Apoyo hemodinámico en las prácticas de sepsis

7/31/2019 Apoyo hemodinmico en las prcticas de sepsis

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Special Articles

Practice parameters for hemodynamic support of sepsis in adult

patients: 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-t i at i ng c a us e s; a s t his s y nd r om eprogresses, 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 infectious

agents or infection-induced mediatorsin the bloodstream produce hemody-namic decompensation. Septic shock is

primarily a form of distributive shockand is characterized by ineffective tis-sue oxygen delivery and extraction as-sociated with inappropriate peripheral

vasodilati on despite prese rved 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 of

cardiac 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 from

myocardial failure is rare (1).Cellular dysfunction in sepsis is the

final 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 of

caspases and induction of heat shockproteins may lead to apoptotic celldeath. In early shock, compensatorymechanisms are activated in an attemptto restore pressure and flow to vital

organs. When these compensatorymechanisms begin to fail, damage tocellular membranes, loss of ion gradi-ents, leakage of lysosomal enzymes,proteolysis due to activation of cellular

proteases, and reductions in cellularenergy stores occur and may result incell death (3). Once enough cells from

vital 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 Care

Medicine with updated guidelines for hemodynamic support of

adult patients with sepsis.

Data Source:Publications relevant to hemodynamic support of

septic 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 the

Society of Critical Care Medicine.

Study Selection: Both human studies and relevant animal

studies were considered.

Data Synthesis: The experts articles reviewed the literature

and classified the strength of evidence of human studies accord-

ing to study design and scientific value. Recommendations were

drafted and graded levels based on an evidence-based rating

system described in the text. The recommendations were de-

bated, and the task force chairman modified the document until


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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 interrupt

the 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 OF

PRACTICE PARAMETERS FOR

HEMODYNAMIC SUPPORT IN

SEPSIS

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 patients

with seps is 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 a

wide 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 recommendations

has been graded as modified from theguidelines of Evidence-Based Medicine

Working 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 patients

with septic shock, activated protein C isnot a hemodynamic therapy per se, nor

was 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 using

vasoactive agents directed to physiologic

and clinical end points.Patients with septic shock should be

treated 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 and

repeated 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 of

Hemodynamic Support in Septic

Patients

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


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Figure 1. Suggested algorithm for hemodynamic support of adult patients with severe sepsis and septic shock. SBP, systolic blood pressure; MAP, mean

arterial pressure; ICU, intensive care unit; BP, blood pressure; HR, heart rate; Hgb, hemoglobin. *Adequate cardiac filling pressures can be assessed by

response of cardiac output (CO) to increases of pulmonary artery occlusion pressure. Maximal benefit is usually achieved at pulmonary artery occlusion

pressure 1215 mm Hg. Variation in arterial pressure with respiration can also be used to identify patients who would benefit from increased fluid

administration. Cardiac output can be assessed by echocardiography or by measuring cardiac index and/or mixed-venous oxygen saturation with a

pulmonary artery catheter. Perfusion can be assessed using a combination of clinical and laboratory variables, as described in the text. A corticotropin

stimulation test is recommended. See text for details.

1930 Crit Care Med 2004 Vol. 32, No. 9


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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 only

from 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 flow

within 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 the

specific recommendations, which willcertainly change as our understanding ofsepsis improves. For example, although

which 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 of

variables. 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 central

venous 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 lower

Acute Physiology and Chronic HealthEvaluation II scores, indicating less se-

vere organ dysfunction (7). More impor-tantly, in-hospital mortality rate was sig-nific antl y d ec re as ed i n t he g ro upassigned 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 glycolysis

with 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(1517). The trend of lactate concentra-tions is a better indicator than a single

value (15, 16). It is also of interest tonote that blood lactate concentrationsare a better prognostic indicator thanoxygen-derived variables (calculated ox-

ygen delivery and consump tion) (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 the

oxygen 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



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recent study showed that monitoring of

c e ntr a l v e nous o x yg e n s a tur at i on

(ScvO2) can be a valuable guide to early

resuscitation (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, increased

serum concentrations of transaminases,

lactic dehydrogenase, and bilirubin, and

prolonged clotting tests (3). Methods of

measuring 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 oxygen

supply may be inadequate in some pa-

tients, even when more global variables

appear adequate (19). Second, the gut

(especially the stomach) may be accessi-

ble to monitoring systems. Third, the

countercurrent flow in the gut microcir-

culation increases the risk of mucosal

hypoxia. Finally, the gut may have a

higher critical oxygen delivery threshold

than other organs (20), and gut ischemiaincreases intestinal permeability.

