cardiovascular dysfunction in septic shock · is initially normal or elevated in more than 80...

DOI 10.1378/chest.99.4.1000 1991;99;1000-1009 Chest

RJ Snell and JE Parrillo

Cardiovascular dysfunction in septic shock

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*Fr�mi� the I)epartment of Medicine, Section of Cardiology; Rush-

Preslwterian-St. Lt,ke�s Medical Center and Rush Medical Col-lege, Chicago.

Reprint requests: 1)r Pa,’rillo, Rush-Presbmjterian St. IJ1k(’:c ?%fC(hC(ZlCenter, 1653 West Congress Parkway, Chicago 60612

1000 Cardiovascular Dysfunction in Septic Shock (Snell, Parrillo)

___ i� clinical implications of basic research- Cardiovascular Dysfunction in Septic Shock*

R. Jeffrey Snell, M. D. ; and Joseph E. Parrillo, M.D.

(Chest 1991; 99:1000-09)

EDVI = end-diastolic volume index; LVEF left ventricularejection fraction; LVSWI left ventricular stroke-work index;MDS = myocardial depressant substance; SVR systemic vas-cular resistance; TNF tumor necrosis factor

Septic shock has l)een increasing in incidence since

the 1930s and is presently the most common cause

of death in intensive care units (ICUs) in the United

1 Reasonable current estimates of annual mci-

dence are 400,000 cases of sepsis, 200,000 bouts of

septic shock, and 100,000 deaths due to this syn-

om’2 Reasons underlying this rising incidence and

continued high mortality include increased use of

cytotoxmc and immunosuppressive drug therapies, mn-

creased patient age, increased presence of concomi-

tant medical illnesses, increased use of invasive de-

vices for diagnosis and therapy, and rising incidence

of infections due to organisms other than Gram-

negative bacteria (Gram-positive bacteria, fungi, and

possil)ly viruses), and, perhaps, the emergence of

antil)iotic-resistant organisms. All estimates suggest

that these numbers will continue to rise.

Septic shock is traditionally classified as the proto-

typic example of distributive shock (Table 1). A severe

decrease in systemic vascular resistance (SVR) and

generalized blood flow maldistribution develop in

almost all affected patients. After aggressive volume

loading to ensure adequate preload, the cardiac output

is initially normal or elevated in more than 80 percent

of patients with septic shock.3 This is in contrast to

the cardiogenic, extracardiac obstructive, and olige-

mic (hypovolemic) forms of shock, which produce the

acute phase of the shock syndrome via a decrease in

cardiac output.

During the past several years, however, abnormali-

ties of cardiac performance have also been clearly

demonstrated during human septic shock. While car-

diac output and stroke volume are usually well main-

tamed during the initial stages of human septic shock,

these parameters are very sensitive to small changes

in ventricular preload and afterload. Better measures

of intrinsic cardiac performance were needed to

evaluate myocardial function in human sepsis. With

the use of radionuclide-gated blood pool scanning and

simultaneous catheter-derived thermodilution hemo-

dynamics, highly accurate measurements of both yen-

tricular performance and volumes could be obtained.

The radionuclide-determined ejection fraction is ret-

atively unchanged by acute changes in preload and

afterload.4 Human studies utilizing these techniques5’6

demonstrated that the characteristic pattern of septic

shock consists of an initial decrease in left ventricular

ejection fraction (LVEF) occurring within 24 h of

septic shock onset associated with an increase in both

end-diastolic and end-systolic volume indices (Fig 1).

This pattern of decreased LVEF and ventricular

dilatation was found to be most characteristic of

survivors during the initial few days of the disease

Table 1 -Class4fication of Shock

Cardiogenic

Myopathic (reduced systolic function)

Acute mv()cardial infarction

Dilated car(liomyopathy

Mvocardial depression in septic shock

Mechanical

Mitral regurgitation

Ventricular septal defect

Ventricular aneurysm

Severe left ventricular outHow ohstruction (aortic stenosis,

hypertrophic cardiomyopathy with obstruction)

Arrhythmia

Extracardiac obstructive

Pericardial tamp()Ilade

Constrictive pericar(litis

Pulnunarv carl)()lisn� (massive)

Severe Ptmlmn�narY hypertension (primary or Eisenmenger)

Coarctation of the aorta

Oligemic (h�iovoleniic)

Ilernorrlmge

Fluid depletion

I)istributive

Septic shock

Resixnse to toxic products (eg. overdose)

