel convened by the Ameri-can College of Critical Care Medicine ofthe Society of Critical Care Medicine, andupdated by a similar panel, to assisthealth care providers in the managementof hemodynamic support for patientswith sepsis and septic shock. Theseguidelines are intended for adult patientsand do not cover all conceivable clinicalscenarios. Nonetheless, they do representan attempt to review the state of knowl-edge concerning hemodynamic therapyof sepsis and to supplement specific ther-apeutic recommendations with guide-lines about how to optimize therapy andhow to evaluate the results of therapeuticinterventions. The information and rec-ommendations are predicated upon anexpert-based review of the available sci-entific data, clinical investigations, andoutcomes research. Where such data areunavailable or limited in scope, consen-sus was attained by considering publishedexpert opinion and discussion among awide range of experts. The citations ofhuman studies have been annotated intolevels of scientific support as per Co-chrane group recommendations (4) asfollows:

Level I: large, randomized trials withclear-cut results; low risk of false-positive (�) error or false-negative (�)error

Level II: small, randomized trials withuncertain results; moderate to high

risk of false-positive (�) error and/orfalse-negative (�) error

Level III: nonrandomized, contempo-raneous controls

Level IV: nonrandomized, historicalcontrols and expert opinion

Level V: case series, uncontrolled stud-ies, and expert opinion

The strength of the recommendationshas been graded as modified from theguidelines of Evidence-Based MedicineWorking Group as follows: (5)

A: Supported by at least two level Iinvestigations

B: Supported by only one level I inves-tigation

C: Supported by level II investigationsonly

D: Supported by at least one level IIIinvestigation

E: Supported by level IV or level Vinvestigations only

Hemodynamic therapy of sepsis hasbeen considered in each of three catego-ries: fluid resuscitation, vasopressor ther-apy, and inotropic therapy. Since the ini-tial formulation of the guidelines, arandomized, double-blind, placebo-con-trolled, multiple-center trial of recombi-nant human activated protein C has beencompleted (6). Although this trial showedthat treatment with recombinant acti-vated protein C is effective in patientswith septic shock, activated protein C isnot a hemodynamic therapy per se, norwas hemodynamic instability a requisitefor inclusion in the trial. Thus, consider-ation of activated protein C and othertherapies not directed at hemodynamicstabilization is outside the scope of thesepractice parameters.

An algorithm outlining an approach tohemodynamic support of patients withseptic shock based on the recommenda-tions in these parameters is shown inFigure 1.

BASIC PRINCIPLES

Septic shock requires early, vigorousresuscitation. An integrated approach di-rected at rapidly restoring systemic oxy-gen delivery and improving tissue oxy-genation has been demonstrated toimprove survival significantly in septicshock (7). Although the specific approachthat is used may vary, there are criticalelements that should be incorporated in

any resuscitative effort. Therapy shouldbe guided by parameters that reflect theadequacy of tissue and organ perfusion.Fluid infusion should be vigorous andtitrated to clinical end points of volumerepletion. Systemic oxygen deliveryshould be supported by ensuring arterialoxygen saturation, maintaining adequateconcentrations of hemoglobin, and usingvasoactive agents directed to physiologicand clinical end points.

Patients with septic shock should betreated in an intensive care unit. Contin-uous electrocardiographic monitoringshould be performed for detection ofrhythm disturbances, and pulse oximetryis useful to detect fluctuations in arterialoxygenation. Urine output is monitoredcontinuously as well. Laboratory mea-surements such as arterial blood gases,serum electrolytes, complete bloodcounts, coagulation variables, and lactateconcentrations should be done early andrepeated as indicated.

In shock states, estimation of bloodpressure using a cuff is commonly inac-curate, and use of an arterial cannulaprovides a more appropriate and repro-ducible measurement of arterial pressure(3). These catheters also allow beat-to-beat analysis so that decisions regardingtherapy can be based on immediate andreproducible blood pressure information.Such monitoring facilitates the adminis-tration of large quantities of fluids andpotent vasopressor and inotropic agentsto critically ill patients (3).

Although patients with shock andmild hypovolemia may be treated suc-cessfully with rapid fluid replacement,right heart catheterization may be usefulto provide a diagnostic hemodynamic as-sessment in patients with moderate orsevere shock. In addition, because hemo-dynamics can change rapidly in sepsis,and because noninvasive evaluation isfrequently incorrect in estimating fillingpressures and cardiac output, pulmonaryartery catheterization is often useful formonitoring the response to therapy.

Goals and End Points ofHemodynamic Support in SepticPatients

Shock represents the failure of the cir-culatory system to maintain adequate de-livery of oxygen and other nutrients totissues, causing cellular and then organdysfunction. Thus the ultimate goals ofhemodynamic therapy in shock are to

1929Crit Care Med 2004 Vol. 32, No. 9

Figure 1. Suggested algorithm for hemodynamic support of adult patients with severe sepsis and septic shock. SBP, systolic blood pressure; MAP, meanarterial pressure; ICU, intensive care unit; BP, blood pressure; HR, heart rate; Hgb, hemoglobin. *Adequate cardiac filling pressures can be assessed byresponse of cardiac output (CO) to increases of pulmonary artery occlusion pressure. Maximal benefit is usually achieved at pulmonary artery occlusionpressure 12–15 mm Hg. Variation in arterial pressure with respiration can also be used to identify patients who would benefit from increased fluidadministration. �Cardiac output can be assessed by echocardiography or by measuring cardiac index and/or mixed-venous oxygen saturation with apulmonary artery catheter. ‡Perfusion can be assessed using a combination of clinical and laboratory variables, as described in the text. �A corticotropinstimulation test is recommended. See text for details.


restore effective tissue perfusion and tonormalize cellular metabolism.

In hypovolemic, cardiogenic, and ex-tracardiac obstructive shock, hypoten-sion results from a decrease in cardiacoutput, with consequent anaerobic tissuemetabolism. Septic shock, the prototypi-cal form of distributive shock, is differentand more complicated. In septic patients,tissue hypoperfusion results not onlyfrom decreased perfusion pressure attrib-utable to hypotension but also from ab-normal shunting of a normal or increasedcardiac output (3). Cellular alterationsmay also occur. Hemodynamic support ofsepsis thus requires consideration of bothglobal and regional perfusion.

The practical import of the complex-ity of hemodynamics in sepsis is thatthe goals of therapy are much moredifficult to define with certainty than inother forms of shock in which globalhypoperfusion is the dominant pathol-ogy. In cardiogenic shock, for example,the goal of therapy is to increase car-diac output, although the degree of hy-poperfusion may vary in different or-gans. Indexes of regional perfusionusually correlate well with indexes ofglobal perfusion, and both can be usedto monitor the effects of therapy. Insepsis, maldistribution of a normal car-diac output can impair organ perfusion,and maldistribution of blood flowwithin organs due to perturbation ofresistance vessel tone or microvascularobstruction can exacerbate organ dys-function. To add to the complexity, me-diators of sepsis can perturb cellularmetabolism, leading to inadequate uti-lization of oxygen and other nutrientsdespite adequate perfusion. One wouldnot expect such abnormalities to becorrected by hemodynamic therapy.

Despite the complexity of the patho-physiology of sepsis, an underlying ap-proach to the hemodynamic support ofsepsis can be formulated, with the under-standing that the basic principles of theapproach are more important than thespecific recommendations, which willcertainly change as our understanding ofsepsis improves. For example, althoughwhich variables most accurately reflectthe effects of therapy in septic patientsmay be uncertain, it should be apparentthat therapeutic efficacy should be as-sessed by monitoring a combination ofvariables. Similarly, although specific endpoints may be arguable, the idea thatclinicians should define specific goals andend points, titrate therapies to those end

points, and evaluate the results of theirinterventions on an ongoing basis re-mains a fundamental principle.

An important recent trial supportsearly goal-directed therapy in sepsis. Atotal of 263 patients with severe sepsis orseptic shock were randomized to receiveeither 6 hrs of early goal-directed therapyor standard therapy in the emergency de-partment before admission to the inten-sive care unit (7). The resuscitation strat-egy involved rapid administration ofintravenous fluids targeted to a centralvenous pressure of 8–12 mm Hg, correc-tion of anemia to a hematocrit �30%,vasopressor agents as necessary to main-tain mean arterial pressure �65 mm Hg,and administration of dobutamine in anattempt to achieve a central venous oxy-gen saturation �70%. Patients assignedto early goal-directed therapy had a sig-nificantly higher central venous oxygensaturation, lower lactate concentrationand base deficit, and significantly lowerAcute Physiology and Chronic HealthEvaluation II scores, indicating less se-vere organ dysfunction (7). More impor-tantly, in-hospital mortality rate was sig-nificantly decreased in the groupassigned to early goal-directed therapy,from 46.5% to 30.5% (p � .009) (7). Thisstudy provides strong support for the no-tion that therapy for sepsis should beinitiated as early as possible and shouldbe directed toward clearly defined goals.

Indexes of Global Perfusion

Bedside clinical assessment provides agood indication of global perfusion. Sep-tic shock is by definition characterized byhypotension, which generally refers to amean arterial pressure below 60–70 mmHg in adults. Mean arterial pressure ispreferable to systolic pressure because ofits closer relationship to the autoregula-tory limits of organ blood flow (3). Ininterpreting any given level of arterialpressure, however, the chronic level ofpressure must be considered. Hypoten-sion is usually accompanied by tachycar-dia.

Indications of decreased perfusion in-clude oliguria, clouded sensorium, de-layed capillary refill, and cool skin. Somecaution is necessary in interpreting thesesigns in septic patients, however, sinceorgan dysfunction can occur in the ab-sence of global hypoperfusion.

In most forms of shock, elevatedblood lactate concentrations reflect an-aerobic metabolism due to hypoperfu-

sion, but the interpretation of bloodlactate concentrations in septic patientsis not always straightforward. Somestudies in animal models of sepsis havefound normal high-energy phosphateconcentrations (8) but others have not(9); the differences may relate to theseverity of the septic model, with moresevere sepsis being associated with de-pletion of adenosine triphosphate de-spite maintenance of systemic oxygendelivery and tissue oxygenation. A num-ber of studies have indicated that in-creasing either global (10) or regional(11) oxygen delivery fails to alter ele-vated lactate concentrations in patientswith sepsis. A number of studies havesuggested that elevated lactate may re-sult from cellular metabolic alterationsrather than from global hypoperfusionin sepsis (12, 13). Accelerated glycolysiswith high pyruvate production (14), in-hibited pyruvate dehydrogenase, anddecreased clearance by the liver maycontribute to elevated lactate concen-trations. Nonetheless, although lactateconcentrations should not be consid-ered to represent tissue hypoxia in thestrict sense, the prognostic value of el-evations of blood lactate has been wellestablished in septic shock patients(15–17). The trend of lactate concentra-tions is a better indicator than a singlevalue (15, 16). It is also of interest tonote that blood lactate concentrationsare a better prognostic indicator thanoxygen-derived variables (calculated ox-ygen delivery and consumption) (18).

Mixed venous oxyhemoglobin satu-ration (SvO2) can be measured in pa-tients with a right heart catheter inplace, either intermittently by samplingblood from the pulmonary artery portor continuously using a fiberopticoximeter. SvO2 is dependent on cardiacoutput, oxygen demand, hemoglobin,and oxygen saturation. SvO2 reflects thebalance between oxygen delivery andconsumption and can decrease whenoxygen delivery falls in relation to theoxygen requirements of the tissues. Thenormal SvO2 value is 70 –75% in criti-cally ill patients, but SvO2 can be ele-vated in septic patients due to maldis-tribution of blood flow, and so valuesmust be interpreted in the context ofthe wider hemodynamic picture. None-theless, If SvO2 remains low despiteachievement of other end points of re-suscitation, this suggests increased ox-ygen extraction and therefore poten-tially incomplete resuscitation. A


recent study showed that monitoring ofcentral venous oxygen saturation(ScvO2) can be a valuable guide to earlyresuscitation (7).

Indexes of Regional Perfusion

Adequacy of regional perfusion is usu-ally assessed clinically by evaluating in-dexes of organ function, such as myocar-dial ischemia, decreased urine output,increased blood urea nitrogen and creat-inine, an abnormal sensorium, increasedserum concentrations of transaminases,lactic dehydrogenase, and bilirubin, andprolonged clotting tests (3). Methods ofmeasuring regional perfusion more di-rectly have been under investigation,with a focus on the splanchnic circula-tion, for several reasons. First, the hepa-tosplanchnic circulation may be compro-mised early in acute circulatory failure.Measurements of oxygen saturation inthe hepatic vein have revealed oxygen de-saturation in a subset of septic patients,suggesting that hepatosplanchnic oxygensupply may be inadequate in some pa-tients, even when more global variablesappear adequate (19). Second, the gut(especially the stomach) may be accessi-ble to monitoring systems. Third, thecountercurrent flow in the gut microcir-culation increases the risk of mucosalhypoxia. Finally, the gut may have ahigher critical oxygen delivery thresholdthan other organs (20), and gut ischemiaincreases intestinal permeability.

Gastric tonometry is a method to as-sess regional perfusion in the gut thatemploys a balloon in the stomach to mea-sure intramucosal PCO2. Gastric mucosalPCO2 is influenced directly by systemicarterial PCO2, however, and so use of gas-tric-arterial PCO2 difference has been pro-posed as the primary tonometric variableof interest, although even this measure isnot a simple measure of gastric mucosalhypoxia (21). Despite its complexity,tonometry is a reasonably good predictorfor the ultimate outcome of critically illpatients (22–26). Its utility to guide ther-apy in patients with sepsis and septicshock, however, has not been proven.More recently, capnography in the sub-lingual area, a technique that is less in-vasive and easier to use, has been shownto yield tissue PCO2 measurements thatcorrelate with those obtained by gastrictonometry (27).

FLUID RESUSCITATION INSEPSIS

Goals and Monitoring of FluidResuscitation

Septic shock is characterized by de-creased effective capillary perfusion re-sulting from both global and distributiveabnormalities of systemic and microcir-culatory blood flow. An important factorcontributing to the impairment in tissueperfusion is hypovolemia (13, 28 –30).The initial phases of experimental andclinical septic shock present as a low car-diac output syndrome with low fillingpressures and evolve to a hyperdynamicstate only after volume repletion (13, 28).Increased blood and plasma volumes areassociated with increased cardiac outputand enhanced survival from septic shock(31). Failure to appreciate the degree ofunderlying hypovolemia may result in alow cardiac output.

Large fluid deficits exist in patientswith septic shock. Up to 6–10 L of crys-talloid solutions or 2 to 4 L of colloidsolutions may be required for initial re-suscitation in the first 24 hrs (7, 32).Volume repletion in patients with septicshock produces significant improvementin cardiac function and systemic oxygendelivery, thereby enhancing tissue perfu-sion and reversing anaerobic metabolism(33). Despite sepsis-induced myocardialdepression, cardiac index will usually im-prove by 25–40% during fluid resuscita-tion (34). In approximately 50% of septicpatients who initially present with hypo-tension, fluids alone will reverse hypoten-sion and restore hemodynamic stability(35).

In sepsis, increases in interstitial fluidvolume may already exist and venous ca-pacitance changes play a major role incontributing to hypovolemia, and so re-pleting the interstitial space, which mayhave a role in hemorrhagic shock, doesnot appear to be as important. Intravas-cular volume can be repleted through theuse of packed red cells, crystalloid solu-tions, and colloid solutions.

The goal of fluid resuscitation in sep-tic shock is restoration of tissue perfusionand normalization of oxidative metabo-lism. Increasing cardiac output and oxy-gen delivery is dependent on expansion ofblood and plasma volume. Fluid infusionis best initiated with predetermined bo-luses (250–500 mL every 15 mins) ti-trated to clinical end points of heart rate,urine output, and blood pressure. Pa-

tients who do not respond rapidly to ini-tial fluid boluses or those with poor phys-iologic reserve should be considered forinvasive hemodynamic monitoring. Fill-ing pressures should be increased to alevel associated with maximal increasesin cardiac output. In most patients withseptic shock, cardiac output will be opti-mized at pulmonary artery occlusionpressures between 12 and 15 mm Hg(34). Increases above this range usuallydo not significantly enhance end-diastolicvolume or stroke volume and increasethe risk for developing pulmonary edema.If only central venous pressure is avail-able, levels of 8–12 mm Hg should betargeted (7).