Gastric tonometry is a method to as-

sess regional perfusion in the gut that

employs a balloon in the stomach to mea-

sure intramucosal PCO2. Gastric mucosal

PCO2 is influenced directly by systemic

arterial PCO2, however, and so use of gas-

tric-arterial PCO2 difference has been pro-

posed as the primary tonometric variable

of interest, although even this measure is

not a simple measure of gastric mucosal

hypoxia (21). Despite its complexity,

tonometry is a reasonably good predictor

for the ultimate outcome of critically ill

patients (2226). Its utility to guide ther-

apy in patients with sepsis and septic

shock, 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 shown

to yield tissue PCO2 measurements that

correlate with those obtained by gastric

tonometry (27).

FLUID RESUSCITATION IN

SEPSIS

Goals and Monitoring of Fluid

Resuscitation

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 the

use 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 (250500 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(3638). 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 offluid 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. Evaluation

of the response to fluid infusion is muchmore useful than one measurement at asingle time point. This is particularly truein unstable patients, since cardiac and

vascular 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 in

gastric 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 Ringers solution. The lac-tate content of Ringers solution is rap-idly metabolized during resuscitation and



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

The volume of distribution of normalsaline and Ringers 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, 100200 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 natura lly occurr ing

plasma 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 volume

when 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 hydroxyethyl

starch 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 activity

and 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 solutions

will 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 associated

with 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 in

plasma 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 of

pulmonary edema (5557). 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 of

extravascular 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).



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The acute respiratory distress syn-drome occurs in 30 60% of patients withseptic shock. Of concern has been thepossibility that in the setting of increased

microvascular permeability, colloid parti-cles could migrate into the interstitium

where they would favor fluid retention in

the 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 acute

respiratory 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 area

when 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 despite

significant 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 and

the 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 choice

of fluids was the major determinant ofbacterial translocation (66).

Finally, there have been multiple

meta-analyses of the clinical studies com-paring crystalloids with colloids, which

have 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 patients

with 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 13 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 patients

with 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 arterial

oxygen 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 (7274). 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 fails

to 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, even

when 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 restoration

of 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).



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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 to

supplement 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 (8595). 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 patients

with 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 of

60 or 65 mm Hg.The gastrointestinal tract, particularly

perfusion 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 of

vasopressor 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 impairs

stroke 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 gkg1min1, 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 of510 gkg1min1, 1-adrenergic ef-fects predominate, increasing cardiaccontractility and heart rate. Dopaminecauses the release of norepinephrine

from nerve terminals, which contributesto its effects on the heart. At doses 10gkg1min1, 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, 100111). 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 torestor e b lood p ressu re was 1 5gkg1min1. In most studies central

venous, 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 20gkg1min1 did show increases inright heart pressures as well as heart rate.Dopamine has been shown to improveright ventricular contractility in patients

with underlying right ventricular failure(112).

Dopamine increases pulmonary shunt

fraction, 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 flow

in 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 been

associated 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 delivery

and 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 mucosal

oxygen 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 filtration

rate 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 with

early renal dysfunction (urine output0.5 mLkg1hr1 over 4 hrs, creatine150 mol/L or an increase of 80mol/L over 24 hrs) (117). Patients wererandomized to low (renal) dose dopa-

mine (2 gkg1min1) or placebo, andthe primary end point was peak serumcreatinine. No difference was found in

either 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



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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 with

compromised 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 1020% 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 (13 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 norepinephrine

with 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 gkg1min1

(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 gkg1min1) re-sulted in successful treatment in only 31%of patients whereas norepinephrine admin-

istration (1.5 1.2 gkg1

min1

) 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(123125). 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 (13 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 can

even 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 study

compared 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 pressure

without causing a deterioration in car-diac index and organ function (128). Usedin doses of 0.013 gkg1min1, 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 and

lactate concentration, are significantlyimproved in most studies. Unfortunately,only one report was controlled (106), and

whether 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 the

hemodynamic 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 not

withheld 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



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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 have

evaluated 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 70g/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 gkg1min1 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 Lmin1m2) receiving eitherlow-dose dopamine or dobutamine, whoremained hypotensive despite fluid ad-ministration (mean arterial pressure 57mm Hg), phenylephrine was begun at 0.5gkg1min1 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 3.7gkg1mi n1 (range 0.4 9. 1gkg1min1). Phenylephrine resulted

in 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 choice

when tachya rrhythmias limit therap ywith 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, primarily

by increasing cardiac index and strokevolume with more modest increases insystemic vascular resistance and heartrate (90, 133135). 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 (133137).