Anaphvlaxis

Nemirogenic

Endocrinologic



MYOCARDIUM J. D.prsaslon

. Dilatation

RECOVERY

#{149}Vaaodliatation#{149}Vaaoconstriction#{149}Maldiatribution of Blood Flow#{149}Endothsilal Diatruction

ACUTE PHASE OF SEPTIC SHOCK

CHEST I 99 I 4 1 APRIL, 1991 1001

Left Ventricular Left VentricularEnd Diastolic End Systolic

Volume = 200 ml Volume = 150 ml

Stroke Volume = 50 ml

Ejection Fraction = 200 ml - 150 ml

200 ml

RECOVERY PHASE OF SEPTIC SHOCK

Left VentricularEnd Diastolic

Volume = 100 ml

Left VentricularEnd Systolic

Volume = 50 ml

Stroke Volume = 50 ml

Ejection Fraction = 100 ml - 50 ml100 ml FIGURE 1. Cardiac functional and volume

changes seen in survivors ofseptic shock.(From Parker et at. Ann Intern Med

1984; 100:483-90. Reproduced by per-

mission.)

process (compensated myocardial depression). Inter-

estingly, in survivors, these changes are reversible,

and the ventricular function and size return to normal

by seven to ten days after septic shock onset. This

pattern has been confirmed by other radionucide

studies7 and has also been documented with two-

dimensional echocardiography.� Thus, human septic

shock is actually best classified in both the distributive

and the cardiogenic categories.

The pathogenetic mechanisms underlying this car-

diovascular dysfunction are very complex (Fig 2). The

sequence begins with a nidus of infection leading

either to bloodstream invasion or release of large

amounts of various mediators into the circulation.

These mediators may consist of microorganism-elab-

orated exotoxins; microorganism-derived structural

components, such as endotoxin and teichoic acid

antigens; or host-manufactured products, such as

NIDUS OF INFECTION � ORGANISMS � EXOGENOUS TOXINS � ENDOGENOUS MEDIATORSPn.umonltls Organism CYTOKINES

Psrttonltls Structural Component #{149}tntertiukln 1,2.8

C#{149}llulltts Exotoxln ( TSST-1. Toxin A) #{149}Tumor N.crosla Factor I TNF)

Abscess Endotoxln PLATELET ACTIVATING FACTOR (PAF)

Othir infiction sltss ARACHIDONIC ACID METABOLITES

HUMORAL DEFENSE SYSTEMS

. Corrpl.m.nt#{149}Klnlns. Coagulation

OTHERS

sMyocardlal Depressant Substancs (MDS). Endorphlns. Hiatamln.

FIGURE 2. Sequence of pathogenetic steps leading from a nidus of infection to cardiovascular dysfunctionand shock during human sepsis. SVR = systemic vascular resistance; CO = cardiac output;

MOSF = multiorgan system failure.



Table 2-Hemodynamic Variables in Survivors and

Nonsurvivors ofSeptk Shock

I

I

50

40

I’d

EE0)

(I)

t i I 1

-i 80 90 100 110 120

EDVI (mI/mI2)

Ftcuin� 3. Frank-Starling relationships for each ofthe three patient

groups. Data points represent mean prevolume and postvolurne

infusion values of end-diastolic volume index (EDVI) and leftventricular stroke work index (LVSWI) for each patient group.(From Ognibene et a). Chest 1988; 93:903-100. Reproduced bypermission.)

1002 CaidI�cuIar Dysfunction taoSeptic Shock (Snot. Pteruit�)

cytokines (eg, tumor necrosis factor [TNF], interleu-kins), complement components, and others. Although

some of these mediators are more important than

others, there are probably 20 or 30 molecular sub-

stances that can exert profound effects on the periph-

eral and pulmonary vasculature, and some substances

(eg, myocardial depressant substance) that appear to

have direct myocardial effects. These vascular and

myocardial abnormalities combine to produce gener-

alized “cardiovascular insufficiency.” Aggressive ther-

apy in patients wth septic shock will reverse this

process in approximately 50 percent, and these pa-

tients will survive . ‘� Unfortunately, the other 50

percent will not respond, but will die as a result of

the mechanisms shown in Figure 2.