In patients requiring mechanical venti-lation, changes in arterial pressure duringmechanical breaths may also serve as auseful indicator of underlying hypovolemia(36–38). The effects of increased pleuralpressure on ventricular filling are accentu-ated in preload-deficient states, resulting incyclic decreases in systolic arterial pressureand widening of the arterial pulse pressure.When these changes are present, they ap-pear to be predictive of fluid responsivenessin septic patients with circulatory failure(37, 38). These measurements require thatthe patient have minimal or absent sponta-neous respiratory efforts, which may neces-sitate the use of neuromuscular blockingagents (37, 38).

Far more important than the specificmethod of monitoring is the use of thatmethod in a dynamic fashion. Evaluationof the response to fluid infusion is muchmore useful than one measurement at asingle time point. This is particularly truein unstable patients, since cardiac andvascular compliance may change overtime.

Resuscitation should be titrated to endpoints of oxygen metabolism and organfunction. Associations have been ob-served between improved survival and in-creased levels of central venous oxygensaturation, systemic oxygen delivery, re-versal of lactic acidosis, and increases ingastric intramucosal pH (7, 18, 24, 39).However, the specific choice of endpoints remains controversial.

Fluid Resuscitation Therapies

Crystalloids. The crystalloid solutionsused most commonly for resuscitationare 0.9% sodium chloride (normal saline)and lactated Ringer’s solution. The lac-tate content of Ringer’s solution is rap-idly metabolized during resuscitation and


does not significantly affect the use ofarterial lactate concentration as a markerof tissue hypoperfusion (40).

The volume of distribution of normalsaline and Ringer’s lactate is the extracel-lular compartment. Under ideal condi-tions, approximately 25% of the infusedamount will remain intravascular whilethe rest is distributed to the extravascularspace. Clinically, 100–200 mL of intra-vascular volume expansion can be ex-pected after the infusion of 1 L of isotoniccrystalloids (41, 42). Resuscitation fromseptic shock frequently requires crystal-loid volumes ranging from 6 to 10 Lduring the initial 24-hr period, which re-sults in significant hemodilution ofplasma proteins and decreases in colloidosmotic pressure.

Hypertonic saline solutions have a so-dium content ranging from 400 to 2400mOsm/L. Hypertonic solutions have po-tentially advantageous physiologic effectsincluding improved cardiac contractilityand precapillary vasodilation (43). Theprimary risk when using these fluids isiatrogenically induced hypertonic statesdue to sodium load. Experience with hy-pertonic solutions in septic shock is lim-ited.

Colloids. Many different colloidal solu-tions are available, including plasma pro-tein fraction, albumin, gelatins, dextrans,and hydroxyethyl starch. The principalsolutions used in clinical resuscitationare albumin and hydroxyethyl starch.

Albumin is a naturally occurringplasma protein that accounts for approx-imately 80% of the plasma colloid os-motic pressure in normal subjects. Hu-man serum albumin is available in theUnited States in 5% and 25% solutions;other concentrations are available in Eu-rope. The 5% solution, rather than the25% solution, should be used for initialresuscitation. After 1 L of 5% albumin,plasma volume expansion ranges from500 to 1000 mL (41, 42). Mobilization ofextravascular volume is required for ef-fective increases in intravascular volumewhen using 25% albumin. If fluid is suc-cessfully mobilized from the interstitialspace, a 100-mL aliquot can produce in-creases of 400–500 mL in the intravascu-lar volume 1 hr after infusion (42). In thesetting of increased vascular permeabilitysuch as septic shock, significantly smalleramounts of fluid may be mobilized.

The recently completed Saline versusAlbumin Fluid Evaluation (SAFE) trialrandomized 6,997 critically ill patients toresuscitation with albumin or saline.

There was no difference in 28-day mor-tality rate (20.9% with albumin vs. 21.1%with saline) (44).

Hydroxyethyl starch is a synthetic col-loid formed from hydroxyethyl-substi-tuted branched-chain amylopectin. It isavailable in the United States a 6% solu-tion of normal saline with a colloid os-motic pressure of approximately 30mOsm/L (45). One liter of hydroxyethylstarch solution expands plasma volumeby 700 mL to 1 L with as much as 40% ofmaximum volume expansion persistingfor 24 hrs (41)

There have been reports suggestingthat hydroxyethyl starch molecules mayadversely affect renal function by causingtubular injury (46, 47). In patients withsepsis, resuscitation with hydroxyethylstarch solution, as compared with gela-tin, resulted in significantly higher se-rum creatinine concentrations withoutassociated differences in the need for re-nal replacement (47). Studies in othergroups of patients have not observed dif-ferences in renal function when hydroxy-ethyl starch solution was compared withother fluids (48–51). Importantly, thesestudies were done with a variety of hy-droxyethyl starch solutions, each withdifferent physical properties that mayhave different effects on renal tubularcells. Additional investigations are re-quired to reconcile these divergent obser-vations.

Hydroxyethyl starch can cause dose-dependent decreases in factor VIII activityand prolongation of partial thromboplas-tin time. Although these changes appearto be primarily dilutional, there havebeen reports of increased bleeding, pri-marily in patients undergoing cardiacsurgery (52). However, only minor clot-ting abnormalities and no increased inci-dence of bleeding have been noted inpatients with hypovolemic and septicshock (52).

Efficacy

Patients with septic shock can be suc-cessfully resuscitated with either crystal-loid or colloids. Increases in cardiac out-put and systemic oxygen delivery areproportional to the expansion of intravas-cular volume achieved. When crystalloidsand colloids are titrated to the same levelof filling pressure, they are equally effec-tive in restoring tissue perfusion (32).Resuscitation with crystalloid solutionswill require two to four times more vol-ume than colloids and may require

slightly longer periods to achieve desiredhemodynamic end points. Colloid solu-tions are much more expensive than crys-talloid solutions. Five percent albuminand 6% hydroxyethyl starch solution areequivalent with respect to the amount offluid required during resuscitation.

Complications

The major complications of fluid re-suscitation are pulmonary and systemicedema. These complications are relatedto three principal factors: a) increases inhydrostatic pressures; b) decreases in col-loid osmotic pressure; and c) increases inmicrovascular permeability associatedwith septic shock. The controversy con-cerning crystalloid and colloid resuscita-tion revolves around the importance ofmaintaining plasma colloid osmotic pres-sure. Large volume crystalloid resuscita-tion results in significant decreases inplasma colloid osmotic pressure, whereasplasma colloid osmotic pressure is main-tained with colloid infusion (32). In ex-perimental studies, decreases in plasmacolloid osmotic pressure increase ex-travascular fluid flux in the lungs andlower the level of hydrostatic pressureassociated with lung water accumulation(53, 54). Some, but not all, clinical re-ports have observed a correlation be-tween decreases in the colloid osmoticpressure-pulmonary artery occlusionpressure gradient and the presence ofpulmonary edema (55–57). Several clini-cal studies have randomized subjects tocrystalloid or colloid infusion and exam-ined the development of pulmonaryedema with mixed results, demonstratingeither no differences between solutionsor an increased incidence of pulmonaryedema with crystalloids (32, 58, 59). Ex-perimental reports in septic models dem-onstrate no increase in extravascularlung water when hydrostatic pressuresare maintained at low levels, indicatingthat in sepsis the primary determinant ofextravascular fluid flux appears to be mi-crovascular pressure rather than colloidosmotic pressure (60). Together, thesedata suggest that when lower filling pres-sures are maintained there is no signifi-cant difference in the development of pul-monary edema with crystalloids orcolloids. However, if higher filling pres-sures are required to optimize cardiacperformance in patients with ventriculardysfunction, colloids may mitigateagainst extravascular fluid flux (32).


The acute respiratory distress syn-drome occurs in 30–60% of patients withseptic shock. Of concern has been thepossibility that in the setting of increasedmicrovascular permeability, colloid parti-cles could migrate into the interstitiumwhere they would favor fluid retention inthe lung and worsen pulmonary edema. Anumber of studies, including a variety ofmodels of increased microvascular per-meability, as well as clinical studies inpatients with septic shock and the acuterespiratory distress syndrome, have notfound evidence of increased lung water orcompromised lung function with colloids(32, 61–63).

Systemic edema is a frequent compli-cation of fluid resuscitation. The relativeroles of increased microvascular perme-ability, increases in hydrostatic pressure,and decreases in plasma colloid osmoticpressure in the development of this com-plication during sepsis are unclear. Tis-sue edema may reduce tissue oxygen ten-sions by increasing the distance fordiffusion of oxygen into cells. During ex-perimental peritonitis, crystalloid ther-apy was associated with increased endo-thelial cell swelling and decreasedsystemic capillary cross-sectional areawhen compared with colloid infusion(64). In contrast, other studies compar-ing the impact of large volume crystalloidinfusion on skeletal muscle and intestinaloxygen metabolism have observed no im-pairment of oxidative metabolism despitesignificant edema formation (60, 65). Theintegrity of the gastrointestinal mucosaas a barrier to bacterial translocation alsodoes not appear to be affected by de-creases in colloid osmotic pressure andthe development of tissue edema follow-ing crystalloid resuscitation. A compari-son of crystalloid and colloid resuscita-tion in thermal injury found that theextent of resuscitation and not the choiceof fluids was the major determinant ofbacterial translocation (66).

Finally, there have been multiplemeta-analyses of the clinical studies com-paring crystalloids with colloids, whichhave examined the effect of resuscitationwith these solutions on mortality rate.The results have been conflicting, withsome of the reports suggesting differ-ences in mortality rate favoring crystal-loids, whereas others have shown no dif-ferences (67– 69). These differencesreflect the poor quality of many of theunderlying studies, the heterogeneity inpatient populations, and the fact that

none of the clinical studies was ever de-signed with mortality as an end point.

Transfusion Therapy

The optimal hemoglobin and hemato-crit for patients with septic shock is un-certain. This is a major clinical issuesince hemoglobin concentrations usuallyrange between 8 and 10 g/dL in patientswith septic shock. The decrease in hemo-globin is related to several factors includ-ing ineffective erythropoiesis and he-modilution. Decreases in hemoglobin inthe range of 1–3 g/dL can be expectedduring resuscitation of septic shock witheither crystalloids or colloids (32).

In most patients, this degree of ane-mia is well tolerated because the associ-ated decrease in blood viscosity decreasesafterload and increases venous returnthereby increasing stroke volume andcardiac output. The decrease in blood vis-cosity may also compensate for otherrheologic changes that occur in patientswith septic shock and may enhance mi-crovascular blood flow. However, severalfactors may affect the ability of the pa-tient to tolerate the decrease in hemato-crit and should be considered. Cardiacdysfunction will limit the increase in car-diac output in response to decreased vis-cosity and may result in inadequate levelsof systemic oxygen delivery. In markedlyhypermetabolic states, the increase incardiac output may not be adequate tocompensate for the decrease in arterialoxygen content, potentially compromis-ing systemic oxygen metabolism. The in-ability to extract oxygen, related either toanatomical abnormalities such as in cor-onary artery diseases or physiologic ab-normalities in sepsis, may result ingreater dependence on oxygen content tomaintain oxidative metabolism (70, 71).

To date, studies examining the effectsof transfusing critically ill patients withhemoglobin concentrations in the rangeof 8–10 g/dL have not demonstrated anyconsistent benefit in tissue perfusion.The majority of trials have demonstratedno significant increase in systemic oxy-gen consumption when the major effectof transfusion therapy is to increase oxy-gen content (72–74). Other studies sug-gest that increasing oxygen content bytransfusion therapy is not as effective inrestoring splanchnic perfusion as it is inincreasing cardiac output (75). Indeed,the transfusion of aged, more rigid, redcells has been associated with decreasedgastric intramucosal pH and may accen-

tuate the rheologic abnormalities seen insepsis (76). Blood transfusion may alsohave immunosuppressive effects (77).Moreover, a study randomizing criticallyill patients to transfusion thresholds of 7or 10 g/dL failed to demonstrate any dif-ferences in clinically significant out-comes (78).

Accordingly, the optimal hemoglobinfor patients with hemodynamically signif-icant sepsis has not been defined. Mostpatients will tolerate hemoglobin concen-trations in the range of 8–10 g/dL. Somepatients, however, may have clinical vari-ables that suggest a need for increasedoxygen delivery, including excessivetachycardia, cardiac dysfunction, signifi-cant underlying cardiac or pulmonarydisease, severe mixed venous oxygen de-saturation, or failure to clear lactic aci-dosis. Patients with sepsis and hemody-namic instability tend to be in the secondcategory. Such patients were excludedfrom the randomized trials of transfusionthresholds and may benefit from higherhemoglobin concentrations. Although nodata exist to support transfusion to a pre-defined threshold, most experts recom-mend maintenance of hemoglobin con-centrations in the 8–10 g/dL range inpatients with sepsis and hemodynamicinstability.

Vasopressor Therapy

Goals and Monitoring of VasopressorTherapy. When fluid administration failsto restore an adequate arterial pressureand organ perfusion, therapy with vaso-pressor agents should be initiated (79).Vasopressor therapy may also be requiredtransiently to maintain perfusion in theface of life-threatening hypotension, evenwhen adequate cardiac filling pressureshave not yet been attained. Potentialagents include dopamine, norepineph-rine, phenylephrine, epinephrine, and va-sopressin.

Arterial pressure is the end point ofvasopressor therapy, and the restorationof adequate pressure is the criterion ofeffectiveness. Blood pressure, however,does not always equate to blood flow, andthe precise level of mean arterial pressureto aim for is not necessarily the same inall patients. Animal studies suggest thatbelow a mean arterial pressure of 60 mmHg, autoregulation in the coronary, re-nal, and central nervous system vascularbeds is compromised. When organ auto-regulation is lost, organ flow becomeslinearly dependent on pressure (80, 81).


Thus, maintenance of a mean arterialpressure of 60 mm Hg is usually requiredto maintain and optimize flow (82–84).Loss of autoregulation can occur at dif-ferent levels in different organs, however,and thus some patients may requirehigher blood pressures to maintain ade-quate perfusion. In addition, the degreeto which autoregulation is intact in septicpatients is uncertain. It is important tosupplement end points such as bloodpressure with assessment of regional andglobal perfusion by a combination of themethods outlined previously.

Particular attention should be paid tocertain peripheral circulations during va-sopressor infusion. Vasopressor therapyto augment renal perfusion pressure hasbeen shown to increase urine outputand/or creatinine clearance in a numberof open-label clinical series; the targetedmean blood pressure varied but was ashigh as 75 mm Hg (85–95). However,significant improvements in renal func-tion with an increase in renal perfusionpressure have not been demonstrated inprospective, randomized studies. A recentstudy compared vasopressor therapy tar-geted to 65, 75, and 85 mm Hg in patientswith septic shock and found no signifi-cant effect on systemic oxygen metabo-lism, skin microcirculatory blood flow,urine output, or splanchnic perfusion(96). Vasopressors should be titrated tothe minimum level required to optimizeurine flow; in some patients this can beachieved with a mean arterial pressure of60 or 65 mm Hg.

The gastrointestinal tract, particularlyperfusion of the splanchnic bed and theintegrity of the gut mucosa, occupies akey position in the pathogenesis of mul-tiple organ failure in sepsis. The effects ofvasopressor agents on splanchnic circu-lation may play a role in their selectionfor a given patient.

Whether a potent vasopressor also haspositive inotropic effects is of clinical im-portance in patients with low cardiac out-put (97). If vasopressor infusion impairsstroke volume, addition of an inotropicagent such as dobutamine should be con-sidered (91).

Individual Vasopressor Agents

Dopamine. Dopamine is the naturalprecursor of norepinephrine and epi-nephrine. Dopamine possesses severaldistinct dose-dependent pharmacologiceffects. At doses �5 �g·kg�1·min�1, thepredominant effect of dopamine is to

stimulate dopaminergic DA1 and DA2 re-ceptors to cause vasodilation in the renal,mesenteric, and coronary beds. Infusionof low doses of dopamine increases glo-merular filtration rate, renal blood flow,and sodium excretion (98, 99). At doses of5–10 �g·kg�1·min�1, �1-adrenergic ef-fects predominate, increasing cardiaccontractility and heart rate. Dopaminecauses the release of norepinephrinefrom nerve terminals, which contributesto its effects on the heart. At doses �10�g·kg�1·min�1, �1-adrenergic effectspredominate, leading to arterial vasocon-striction and an increase in blood pres-sure. It should be recognized, however,that there is a great deal of overlap inthese effects, particularly in critically illpatients.