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 by

t he c oncurr ent use o f o ther c at -echolamines. Two more recent studies,however, found increased gastric muco-sal perfusion with epinephrine compared

with 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 global

oxygen 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 in

septic 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 the

phosphoinositide 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 smooth

muscle 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 challenged

with lipopolysaccharide, and in patients



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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, dexamethasone

administration resulted in a complete re-versal of hypotension, improvement inaortic blood flow, and reduced plasmalactate and nitrite/nitrate concentrations

without 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 endotoxin

was 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 gkg1min1 and20 mm Hg at a rate of 1.5 gkg1min1,

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 ACTH9 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 associated

with 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 (0.18mgkg1hr1) for 6 days were investi-gated in 40 hyperdynamic septic shockpatients (160). In this study, as compared

with 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 systemic

vascular resistance was increased (by 260and 369 dynessec/cm5m2 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 dynessec/cm5m2 at peak effect).

The favorable effect of corticosteroidson vascular responsiveness to vasopressor

agents 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 of9 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



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(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 of9 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 blood

volume, 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 patients

with septic shock, concentrations thatwere hypothesized to be inappropriatelylow (172). One potential mechanism for

this 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 concentrations

were 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 patients

with 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 patients

who were not anuric on study entry(175). In another report, in 50 patients

with 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 doses0.05 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 (0.04

units/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 of

vasopressors 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 0.08unit s /m i n. I n t he no re p i ne p hr i negroup, doses were not significantlymodified. Mean arterial pressure and

cardiac index were maintained in bothgroups, and the gastric CO2 gradient

was 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 reported

study (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-



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tent hypotension. Current evidence dem-

onstrates that in catecholamine-resistant

septic shock, the addition of low-dose va-

sopressin (0.01 0.04 units/min) by con-

tinuous infusion to catecholamines can

be used to increase blood pressure and

decrease catecholamine doses. There is

concern, 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 Vasopressor

Therapy

All of the catecholamine vasopressor

agents 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 is

of particular concern in patients treated

with vasopressin. In the presence of

myocardial dysfunction, excessive vaso-

constriction can decrease stroke vol-

ume, cardiac output, and oxygen deliv-

ery. Should this occur, the dose of

vasopressor should be lowered, or the

addition of an inotropic agent such as

dobutamine should be considered (91).Vasopressors can also cause limb isch-

emia and necrosis.

Administration of vasopressors may

impair blood flow to the splanchnic sys-

tem, and this can be manifested by stress

ulceration, ileus, malabsorption, and

even bowel infarction (121, 137). Gut

mucosal integrity occupies a key position

in the pathogenesis of multiple organ

failure, and countercurrent flo w i n

splanchnic microcirculation gives the gut

a higher critical threshold for oxygen de-livery than other organs. If possible, epi-

sodes of intramucosal acidosis, which

might be detected either by a decrease in

gastric mucosal pHi or an increase in

gastric mucosal PCO2, should be avoided,

although no prospective randomized con-

trolled trial has demonstrated a decrease

in mortality rate with pHi or gastric PCO2-

directed care in the management of pa-

tients with septic shock.

INOTROPIC THERAPY IN

SEPSIS

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 usually

maintained 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 to

volume loading, and a low peak systolicpressure/end-systolic volume ratio (a rel-atively load-independent measure of ven-tricular function) (183185). 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 concomitant

with 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 and

variable (196, 197).Some critically ill septic patients are

hypermetabolic 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 4.5Lmin1m2, oxygen delivery 600mLmin1m2, and oxygen consump-tion 170 mLmin1m2 correlated

with improved survival (39). Other inves-tigations, however, have challenged theconcept of pathologic supply-dependencyand hyperresuscitation (199202). 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 produced

conflicting results (199201, 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



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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, this

value 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 patients

with 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 (2225),

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 outcome

with empirical therapy to raise cardiacoutput in patients with normal bloodpressure, but a subpopulation of patientsmight have regional hypoperfusion that

would 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 of

inotropic 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 have

used 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 patients

with a low cardiac index (mean 2.0Lmin1m2), 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 of1-adrenergic stimula-tion can precipitate myocardial ischem

Apoyo hemodinámico en las prácticas de sepsis

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