Unresponsive hypotension is usually due to a very

low SVR, which cannot be corrected by any therapy;

only a small proportion (approximately 10 to 20

percent) ofcases ofunresponsive hypotension are due

to low cardiac output (decompensated myocardial

depression). Multiple organ system dysfunction com-

monly affects the lungs, kidneys, liver, central nervous

system, and heart. Ultimately this process leads to

death due to failure of one or more organ systems. 1.2,9

Investigations regarding cardiovascular dysfunction

in septic shock have included laboratory work, exper-

iments in animal models, and human studies. This

article will review some of the recent data obtainedfrom investigations designed to elucidate better the

pathogenesis and therapy of this disease.

CARDIAC DYSFUNCTION IN HUMAN SEPSIS:

RECENT STUDIES

The most common effect of sepsis on the cardiovas-

cular system is to produce a hemodynamic profile

characterized by an elevated cardiac index and de-

creased. SVR. While some early studies in humans

with septic shock reported a low cardiac index,’#{176}’2 it

is likely that many of the patients had an inadequate

ventricular preload, since the central venous pressure

was used at that time to evaluate volume status. With

use of the pulmonary capillary wedge pressure as a

measure to ensure an adequate left ventricular pre-

load, a low cardiac index has been found to be quite

uncommon, even in the very late stages of septic

shock.3

In addition to this hyperdynamic hemodynamic

profile, reversible depression of LVEF and dilation of

the left ventricle usually occur in human sepsis (Fig

1). This pattern of cardiovascular performance was

recently extended to the right ri’s Table 2

shows the initial and final left and right ventricular

ejection fractions and end-diastolic volume index

(EDVI) in 22 survivors and 17 nonsurvivors of septic

shock. Both LVEF and right ventricular ejectionfraction are initially low, and both ventricles are

Variable

S(

Initial

urvivors

n=22)

Final pt

Nonsurvivo

(n=17)

Initial Final

mm

pt

Left ventricular 0.31 0.47 0.001 40 43 NSejection fraction

Left ventricular end- 145 106 0.012 124 102 NS

diastolic volumemdcx, mi/rn’

Right ventricular 0.35 0.51 0.001 0.41 0.39 NSejection fraction

Right ventricular end. 124 88 0.03 120 114 NSdiastolic volumeindex, mi/rn’

#{176}FmrnParker et al. Chest 1990; 97:126-31. Reproduced by perrnis-

sion.

tPaired-sample t test.

dilated. These values return toward normal in survi-

vors. Thus, the myocardial depression of septic shock

is a biventricular phenomenon.

The response to volume infusion is also abnormal

in patients with septic shock, providing further evi-

dence ofdepressed ventricular performance. A recent

study’4 examined the response to fluid administration

in three groups of patients: critically ill nonseptic

601-

II

I

I/

IIi,

301- ---c�rnmbe

---Sepsis without Shock

- Septic Shock



cHEST I 99 I 4 I APRIL 1991 1003

control patients, patients with sepsis without hypoten-

sion, and patients in septic shock (Fig 3). All groups

received similar amounts of fluid and had similar

increments in pulmonary capillary wedge pressure.

In control patients, volume infusion led to substantial

increases in both EDVI and left ventricular stroke-

work index (LVSWI), changes representing a normal

response. Patients with septic shock had a dilated

ventricle prior to volume challenge, and they had a

markedly diminished cardiac response to volume

administration with only minor increments in both

EDVI and LVSWI. The septic patients without by-

potension demonstrated an intermediate response.

These Frank-Starling relationships further confirm

altered ventricular performance, as measured here by

changes in LVSWI in response to volume loading, in

patients with septic shock.

Serial measurements of some of the cardiovascularvariables mentioned have been studied in an attempt

to identify factors ofprognostic value during the early

stages of septic shock. In a study of traditional hemo-

dynamic parameters,3 the statistically significant pre-

dictors of survival included an initial heart rate of

<106 beats per minute, a 24-h heart rate of <95

beats per minute, or systemic vascular resistance of

>1,529 dynescm5m2, and a change over the initial

24 h manifested by a decrease in heart rate by >18

beats per minute or a decrease in cardiac index by

>0.5 L/miwm2. These findings suggest that nonsur-

vivors have a persistence of the hyperdynamic hemo-

dynamic proffle, while the survivors’ hemodynamic

values begin to return toward normal by 24 h.Serial changes in LVEF and EDVI have also been

shown to distinguish survivors of septic shock from

nonsurvivors.6 In that study, acontrolgroup of criticallyill nonseptic patients was used. The survivors initially

bad a depressed mean LVEF of 0.40 compared with

the control patients’ ejection fraction of0.53. This wasassociated with a dilated left ventricle (EDVI =122

mum2 compared with a control value of 90 mI/rn2).