The hemodynamic effects of dopaminein patients with septic shock have beenreported in a number of open labeledtrials. Dopamine has been shown to pro-duce a median increase in mean arterialpressure of 24% in patients who re-mained hypotensive after optimal fluidresuscitation (29, 100–111). Dopamineincreases mean arterial pressure and car-diac output, primarily due to an increasein stroke volume, and to a lesser extent toan increase in heart rate (29, 100–111).The median dose of dopamine required torestore blood pressure was 15�g·kg�1·min�1. In most studies centralvenous, pulmonary artery, and pulmo-nary occlusion pressures, systemic vascu-lar resistance index, and pulmonary ar-tery resistance index were unchanged. Inpatients with elevated pulmonary arteryocclusion pressures, dopamine may fur-ther increase occlusion pressure by in-creasing venous return. Patients receiv-ing dopamine infusion rates �20�g·kg�1·min�1 did show increases inright heart pressures as well as heart rate.Dopamine has been shown to improveright ventricular contractility in patientswith underlying right ventricular failure(112).

Dopamine increases pulmonary shuntfraction, probably due to the increase incardiac output, which can reopen vesselsin poorly ventilated areas of the lung,(104, 110). PaO2, however, remains rela-tively constant, which may be due to he-modynamic improvement and/or an in-creased mixed venous oxygen saturation(104, 105, 110).

Dopamine has been shown to increaseoxygen delivery, but its effects on calcu-lated or measured oxygen consumptionhave been mixed (100–102). Oxygen ex-

traction ratio typically decreases, sug-gesting no improvement in tissue oxy-genation (100, 102). This may be due to afailure to improve microcirculatory flowin vital organs or lack of a meaningfultissue oxygen debt in some patients(102).

The effect of dopamine on splanchnicperfusion as assessed by gastric tonomet-ric variables has also been mixed. In-creases in splanchnic blood flow havebeen reported but have not always beenassociated with increases in splanchnicoxygen consumption or effects on gastricintramucosal pH (100, 103, 113, 114).One pilot study reported that despite anincrease in both systemic oxygen deliveryand systemic oxygen consumption withdopamine, gastric intramucosal pH wasreduced (101). The authors speculatedthat dopamine might have redistributedblood flow within the gut, reducing mu-cosal blood flow and increasing mucosaloxygen debt. Decreased gastric mucosalblood flow was reported with dopamine inanother study, but gastric PCO2, gastric-arterial PCO2 difference, and calculatedintramucosal pH were unchanged (115).

In laboratory animals and healthy vol-unteers, low doses of dopamine increaserenal blood flow and glomerular filtrationrate and inhibit proximal-tubular resorp-tion of sodium, which result in natriure-sis (116). With this physiologic rationale,low-dose dopamine is commonly admin-istered to critically ill patients in the be-lief that it reduces the risk of renal failureby increasing renal blood flow. This issuehas now been addressed by an adequatelypowered randomized clinical trial, whichenrolled 328 critically ill patients withearly renal dysfunction (urine output�0.5 mL·kg�1·hr�1 over 4 hrs, creatine�150 �mol/L or an increase of �80�mol/L over 24 hrs) (117). Patients wererandomized to low (“renal”) dose dopa-mine (2 �g·kg�1·min�1) or placebo, andthe primary end point was peak serumcreatinine. No difference was found ineither the primary outcome (peak serumcreatinine 245 vs. 249 �mol/L, p � .92),other renal outcomes (increase in creat-inine, need for renal replacement), urineoutput (increased in both groups, per-haps due to furosemide administration),time to recovery of normal renal func-tion, or secondary outcomes (survival toeither intensive care unit or hospital dis-charge, intensive care unit stay, hospitalstay, arrhythmias) (117). Thus, the avail-able data do not support administration


of low doses of dopamine solely to main-tain renal function.

In summary, dopamine appears to bevery effective in increasing mean arterialpressure in patients who remain hypoten-sive after optimal volume expansion.Since mean arterial pressure increasesprimarily as a result of increasing cardiacindex, dopamine may be particularly use-ful in patients who are hypotensive withcompromised cardiac function or cardiacreserve. The major undesirable effects ofdopamine are tachycardia and arrhyth-mogenesis, both of which are moreprominent than with other vasopressoragents. Other side effects include in-creased pulmonary artery occlusion pres-sure, increased pulmonary shunt, and thepotential for decreased prolactin releaseand consequent immunosuppression(118).

Norepinephrine. Norepinephrine is apotent �-adrenergic agonist with lesspronounced �-adrenergic agonist effects.Norepinephrine usually causes a clini-cally significant increase in mean arterialpressure attributable to its vasoconstric-tive effects, with little change in heartrate or cardiac output, leading to in-creased systemic vascular resistance.Norepinephrine generally increases car-diac output by 10–20% and increasesstroke volume by 10–15% (85, 86, 89, 91,93, 119). Clinical studies have reportedeither no change (85, 86, 89, 93, 112) ormodest increases (1–3 mm Hg) (92, 94,101, 103, 106) in pulmonary artery occlu-sion pressure. Mean pulmonary arterialpressure is either unchanged (86, 89, 91,94, 106) or increased slightly (93, 94, 106,112). The combination of norepinephrinewith dobutamine may be attractive in thesetting of sepsis. In one study, addition ofnorepinephrine in patients with septicshock unresponsive to dobutamine sig-nificantly improved both mean arterialpressure and cardiac output (120).

Norepinephrine is more potent thandopamine and may be more effective atreversing hypotension in septic shock pa-tients. In open labeled trials, norepineph-rine has been shown to increase meanarterial pressure in patients who re-mained hypotensive after fluid resuscita-tion and dopamine (86, 89, 91, 93, 94,103, 106, 112, 121). Reported doses haveranged from 0.01 to 3.3 �g·kg�1·min�1

(91, 93). Thus, large doses of the drugmay be required in some patients withseptic shock, possibly due to �-receptordown-regulation in sepsis (122).

In the only randomized trial compar-

ing vasopressor agents, 32 volume-resuscitated patients with hyperdynamicsepsis syndrome were prospectively ran-domized to receive either dopamine or nor-epinephrine to achieve and maintain nor-mal hemodynamic and oxygen transportparameters for �6 hrs (106). Dopamineadministration (10–25 �g·kg�1·min�1) re-sulted in successful treatment in only 31%of patients whereas norepinephrine admin-istration (1.5 1.2 �g·kg�1·min�1) wassuccessful in 93% (p � .001). Of the 11patients who did not respond to dopamine,ten responded when norepinephrine wasadded (106).

In patients with hypotension and hy-povolemia, that is, during hemorrhagicor hypovolemic shock, the vasoconstric-tive effects of norepinephrine can havedetrimental effects on renal hemodynam-ics, with the potential for renal ischemia(123–125). The situation may differ inhyperdynamic septic shock (92). Norepi-nephrine has a greater effect on efferentthan afferent renal arteriolar resistanceand increases the filtration fraction. Sev-eral studies have shown increases inurine output, creatinine clearance, andosmolar clearance in patients with septicshock treated with norepinephrine aloneor norepinephrine added to dobutamine(29, 85, 88, 92, 94, 101, 106, 112). Thesestudies support the hypothesis that influid-resuscitated patients with septicshock, norepinephrine may optimize re-nal blood flow and renal vascular resis-tance (85, 92, 94).

Although early studies in patients withonly mildly elevated serum lactate con-centrations showed no significantchanges over a relatively short period oftime (1–3 hrs) with norepinephrine, (89,101, 103, 112) in a later study in whichinitial lactate concentrations were ele-vated (4.8 1.6 mmol/L), a statisticallyand clinically significant decrease (2.9 0.8 mmol/L) was observed at the end ofthe 6-hr study period (106). The results ofthese studies suggest that the use of nor-epinephrine does not worsen and caneven improve tissue oxygenation of pa-tients with septic shock.

Results of studies of the effects of nor-epinephrine on splanchnic blood flow inpatients with septic shock have beenmixed. In one study, the effect of norepi-nephrine on splanchnic blood flow wasunpredictable (103), whereas anotherstudy showed that septic patients whoswitched from dobutamine to norepi-nephrine or from dobutamine and nor-epinephrine to norepinephrine alone had

a decrease in cardiac output and a paralleldecrease in splanchnic blood flow (100).In these studies, however, splanchnic ox-ygen consumption remained unchanged(100, 103, 126). One pilot study foundthat gastric mucosal pHi was significantlyincreased during a 3-hr treatment withnorepinephrine whereas it was signifi-cantly decreased during treatment withdopamine (101). A more recent studycompared the effects of norepinephrine,epinephrine, and dopamine in 20 patientswith septic shock (127). In the ten pa-tients with moderate shock, no differ-ences in splanchnic blood flow or gastric-arterial PCO2 difference were observed(127). In the ten with severe shock, car-diac index was higher and the effects ofnorepinephrine and dopamine were sim-ilar, but splanchnic blood flow was lowerdespite a higher cardiac index with epi-nephrine than with norepinephrine(127).

In summary, the clinical experiencewith norepinephrine in septic shock pa-tients strongly suggests that this drugcan successfully increase blood pressurewithout causing a deterioration in car-diac index and organ function (128). Usedin doses of 0.01–3 �g·kg�1·min�1, nor-epinephrine reliably improves hemody-namic variables in most patients withseptic shock. The effect of the drug onoxygen transport variables cannot be de-termined fully from the available data.However, other clinical variables of pe-ripheral perfusion, such as urine flow andlactate concentration, are significantlyimproved in most studies. Unfortunately,only one report was controlled (106), andwhether using norepinephrine in septicshock patients affects mortality rate ascompared with dopamine or epinephrinestill requires a prospective clinical trial.The available data do not support a det-rimental effect of norepinephrine, how-ever. In a recent multivariate analysis in-cluding 97 septic shock patients,mortality rate was favorably influenced bythe use of norepinephrine as part of thehemodynamic management; use of high-dose dopamine, epinephrine, or dobut-amine had no significant effect (129).When the use of norepinephrine is con-templated, it should be used early and notwithheld as a last resort (130).

Phenylephrine. Phenylephrine, a se-lective �-1 adrenergic agonist, has beenused by rapid intravenous administrationto treat supraventricular tachycardia bycausing a reflex vagal stimulation to theheart resulting from a rapid increase in


blood pressure. It is also used intrave-nously in anesthesia to increase bloodpressure. Its rapid onset, short duration,and primary vascular effects make it anattractive agent in the management ofhypotension associated with sepsis. How-ever, there are concerns about its poten-tial to reduce cardiac output and lowerheart rate in these patients.

Unfortunately, only a few studies haveevaluated the use of phenylephrine in hy-perdynamic sepsis. As such, guidelines onits clinical use are limited. One study innormotensive hyperdynamic septic pa-tients showed that short-term adminis-tration of phenylephrine at a dosage of 70�g/min increased mean arterial pressure,cardiac output, and stroke volume (131).In a dose-response study, phenylephrineadministered to normotensive hyperdy-namic septic patients in incrementaldoses of 0.5–8 �g·kg�1·min�1 increasedmean arterial pressure, systemic vascularresistance, and stroke index, whereas nochange was seen in cardiac index (132).Heart rate was slightly but significantlylower, with a decrease ranging from 3 to9 beats/min. This study found no statisti-cally significant changes in either oxygendelivery or consumption overall, but aclinically significant (�15%) increase inoxygen consumption was seen in eight often patients in at least one dosage.

Only one study has evaluated the ef-fects of phenylephrine in treating hypo-tension associated with sepsis (95). In asmall study of 13 patients with hyperdy-namic septic shock (baseline cardiac in-dex 3.3 L·min�1·m�2) receiving eitherlow-dose dopamine or dobutamine, whoremained hypotensive despite fluid ad-ministration (mean arterial pressure 57mm Hg), phenylephrine was begun at 0.5�g·kg�1·min�1 and was titrated to main-tain a mean arterial pressure �70 mmHg. Patients required phenylephrine foran average of 65 hrs, and the maximumdosage in each patient averaged 3.7�g·kg�1·min�1 (range 0.4 –9.1�g·kg�1·min�1). Phenylephrine resultedin an increase in mean arterial pressure,systemic vascular resistance, cardiac in-dex, and stroke index. There was nochange in heart rate. A significant in-crease in urine output without a changein serum creatinine was observed duringphenylephrine therapy.

The limited information available withphenylephrine suggests that this drugcan increase blood pressure modestly influid-resuscitated septic shock patients.In addition, phenylephrine therapy does

not impair cardiac or renal function.Phenylephrine may be a good choicewhen tachyarrhythmias limit therapywith other vasopressors. An increase inoxygen consumption and delivery mayoccur during therapy.

Epinephrine. In patients unresponsiveto volume expansion or other catechol-amine infusions, epinephrine can in-crease mean arterial pressure, primarilyby increasing cardiac index and strokevolume with more modest increases insystemic vascular resistance and heartrate (90, 133–135). The dose-response re-lationship is more predictable in somestudies (134) than others (90, 133). Inpatients with right ventricular failure,epinephrine increases right ventricularfunction by improving contractility(136). Epinephrine can increase oxygendelivery, but oxygen consumption may beincreased as well (133–137).

Epinephrine decreases splanchnicblood flow, with transient increases inarterial, splanchnic, and hepatic venouslactate concentrations, decreases in pHi,and increases in PCO2 gap (100, 121, 138).These effects may be due to a reduction insplanchnic oxygen delivery to a level thatimpairs nutrient blood flow and results ina reduction in global tissue oxygenation,(100, 121) and may potentially be re-versed by the concomitant administra-tion of dobutamine (121). Alternatively,CO2 production secondary to the thermo-genic effect of epinephrine may play arole. These studies have been limited bythe concurrent use of other cat-echolamines. Two more recent studies,however, found increased gastric muco-sal perfusion with epinephrine comparedwith norepinephrine alone, to an extentsimilar to that of norepinephrine in com-bination with dobutamine (139, 140). In arecent study of 20 patients with septicshock, dopamine was replaced by eithernorepinephrine or epinephrine. In tenpatients with severe shock (mean arterialpressure �65 mm Hg despite high-dosedopamine), epinephrine increased globaloxygen delivery and consumption butcaused a lower absolute and fractionalsplanchnic blood flow and lower indocya-nine green clearance, thus validating theadverse effects of epinephrine alone onthe splanchnic circulation (127).

Epinephrine administration has beenassociated with increases in systemic andregional lactate concentrations (121, 133,137). Despite respiratory compensationand decreased arterial PCO2, the increasein plasma lactate was associated with de-

creases in arterial pH and base excess(137). The monitoring periods wereshort, and so it is unclear if these in-creases are transient; in the one longerstudy, arterial lactate and pHi returned tonormal values within 24 hrs (121). Otheradverse effects of epinephrine include in-creases in heart rate, but electrocardio-graphic changes indicating ischemia orarrhythmias have not been reported inseptic patients (133, 134). Epinephrinehas had minimal effects on pulmonaryartery pressures and pulmonary vascularresistance in sepsis (133, 134).

In summary, epinephrine clearly in-creases blood pressure in patients unre-sponsive to traditional agents. However,because of its effects on gastric blood flowand its propensity to increase lactate con-centrations, its use should be limited topatients who fail to respond to traditionaltherapies for increasing or maintainingblood pressure.

