Elevation of cardiac output and oxygen delivery improves outcome in septic shock

DOI 10.1378/chest.102.1.216 1992;102;216-220Chest

 J Tuchschmidt, J Fried, M Astiz and E Rackow improves outcome in septic shock.Elevation of cardiac output and oxygen delivery

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216 Improved Outcome In Septic Shock (Tuchschmidtet&)

Elevation of Cardiac Output and OxygenDelivery Improves Outcome in SepticShock*James Tuchschmidt, M.D., FC.C.P;Jeffrey Fried, M.D., FC.C.P;

Mark Astiz, M.D., F.C.C.P; and Eric Rackou� M.D., F.C.C.P

Septic shock is characterized by hypoperfusion and tissueenergy defects. We prospectively evaluated the therapeutic

benefit of augmenting cardiac output and therefore oxygen

delivery (Do,) on mortality in patients with septic shock.

Twenty-five patients were randomized to a normal treat-

ment (NT) group and 26 patients were randomized to an

optimal treatment (�YF) group. All patients had a clinically

evident site of infection, sepsis as defined by a systemic

response to the infection, and shock indicated by systemic

hypoperfusion. Patients were treated during the initial 72

h by an algorithm differing only in the end point ofresuscitation. The cardiac index (CI) was increased to 3.0

Ijmin/m’ in the NT group and to 6 IJniin/m’ in the OT

group. There were no significant differences in cardiores-

piratory parameters in the NT and OT groups on entrance

into the study. During treatment, CI averaged 3.6 ± 0.2 L/

min/m’ and Do, averaged 8.6±0.8 mI/mm/kg in the NT

group and CI averaged 5. 1 ±0.2 Lfmin/m’ and Do, aver-

aged 12.2±0.7 mI/mm/hg in the OT group (p<O.Ol). A

significant correlation between Do, and survival was oh-

served. Seventy-two percent of the (Yf patients died vs 50

percent ofthe NT patients (p 0.14) Surviving NT patients

stayed 13.7±3 days in the ICU vs 7.4±0.6 days (p<O.OS)

for the OT patients. Since some of the NT patients were

spontaneously hyperdynamic and some of the (fl patients

did not achieve their desired end point, patients were

arbitrarily subsetted using a midpoint CI of 4.5 IJmin/m’.

The NT <4.5 group had a CI of3.1±0.2 L/min/m’ and

Do, of 10.9± 1.0 mI/mm/kg while the (YI� group >4.5 L/

min/m’ had a CI of 5.7±0.2 L/min/m’ and a Do, of

13.8±0.7 mI/mm/kg (p<O.Ol) Mortality in the NT <4.5

group was 74 percent as compared with 40 percent in the

OT >4.5 group (p<0.05). (Chest 1992; 102:216-20)

Clcardiac index; COcardiac output; Dooxygen dcliv-cry; NT = normal treatment; OT optimal treatment;PAOPpulmonary artery occlusion pressure; SAP systolicarterial pressure; Vo, oxygen consumption

Septic shock is characterized by an imbalance be-

tween systemic oxygen demand and oxygen sup-

ply. The marked lactic acidosis observed during septic

shock is indicative of a severe tissue energy deficit. ‘�

Primary metabolic failure, shifts in the oxygen disso-

ciation curve, and circulatory flow abnormalities have

all been postulated to contribute to impaired oxygen

utilization during sepsis.4 Experimental studies have

demonstrated a relationship between tissue energy

deficits and effective organ perfusion.56 Clinical ob-

servations of regional hypoperfusion and altered mi-

crovascular response to reactive hyperemia are consis-

tent with circulatory maldistribution.7’8 These studies

suggest the potential for reversing tissue energy defi-

cits by increasing oxygen delivery during septic shock.