These abnormalities persisted for the first two to five

days and then returned toward normal by one to two

weeks after the onset of septic shock. Nonsurvivors,

on the other hand, had an LVEF and an EDVI that

were not significantly different from those of the

control patients and that did not change significantlyover the course of their septic shock. In addition, in

survivors there was a strong negative correlation

between LVEF and EDVI (r= -0.62, p<O.OOl),

whereas no such statistically signfficant correlation

occurred in nonsurvivors. In other words, in the

nonsurvivors, a decrease in LVEF was not consistently

associated with left ventricular dilatation. Thus, yen-

tricular dilatation may in part be a normal compensa-

tory mechanism, and a ventricle that is unable to

dilate may predispose to a higher mortality in human

septic shock.

Two different hypotheses have been offered to

account for the myocardial depression in sepsis. The

first postulated mechanism is that coronary hypoper-

fusion leads to ischemic myocardial dysfunction. Ar-

guments for this mechanism have been based on

animal models that were hemodynamically very di-

ferent from human sepsis.’5”8 A recent study investi-

gated the coronary circulation during human septic

shock using coronary sinus thermodilution catheters

to measure coronary sinus blood flow and myocardial

lactate extraction.’7 The patients with septic shock had

coronary blood flows equal to or greater than those of

controls. In addition, there was no difference in

myocardial lactate extraction between patients withseptic shock and myocardial depression and those with

sepsis but no myocardial depression. Thken together,

these findings exclude global iscbemia as the cause of

myocardial depression in septic shock. These findings

were corroborated in a subsequent tu’8

A second postulated mechanism is the presence in

the bloodstream of one or more active circulating

myocardial depressant substances (MDSs). As with

earlier studies of coronary perfusion, most early

investigations of circulating MDS activity employed

sera from animal models of questionable human rele-

vance.’9’� Furthermore, these studies utilized isolated

papillary muscle preparations to assay MDS activity,

assays that were difficult to establish and reproduce.

Clearly, evaluation of the role of MDSs in human

sepsis would benefit from a less cumbersome in vitro

myocardial contractility assay that could be correlated

with in vivo measurements of cardiac performance.

IN ViTRO STUDIES OF MYOCARDIAL DEPRESSION

In 1985 a biologic system for assaying MDS activity

in human serum with use of newborn rat myocytes in

primary tissue culture was reported.2’ These myocytes

adhere to the bottom of a petri dish and after several

days of growth they exhibit spontaneous contractions

at rates of 30 to 100 beats per minute. Videodensi-

tometry was used to evaluate the movement of the

cell, permitting quantitative recording of the extent

and velocity of shortening during a single myocyte

contraction. This system allowed serum to be assayed

for effects on myocardial cell contractility. When

newborn rat myocytes were exposed In vitro to sera

from patients in the acute phase of septic shock, theextent and velocity of myocyte shortening were de-

pressed significantly (Fig 4),21 The degree of depres-

sion In vitro correlated with the amount of decrease

in LVEF in vivo. Furthermore, this In vitro depression

did not occur with sera from normal volunteers, crit-

ically ill nonseptic patients, or patients with reduced

ejection fractions due to structural heart disease; nor

was depression seen with sera taken from the patients



+50 -

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-30 - __E___ Patients:RecoveryPhase or

-40 - � Pre-sepsis0 = Patient who survived S Phase

- 50 - S = Patient who died0

- = Mean for patient-60 - group

§-70 -

FIGURE 4. Effect of serum from different patient groups on the extent of shortening of spontaneouslyheating rat heart cells in vitro. (From Parrillo et al Clin Invest 1985; 76:1539-53. Reproduced by

permission.)

+ 60

1004 Cardiovascular Dysfunction in Septic Shock (Smell, PterriIIO)

during the recovery phase ofseptic shock. These find-

ings provided the first strong evidence that circulating

MDSs play a pathophysiologic role in the myocardial

dysfunction ofhuman septic shock.

The assay system has since been revised by placing

latex beads onto the cultured myocytes, allowing the

use of a video closed-loop-tracking system to quanti-

tate myocyte shortening with greater ease than video-

densitometry.� Instantaneous movement of the latex

bead is tracked electronically and converted to an

analog signal. Experiments utilizing this modified

assay system have confirmed the initial results and

provided further clinical correlations.