Corticosteroids. Corticosteroids exertimportant actions on various elements ofthe cardiovascular system including thecapillaries, the arterioles, and the myo-cardium. Topical glucocorticoids con-strict the dermal vessels, provokingblanching (141), although the mecha-nisms of this vasoconstriction remainpoorly understood. Corticosteroids mayup-regulate the sympathetic nervous sys-tem and the renin-angiotensin system(142, 143) and also enhance vascular re-sponses to norepinephrine and angioten-sin II, possibly through stimulation of thephosphoinositide signaling system insmooth muscle cells (144). Glucocorti-coids also inhibit nitric oxide productionby inducible nitric oxide synthase (145).Corticosteroids may potentiate catechol-amine activity by several mechanisms: in-creasing phenylethanolamine N-methyl-transferase activity and epinephrinesynthesis (146), inhibiting catecholaminereuptake in neuromuscular junctions anddecreasing their metabolism (147), in-creasing binding capacity and affinity of�-adrenergic receptors in arterial smoothmuscle cells (148), and potentiating re-ceptor G coupling and catecholamine-induced cyclic adenosine monophosphatesynthesis (149). Corticosteroids also in-crease angiotensin II type I receptor ex-pression in vascular smooth muscles(150) and significantly enhance centralpressor effects of exogenous angiotensinII (151).

Numerous studies in various animalmodels, in healthy volunteers challengedwith lipopolysaccharide, and in patients


consistently show that corticosteroids en-hance vascular responsiveness to vasoac-tive agents. In a rodent endotoxemiamodel, pretreatment with dexametha-sone prevented endotoxin-induced vascu-lar hyporesponsiveness to norepineph-rine (152), probably by inhibitingextracellular release of lipocortin-1 (153).In a rodent model of hypotensive andhypokinetic septic shock, dexamethasoneadministration resulted in a complete re-versal of hypotension, improvement inaortic blood flow, and reduced plasmalactate and nitrite/nitrate concentrationswithout affecting myocardial �-adrener-gic receptor numbers or myocardial cy-clic adenosine monophosphate, suggest-ing an effect on inducible nitric oxidesynthase rather than on adrenergic re-ceptor sensitivity (154). In healthy volun-teers, the profound reduction in venouscontractile response to norepinephrineinduced by local instillation of endotoxinwas completely prevented with pretreat-ment with 100 mg of oral hydrocortisone(155).

In another experiment, hydrocorti-sone given before or concurrent with anintravenous endotoxin challenge in 23healthy subjects prevented the decreasesin blood pressure and increases in heartrate and circulating epinephrine concen-trations (156). In nine patients with sep-tic shock, the relationship between thecortisol response to corticotropin (ACTH;defined by an increment in plasma corti-sol concentrations of less than 9 �g/dL(250 nmol/L) after an intravenous bolusof 250 �g of ACTH) and pressor responseto norepinephrine was investigated; fiveof the nine had such an impaired re-sponse (157). These five patients had aprofound decrease in pressor response toincremental dose of norepinephrine (dif-ference of 7 mm Hg at a norepinephrineinfusion rate of 0.05 �g·kg�1·min�1 and20 mm Hg at a rate of 1.5 �g·kg�1·min�1,p � .028) when compared with the otherfour. In addition, the maximal increase inmean arterial pressure during norepi-nephrine infusion correlated positivelywith the maximal increment in plasmacortisol concentrations after cortico-tropin (r � .783, p � .013). In the pa-tients with a cortisol response to ACTH�9 �g/dL, a single intravenous bolus of50 mg of hydrocortisone normalized thepressor response to norepinephrine. An-other study investigated the effects of asingle intravenous bolus of 50 mg of hy-drocortisone on phenylephrine-mean ar-terial pressure response curves in 12 pa-

tients with septic shock and 12 healthyvolunteers (158). Septic patients had de-creased maximum responses to phenyl-ephrine compared with healthy volun-teers, an effect that was mostly reversedby hydrocortisone. In this experiment,the effects of hydrocortisone did not cor-relate with circulating catecholaminesconcentrations, plasma renin activity, orcyclic guanosine monophosphate con-centrations.

Prolonged treatment (�5 days) withintravenous hydrocortisone at stressdoses (around 300 mg daily) increasesmean systemic arterial pressure and sys-temic vascular resistance with no signif-icant change in pulmonary hemodynam-ics and cardiac index. In three phase II(159–161) and one phase III trial (162) ofpatients with vasopressor-dependent sep-tic shock, prolonged treatment with a lowdose of corticosteroids was associatedwith a significant reduction in the dura-tion of shock.

In patients with septic shock, the ef-fects of corticosteroids on systemic andpulmonary hemodynamics vary accord-ing to concomitant vasopressor therapy.In septic shock not treated by vasocon-strictors, intravenous administration of50 mg of hydrocortisone had little effecton systemic blood pressure (157, 158). Inone randomized, placebo-controlled,double-blind trial, the hemodynamic ef-fects of 100 mg of hydrocortisone every 8hrs for 5 days were investigated in 41septic shock patients (159). In this study,mean arterial pressure increased in thehydrocortisone group (�10% at peak ef-fects) and decreased (�7% at peak ef-fects) in the placebo group, with no effecton cardiac output. In a second random-ized, placebo-controlled, double-blindtrial, the hemodynamic effects of a con-tinuous infusion of hydrocortisone (0.18mg·kg�1·hr�1) for 6 days were investi-gated in 40 hyperdynamic septic shockpatients (160). In this study, as comparedwith placebo, hydrocortisone increasedmean arterial pressure from study day 1(�7 mm Hg) to study day 5 (�8 mm Hg).Cardiac output decreased in the hydro-cortisone group (�25%) compared withthe placebo group (�6%), and systemicvascular resistance was increased (by 260and 369 dynes·sec/cm5·m2 at study day 1and 5, respectively). In a third random-ized, placebo-controlled trial, the hemo-dynamic effects of a continuous infusionof hydrocortisone (10 mg/hr) were inves-tigated in 40 septic shock patients (163).As compared with placebo, hydrocorti-

sone significantly improved mean arterialpressure (�14 mm Hg vs. � 1 mm Hg atpeak effect), again with a slight decreasein cardiac output in the hydrocortisonegroup (�11%) as compared with the pla-cebo group (�9%) and an increase insystemic vascular resistance (�237 vs. �10 dynes·sec/cm5·m2 at peak effect).

The favorable effect of corticosteroidson vascular responsiveness to vasopressoragents is manifested at the bedside by ashortening of the time on vasoconstrictordrugs. Five randomized, placebo-con-trolled, double-blind trials have investi-gated the effects of prolonged (�3 days)treatment with moderate doses of hydro-cortisone (200–300 mg per day) on shockduration and vasopressor withdrawal inseptic shock. In one study, hydrocorti-sone significantly reduced the amount ofcatecholamine needed to maintain ade-quate systemic hemodynamics on dayone (�40% from baseline vs. � 43%) andshortened mean time to cessation of va-sopressor therapy (4 days vs. 13) (159). Atstudy day 7, the rate of shock reversal was68% in the hydrocortisone group and21% in the placebo group. In a secondstudy, at study day 7, the rate of shockreversal was 85% in the hydrocortisonegroup and 60% in the placebo group. Themedian time to vasopressor therapy with-drawal was 2 days in the treated groupand 7 days in the placebo group (160). Ina third study, hydrocortisone increasedthe rate of shock reversal at study day 3compared with placebo (70% vs. 33%)and decreased the median time to cessa-tion of vasopressor therapy (3 days vs. 5days) (161). In a fourth study, at studyday 3, the rate of shock reversal was 70%in the hydrocortisone group and 30% inthe placebo group (163). Finally, in thefifth study, a phase III randomized place-bo-controlled, double-blind trial of 300septic shock patients, hydrocortisonecombined with fludrocortisone signifi-cantly reduced the time on vasopressorsin nonresponders to ACTH (increment inplasma cortisol concentrations of �9�g/dL [248 nmol/L]) with a median timeto vasopressor therapy withdrawal of 7 vs.10 days (log rank p � .009). The rate ofshock reversal at study day 7 was 70% vs.50% (162). These effects were not seen inseptic shock patients who had a cortisolincrement of �9 �g/dL (248 nmol/L) inresponse to ACTH.

High doses of corticosteroids (i.e., 30mg/kg of methylprednisolone or equiva-lent) once to four times had no effect onsurvival in severe sepsis or septic shock


(164). By contrast, in septic shock, lowdoses ranging from 200 to 300 mg dailyof corticosteroids given for a prolongedperiod of time (�5 days) have beenshown to improve outcome in severalcontrolled clinical trials. In 18 criticallyill patients, compared with standardtreatment alone, 100 mg twice daily ofhydrocortisone dramatically improved in-tensive care unit survival rate (90% vs.12.5%) (165). In another study of 41 sep-tic shock patients, as compared with pla-cebo, a 100-mg bolus of hydrocortisoneevery 8 hrs for 5 days improved the 28-day survival rate (68% vs. 37%) (159).Similar findings have been reported inanother study in abstract form (161). Fi-nally, a phase III, multiple-center, place-bo-controlled, randomized, double-blindstudy evaluated the efficacy and safety ofa combination of hydrocortisone (50-mgintravenous bolus four times per day) andfludrocortisone (50 �g orally once a day)given for 7 days in 300 patients withseptic shock (162). In this trial, nonre-sponders to ACTH were more likely tobenefit from cortisol replacement, with30-day survival rates 47% vs. 37% (logrank p � .02), intensive care unit survivalrates 42% vs. 30% (log rank p � .01), andhospital survival rates 39% vs. 28% (logrank p � .02). Patients who respondednormally to ACTH (cortisol increment of�9 �g/dL [250 nmol/L] after 250 �g ofcorticotropin) had no benefit from corti-costeroid therapy (1-month mortalityrates: 61% vs. 53%, log rank p � .81).

Vasopressin. Vasopressin is a peptidehormone synthesized in the hypothala-mus and then transported to and storedin the pituitary gland. Vasopressin is re-leased in response to decreases in bloodvolume, decreased intravascular volume,and increased plasma osmolality. Vaso-pressin constricts vascular smooth mus-cle directly via V1 receptors and also in-creases responsiveness of the vasculatureto catecholamines (166). Vasopressinmay also increase blood pressure by inhi-bition of vascular smooth muscle NO pro-duction (167) and K�-ATP channels(168).

Normal concentrations of vasopressinhave little effect on blood pressure inphysiologic conditions (166), but vaso-pressin helps maintain blood pressureduring hypovolemia, (169) and seems torestore impaired hemodynamic mecha-nisms and also inhibit pathologic vascu-lar responses in shock. Increased concen-trations of vasopressin have beendocumented in several types of shock

(170, 171), but a growing body of evi-dence indicates that this response is ab-normal or blunted in septic shock. Onestudy found markedly increased concen-trations of circulating vasopressin in 12patients with cardiogenic shock butmuch lower concentrations in 19 patientswith septic shock, concentrations thatwere hypothesized to be inappropriatelylow (172). One potential mechanism forthis relative vasopressin deficiency wouldbe depletion of pituitary stores, possiblyin conjunction with impaired synthesis.Depletion of vasopressin stores in theneurohypophysis evaluated by magneticresonance imaging has in fact been de-scribed in a small group of septic shockpatients (173). A recent prospective co-hort study of patients with septic shockfound that vasopressin concentrationswere almost always elevated in the initialhours of septic shock and decreased af-terward; one third of patients developedrelative vasopressin deficiency as definedby the investigators (174).

Given this theoretical rationale, sev-eral small observational studies have ex-amined the effects of addition of vaso-pressin to catecholamines in patientswith pressor-refractory septic shock. Thefirst report showed that with infusion oflow dose of vasopressin (0.04 units/min)in five patients with septic shock, vaso-pressin plasma concentrations reached100 pg/mol (a concentration commensu-rate with those in patients with normalstress responses), and blood pressure in-creased significantly (172). Discontinua-tion of vasopressin was followed by amarked decrease in the arterial pressure.Similar findings were noted by the samegroup with low-dose vasopressin admin-istration in the 19 patients with sepsisand low vasopressin concentrations inthe study cited previously (172). Otherstudies have tested longer infusions. Onereport examined the effects of infusion of0.04 units/min of vasopressin for 16 hrsin 16 patients with catecholamine-refractory septic shock and found an in-crease in mean arterial pressure in 14–16, with stable cardiac output, andincreased urine output in the ten patientswho were not anuric on study entry(175). In another report, in 50 patientswith severe septic shock who had re-ceived continuous vasopressin infusionfor 48 hrs, mean arterial pressure in-creased by 18% in the 4 hrs after thebeginning of the infusion and then stabi-lized at 24 and 48 hrs; catecholaminedoses were reduced by 33% at the 4th

hour (p � .01) and by 50% at the 48thhour (166). Of note, five of the six pa-tients with cardiac arrest during thestudy had received vasopressin doses�0.05 units/min (166).

Randomized studies of vasopressininfusion have been small. In one, tenpatients with hyperdynamic septicshock on catecholamines were random-ized to a low dose of vasopressin (0.04units/min) or placebo (176). The pa-tients who received vasopressin had asignificant increase in systolic arterialpressure (from 98 to 125 mm Hg, p �.05) with successful weaning of cat-echolamines. No variation in arterialpressure was noted in the placebogroup. The cardiac index did not differin the two groups. Before terminationof the study at 24 hrs, two of the fivepatients in the placebo group died ofrefractory hypotension; there were nodeaths during the study in vasopressin-treated patients. Another group ran-domized 24 patients with septic shockon high-dose vasopressors to a 4-hr in-fusion of either norepinephrine or va-sopressin, with open-label titration ofvasopressors to maintain mean arterialpressure (177). In the vasopressingroup, norepinephrine doses were sig-nificantly reduced at the 4th hour (25to 5 �g/min, p � .001). Vasopressindoses varied between 0.01 and 0.08units/min. In the norepinephrinegroup, doses were not significantlymodified. Mean arterial pressure andcardiac index were maintained in bothgroups, and the gastric CO2 gradientwas unchanged as well. Urine outputand creatinine clearance increased sig-nificantly in the vasopressin group butdid not vary in the norepinephrinegroup (177).

All of the previously cited studies in-fused arginine-vasopressin, the vasopressinthat is naturally present in humans. Lysine-vasopressin or terlipressin, the vasopressinpresent in the pig, has been evaluated inpatients with septic shock in one reportedstudy (178). Terlipressin administered as asingle bolus of 1 mg to eight patients withseptic shock refractory to catecholamines,hydrocortisone, and methylene blue im-proved blood pressure during the first 5 hrsand enabled partial or total weaning of cat-echolamines (178).

In summary, vasopressin plays an im-portant role in normalizing blood pres-sure in states of shock. There is evidencethat in septic shock, a relative deficiencyof vasopressin may contribute to persis-


tent hypotension. Current evidence dem-onstrates that in catecholamine-resistantseptic shock, the addition of low-dose va-sopressin (0.01–0.04 units/min) by con-tinuous infusion to catecholamines canbe used to increase blood pressure anddecrease catecholamine doses. There isconcern, however, that vasopressin infu-sion in septic patients may either de-crease splanchnic perfusion or redistrib-ute blood flow away from the splanchnicmucosa (179, 180). Data examining out-comes and clinical side effects are lim-ited.

Complications of VasopressorTherapy

All of the catecholamine vasopressoragents can cause significant tachycar-dia, especially in patients who are inad-equately volume resuscitated. Tachyar-rhythmias can occur as well. In patientswith significant coronary atherosclero-sis, vasopressor-induced coronary ar-tery constriction may precipitate myo-cardial ischemia and infarction; this isof particular concern in patients treatedwith vasopressin. In the presence ofmyocardial dysfunction, excessive vaso-constriction can decrease stroke vol-ume, cardiac output, and oxygen deliv-ery. Should this occur, the dose ofvasopressor should be lowered, or theaddition of an inotropic agent such asdobutamine should be considered (91).Vasopressors can also cause limb isch-emia and necrosis.

Administration of vasopressors mayimpair blood flow to the splanchnic sys-tem, and this can be manifested by stressulceration, ileus, malabsorption, andeven bowel infarction (121, 137). Gutmucosal integrity occupies a key positionin the pathogenesis of multiple organfailure, and countercurrent flow insplanchnic microcirculation gives the guta higher critical threshold for oxygen de-livery than other organs. If possible, epi-sodes of intramucosal acidosis, whichmight be detected either by a decrease ingastric mucosal pHi or an increase ingastric mucosal PCO2, should be avoided,although no prospective randomized con-trolled trial has demonstrated a decreasein mortality rate with pHi or gastric PCO2-directed care in the management of pa-tients with septic shock.