The optimal levels of oxygen delivery appear to be

significantly higher than under normal physiologic

conditions both because of increased metabolic de-

mands and decreased oxygen extraction.9”#{176} Recently,

Shoemaker et al’#{176}and Edwards et al” reported

improved survival in critically ill patients, some of

*From the Section of Pulmonary Disease and Critical Care Medi-

cine, the Department of Medicine, the University of SouthernCalifornia School of Medicine, Los Angeles (Drs. Tuchschmidtand Fried), and Section ofCritical Care Medicine, Department ofMedicine, St. Vincent�s Hospital and Medical Center ofNew York,New York Medical College, New York, NY(Drs. Astiz and Rackow).

Manuscript received September 17; revision accepted January 31.Reprint requests: Dr Schobe#{231} St. Vsncent�s Hospital Medical Center,LS3 West 11th Street, New York City 10011

whom were septic, when therapy was titrated to

increased indices of flow and oxygen metabolism.

The purpose of this study was to prospectively

evaluate the therapeutic effect of augmenting cardiac

output and therefore oxygen delivery on mortality in

patients with septic shock. Our data suggest that

mortality may be reduced by increasing cardiac output

and oxygen delivery.

METHODS

Patients

All patients admitted over a 24-month period to the Critical Care

Service at Los Angeles County/University of Southern California

Medical Center, Los Angeles, with a suspected diagnosis of septic

shock had their conditions evaluated. The study was approved by

the Institutional Review Board. Infection was confirmed in patientswith bacteremia or an identifiable site ofinfection. Sites of infection

were identified by positive bacterial cultures with evidence of

inflammatory cells on Gram stain of exudates. Sepsis was defined

as a systemic response to infection as characterized by four of the

following clinical signs: (1) fever (temperature >38.3#{176}C) or hypo-thermia (temperature <35.5#{176}C); (2) tachycardia (heart rate >90

heats/mm); (3) tachypnea (>20 breathsfmin); (4) leukocytosis (WBC

>11,00Wcu mm3); or (5) delirium. Shock was identified by any oneof the following signs: (1) systolic intra-arterial pressure <90 mm

Hg on two measurements, 1 h apart; (2) intravenous (IV) infusion of

dopamine for greater than 1 h to maintain intra-arterial systolic

pressure �90 mm Hg; or (3) arterial lactate �3.0 mmolfL. All

patients were entered within 4 h of diagnosing shock and enrolled

with a suspected site of infection, evidence of sepsis, and criteria

for shock. Patients without an identified site of infection at 48 h

were removed from the study. Once entered, the patients were

assigned to the normal treatment (NT) group or optimal treatment

 © 1992 American College of Chest Physicians by guest on July 10, 2011chestjournal.chestpubs.orgDownloaded from

Table 1-Hemodyna,nic Profiles PYcresusCitatiOn and Postresuscitation in the Normal Treatment (NT) and Optimal

Treatment (OT) Patients

Preresuscitation Fbstresuscitation

NT cir r�’r irVariable (n 25) (n = 26) (n 25) (n 26)

Age,yr 53±4 49±3 - -

Apache!! 21±1 22±1 - -

Temp. #{176}C 37.7±0.17 37.8±0.11 37.3±0.11 37±0.06

RR,breaths/min 24±2 26±1 22±3 22±1

Pulse,beats/min 124±4 112±4 112±3 110±3

MAP,mmHg 74±3 74±3 73±2 75±2

MPAP,mmHg 27±2 26±1 30±1 27±1

PAOP, mm Hg 13± 1 15± 1 16 ± 1 16±1

CI, 11mm/rn’ 3.9±0.3 4.0±0.3 3.6±0.2 5.1±2*

HGB, g/dl 11.0±0.5 11.0±0.4 10.3±0.4 10.2±0.3Do,, mi/mitt/kg 14.9±1.5 16.1±1.2 14.0±0.3 18.8±0.4*

Vo,, mI/mm/kg 3.5±0.2 3.6±0.3 3.7±0.6 3.7±0.1

Lactate,mmolfL 5.1±0.6 4.7±0.1 4.5±0.8 3.8±0.6

*N5 vs 0’!’, p<O.Ol.