In one study, sera from 34 consecutive patients with

septic shock were assayed for MDS activity.2� A patient

was considered positive for MDS if his serum consis-

tently depressed myocyte contractility by 20 percent

or more; almost half (43 percent) of the patients with

septic shock in this series were positive for MDS . As

in the 1985 study by Parrillo et al,21 �g vitro depression

of myocardial cell contractility correlated with in vivo

depression ofejection fraction. Further, MDS-positive

patients had higher pulmonary artery wedge pressures

and larger EDVI values than MDS-negative patients

(Table 3). In addition, MDS-positive patients had

higher mean peak lactic acid levels, suggesting greater

inadequacy of tissue blood flow or perhaps a direct

mediator-induced peripheral vascular effect. High

levels of MDS activity were found in sera from a high

percentage of patients with septic shock, particularly

those with the most severe cardiovascular insuffi-

ciency. The presence ofMDS activity is also associated

with a trend toward increased mortality (36 percent

mortality in MDS-positive vs 10 percent in MDS-

negative patients) in this study.

Recent attention has focused on the nature and

identity of this MDS. Previous experiments have

shown a number of specific characteristics.2’ As the

concentration of depressant serum placed onto the

Table 3-Characteristks ofl4 Thtients with MDS and 20Ibtients without MDS*

Characteristics

MDS-positive

(n = 14)MDS-negative

(n = 20) p

Plasma lactate, mmol/L 6.9± 1.7 2.7±0.4 <0.01

Pulmonary artery wedge 17 ± 2 12 ± 1 <0.01pressure, mm/Hg

DVI,ml/m2 162±16 118±10 <0.05

Ejection fraction, %t 28 ± 3 39± 3 <0.01

*All values are expressed as mean ± SE. (Adapted from Reilly et nil.

Chest 1989; 95:1072-80. Reproduced with permission.)

tDetermined two to four days after the onset of septic shock.



CHEST I 99 I 4 I APRIL, 1991 1005

myocytes is increased in a stepwise manner, there is a

concentration-dependent decrease in both the extent

and velocity of myocardial cell contraction. Depres-

sant activity is water soluble and will not diffuse

through a dialysis membrane. Recent molecular filtra-

tion experiments with Amicon filters suggest that

MDS is a moderate-size molecule weighing at least

10,000 d.�

Most recently, the myocyte assay has been used to

study the activity of several possible mediators of

septic shock.� Purified preparations of interleukin-1,

interleukin-2, and endotoxin produced no depression

of myocyte contraction even in concentrations sub-

stantially higher than those measured during human

septic shock. However, TNF at a dose of 250 units/ml

did produce significant depression of myocyte short-

ening, with a mean decrease of24 percent. Thus, TNF

may be one of several molecules that directly produce

the myocardial depression of human septic shock.

Experiments attempting to further identify such mol-

ecules utilizing this in vitro assay are ongoing.

A CANINE MODEL OF SEPTIC SHOCK

Further investigation into the nature of myocardial

depression in sepsis required the development of an

appropriate animal model. Previous animal models

were modified to produce one that more closely

simulates the cardiovascular pattern of human septic

shock.� In this model, live bacteria contained in a

fibrin clot are implanted surgically into the perito-

neum as a nidus of infection, leading to sustained

bacteremia in all animals. Serial hemodynamic assess-

ments were performed in conscious, unsedated ani-

mals both before and after volume loading, using

arterial and pulmonary artery catheters and simulta-

neous radionuclide ventriculography. With this model,

hypotension occurred at 12 to 24 h. Two to four days

after sepsis onset, a substantial decrease in LVEF

developed. With adequate volume loading, animals

manifested left ventricular dilatation, high cardiac

output, and low SVR. In surviving animals, these

hemodynamic changes returned toward normal in

seven to ten days. This time course and cardiovascular

pattern are remarkably similar to those of human

septic shock.5

In further studies, the canine model demonstrated

a relationship between the number of organisms

placed into the nidus and the amount of myocardial

depression. Increasing doses of bacteria corresponded

to progressive decreases in LVEF and progressive

downward shifts on both Frank-Starling and end-

systolic volume/pressure left ventricular function

plots.� Some types of bacteria (despite equivalent

doses) were more potent inducers of cardiovascular

changes and lethality. However, all bacteria (whether

Gram-positive or Gram-negative, viable or nonviable)

produced the same general pattern of cardiovascular

insufficiency.� The fact that structurally and function-

ally distinct bacteria and bacterial products induce

the same pattern of cardiovascular injury strongly

supports the presence of a final common pathway of

cardiovascular insufficiency in septic shock.