INOTROPIC THERAPY INSEPSIS

Overview

Sepsis is characterized by a hyperdy-namic state with normal to low bloodpressure, normal to high cardiac index,and a low systemic vascular resistance (1,29). Although cardiac output is usuallymaintained in the volume-resuscitatedseptic patient, a number of investigationshave demonstrated that cardiac functionis impaired (97, 181, 182). This myocar-dial dysfunction is characterized by a de-creased ejection fraction, ventricular di-lation, impaired contractile response tovolume loading, and a low peak systolicpressure/end-systolic volume ratio (a rel-atively load-independent measure of ven-tricular function) (183–185). The mech-anism of this cardiac dysfunction iscomplex. Myocardial ischemia is unlikely,as coronary blood flow is normal andthere is no net lactate production acrossthe coronary vascular bed (186, 187). An-imal studies of endotoxemia or bacterialinfection have suggested that myocardialedema (188), alterations in sarcolemmalor intracellular calcium homeostasis(189), and uncoupling or disruption of�-adrenergic signal transduction maycontribute to the cardiac contractile dys-function (190). A variety of inflammatorymediators, including prostanoids (191),platelet-activating factor (65), tumor ne-crosis factor-�, interleukin-1 and inter-leukin-2, (192), and nitric oxide (193,194) have been shown to cause myocar-dial depression in a number of animalmodels, possibly through the sphinomy-elinase pathway (195). Although it isclear that myocardial performance is al-tered during sepsis and septic shock, endpoints for cardiac resuscitation are un-certain.

Inotropic therapy in septic shock iscomplex, because different approachesendeavor to achieve different goals. Inpatients with decreased cardiac output,the goals of therapy are straightforwardand are aimed at restoring normal phys-iology. Because of the complexity of as-sessment of clinical variables in septicpatients, measurement of cardiac outputis advisable. Such measurements need tobe interpreted in the clinical context; apatient with preexisting cardiac diseasemay have a limited ability to increasecardiac output, and thus values withinthe normal range or even slightly belownormal may actually represent a hyper-

dynamic response for that particular pa-tient. Thus, other end points of globalperfusion should be followed as well.When global hypoperfusion is manifestedby decreased mixed venous oxygen satu-ration, this measure may be followed asan index of the efficacy of inotropic ther-apy. Similarly, although lactate produc-tion in sepsis is complex, a decrease inblood lactate concentrations concomitantwith increased cardiac output is a goodprognostic sign. To further complicatematters, the pharmacokinetics and phar-macodynamics of inotropic agents in sep-tic patients can be quite complex andvariable (196, 197).

Some critically ill septic patients arehypermetabolic and may require highlevels of oxygen delivery to maintain ox-idative metabolism. Data from the 1980sand early 1990s suggested that a linearrelationship between oxygen delivery andoxygen consumption (“pathologic supplydependency”) was common in septic pa-tients, (33, 198) with the inference thatoxygen delivery was insufficient to meetthe metabolic needs of the patient. Theseobservations led to the hypothesis thatresuscitation to predetermined elevatedend points of cardiac index and oxygendelivery and consumption (“hyperresus-citation”) might improve patient out-come. Retrospective analyses showed thatachievement of cardiac index �4.5L·min�1·m�2, oxygen delivery �600mL·min�1·m�2, and oxygen consump-tion �170 mL·min�1·m�2 correlatedwith improved survival (39). Other inves-tigations, however, have challenged theconcept of pathologic supply-dependencyand hyperresuscitation (199 –202). Al-though cardiac index and oxygen deliveryare correlated with outcome (39), it isunclear if increases in these variables arethe cause of increased survival or repre-sent the underlying physiologic reserve ofthe patient. Randomized studies to testthe practice of routinely increasing oxy-gen delivery to these predefined levels inall critically ill patients have producedconflicting results (199–201, 203, 204),and it is unclear if increases in cardiacindex and oxygen delivery are the cause ofincreased survival or represent underly-ing physiologic reserve of the patient.Thus, a strategy of routinely increasingoxygen delivery to predetermined ele-vated end points of cardiac index andoxygen delivery cannot be recommendedon the basis of current data (205). None-theless, some clinicians believe that thisissue has not been settled definitively in


those patients with septic shock and ar-gue that a subset of these patients maybenefit from therapy aimed at supranor-mal oxygen delivery.

Uncertainty exists in regard to otherend points for inotropic therapy. Deficitsin oxygen delivery can clearly cause alactic acidosis, but the converse is nottrue: elevated lactate concentrations inpatients with sepsis or septic shock donot necessarily reflect deficits in oxygendelivery (206). In adequately resuscitatedseptic patients, mixed venous oxygen sat-uration is usually normal or high, thisvalue correlates poorly with cardiac out-put, and several studies have questionedthe value of SvO2 as the end point forinotropic therapy in critically ill patients(207, 208). Low mixed venous oxygen sat-uration may indicate decreased global ox-ygen delivery, however (207).

Despite seemingly adequate resuscita-tion, some septic shock patients developmultiple organ failure, resulting in death.It has been argued that even after hypo-tension has been corrected and globaloxygen delivery is adequate in patientswith septic shock, blood flow and tissueperfusion can remain suboptimal. Gastrictonometry and sublingual capnometrymonitor gastric and sublingual PCO2 as aproxy for determining the adequacy ofgut perfusion. Although these monitorsserve as good predictors for the ultimateoutcome of critically ill patients (22–25),their utility to guide therapy in patientswith sepsis and septic shock has not beenproven. In dysoxic states with normal orelevated blood flow, these monitors gen-erally fail to detect an elevated intramu-cosal-arterial PCO2 gap (209). No currentevidence supports improved outcomewith empirical therapy to raise cardiacoutput in patients with normal bloodpressure, but a subpopulation of patientsmight have regional hypoperfusion thatwould respond to additional therapy. One

would want to titrate such therapy to anindex of regional perfusion, although theprecise end points are uncertain. In thiscontext, it is important to realize thatdifferent interventions to increase oxygendelivery, such as fluid resuscitation,blood transfusion, or infusion of vasoac-tive agents, can have different effects onregional perfusion (101, 112, 121). Differ-ent vasoactive agents have been shown tohave divergent effects on gastric intramu-cosal pH.

An inotropic agent should be consid-ered to maintain an adequate cardiac in-dex, mean arterial pressure, SvO2, andurine output. Cardiac output can be mea-sured using a pulmonary artery catheter,by echocardiography, with an esophagealDoppler probe, or by pulse contour anal-ysis. Regardless of the measurementmethod chosen, clinicians should definespecific goals and desired end points ofinotropic therapy in septic patients andtitrate therapy to those end points. Thesegoals and end points should be refined atfrequent intervals as patients’ clinical sta-tus changes.

Therapies and Efficacy

Most investigations evaluating inotro-pic agents have been observational andhave used the baseline hemodynamiccharacteristics of the patient as the con-trols. The majority of these studies haveused heart rate, cardiac index or output,and/or stroke volume or stroke volumeindex as the outcome variables. Only afew studies have assessed ventricularfunction by reporting left (or right) ven-tricular stroke work index. The resultsare summarized in Table 1.

Individual Inotropic Agents

Isoproterenol. Isoproterenol is a �1-and �2-adrenergic agonist. Few studies

have evaluated isoproterenol in sepsisand septic shock. In septic shock patientswith a low cardiac index (mean �2.0L·min�1·m�2), isoproterenol (2– 8 �g/min) will significantly increase cardiacindex without decreasing blood pressurebut at the expense of increasing heartrate (29, 210). In patients with a normalcardiac index, however, isoproterenol candecrease blood pressure through its �2-adrenergic effects. In addition, the chro-notropic effects of �1-adrenergic stimula-tion can precipitate myocardial ischemia.

Dopamine. Dopamine is an adrenergicagonist with predominant dopaminergicproperties at doses �5 �g·kg�1·min�1

and increased � and � activity at doses�5 �g·kg�1·min�1. However, even at lowdoses, significant � and � agonism mayoccur since the pharmacokinetics of do-pamine in critically ill patients is highlyvariable (197).

In patients with severe sepsis and/orseptic shock, most studies have shownthat dopamine will increase cardiac indexwith a range from 4% to 44%, left ven-tricular stroke work index by 5–91%, andright ventricular stroke work index by amodest 5–10% (101, 103, 104, 106, 108,109, 111–113, 137, 210–213). These im-provements in cardiac performance comeat the expense of an increase in the heartrate of approximately 15% (range up to23%). The greatest increase in these vari-ables occurs at doses ranging from 3 to12 �g·kg�1·min�1. At higher doses, therate of improvement in cardiac functiondecreases. Although dopamine may in-crease mesenteric blood flow, it may alsodecrease mesenteric oxygen consumption(113). It is not clear whether effects ofdopamine are superior to any other ad-renergic agent.

Dobutamine. Dobutamine is a race-mic mixture of two isomers, a D isomerwith �1- and �2-adrenergic effects, and anL isomer with �1- and �1-adrenergic ef-

Table 1. Summary of cardiac effects of inotropes used in sepsis and septic shock: Physiologic values are reported as percent change from baseline

DrugDose Range,

�g � kg�1 � m�1HeartRate

CardiacIndex

StrokeVolume Index SVRI LVSWI References

Isoproterenol 1.5 to 18 �g/min 11 to 20 47 to 119 22 to 89 �24 to �44 74 to 157 (29, 230)Dopamine 2 to 55 1 to 23 4 to 44 7 to 32 �6 to 18 5 to 91 (102, 104, 105, 107, 109, 110,

112–114, 138, 211–214)Epinephrine 0.06 to 0.47 �6 to 27 24 to 54 12 �7 to 34 32 to 95 (135, 136, 138)Norepinephrine 0.03 to 3.3 �6 to 8 �3 to 21 5 to 15 13 to 111 42 to 142 (91, 94, 102, 104, 107, 113, 120)Dobutamine 2 to 28 9 to 23 12 to 61 15 �6 to �21 23 to 58 (16, 92, 203, 215–218)Milrinonea 0.5 1 41 to 49 47 �30 to �35 51 to 56 (228, 229)

SVRI, systemic vascular resistance index; LVSWI, left ventricular stroke work index.aWith other inotropes including dopamine, dobutamine, norepinephrine and/or epinephrine.


fects; its predominant effect is inotropicvia stimulation of �1 receptors, with avariable effect on blood pressure.

A number of studies have investigatedthe effect of dobutamine on cardiac func-tion during sepsis or septic shock at dosesranging from 2 to 28 �g·kg�1·min�1 (91,202, 214–218). In these studies, increasesin cardiac index ranged from 12% to61%. However, heart rate increases, oftensignificantly (9–23%). Two studies re-ported that left ventricular stroke workindex increased by 23–58% at mean do-butamine doses of 5–12 �g·kg�1·min�1

(214, 215). Similar increases in right ven-tricular stroke work were also observed inthese studies.

Although dobutamine does not influ-ence the distribution of blood flow, ther-apy is often aimed at increasing bloodflow to organs such as the gut or thekidneys.

Epinephrine. Epinephrine stimulatesboth � and � receptors. At low doses, the�-adrenergic effects predominate. A fewrecent studies have examined the hemo-dynamic effects of epinephrine in septicshock at doses ranging from 0.1 to 0.5�g·kg�1·min�1 (134, 135, 137). The in-crease in cardiac index varied from 24%to 54%, and the heart rate response wasvariable. Increases in left ventricularstroke work index as high as 95% havebeen noted (135). Other studies indicatedthat lactic acidosis is increased and per-fusion to the gut is altered with the use ofepinephrine (121, 127, 137).

Norepinephrine. Like epinephrine,norepinephrine stimulates both � and �receptors; however, the �-adrenergic re-sponse is the predominant effect. The ef-fect of norepinephrine on cardiac index ismodest, with the majority of studiesshowing no change or increases of up to21% while heart rate is unaffected oreven decreases by up to 8% (91, 93, 101,103, 106, 112, 119). However, severalstudies have shown a marked increase inleft and right ventricular stroke work in-dex due to increased blood pressure (93,101, 112, 119).

Combination and Comparative Stud-ies. A number of studies have investigatedcatecholamine combinations (86, 94,121, 126, 219–222). The majority of thesestudies did not study the catecholaminecombination in a standardized fashion,thus limiting the conclusions that can bedrawn about the effects of these catechol-amine combinations on cardiac function.Patients who do not respond to dopaminewith an increase in cardiac index may

reach the desired end point with a dopa-mine/norepinephrine combination (106).Dobutamine and norepinephrine appearto be an effective combination to improvecardiac index and blood pressure (91) Inaddition, some (223) but not all (224,225) studies have shown that dobutamineor a dobutamine/norepinephrine combi-nation will also enhance mesenteric per-fusion.

A few investigations have been per-formed comparing different inotropicregimens (87–90, 101, 112, 121, 137).Epinephrine appears to be as good if notbetter at improving cardiac performancethan dopamine or a dobutamine/norepi-nephrine combination (121, 137). How-ever, with one exception (140), studieshave shown that when epinephrine iscompared with other adrenergic agentsor their combinations, there are in-creases in arterial lactate and decreases ingastric intramucosal pH, suggesting thatperfusion to regional vascular beds maybe impaired (121, 127, 137, 139, 226). Inseveral studies, dopamine increased car-diac index and stroke volume index to agreater extent than norepinephrine, butincreases in left and right ventricularstroke volume index were about the samewith the two agents (101, 112). There wasless prominent tachycardia with norepi-nephrine, and one unconfirmed pilotstudy suggested that mesenteric perfu-sion is impaired with dopamine com-pared with norepinephrine (101, 112).

Phosphodiesterase Inhibitors. Phos-phodiesterase inhibitors are vasodilatorswith long half-lives, raising the potentialfor prolonged decreases in blood pressurewhen used in septic patients. There are afew small studies of these agents in pa-tients with sepsis, but meaningful con-clusions cannot be made because of thesize of the studies and the concomitantuse of disparate adrenergic agents (227–230).

Complications

In the septic patient who has beeninadequately volume resuscitated, all ofthe inotropic agents can cause significanttachycardia and other cardiac arrhyth-mias (77). In patients with coexisting cor-onary disease, the change in myocardialoxygen consumption may precipitatemyocardial ischemia and infarction(199). Excessive doses of catecholaminescan also result in myocardial band necro-sis independent of the presence of coro-nary disease.

Sole use of inotropic agents that alsohave vasodilatory activity (e.g., isoproter-enol, milrinone) is likely to reduce bloodpressure. These reductions can be long-lasting with agents that have long half-lives.

Administration of inotropic agentsthat have pressor activity may impairblood flow to other organ beds, such asthe splanchnic circulation (121, 137). Ef-forts to ensure adequate volume resusci-tation and to assess end-organ functionmust be made.

RECOMMENDATIONS FORHEMODYNAMIC SUPPORT OFSEPTIC PATIENTS

Basic Principles

1. Resuscitation of patients with sepsisshould be initiated expeditiouslyand pursued vigorously. Measuresto improve tissue and organ perfu-sion are most effective when appliedearly.

2. Patients with septic shock shouldbe treated in an intensive care unit,with continuous electrocardio-graphic monitoring and monitoringof arterial oxygenation.

3. Arterial cannulation should be per-formed in patients with shock toprovide a more accurate measure-ment of intra-arterial pressure andto allow beat-to-beat analysis sothat decisions regarding therapycan be based on immediate and re-producible blood pressure informa-tion.

4. Resuscitation should be titrated toclinical end points of arterial pres-sure, heart rate, urine output, skinperfusion, and mental status, andindexes of tissue perfusion such asblood lactate concentrations andmixed venous oxygen saturation.

5. Assessment of cardiac filling pres-sures may require central venous orpulmonary artery catheterization.Pulmonary artery catheterizationalso allows for assessment of pul-monary artery pressures, cardiacoutput measurement, and measure-ment of mixed venous oxygen satu-ration. Echocardiography may alsobe useful to assess ventricular vol-umes and cardiac performance.


Fluid Resuscitation

Recommendation 1—Level B. Fluidinfusion should be the initial step in he-modynamic support of patients with sep-tic shock. Initial fluid resuscitationshould be titrated to clinical end points.

Recommendation 2—Level B. Iso-tonic crystalloids or iso-oncotic colloidsare equally effective when titrated to thesame hemodynamic end points.