CHEST I 102 I 1 I JULY, 1992 217

(OlD group by dynamic randomization.

Patient Management

After obtaining appropriate blood and site cultures, all patients

received gentamicin 2 mg/kg IV followed by 1.7 ms/kg IV every 8

h (monitored with serum levels) and clindamycin 900 mg IV every

8 h. Additional antibiotics were added depending on the presumed

site of infection and suspected becteriolog� Once an organism was

identified, the antibiotic regimen was tailored appropriately. Every

effort was made to identify and drain infected sites.

Resuscitation from shock was standardized by the use ofa printed

algorithm, which also served as a notification ofgroup assignment.

The algorithms for the NT and OT groups were identical except

with respect to the end point ofresuscitation. The NT resuscitativeefforts were considered to be complete when a cardiac index (CI)�3.0 Llmin/m’ and a systolic arterial pressure (SAP) of �90 mm

Hg were achieved. A CI �6.0 Llmin/m’ and a SAP �90 mm Hg

defined resuscitative end points for the OT patients. The algorithm

consisted of first determining whether patients satisfied the resus-

citation goals. Ifthey did not, 5 percent albumin was administered

by aliquots to achieve a pulmonary artery occlusion pressure (PAOP)

�15 mm Hg. In hypotensive patients with a PAOP �15 mm Hg, a

dopamine infusion was titrated to maintain a SAP �90 mm Hg.

When the PAOP was �15 mm Hg, the SAP was �90 mm Hg, and

the CI was below the desired goal, dobutamine was infused andtitrated to obtain the desired CI. Patients receiving dopamine with

a PAOP <15 mm Hg, who otherwise met the assigned goals� were

fluid challenged with 5 percent albumin in an effort to withdraw

vasopressor support.

The resuscitative goals were maintained for 72 h. Patients were

transfused to maintain a hemoglobin ofat least 10 g/dl. All patientswere intubated and mechanically ventilated. Supplemental oxygen

and PEEP were adjusted to maintain the arterial oxygen saturation

�90 percent, with the least possible Flo,. Nutritional support was

initiated in all patients after hemodynamic stability was achieved,

usually within 48 to 72 h ofhospital admission.

HemOdynamiC Measurements

Intravascular pressures were measured with strain gauge trans-

ducers (Baxter Edwards Laboratories, Irvine, Calil), zeroed to

atmospheric pressure at the midaxillary line, and calibrated against

a mercury manometer. Cardiac output (CO) values were obtainedin triplicate by thermodilution using iced saline solution cooled to

<1#{176}C.Hemoglobin saturation was measured with a COoximeter

(282, Instrumentation Laboratories, Lexington, Mass). Hemody-

namic variables, arterial and mixed venous blood gases, and arterial

lactate were obtained simultaneously, at least every 6 h. Oxygen

delivery (Do,) was calculated as Do,= CO x CaO,; and oxygen

consumption (Vo,) as VO2 = CO x (CaO,- CvO,). Oxygen content

was calculated as follows: CaO, 1 .39 x (Hgb) x SaO, and

CvO, = 1.39 x (Hgb) x SvO,, where SaO, and SvO, are the arterial

and mixed venous oxygen saturations, respectively.

Statistical Analysis

We compared continuous variable data using the Student’s t test

and compared mortality data using x’ analysis. The CI and other

variables were averaged over the 72-h period following the initial

resuscitative efforts (>6 h after entry) to obtain the postresuscitation

values.

Some patients assigned to the NT group exceeded their treatment

goal on admission to the study, and some patients randomized to

the �YF group failed to achieve a CI �6.0 Iimin/m2. We therefore

subsetted patients into two groups using a midpoint CI value of 4.5

lJmin/m’ and compared the NT group with a postresuscitation CI

<4.5 LJmiWm’ to the OT group with a CI >4.5 11mm/rn’. These

groups were then compared using the same statistical methods.