Recent investigations have utilized the canine model

to study potential mediators of this common pathway.

Endotoxin, a mediator known to trigger the release of

a large number of other mediators, was placed into a

fibrin clot and implanted into the peritoneum.� The

subsequent pattern of cardiovascular changes was

identical to that previously described for septic shock

induced by live organisms in the canine model.�

However, as was previously mentioned, experiments

with Gram-positive organisms (with absent measured

blood endotoxin levels) showed this same cardiovas-

cular pattern.� Thus, endotoxin is sufficient but not

necessary to produce septic shock.

In other experiments testing possible mediators,

TNF was infused intravenously into dogs and found to

induce all of the progressive changes in cardiovascular

function seen with viable bacteria (Fig 5).� In a similar

canine study, interleukin-! was infused; however, in

contrast to the TNF findings, high doses of interleukin-

1 produced brief hypotension and none of the other

sepsis-associated cardiovascular changes.rn Thus, as

with the in vivo experiments, canine studies support

the importance ofTNF as one ofthe major mediators

of the final common pathway of cardiovascular insuf-

ficiency in septic shock.

HUMAN RESPONSES TO POSSIBLE MEDIATORS

With the establishments of a clear pattern of cardi-

ovascular dysfunction in septic shock and preliminary

data on probable mediators from in vitro and canine

work as background, recent investigation has focused

on mediator effects in humans.

While endotoxin has been administered to humans

in clinical or research settings for years to evaluate a

variety of clinical responses, limited information is

available defining its effects on the human cardiovas-

cular system. Hence, a recent study was performed

during which the cardiovascular response to endotoxin

administration was evaluated in normal humans by

monitoring with radial and pulmonary artery catheters

and nuclear heart scans.�#{176}After evaluating the initial

effects ofendotoxin for 3 h, each volunteer received a

volume infusion to simulate the clinical management

of sepsis and to evaluate ventricular performance in

response to increased preload.

The core temperature rose and peaked by 3 to 4 h

following endotoxin administration. At 3 h, the cardiac

index and heart rate rose and the SVR fell compared

with control values.�#{176}The LVEF fell below baseline

and below that ofthe similarly treated control patients



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Days Pre and Post Tumor Necrosis Factor Infusion

Ficutu� 5. Serial mean changes (± SE) in ejection fraction, EDVI,

and end-systolic volume index In dogs challenged intravenously

with TNF. Solid lines ounnect mean hemodynasnic values in serial

dogs. Dashed arrow indicates response to volume fur each group of

dogs� (From Natanson et al. J Exp Med 1989; 100:82.3-32. Repro-

duced with permission.)

at 5 and 6 h following endotoxin administration. The

left ventricular EDVI and end-systolic volume index

increased. Ventricular performance was also described

with use of the load-independent relationship of peak

systolic pressure to end-systolic volume index, corn-

paring changes from baseline to maximum fluid load-

ing in endotoxin and control groups. The change in

this ratio was abnormal in the subjects who received

endotoxin (Fig 6, panel D). Left ventricular function

was further evaluated by measuring the stroke volume

index and LVSWI normalized to the end-diastolic

volume (Fig 6, panels B and C). These data demon-

strate reduced systolic performance during endotox-

ernia independent of preload and afterload. Further-

more, the left ventricular pressure to volume ratio

.

a

a

. CONTROL ENDOTOXIN � CONTROl. ENOOTOXIN

Ficua� 6. Change from baseline to the point of maximal volume

load in ratios reflecting ventricular performance. A, Ratio ofpulmonary capillary wedge pressure (PCW) to left ventricular end-

diastolic volume index (EDVI). B, Ratio of stroke-volume index

(SW) toleft ventricular EDVI. C, Ratio OfLVSWI toleft ventricular

EDVI. D, Ratio of peak systolic pressure (PSP) to left ventricular

end-systolic volume index (ESVI). Three subjects who participated

in both control and endotoxin parts of the study at three-month

intervals are depicted by circles, rectangles, and diamonds sur-

rounding data points. (From Suifredini at al. N Engi J Med 1989;

321:280-87. Reproduced with permission.)

was reduced, suggesting that ventricular compliance

may have increased after endotoxin administration(Fig 6, panel A). Follow-up echocardiograms at 24 and

48 h after endotoxin administration revealed no per-

sistent abnormalities.Thus, the cardiovascular changes following endo-

toxin administration to normal humans were qualita-

lively similar to those seen in clinical septic shock: a

hyperdynamic cardiovascular state with a depressed

and dilated left ventricle and abnormalities of ventric-

ular performance and volume that were reversible.