Recommendation 3—Level D. Inva-sive hemodynamic monitoring should beconsidered in those patients not respond-ing promptly to initial resuscitative ef-forts. Pulmonary edema may occur as acomplication of fluid resuscitation andnecessitates monitoring of arterial oxy-genation. Fluid infusion should be ti-trated to a level of filling pressure asso-ciated with the greatest increase incardiac output and stroke volume. Formost patients, this will be a pulmonaryartery occlusion pressure in the range of12–15 mm Hg. An increase in the varia-tion of arterial pressure with respirationmay also be used to identify patientslikely to respond to additional fluid ad-ministration.

Recommendation 4—Level C. Hemo-globin concentrations should be main-tained between 8 and 10 gm/dL. In pa-tients with low cardiac output, mixedvenous oxygen desaturation, lactic acido-sis, widened gastric-arterial PCO2 gradi-ents, or significant cardiac or pulmonary

disease, transfusion to a higher concen-tration of hemoglobin may be desirable.

Vasopressor Therapy

Recommendation 1—Level C. Dopa-mine and norepinephrine are both effec-tive for increasing arterial blood pres-sure. It is imperative to ensure thatpatients are adequately fluid resuscitated.Dopamine raises cardiac output morethan norepinephrine, but its use may belimited by tachycardia. Norepinephrinemay be a more effective vasopressor insome patients.

Recommendation 2—Level D. Phenyl-ephrine is an alternative to increase bloodpressure, especially in the setting oftachyarrhythmias. Epinephrine can beconsidered for refractory hypotension, al-though adverse effects are common, andepinephrine may potentially decreasemesenteric perfusion.

Recommendation 3—Level B. Admin-istration of low doses of dopamine tomaintain renal function is not recom-mended.

Recommendation 4 —Level C. Pa-tients with hypotension refractory to cat-echolamine vasopressors may benefitfrom addition of replacement dose ste-roids.

Recommendation 5—Level D. Lowdoses of vasopressin given after 24 hrs ashormone replacement may be effective inraising blood pressure in patients refrac-tory to other vasopressors, although noconclusive data are yet available regard-ing outcome.

Inotropic Therapy

Recommendation 1—Level C. Dobut-amine is the first choice for patients withlow cardiac index and/or low mixed ve-nous oxygen saturation and an adequatemean arterial pressure following fluid re-suscitation. Dobutamine may cause hy-potension and/or tachycardia in some pa-tients, especially those with decreasedfilling pressures.

Recommendation 2—Level B. In pa-tients with evidence of tissue hypoperfu-sion, addition of dobutamine may behelpful to increase cardiac output andimprove organ perfusion. A strategy ofroutinely increasing cardiac index to pre-defined “supranormal” levels (�4.5L·min�1·m�2) has not been shown to im-prove outcome.

Recommendation 3—Level C. A vaso-pressor such as norepinephrine and an

inotrope such as dobutamine can be ti-trated separately to maintain both meanarterial pressure and cardiac output.

REFERENCES

1. Parrillo JE, Parker MM, Natanson C, et al:Septic shock in humans: Advances in theunderstanding of pathogenesis, cardiovas-cular dysfunction, and therapy. Ann InternMed 1990; 113:227–242

2. Ince C, Sinaasappel M: Microcirculatory ox-ygenation and shunting in sepsis and shock.Crit Care Med 1999; 27:1369–1377

3. Hollenberg SM, Parrillo JE: Shock. In: Har-rison’s Principles of Internal Medicine.Fourteenth Edition. Fauci AS, BraunwaldE, Isselbacher KJ, et al. (Eds). New York,McGraw-Hill, 1997, pp 214–222

4. Cook DJ, Guyatt GH, Laupacis A, et al:Rules of evidence and clinical recommen-dations on the use of antithromboticagents. Chest 1992 102(4 Suppl):305S–311S

5. Evidence-Based Medicine Working Group.Evidence-based medicine: A new approachto teaching the practice of medicine. JAMA1992; 268:2420–2425

6. (I) Bernard GR, Vincent JL, Laterre PF, etal: Efficacy and safety of recombinant hu-man activated protein C for severe sepsis.N Engl J Med 2001; 344:699–709

7. (I) Rivers E, Nguyen B, Havstad S, et al:Early goal-directed therapy in the treat-ment of severe sepsis and septic shock.N Engl J Med 2001; 345:1368–1377

8. Hotchkiss RS, Karl IE: Reevaluation of therole of cellular hypoxia and bioenergeticfailure in sepsis. JAMA 1992; 267:1503–1510

9. Astiz M, Rackow EC, Weil MH, et al: Earlyimpairment of oxidative metabolism andenergy production in severe sepsis. CircShock 1988; 26:311–320

10. (II) Hayes MA, Timmins AC, Yau EH, et al:Oxygen transport patterns in patients withsepsis syndrome or septic shock: Influenceof treatment and relationship to outcome.Crit Care Med 1997; 25:926–936

11. (V) Steffes CP, Dahn MS, Lange MP: Oxygentransport-dependent splanchnic metabo-lism in the sepsis syndrome. Arch Surg1994; 129:46–52

12. Bredle D, Samsel R, Schumacker P: CriticalO2 delivery to skeletal muscle at high andlow PO2 in endotoxemic dogs. J ApplPhysiol 1989; 66:2553–2558

13. Rackow E, Astiz ME, Weil MH: Increases inoxygen extraction during rapidly fatal septicshock in rats. J Lab Clin Med 1987; 109:660–664

14. Gore DC, Jahoor F, Hibbert JM, et al: Lacticacidosis during sepsis is related to increasedpyruvate production, not deficits in tissueoxygen availability. Ann Surg 1996; 224:97–102

15. (V) Friedman G, Berlot G, Kahn RJ: Com-

T he fundamental

principle is that

clinicians using

hemodynamic therapies

should define specific goals

and end points, titrate ther-

apies to those end points,

and evaluate the results of

their interventions on an on-

going basis by monitoring a

combination of variables of

global and regional

perfusion.


bined measurements of blood lactate levelsand gastric intramucosal pH in patientswith severe sepsis. Crit Care Med 1995; 23:1184–1193

16. (V) Vincent JL, Dufaye P, Berre J: Seriallactate determinations during circulatoryshock. Crit Care Med 1983; 11:449–451

17. (V) Weil MH, Afifi AA: Experimental andclinical studies on lactate and pyruvate asindicators of the severity of acute circula-tory failure (shock). Circulation 1970; 41:989–1001

18. (V) Bakker J, Coffemils M, Leon M, et al:Blood lactates are superior to oxygen-derived variables in predicting outcome inhuman septic shock. Chest 1992; 99:956–962

19. (V) De Backer D, Creteur J, Noordally O, etal: Does hepato-splanchnic VO2/DO2 de-pendency exist in critically ill septic pa-tients? Am J Respir Crit Care Med 1988;157:1219–1225

20. Nelson D, Beyer C, Samsel R, et al: Patho-logic supply dependence of systemic andintestinal O2 uptake during bacteremia inthe dog. J Appl Physiol 1987; 63:1487–1489

21. Russell JA: Gastric tonometry: Does itwork? Intensive Care Med 1997; 23:3–6

22. (V) Marik PE: Gastric intramucosal pH. Abetter predictor of multiorgan dysfunctionsyndrome and death than oxygen-derivedvariables in patients with sepsis. Chest1993; 104:225–229

23. (V) Maynard N, Bihari D, Beale R, et al:Assessment of splanchnic oxygenation bygastric tonometry in patients with acutecirculatory failure. JAMA 1993; 270:1203–1210

24. (II) Gutierrez G, Palizas F, Doglio G, et al:Gastric intramucosal pH as a therapeuticindex of tissue oxygenation in critically illpatients. Lancet 1992; 339:195–199

25. (V) Doglio GR, Pusajo JF, Egurrola MA, etal: Gastric mucosal pH as a prognostic in-dex of mortality in critically ill patients. CritCare Med 1991; 19:1037–1040

26. (III) Weil MH, Nakagawa Y, Tang W, et al:Sublingual capnometry: A new noninvasivemeasurement for diagnosis and quantita-tion of severity of circulatory shock. CritCare Med 1999; 27:1225–1229

27. (III) Marik PE: Sublingual capnography: Aclinical validation study. Chest 2001; 120:923–927

28. Carroll G, Snyder J: Hyperdynamic severeintravascular sepsis depends on fluid ad-ministration in cynomolgus monkey. Am JPhysiol 1982; 243:R131–R141

29. (V) Winslow EJ, Loeb HS, Rahimtoola SH,et al: Hemodynamic studies and results oftherapy in 50 patients with bacteremicshock. Am J Med 1973; 54:421–432

30. Greenfield LJ, Jackson RH, Elkins RC: Car-diopulmonary effects of volume loading ofprimates in endotoxin shock. Surgery 1974;76:560–570

31. (V) Weil MH, Nishijima H: Cardiac output

in bacterial shock. Am J Med 1978; 64:920–923

32. (V) Rackow EC, Falk JL, Fein IA: Fluid re-suscitation in shock: A comparison of car-diorespiratory effects of albumin,hetastarch and saline solutions in patientswith hypovolemic shock. Crit Care Med1983; 11:839–850

33. (III) Haupt MT, Gilbert EM, Carlson RW:Fluid loading increases oxygen consump-tion in septic patients with lactic acidosis.Am Rev Respir Dis 1985; 131:912–916

34. (III) Packman MJ, Rackow EC: Optimumleft heart filling pressure during fluid resus-citation of patients with hypovolemic andseptic shock. Crit Care Med 1983; 11:165–169

35. Sugerman H, Diaco J, Pollack T, et al: Phys-iologic management of septicemic shock inman. Surg Forum 1971; 22:3–5

36. (V) Michard F, Boussat S, Chemla D, et al:Relation between respiratory changes in ar-terial pulse pressure and fluid responsive-ness in septic patients with acute circula-tory failure. Am J Respir Crit Care Med2000; 162:134–138

37. (V) Tavernier B, Makhotine O, Lebuffe G, etal: Systolic pressure variation as a guide tofluid therapy in patients with sepsis-induced hypotension. Anesthesiology 1998;89:1313–1321

38. (V) Michard F, Teboul JL: Predicting fluidresponsiveness in ICU patients: A criticalanalysis of the evidence. Chest 2002; 121:2000–2008

39. (II) Tuchschmidt J, Fried J, Astiz M, et al:Elevation of cardiac output and oxygen de-livery improves outcome in septic shock.Chest 1992; 102:216–220

40. (V) Canizaro PC, Prager MD, Shires GT: Theinfusion of Ringer’s lactate solution duringshock. Changes in lactate, excess lactate,and pH. Am J Surg 1971; 122:494–501

41. (III) Lamke LO, Liljedahl SO: Plasma vol-ume changes after infusion of variousplasma expanders. Resuscitation 1976;5:93–102

42. (III) Shoemaker WC: Comparisons of therelative effectiveness of whole blood trans-fusions and various types of fluid therapy inresuscitation. Crit Care Med 1976; 4:71–78

43. Holcroft JW: Hypertonic saline for resusci-tation of the patient in shock. Adv Surg2001; 35:297–318

44. (I) Finfer S, Bellomo R, Boyce N, et al: Acomparison of albumin and saline for fluidresuscitation in the intensive care unit.N Engl J Med 2004; 350:2247–2256

45. (II) Gan TJ, Bennett-Guerrero E, Phillips-Bute B, et al: Hextend, a physiologicallybalanced plasma expander for large volumeuse in major surgery: A randomized phaseIII clinical trial. Hextend Study Group.Anesth Analg 1999; 88:992–998

46. (V) Cittanova ML, Leblanc I, Legendre C, etal: Effect of hydroxyethylstarch in brain-dead kidney donors on renal function in

kidney-transplant recipients. Lancet 1996;348:1620–1622

47. (II) Schortgen F, Lacherade JC, Bruneel F,et al: Effects of hydroxyethylstarch and gel-atin on renal function in severe sepsis: Amulticentre randomised study. Lancet2001; 357:911–916

48. (V) Kumle B, Boldt J, Piper S, et al: Theinfluence of different intravascular volumereplacement regimens on renal function inthe elderly. Anesth Analg 1999; 89:1124–1130

49. (V) Shatney CH, Deepika K, Militello PR, etal: Efficacy of hetastarch in the resuscita-tion of patients with multisystem traumaand shock. Arch Surg 1983; 118:804–809

50. (II) Boldt J, Muller M, Mentges D, et al:Volume therapy in the critically ill: Is therea difference? Intensive Care Med 1998; 24:28–36

51. (V) Dehne MG, Muhling J, Sablotzki A, et al:Hydroxyethyl starch (HES) does not di-rectly affect renal function in patients withno prior renal impairment. J Clin Anesth2001; 13:103–111

52. (V) de Jonge E, Levi M: Effects of differentplasma substitutes on blood coagulation: Acomparative review. Crit Care Med 2001;29:1261–1267

53. Guyton AC, Lindsey AW: Effect of elevatedleft atrial pressure and decreased plasmaprotein concentration on the developmentof pulmonary edema. Circ Res 1959;7:649–657

54. Kramer GC, Harms BA, Bodai BI, et al:Effects of hypoproteinemia and increasedvascular pressure on lung fluid balance insheep. J Appl Physiol 1983; 55:1514–1522

55. (V) Rackow EC, Fein AI, Siegel J: The rela-tionships of colloid osmotic-pulmonary ar-tery wedge pressure gradient to pulmonaryedema and mortality in critically ill pa-tients. Chest 1982; 82:433–437

56. (V) Finley RJ, Holliday RL, Lefcoe M, et al:Pulmonary edema in patients with sepsis.Surg Gynecol Obstet 1975; 140:851–857

57. (V) Sise MJ, Shackford SR, Peters RM, et al:Serum oncotic-hydrostatic pressure differ-ences in critically ill patients. Anesth Analg1982; 61:496–498

58. (II) Virgilio RW, Rice CL, Smith DE, et al:Crystalloid vs. colloid resuscitation. Is onebetter? A randomized clinical study. Sur-gery 1979; 85:129–139

59. (II) Moss G, Lower R, Jilek J: Colloid orcrystalloid in the resuscitation of hemor-rhagic shock: A controlled clinical trial.Surgery 1981; 89:434–437

60. Rackow EC, Astiz ME, Schumer W, et al:Lung and muscle water after crystalloid andcolloid infusion in septic rats: Effect onoxygen delivery and metabolism. J Lab ClinMed 1989; 113:184–189

61. Nylander WAJ, Hammon JWJ, Roselli RJ, etal: Comparison of the effects of saline andhomologous plasma infusion on lung fluidbalance during endotoxemia in unanesthe-tized sheep. Surgery 1981; 90:221–228


62. (II) Metildi LA, Shackford SR, Virgilio RW,et al: Crystalloid versus colloid in fluid re-suscitation of patients with severe pulmo-nary insufficiency. Surg Gynecol Obstet1984; 158:207–212

63. (V) Appel P, Shoemaker WC: Evaluation offluid therapy in adult respiratory failure.Crit Care Med 1981; 9:862–869

64. (V) Morisaki H, Bloos F, Keys J, et al: Com-pared with crystalloid, colloid therapy slowsprogression of extrapulmonary tissue injuryin septic sheep. J Appl Physiol 1994; 77:1507–1518

65. Baum TD, Wang H, Rothschild HR, et al:Mesenteric oxygen metabolism, ileal muco-sal hydrogen ion concentration and tissueedema after crystalloid or colloid resuscita-tion in porcine endotoxic shock: Compari-son of Ringer’s lactate and 6% hetastarch.Circ Shock 1990; 30:385–397

66. O’Brien R, Murdoch J, Kuehn R, et al: Theeffect of albumin or crystalloid resuscita-tion on bacterial translocation and endo-toxin absorption following experimentalburn injury. J Surg Res 1992; 52:161–166

67. (V) Cochrane Injuries Group Albumin Re-viewers. Human albumin administration incritically ill patients: Systematic review ofrandomised controlled trials. BMJ1998;317:235–240

68. (V) Choi PT, Yip G, Quinonez LG, et al:Crystalloids vs. colloids in fluid resuscita-tion: A systematic review. Crit Care Med1999; 27:200–210

69. (V) Wilkes MM, Navickis RJ: Patient survivalafter human albumin administration. Ameta-analysis of randomized, controlled tri-als. Ann Intern Med 2001; 135:149–164