Results are reported as mean±SEM. Statistical significance isreported at a p<O.05.

RESULTS

Seventy patients were enrolled during the course of

the study. Nineteen of these were not included in the

analysis for the following reasons: in nine patients,

blood and site cultures were negative; six patients died

prior to treatment; three patients did not meet shock

criteria. Fifty-one subjects were analyzed, 25 patients

in the NT group and 26 patients in the OT group. The

most common infections were pneumonia in 53 per-

cent, urosepsis in 10 percent, and peritonitis in 8

percent. Fifty-seven percent of the patients had posi-

tive blood cultures. Sixty-five percent of the patients

had Gram-negative infections and 35 percent had

Gram-positive infections.

Normal vs Optimal Treatment

The clinical and hemodynamic profiles of the pa-

tients on entry into the study are shown in Table 1.

 © 1992 American College of Chest Physicians by guest on July 10, 2011chestjournal.chestpubs.orgDownloaded from

fI��

0 6 12 18 24 30 36 42 48 54 60 66 72TIME (HRS)

0-8.5 9042.9 13.0.16.9 17.0-20.9 21.0.24.9 25.0.

6

218 Improved Outcome in Septic Shock (Tuchschmidt et a!)

2

FIGURE 1 . Cardiac index over 72 h in normal treatment (NT) (circles)and optimal treatment (OT) (squares) patients. Mean ± SEM (aster-

isk p<O.05).

OT patients required 775 ± 25 ml of5 percent albumin

for volume repletion compared with 938 ± 33 ml for

the NT group. Twenty-one of 26 OT patients received

dobutamine at an average dose of 30 ± 1 p�gfkg/min,

whereas 12 of 25 NT patients received dobutamine at

12 ± 1 p�gfkg’min (p<O.Ol). CI increased by 4 ± 2

percent with therapy in the NT group and by 30 ± 2

percent in the OT group (p<O.Ol). After resuscitation,

OT patients had a significantly higher CI and Do2

throughout their course (Table 1 , Fig 1 and 2). Mor-

tality was strongly correlated (r� 0.94, p = 0.016) with

the postresuscitation level of oxygen delivery (Fig 3).

In the NT patients, mortality rate was 72 percent and

50 percent in the OT patients (p = 0. 14) (Fig 4). Of the

patients who died during the study, the OT patients

survived 6. 1 ± 0.3 days and the NT patients survived

4.3±0.3 days (p<O.00l).

We also examined the length ofICU stay for patients

in the NT and OT groups. NT patients received ICU

care for 8.9 ± 0.6 days compared with 5.3 ± 0.2 days

for patients in the OT group (p<0.05). When only

survivors were considered, NT survivors stayed in the

ICU 13.7 ± 3 days in contrast to 7.4 ± 0.6 days for OT

0 21z� 19

18�17>. 16� 15� 14‘U 13� 12w 11

� 10

0 6 12 18 24 30 36 42 48 54 60 66 72

TIME (HRS)

FIGURE 2. Oxygen delivery over 72 h in normal treatment (NT)

(circles) and optimal treatment (OT) (squares) patients. At 72 h theNT group Do2 was increased because of variability of hemoglobin

measurements in the remaining six surviving NT patients. The Do,value at 66 h and 78 h was 14.1 mI/mm/kg. Mean±SEM (aster-

isk = p<O.O5).

OXYGEN DELWERY (mi/mm/kg)

FIcURE 3. Hospital mortality rate vs oxygen delivery in all patients;

r�O.94,y=135-.7x+.1x2(p=0.016).

survivors (p<O.O5).