Other evidence has implicated endotoxin as a major

mediator of human septic shock as well. Endotoxin

has biologic effects analogous to those observed during

septic shock: it has been shown to cause fever,



CHEST I 99 I 4 I APRIL 1991 1001

interleukin-1 and TNF release, complement activa-

tion, disseminated intravascular coagulation, and

shock in animals.3’ Further, naturally occurring anti-

bodies to endotoxin are associated with increased

survival in Gram-negative septic shock in humans.�

In addition, it has been demonstrated that immuneplasma from volunteers vaccinated with the Esche-

richia coli J5 mutant prevented death in patients with

Gram-negative septicemia.tm Recent human trails em-

ploying monoclonal antibodies to lipid A, the toxic

component of endotoxin, have shown efficacy in re-

ducing the mortality of Gram-negative bacteremia.�

However, several areas ofinvestigation speak against

endotoxin as the exclusive or dominant mediator of

human septic shock. Endotoxin alone did not produce

consistent myocardial depression in the in vitro assay

discussed previously.”� In the canine model, other

mediators (eg, TNF) were found to produce changes

in cardiovascular function similar to those seen with

endotoxin.50 Of note, in the human study, TNF func-

tional activity rose and fell following endotoxin admin-

istration.� However, these changes temporally pre-

ceded the alterations in cardiac systolic and diastolic

function that occurred at 5 to 6 h following endotoxin

administration, suggesting either a delayed effect of

TNF activity on cardiac function or the generation of

other cardiodepressant mediators during endotoxe-

mia.� In another human study, interleukin-2 (a cyto-

kine being used in antiturnor immunotherapy) was

found to induce multiple reversible cardiovascular

abnormalities that are similar to the hemodynamic

manifestations of human septic shock,� suggesting a

possible role for this mediator as well. Finally, direct

measurement of circulating endotoxin has not consis-

tently correlated with the clinical manifestations and

outcome of Gram-negative septicemia.�

In an effort to clarify the incidence and signfficance

ofendotoxemia in humans, a recent study determined

serial endotoxin levels every 4 h for 24 h in 100

consecutive patients admitted to an ICU with septic

shock.� Blood endotoxin was measured with a sensi-

tive chrornogenic limulus amebocyte lysate assay.

Detectable endotoxemia was found in 43 patients;

however, only 20 of the 43 patients with endotoxemia

had a positive limulus assay on initial determination.

The level ofendotoxin in many ofthese patients would

not have been detectable with the older limulus

gelation assay. In addition, endotoxernia often oc-

curred intermittently, underscoring the need for fre-

quent serial sample collection. The presence of en-

dotoxernia was correlated with blood culture positivity

(54 percent vs 25 percent, p<O.Ol), lactic acid level

(5.5±0.8 vs 3.0±0.3 mmolfL, p<O.005), low SVR

(456±30 vs 582±33 dynescm5, p<O.05), and a

depressed radionuclide determined LVEF (34 ± 2 per-

cent vs 45 ± 2 percent, p<O.OOl). In the subgroup of

patients with septic shock and positive blood cultures

(n = 37), endotoxemia was associated with a highermortality (39 percent vs 7 percent, p<O.05). Of note,

only 26 percent ofthe endotoxin-positive patients had

Gram-negative bacteremia, suggesting that endotoxe-

mia may play a pathogenetic role in many cases of

clinical septic shock even when Gram-negative organ-

isms are not isolated from the blood.

When all these data are analyzed, as was true withcanine data, it appears that endotoxin is probably

sufficient but not necessary to produce septic shock

in humans. Most likely it is one of several important

mediators of this process (Fig 2).

THERAPEUTIC IMPLICATIONS

Much of this research into the patterns and mech-

anisms of myocardial dysfunction in septic shock has

implications for therapy of this complicated disease.