70. (V) Nelson AH, Fleisher LA, Rosenbaum SH:Relationship between postoperative anemiaand cardiac morbidity in high-risk vascularpatients in the intensive care unit. Crit CareMed 1993; 216:860–866

71. Morisaki H, Sibbald W, Martin C, et al:Hyperdynamic sepsis depresses the circula-tory compensation of normovolemic ane-mia in conscious rats. J Appl Physiol 1996;80:656–664

72. (V) Conrad S, Dietch K, Hebert C: Effect ofred cell transfusion on oxygen consumptionfollowing fluid resuscitation in septicshock. Circ Shock 1990; 31:419–420

73. (V) Steffes C, Bender J, Levison M: Bloodtransfusion and oxygen consumption insurgical sepsis. Crit Care Med 1991; 19:512–517

74. (V) Mink R, Pollack M: Effect of blood trans-fusion on oxygen consumption in pediatricseptic shock. Crit Care Med 1990; 18:1087–1091

75. (III) Silverman H, Tuma P: Gastric tonom-etry in patients with sepsis. Effects of do-butamine infusions and packed red bloodcell transfusions. Chest 1992; 102:184–189

76. (V) Marik P, Sibbald W: Effect of stored-blood transfusion on oxygen delivery in pa-tients with sepsis. JAMA 1993; 269:3024–3029

77. Bordin JO, Heddle NM, Blajchman MA: Bi-ologic effects of leukocytes present in trans-fused cellular blood products. Blood 1994;84:1703–1721

78. (I) Hebert PC, Wells G, Blajchman M, et al:A multicenter, randomized, controlled clin-ical trial of transfusion requirements incritical care. N Engl J Med 1999; 340:409–417

79. Hollenberg SM, Ahrens TS, Astiz ME, et al:Task Force of the American College of Crit-ical Care Medicine. Practice parameters forhemodynamic support of sepsis in adult pa-tients. Crit Care Med 1999; 27:639–660

80. Bersten AD, Holt AW: Vasoactive drugs andthe importance of renal perfusion pressure.New Horiz 1995; 3:650–661

81. Kirchheim HR, Ehmke H, Hackenthal E, etal: Autoregulation of renal blood flow, glo-merular filtration rate and renin release inconscious dogs. Pflugers Arch 1987; 410:441–449

82. (V) Barry K, Mazze R, Schwarz F: Preven-tion of surgical oliguria and renal hemody-namic suppression by sustained hydration.N Engl J Med 1967; 270:1371–1377

83. (V) Bush HL Jr, Huse JB, Johnson WC, et al:Prevention of renal insufficiency after ab-dominal aortic aneurysm resection by opti-mal volume loading. Arch Surg 1981; 116:1517–1524

84. Kelleher SP, Robinette JB, Conger JD: Sym-pathetic nervous system in the loss of au-toregulation in acute renal failure. Am JPhysiol 1984; 246:F379–F386

85. (V) Desjars P, Pinaud M, Bugnon D, et al:Norepinephrine therapy has no deleteriousrenal effects in human septic shock. CritCare Med 1989; 17:426–429

86. (V) Desjars P, Pinaud M, Tasseau F, et al: Areappraisal of norepinephrine therapy inhuman septic shock. Crit Care Med 1987;15:134–137

87. (V) Bollaert PE, Bauer P, Audibert G, et al:Effects of epinephrine on hemodynamicsand oxygen metabolism in dopamine-resistant septic shock. Chest 1990; 98:949–953

88. (V) Fukuoka T, Nishimura M, Imanaka H, etal: Effects of norepinephrine on renal func-tion in septic patients with normal and el-evated serum lactate levels. Crit Care Med1989; 17:1104–1107

89. (V) Hesselvik JF, Brodin B: Low dose nor-epinephrine in patients with septic shockand oliguria: Effects on afterload, urineflow, and oxygen transport. Crit Care Med1989; 17:179–180

90. (V) Lipman J, Roux A, Kraus P: Vasocon-strictor effects of adrenaline in human sep-tic shock. Anaesth Intensive Care 1991; 19:61–65

91. (III) Martin C, Saux P, Eon B, et al: Septicshock: A goal-directed therapy using vol-ume loading, dobutamine and/or norepi-nephrine. Acta Anaesthesiol Scand 1990;34:413–417

92. (V) Martin C, Eon B, Saux P, et al: Renal

effects of norepinephrine used to treat sep-tic shock patients. Crit Care Med 1990; 18:282–285

93. (V) Meadows D, Edwards JD, Wilkins RG, etal: Reversal of intractable septic shock withnorepinephrine therapy. Crit Care Med1988; 16:663–667

94. (V) Redl-Wenzl EM, Armbruster C, Edel-mann G, et al: The effects of norepinephrineon hemodynamics and renal function insevere septic shock states. Intensive CareMed 1993; 19:151–154

95. (V) Gregory JS, Bonfiglio MF, Dasta JF, etal: Experience with phenylephrine as acomponent of the pharmacologic support ofseptic shock. Crit Care Med 1991; 19:1395–1400

96. (III) LeDoux D, Astiz ME, Carpati CM, et al:Effects of perfusion pressure on tissue per-fusion in septic shock. Crit Care Med 2000;28:2729–2732

97. (V) Parker MM, Shelhamer JH, BacharachSL, et al: Profound but reversible myocar-dial depression in patients with septicshock. Ann Intern Med 1984; 100:483–490

98. (V) Hoogenberg K, Smit AJ, Girbes ARJ:Effects of low-dose dopamine on renal andsystemic hemodynamics during incremen-tal norepinephrine infusion in healthy vol-unteers. Crit Care Med 1998; 26:260–265

99. (V) Lherm T, Troche G, Rossignol M, et al:Renal effects of low-dose dopamine in pa-tients with sepsis syndrome or septic shocktreated with catecholamines. Intensive CareMed 1996; 22:213–219

100. (V) Meier-Hellmann A, Bredle DL, SpechtM, et al: The effects of low-dose dopamineon splanchnic blood flow and oxygen utili-zation in patients with septic shock. Inten-sive Care Med 1997; 23:31–37

101. (II) Marik PE, Mohedin M: The contrastingeffects of dopamine and norepinephrine onsystemic and splanchnic oxygen utilizationin hyperdynamic sepsis. JAMA 1994; 272:1354–1357

102. (III) Hannemann L, Reinhart K, Grenzer O,et al: Comparison of dopamine to dobut-amine and norepinephrine for oxygen deliv-ery and uptake in septic shock. Crit CareMed 1995; 23:1962–1970

103. (III) Ruokonen E, Takala J, Kari A, et al:Regional blood flow and oxygen transport inseptic shock. Crit Care Med 1993; 21:1296–1303

104. (III) Jardin F, Gurdjian F, Desfonds P, et al:Effect of dopamine on intrapulmonaryshunt fraction and oxygen transport in se-vere sepsis with circulatory and respiratoryfailure. Crit Care Med 1979; 7:273–277

105. (III) Jardin F, Eveleigh MC, Gurdjian F, etal: Venous admixture in human septicshock. Comparative effects of blood volumeexpansion, dopamine infusion and isopro-terenol infusion in mismatching of ventila-tion and pulmonary blood flow in peritoni-tis. Circulation 1979; 60:155–159

106. (II) Martin C, Papazian L, Perrin G, et al:Norepinephrine or dopamine for the treat-


ment of hyperdynamic septic shock. Chest1993; 103:1826–1831

107. (II) Regnier B, Safran D, Carlet J, et al:Comparative haemodynamic effects of do-pamine and dobutamine in septic shock.Intensive Care Med 1979; 5:115–120

108. (V) Samii K, Le Gall JR, Regnier B, et al:Hemodynamic effects of dopamine in septicshock with and without acute renal failure.Arch Surg 1978; 113:1414–1416

109. (V) Drueck C, Welch GW, Pruitt BA Jr: He-modynamic analysis of septic shock in ther-mal injury: Treatment with dopamine. AmSurg 1978; 44:424–427

110. (V) Regnier B, Rapin M, Gory G, et al: Hae-modynamic effects of dopamine in septicshock. Intensive Care Med 1977; 3:47–53

111. (V) Wilson RF, Sibbald WJ, Jaanimagi JL:Hemodynamic effects of dopamine in criti-cally ill septic patients. J Surg Res 1976;20:163–172

112. (II) Schreuder WO, Schneider AJ, Groen-eveld ABJ, et al: Effect of dopamine vs nor-epinephrine on hemodynamics in septicshock. Chest 1989; 95:1282–1288

113. (IV) Jakob SM, Ruokonen E, Takala J: Ef-fects of dopamine on systemic and regionalblood flow and metabolism in septic andcardiac surgery patients. Shock 2002; 18:8–13

114. (IV) Maynard ND, Bihari DJ, Dalton RN, etal: Increasing splanchnic blood flow in thecritically ill. Chest 1995; 108:1648–1654

115. (II) Neviere R, Chagnon JL, Vallet B, et al:Dobutamine improves gastrointestinal mu-cosal blood flow in a porcine model of en-dotoxic shock. Crit Care Med 1997; 25:1371–1377

116. Denton MD, Chertow GM, Brady HR: “Re-nal-dose” dopamine for the treatment ofacute renal failure: Scientific rationale, ex-perimental studies and clinical trials. Kid-ney Int 1996; 50:4–14

117. (I) Bellomo R, Chapman M, Finfer S, et al J:Low-dose dopamine in patients with earlyrenal dysfunction: A placebo-controlledrandomised trial. Australian and New Zea-land Intensive Care Society (ANZICS) Clin-ical Trials Group. Lancet 2000; 356:2139–2143

118. Van den Berghe G, de Zegher F: Anteriorpituitary function during critical illness anddopamine treatment. Crit Care Med 1996;24:1580–1590

119. (V) Martin C, Perrin G, Saux P, et al: Effectsof norepinephrine on right ventricularfunction in septic shock patients. IntensiveCare Med 1994; 20:444–447

120. (III) Martin C, Viviand X, Arnaud S, et al:Effects of norepinephrine plus dobutamineor norepinephrine alone on left ventricularperformance of septic shock patients. CritCare Med 1999; 27:1708–1713

121. (II) Levy B, Bollaert PE, Charpentier C, etal: Comparison of norepinephrine and do-butamine to epinephrine for hemodynam-ics, lactate metabolism, and gastric tono-metric variables in septic shock: A

prospective, randomized study. IntensiveCare Med 1997; 23:282–287

122. Chernow B, Roth BL: Pharmacologic ma-nipulation of the peripheral vasculature inshock: Clinical and experimental ap-proaches. Circulatory Shock 1986; 18:141–155

123. Murakawa K, Kobayashi A: Effects of vaso-pressors on renal tissue gas tensions duringhemorrhagic shock in dogs. Crit Care Med1988; 16:789–792

124. Conger JD, Robinette JB, Guggenheim SJ:Effect of acetylcholine on the early phase ofreversible norepinephrine-induced acuterenal failure. Kidney Int 1981; 19:399–409

125. Schaer GL, Fink MP, Parrillo JE: Norepi-nephrine alone versus norepinephrine pluslow-dose dopamine: Enhanced renal bloodflow with combination pressor therapy. CritCare Med 1985; 13:492–496

126. (V) Reinelt H, Radermacher P, Fischer G, etal: Effects of a dobutamine-induced in-crease in splanchnic blood flow on hepaticmetabolic activity in patients with septicshock. Anesthesiology 1997; 86:818–824

127. (V) De Backer D, Creteur J, Silva E, et al:Effects of dopamine, norepinephrine, andepinephrine on the splanchnic circulationin septic shock: Which is best? Crit CareMed 2003; 31:1659–1667

128. Dasta JF: Norepinephrine in septic shock:Renewed interest in an old drug. DICP AnnPharmacother 1990; 24:153–156

129. (V) Martin C, Viviand X, Leone M, et al:Effect of norepinephrine on the outcome ofseptic shock. Crit Care Med 2000; 28:2758–2765

130. (V) Moyer J, Skelton J, Mills L: Norepineph-rine: effect in normal subjects: Use in treat-ment of shock unresponsive to other mea-sures. Am J Med 1953; 15:330–343

131. (V) Yamazaki T, Shimada Y, Taenaka N, etal: Circulatory responses to afterloadingwith phenylephrine in hyperdynamic sepsis.Crit Care Med 1982; 10:432–435

132. (III) Flancbaum L, Dick M, Dasta J, et al: Adose-response study of phenylephrine incritically ill, septic surgical patients. EurJ Clin Pharmacol 1997; 51:461–465

133. (V) Wilson W, Lipman J, Scribante J, et al:Septic shock: Does adrenaline have a role asa first-line inotropic agent? Anesth Inten-sive Care 1992; 20:470–474

134. (III) Moran JL, MS O’Fathartaigh, PeisachAR, et al: Epinephrine as an inotropic agentin septic shock: A dose-profile analysis. CritCare Med 1993; 21:70–77

135. (III) Mackenzie SJ, Kapadia F, Nimmo GR,et al: Adrenaline in treatment of septicshock: Effects on haemodynamics and oxy-gen transport. Intensive Care Med 1991;17:36–39

136. (V) Le Tulzo Y, Seguin P, Gacouin A, et al:Effects of epinephrine on right ventricularfunction in patients with severe septicshock and right ventricular failure: A pre-liminary study. Intensive Care Med 1997;23:664–670

137. (II) Day NP, Phu NH, Bethell DP, et al: Theeffects of dopamine and adrenaline infu-sions on acid-base balance and systemichaemodynamics in severe infection. Lancet1996; 348:219–223

138. (V) Zhou SX, Qiu HB, Huang YZ, et al:Effects of norepinephrine, epinephrine, andnorepinephrine-dobutamine on systemicand gastric mucosal oxygenation in septicshock. Acta Pharmacol Sin 2002; 23:654–658

139. (V) Duranteau J, Sitbon P, Teboul JL, et al:Effects of epinephrine, norepinephrine, orthe combination of norepinephrine and do-butamine on gastric mucosa in septicshock. Crit Care Med 1999; 27:893–900

140. Seguin P, Bellissant E, Le Tulzo Y, et al:Effects of epinephrine compared with thecombination of dobutamine and norepi-nephrine on gastric perfusion in septicshock. Clin Pharmacol Ther 2002; 71:381–388

141. McKenzie A, Stoughton RB: Method forcomparing percutaneous absorption of ste-roids. Arch Dermatol 1962; 86:608–610

142. Yard AC, Kadowitz PJ: Studies on the mech-anism of hydrocortisone potentiation of va-soconstrictor responses to epinephrine inthe anesthetized animal. Eur J Pharmacol1972; 20:1–9

143. Grunfeld JP, Eloy L: Glucocorticoids mod-ulate vascular reactivity in the rat. Hyper-tension 1987; 10:608–618

144. Steiner A, Vogt E, Locher R, et al: Stimula-tion of the phosphoinositide signalling sys-tem as a possible mechanism for glucocor-ticoid action in blood pressure control.J Hypertens Suppl 1988; 6:S366–S368

145. Rees DD, Cellek S, Palmer RMJ, et al: Dexa-methasone prevents the induction by endo-toxin of a nitric oxide synthase and theassociated effects on vascular tone: An in-sight into endotoxin shock. Biochem Bio-phys Res Commun 1990; 173:541–547

146. Kennedy B, Ziegler MG: Cardiac epineph-rine synthesis. Regulation by a glucocorti-coid. Circulation 1991; 84:891–895

147. Dailey JW, Westfall TC: Effects of adrenal-ectomy and adrenal steroids on norepineph-rine synthesis and monamine oxidase activ-ity. Eur J Pharmacol 1978; 48:383–391

148. Sakaue M, Hoffman BB: Glucocorticoids in-duce transcription and expression of thealpha 1B adrenergic receptor gene in DTT1MF-2 smooth muscle cells. J Clin Invest1991; 88:385–389

149. Haigh RM, Jones CT: Effect of glucocorti-coids on alpha 1-adrenergic receptor bind-ing in rat vascular smooth muscle. J MolEndocrinol 1990; 5:41–48

150. Sato A, Suzuki H, Murakami M, et al: Glu-cocorticoid increases angiotensin II type 1receptor and its gene expression. Hyperten-sion 1994; 23:25–30