Subset Analysis

There were 19 patients in the NT group with a

postresuscitation CI <4.5 IJmin/m and 19 patients

in the OT group with a postresuscitation CI >4.5 L/

minim2. There were no significant differences in these

groups preresuscitation. Postresuscitation Do2 aver-

aged 13.8 ± 0.7 mI/mm/kg and Vo2 averaged 4.3 ± 0.3

mi/mm/kg in the OT >4.5 patients and Do2 averaged

7.2 ± 0.7 mI/mm/kg and the Vo2 averaged 3.5 ± 0.3

mi/mm/kg in the NT <4.5 patients (p<O.O5). Lactate

levels averaged 2.5±0.3 mmolJL in the OT >4.5

group and 4.8±0.1 mmolIL in the NT <4.5 group

(p<O.O5). CI increased by 1 ± 2 percent in the NT

patients with therapy and by 40 ± 2 percent in the OT

patients (p<O.OS). Mortality was 74 percent in the NT

<4.5 group and 40 percent in the OT >4.5 group

(p<O.OS) (Fig 5).

DISCUSSION

The development of septic shock is associated with

systemic hypoperfusion and a tissue energy deficit. ‘-�

Tissue hypoperfusion appears to be a major factor

U)

100

90

80

70

60

50

40

30

20

10

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days After Entry

FIGURE 4. Survival rate for the normal treatment (NT) group

(dashed line) and optimal treatment (OT) group (solid line) over 14

days.

 © 1992 American College of Chest Physicians by guest on July 10, 2011chestjournal.chestpubs.orgDownloaded from

CHEST I 102 I 1 I JULY, 1992 219

100 _____90

80

m 70C

�60

n 50U)�4o

30

20

10

0-.�-�0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days After Entry

FIGURE 5. Survival rate for the normal treatment (NT) group with

a cardiac index (CI) <4.5 Lfmin/m’ (dashed line) and optimaltreatment (OT) group with a CI >4.5 Lfmin/m’ (solid line) over 14

days.

contributing to impaired oxidative metabolism during

septic shock. Mitochondrial oxidative function appears

to be maintained during septic shock.’2”3 Alterations

in systemic and microvascular flow have been reported

in both experimental and clinical studies that may

compromise effective organ perfusion.5’7’8 Clearance

oflactic acid levels following resuscitation is associated

with survival emphasizing the importance in increas-

ing systemic oxygen delivery in restoring tissue per-

fusion and enhancing outcome during septic

1416

The concept of titrating hemodynamic therapy to

supranormal levels has been advanced ‘#{176}

Sepsis and septic shock are hypermetabolic syndromes

with increased tissue oxygen requirements.’7”8 In-

creased levels of systemic oxygen delivery and con-

sumption have been associated with improved out-

come from severe sepsis.9”9’2#{176}The increased levels of

oxygen consumption require increased systemic blood

flow and oxygen delivery both because of increased

metabolic rate and because of circulatory abnormali-

ties that impair the ability of tissues to maximumly

extract xy’7”8 Recently, Shoemaker et albo re-

ported that titration of therapy to supranormal values

of CI and oxygen metabolism in critically ill surgical

patients was associated with a marked reduction in

mortality rate from 33 percent to 4 percent. Using the

same end points, Edwards et al” noted a reduction in

mortality from septic shock when compared with

historic controls.Our study suggests that increased levels of CO and

systemic oxygen delivery are important in improving

outcome from septic shock. A 28 percent reduction in

hospital mortality was observed when CI was titrated

to 6 Iimin/m2. The importance of oxygen delivery in

determining outcome is further emphasized by the

relationship of increases in systemic oxygen delivery

to decreases in mortality. In the OT patients who died

of septic shock, survival time was significantly in-

creased allowing for the potential impact of other

therapeutic interventions to take their clinical effect.

ICU stay was also significantly reduced in the OT

group suggesting decreased morbidities and more

rapid clinical improvement in the survivors. Presum-

ably this was related to enhanced recovery and a

decrease in patient morbidity. This decrement in ICU

stay should translate into a significant cost savings.

Indeed, Shoemaker et al’#{176}reported that hospital costs

were significantly decreased in the group of patients

where therapy was titrated to optimal hemodynamic

end points. The substantial increase in CI following

therapy in the OT group as compared with the NT

group suggests that these benefits were related to the

therapeutic interventions.