Optimal treatment for patients with septic shock

involves prompt diagnosis and initiation of therapy,

aggressive hemodynamic monitoring, and manage-

ment in an ICU. Several retrospective studies have

demonstrated a decreased mortality for septic shock

patients who are cared for in a modern ICU setting.�’40

This environment permits physicians to use invasive

techniques, including indwelling peripheral and pul-monary artery catheters to rapidly detect hemody-

namic, respiratory, and acid-base changes and to

initiate appropriate therapy.

Volume resuscitation with hemodynamic monitoring

should be one of the first therapeutic steps in the

management of patients with septic shock. However,

as was discussed previously, patients with septic shock

have a markedly diminished myocardial response to

volume infu’4 Hence, hypotension frequently

persists, necessitating the addition of vasopressor

agents.

if a patients in septic shock remains hypotensive

after volume has raised the pulmonary artery wedge

pressure to 15 to 18 mm Hg, then dopamine should

be added for its inotropic and vasopressor capability

to raise the mean blood pressure to at least 60 mm

Hg. ifthe dopamine dose required to achieve this goalexceeds 20 p.g/kg/min, another vasopressor, typically

norepinephrine, is begun. Dobutamine may be added

to enhance cardiac inotropy in patients with evidence

of profound myocardial depression.

The use of norepinephrine in patients in septic

shock who fail to respond to dopamine has been acontroversial topic. Some investigators have voiced

concern that this potent vasoconstrictor might worsen

the shock syndrome in certain patients. However,

recent data demonstrate that norepinephrine canreverse septic shock in patients unresponsive to both

volume and dopamine.�”�

Of note, the effects of norepinephrine with and



1008 Cardiovascular Dysfunction in Septic Shock (Snel!, Panillo)

without dopamine on renal blood flow were assessed

in a canine model.1’ The addition of dopamine to

pressor doses of norepinephrine resulted in signifi-

cantly higher renal blood flow and lower renal vascular

resistance than norepinephrine infusions alone. In the

clinical setting, patients requiring therapy with nor-

epinephrine to support blood pressure may benefit

from the simultaneous administration of low-dose

dopamine (approximately 1 to 4 ji.g/kg/min) to increase

renal blood flow. Once blood pressure is normalized

with norepinephrine, the lowest dosage that maintains

blood pressure should be utilized to minimize any

potential vasoconstrictor effects on organ blood flow

Overall survival in norepinephrine-treated patients is

approximately 40 percent, a substantial survival rate

for such a critically ill patient group.

In addition to hemodynamic support, other therapy

for septic shock is critical. Prompt initiation of an

empiric antibiotic regimen that includes an agent

effective against the subsequently identified microor-

ganisms has been associated with improved survival

and decreased frequency of shock.�’� Clearly, it is

essential that broad-spectrum antibiotic coverage be

started immediately pending culture results.

High-dose corticosteroid therapy has also fre-

quently been advocated for treatment of septic shock

based on efficacy in some animal models. Recently,

however, three large clinical trials have revealed no

difference in mortality in corticosteroid-treated pa-

tients compared with control patients.� In addition,

these data demonstrate an inability of corticosteroids

to prevent or reverse shock, as well as the occurrence

of superinfections in corticosteroid-treated patients.

Based on these studies, corticosteroid therapy in

patients in septic shock should be reserved only for

suspected or documented adrenal insufficiency.

Many of the recent clinical investigations into ther-

apy have focused on the inhibition of the mediators of

the toxic process involved in the septic shock cascade

(Fig 2). Antihistamines have not proved effective, and

recent studies have failed to document elevated his-

tamine levels during human septic shock.49,m Although

arachidonic acid metabolites ma� account for some of

the vascular effects of sepsis, inhibition of eicosanoids

has not been shown to be therapeutically useful to

date. Some animal models ofshock are very dependent

on endorphins; however, clinical trials using naloxone

to inhibit endorphin receptors have not convincingly

shown efficacy. On the other hand, inhibition of

endotoxin by use of antisera has been associated with

improved survival from Gram-negative bacteremia.�

This remains an area of active investigation. Several

very recent trials employing monoclonal antibodies

against endotoxin have shown promise of efficacy in

patients with Gram-negative sepsis.�

Continued research into the pathogenesis of septic

shock should allow the continued development of the

best supportive strategies, as well as specific measures

directed against key steps in the process, which should

in turn lead to further reductions in the high mortality

from this disease.

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DOI 10.1378/chest.99.4.1000 1991;99;1000-1009 Chest

RJ Snell and JE Parrillo Cardiovascular dysfunction in septic shock

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