151. Scheuer DA, Bechtold AG: Glucocorticoidspotentiate central actions of angiotensin toincrease arterial pressure. Am J Physiol


Regul Integr Comp Physiol 2001; 280:R1719–R1726

152. Paya D, Gray GA, Fleming I, et al: Effect ofdexamethasone on the onset and persis-tence of vascular hyporeactivity induced byE coli lipopolysaccharide in rats. Circ Shock1993; 41:103–112

153. Wu CC, Croxtall JD, Perretti M, et al: Li-pocortin 1 mediates the inhibition by dexa-methasone of the induction by endotoxin ofnitric oxide synthase in the rat. Proc NatlAcad Sci U S A 1995; 92:3473–3477

154. Mansart A, Bollaert PE, Seguin C, et al:Hemodynamic effects of early versus lateglucocorticosteroid administration in ex-perimental septic shock. Shock 2003; 19:38–44

155. (V) Bhagat K, Collier J, Vallance P: Localvenous responses to endotoxin in humans.Circulation 1996; 94:490–497

156. (V) Barber AE, Coyle SM, Marano MA, et al:Glucocorticoid therapy alters hormonal andcytokine responses to endotoxin in man.J Immunol 1993; 150:1999–2006

157. (III) Annane D, Bellissant E, Sebille V, et al:Impaired pressor sensitivity to noradrena-line in septic shock patients with and with-out impaired adrenal function reserve. Br JClin Pharmacol 1998; 46:589–597

158. (III) Bellissant E, Annane D: Effect of hy-drocortisone on phenylephrine—Mean ar-terial pressure dose-response relationshipin septic shock. Clin Pharmacol Ther 2000;68:293–303

159. (II) Bollaert PE, Charpentier C, Levy B, etal: Reversal of late septic shock with supra-physiologic doses of hydrocortisone. CritCare Med 1998; 26:645–650

160. (II) Briegel J, Forst H, Haller M, et al: Stressdoses of hydrocortisone reverse hyperdy-namic septic shock: a prospective, random-ized, double-blind, single-center study. CritCare Med 1999; 27:723–732

161. (V) Chawla K, Kupfer Y, Tessler S: Hydro-cortisone reverses refractory septic shock.Abstr. Crit Care Med 1999; 27:A33

162. (I) Annane D, Sebille V, Charpentier C, et al:Effect of treatment with low doses of hydro-cortisone and fludrocortisone on mortalityin patients with septic shock. JAMA 2002;288:862–871

163. (II) Keh D, Boehnke T, Weber-Cartens S, etal: Immunologic and hemodynamic effectsof “low-dose” hydrocortisone in septicshock: A double-blind, randomized, place-bo-controlled, crossover study. Am J RespirCrit Care Med 2003; 167:512–520

164. Cronin L, Cook DJ, Carlet J, et al: Cortico-steroid treatment for sepsis: a critical ap-praisal and meta-analysis of the literature.Crit Care Med 1995; 23:1430–1439

165. (V) McKee JI, Finlay WE: Cortisol replace-ment in severely stressed patients. Lancet1983; 1:484

166. (V) Holmes CL, Walley KR, Chittock DR, etal: The effects of vasopressin on hemody-namics and renal function in severe septic

shock: A case series. Intensive Care Med2001; 27:1416–1421

167. Kusano E, Tian S, Umino T, et al: Argininevasopressin inhibits interleukin-1 beta-stimulated nitric oxide and cyclic guanosinemonophosphate production via the V1 re-ceptor in cultured rat vascular smoothmuscle cells. J Hypertens 1997; 15:627–632

168. Wakatsuki T, Nakaya Y, Inoue I: Vasopressinmodulates K(�)-channel activities of cul-tured smooth muscle cells from porcinecoronary artery. Am J Physiol 1992; 263:H491–H496

169. (V) Abboud FM, Floras JS, Aylward PE, et al:Role of vasopressin in cardiovascular andblood pressure regulation. Blood Vessels1990; 27:106–115

170. Wang BC, Flora-Ginter G, Leadley RJ Jr, etal: Ventricular receptors stimulate vaso-pressin release during hemorrhage. Am JPhysiol 1988; 254:R204–R211

171. Wilson MF, Brackett DJ, Tompkins P, et al:Elevated plasma vasopressin concentrationsduring endotoxin and E. coli shock. AdvShock Res 1981; 6:15–26

172. (III) Landry DW, Levin HR, Gallant EM, etal: Vasopressin deficiency contributes to thevasodilation of septic shock. Circulation1997; 95:1122–1125

173. (V) Sharshar T, Carlier R, Blanchard A, et al:Depletion of neurohypophyseal content ofvasopressin in septic shock. Crit Care Med2002; 30:497–500

174. (V) Sharshar T, Blanchard A, Paillard M, etal: Circulating vasopressin levels in septicshock. Crit Care Med 2003; 31:1752–1758

175. (V) Tsuneyoshi I, Yamada H, Kakihana Y, etal: Hemodynamic and metabolic effects oflow-dose vasopressin infusions in vasodila-tory septic shock. Crit Care Med 2001; 29:487–493

176. (II) Malay MB, Ashton RC Jr, Landry DW, etal: Low-dose vasopressin in the treatment ofvasodilatory septic shock. J Trauma 1999;47:699–705

177. (II) Patel BM, Chittock DR, Russell JA, et al:Beneficial effects of short-term vasopressininfusion during severe septic shock. Anes-thesiology 2002; 96:576–582

178. (V) O’Brien A, Clapp L, Singer M: Terlipres-sin for norepinephrine-resistant septicshock. Lancet 2002; 359:1209–1210

179. (III) van Haren FM, Rozendaal FW, van derHoeven JG: The effect of vasopressin ongastric perfusion in catecholamine-depen-dent patients in septic shock. Chest 2003;124:2256–2260

180. (III) Klinzing S, Simon M, Reinhart K, et al:High-dose vasopressin is not superior tonorepinephrine in septic shock. Crit CareMed 2003; 31:2646–2650

181. (V) Parker M, Suffredini A, Natanson C, etal: Responses of left ventricular function insurvivors and nonsurvivors of septic shock.J Crit Care 1989; 4:19–25

182. Raper R, Sibbald M, Driedger A, et al: Rel-ative myocardial depression in normoten-sive sepsis. J Crit Care 1989; 4:9–18

183. (V) Parker MM, McCarthy K, Ognibene FP,et al: Right ventricular dysfunction and di-latation, similar to left ventricular changes,characterize the cardiac depression of septicshock in humans. Chest 1990; 97:126–131

184. Parker MM, Ognibene FP, Parrillo JE: Peaksystolic pressure/end-systolic volume ratio,a load-independent measure of ventricularfunction, is reversibly decreased in humanseptic shock. Crit Care Med 1994; 22:1955–1959

185. (V) Ognibene FP, Parker MM, Natanson C,et al: Depressed left ventricular perfor-mance. Response to volume infusion in pa-tients with sepsis and septic shock. Chest1988; 93:903–910

186. (V) Dhainaut JF, Huyghebaert MF, Monsal-lier JF, et al: Coronary hemodynamics andmyocardial metabolism of lactate, free fattyacids, glucose, and ketones in patients withseptic shock. Circulation 1987; 75:533–541

187. (V) Cunnion RE, Schaer GL, Parker MM, etal: The coronary circulation in human sep-tic shock. Circulation 1986; 73:637–644

188. Gotloib L, Shostak A, Galdi P, et al: Loss ofmicrovascular negative charges accompa-nied by interstitial edema in septic rats’heart. Circ Shock 1992; 36:45–56

189. Liu MS, Wu LL: Heart sarcolemmal Ca2�transport in endotoxin shock: II. Mecha-nism of impairment in ATP-dependentCa2� transport. Mol Cell Biochem 1992;112:135–142

190. Gulick T, Chung MK, Pieper SJ, et al: In-terleukin 1 and tumor necrosis factor in-hibit cardiac myocyte �-adrenergic respon-siveness. Proc Natl Acad Sci USA 1989; 86:6753–6757

191. Carli A, Auclair MC, Vernimmen C: Indo-methacin suppresses the early cardiode-pressant factor released by endotoxin in therat: Possible involvement of a prostacyclin-related material. Adv Shock Res 1983; 10:161–71

192. Finkel MS, Oddis CV, Jacob TD, et al: Neg-ative inotropic effects of cytokines on theheart mediated by nitric oxide. Science1992; 257:387–389

193. Brady AJB, Poole-Wilson PA, Harding SE, etal: Nitric oxide production within cardiacmyocytes reduces their contractility in en-dotoxemia. Am J Physiol 1992; 263:H1963–H1966

194. Schulz R, Panas DL, Catena R, et al: Therole of nitric oxide in cardiac depressioninduced by interleukin-1 beta and tumournecrosis factor-alpha. Br J Pharmacol 1995;114:27–34

195. Favory R, Lancel S, Marchetti P, et al: En-dotoxin-induced myocardial dysfunction:Evidence for a role of sphingosine produc-tion. Crit Care Med 2004; 32:495–501

196. Klem C, Dasta JF, Reilley TE, et al: Variabil-ity in dobutamine pharmacokinetics in un-stable critically ill surgical patients. CritCare Med 1994; 22:1926–1932

197. (V) Juste RN, Moran L, Hooper J, et al:Dopamine clearance in critically ill pa-


tients. Intensive Care Med 1998; 24:1217–1220

198. (III) Gilbert EM, Haupt MT, Mandanas RY,et al: The effect of fluid loading, blood trans-fusion, and catecholamine infusion on oxy-gen delivery and consumption in patientswith sepsis. Am Rev Respir Dis 1986; 134:873–878

199. (II) Hayes MA, Timmins AC, Yau EHS, et al:Elevation of systemic oxygen delivery in thetreatment of critically ill patients. N EnglJ Med 1994; 330:1717–1722

200. (I) Gattinoni L, Brazzi L, Pelosi P, et al: Atrial of goal-oriented hemodynamic therapyin critically ill patients. N Engl J Med 1995;333:1025–1032

201. (II) Yu M, Levy MM, Smith P, : Effect ofmaximizing oxygen delivery on morbidityand mortality rates in critically ill patients:A prospective, randomized, controlledstudy. Crit Care Med 1993; 21:830–838

202. (III) Ronco JJ, Fenwick JC, Tweeddale MG,et al: Identification of the critical oxygendelivery for anaerobic metabolism in criti-cally ill septic and nonseptic humans. JAMA1993; 270:1724–1730

203. (II) Boyd O, Grounds RM, Bennett ED: Arandomized clinical trial of the effect ofdeliberate perioperative increase of oxygendelivery on mortality in high-risk surgicalpatients. JAMA 1993; 270:2699–2707

204. (I) Sandham JD, Hull RD, Brant RF, et al: Arandomized, controlled trial of the use ofpulmonary-artery catheters in high-risksurgical patients. N Engl J Med 2003; 348:5–14

205. Heyland DK, Cook DJ, King D, et al: Maxi-mizing oxygen delivery in critically ill pa-tients: A methodologic appraisal of the evi-dence. Crit Care Med 1996; 24:517–524

206. McCarter FD, Nierman SR, James JH, et al:Role of skeletal muscle Na�-K� ATPaseactivity in increased lactate production insub-acute sepsis. Life Sci 2002; 70:1875–1888

207. Jain A, Shroff SG, Janicki JS, et al: Relationbetween mixed venous oxygen saturationand cardiac index. Nonlinearity and nor-malization for oxygen uptake and hemoglo-bin. Chest 1991; 99:1403–1409

208. (V) Vaughn S, Puri VK: Cardiac outputchanges and continuous mixed venous ox-ygen saturation measurement in the criti-cally ill. Crit Care Med 1988; 16:495–498

209. Dubin A, Murias G, Estenssoro E, et al:Intramucosal-arterial PCO2 gap fails to re-flect intestinal dysoxia in hypoxic hypoxia.Crit Care 2002; 6:514–520

210. (III) Loeb HS, Winslow EB, Rahimtoola SH,et al: Acute hemodynamic effects of dopa-mine in patients with shock. Circulation1971; 44:163–173

211. (III) Nasraway SA, Rackow EC, Astiz ME, etal: Inotropic response to digoxin and dopa-mine in patients with severe sepsis, cardiacfailure, and systemic hypoperfusion. Chest1989; 95:612–615

212. (III) de la Cal MA, Miravalles E, Pascual T, etal: Dose-related hemodynamic and renal ef-fects of dopamine in septic shock. Crit CareMed 1984; 12:22–25

213. (V) Juste RN, Panikkar K, Soni N: The ef-fects of low-dose dopamine infusions onhaemodynamic and renal parameters in pa-tients with septic shock requiring treat-ment with noradrenaline. Intensive CareMed 1998; 24:564–568

214. (V) Jardin F, Sportiche M, Bazin M, et al:Dobutamine: A hemodynamic evaluation inhuman septic shock. Crit Care Med 1981;9:329–332

215. (II) De Backer D, Berre J, Zhang H, et al:Relationship between oxygen uptake andoxygen delivery in septic patients: effects ofprostacyclin versus dobutamine. Crit CareMed 1993; 21:1658–1664

216. (III) Vallet B, Chopin C, Curtis SE, et al:Prognostic value of the dobutamine test inpatients with sepsis syndrome and normallactate values: A prospective, multicenterstudy. Crit Care Med 1993; 21:1868–1875

217. (III) Gutierrez G, Clark C, Brown SD, et al:Effect of dobutamine on oxygen consump-tion and gastric mucosal pH in septic pa-tients. Am J Respir Crit Care Med 1994;150:324–329

218. (III) De Backer D, Moraine JJ, Berre J, et al:Effects of dobutamine on oxygen consump-tion in septic patients. Direct versus indi-rect determinations. Am J Respir Crit CareMed 1994; 150:95–100

219. Vincent JL, Roman A, Kahn RJ: Dobut-amine administration in septic shock: Addi-tion to a standard protocol. Crit Care Med1990; 18:689–693

220. (III) Mira JP, Fabre JE, Baigorri F, et al:Lack of oxygen supply dependency in pa-tients with severe sepsis. A study of oxygen

delivery increased by military antishocktrouser and dobutamine. Chest 1994; 106:1524–1531

221. (III) Redl-Wenzl EM, Armbruster C, Edel-mann G, et al: Noradrenaline in the “highoutput-low resistance” state of patients withabdominal sepsis. Anaesthesist 1990; 39:525–529

222. (V) Tell B, Majerus TC, Flancbaum L: Do-butamine in elderly septic shock patientsrefractory to dopamine. Intensive Care Med1987; 13:14–18

223. (V) Joly LM, Monchi M, Cariou A, et al:Effects of dobutamine on gastric mucosalperfusion and hepatic metabolism in pa-tients with septic shock. Am J Respir CritCare Med 1999; 160:1983–1986

224. (II) Levy B, Nace L, Bollaert PE, et al: Com-parison of systemic and regional effects ofdobutamine and dopexamine in norepi-nephrine-treated septic shock. IntensiveCare Med 1999; 25:942–948

225. (II) Lebuffe G, Levy B, Neviere R, et al:Dobutamine and gastric-to-arterial carbondioxide gap in severe sepsis without shock.Intensive Care Med 2002; 28:265–271

226. (III) Meier-Hellmann A, Reinhart K, BredleDL, et al: Epinephrine impairs splanchnicperfusion in septic shock. Crit Care Med1997; 25:399–404

227. (II) Barton P, Garcia J, Kouatli A, et al:Hemodynamic effects of i.v. milrinone lac-tate in pediatric patients with septic shock.A prospective, double-blinded, randomized,placebo- controlled, interventional study.Chest 1996; 109:1302–1312

228. (II) Hernandez G, Gigoux J, Bugedo G, et al:Acute effect of dobutamine and amrinoneon hemodynamics and splanchnic perfusionin septic shock patients. Rev Med Chil 1999;127:660–666

229. (III) Heinz G, Geppert A, Delle Karth G, etal: IV milrinone for cardiac output increaseand maintenance: Comparison in nonhy-perdynamic SIRS/sepsis and congestiveheart failure. Intensive Care Med 1999; 25:620–624

230. Weisul JP, O’Donnell TF Jr, Stone MA, et al:Myocardial performance in clinical septicshock: Effects of isoproterenol and glucosepotassium insulin. J Surg Res 1975; 18:357–363


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