The lack of statistical significance in the overall

mortality rates probably reflects the spontaneously

higher CIs of some of the patients in the NT group, as

well as the inability to achieve the desired end point

in a portion of patients in the OT group. In order to

assess this hypothesis, we arbitrarily subsetted the

patients on the basis of achieved CIs at a midpoint

value between the two treatment end points. The 50

percent reduction in mortality observed in the (IF

patients with a CI >4.5 L/min/m2 when compared

with the NT patients with a CI <4.5 L/min/m2 adds

further substance to the interpretation that an im-

provement in outcome was achieved in the (IF group.

The 40 percent increase in CI observed in the OT

patients following randomization supports this thesis.

The associated increases in Do2 and Vo2 with en-

hanced lactate clearance suggest that the benefit

observed in the (IF patients was related to enhanced

tissue perfusion and oxidative metabolism. An alter-

native method of subsetting the data by excluding

outliers in either group would have yielded the same

results. Because of the significance of the reduction in

mortality observed in the subset of (IF patients with

a CI of >4.5 Llmin/m2, the study was discontinued.

The optimal level of CO and oxygen delivery in

patients with septic shock needs to be delineated. We

utilized a higher CI (6.0 L/min/m2) in the treatment

group, which resulted in a higher Do2 of 726 ± 16 ml!

min/m2 than end points reported by Shoemaker et al’#{176}

(CI�4.5 Llmin/m2, Do2�600 mI/minim2). Approxi-

mately one fourth of our patients were not able to

achieve this desired end point. Achieving these end

points required the use ofsignificantly greater amounts

ofcatecholamines in the (IF group reflecting both the

significantly increased level of CI desired and the

degree of myocardial depression resulting from the

septic process.2� In an older group of patients with

less cardiovascular reserve, an even greater percent-

age of patients might not achieve the desired end

points. In addition, patients with septic shock have

widely varying metabolic requirements.’7’� Age,

fever, nutritional status, degree of sedation, and du-

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220 Improved Outcome in Septic Shock (Tuchschm!dtetal)

ration oflilness affect metabolic needs.� An alternative

approach might be to titrate therapy to index of

perfusion that reflects the oxygen demand/supply

relationship, such as clearance oflactic acid.’5’�

Our observations are consistent with studies that

have demonstrated impmved outcome in the patients

who were able to achieve higher CIs.”3 They contrast

with recent reports in which higher CIs were not

associated with improved rviallS,V The reason for

these differences is not entirely clear but may reflect

differences in patient populations and treatment pro-

tocols.

A considerable controversy has arisen as to the risks

and benefits of pulmonary artery catheterization. A

potentially adverse effect on outcome in patients with

acute myocardial infarction has been suggested by the

retrospective study of Gore et al.� In contrast, our

prospective study and the prospective study of Shoe-

maker et al’#{176}indicate that when hemodynamic moni-

toring is employed to titrate therapy to specific end

points, significant benefits in survival can be accrued.

Both studies emphasize the fact that it is not the

hemodynamic monitoring itself, but the therapeutic

end points utilized that determine outcome. The

clinical impact ofhemodynamic monitoring should be

examined with special reference to the way in which

hemodynamic data are interpreted and utiuized.� This

is particularly important given the recent report of

Iberti et al30 demonstrating the widespread deficien-

cies in the interpretation of hemodynamic measure-

ments.

In summary, outcome in patients with septic shock

appears to be related to the level of systemic oxygen

delivery. Titration of therapy to increased levels of CI

and therefore oxygen delivery may be associated with

improved survival from septic shock.

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DOI 10.1378/chest.102.1.216 1992;102; 216-220Chest

J Tuchschmidt, J Fried, M Astiz and E Rackowshock.

Elevation of cardiac output and oxygen delivery improves outcome in septic

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