Oxygen delivery-consumption relationship in septic adult respiratory distress syndrome patients: The effects of positive end-expiratory pressure

Oxygen Delivery-Consumption Relationship in Septic Adult Respiratory Distress Syndrome Patients: The Effects of Positive End-Expiratory Pressure V.M. Ranieri,

FL Giuliani,

N.T. Eissa, C. Corbeil, M. Dambrosio, A. Brienza, and J. Milic-Emili

M. Chassk,

N. Brienza,

J. Braidy,

The o.xygen consumption/delivery relationship (VOz/D02) was studied in 18 sedated, paralyzed, septic adult respiratory distress syndrome patients. Different levels (0 to 15 cm HrO) of positive end-expiratory pressure (PEEP) were applied. DO2 was calculated from cardiac index (thermodilution technique) and arterial oxygen content measurements. VOr was calculated using Fick’s equation. Regression lines were obtained for each patient. The following results were obtained. First, patients with DO2 at zero end-expiratory pressure 5 840 mL/min/m2 showed a highly significant relationship between changes in DO, and VOz with PEEP (suppfy dependency). In all these patients PEEP decreased DO2 by reducing cardiac index without

significant changes in arterial oxygen saturation. All these patients developed multiple organ system failure and died. Second, changes in DO, and VD2 with PEEP were not correlated in patients with a DO2 on zero end-expiratory pressure 2 888 mL/min/m* (nonsupply dependency). As PEEP was applied, changes in DO2 were compensated by changes in oxygen extraction ratio such as to keep V02 constant. On average, DO2 decreased with PEEP, while oxygen extraction ratio and arterial-mixed venous oxygen difference increased as PEEP was applied. Only three of these patients developed multiple organ system failure and died (70% survivors). Copyright 0 1992 by WA Saunders Company

T IS GENERALLY assumed that the normal resting levels of oxygen delivery (DO,) are more than sufficient to supply basal O2 requirements and, hence, reductions in DO2 should be readily compensated by increases in oxygen extraction ratio (0, ER).’ Experimental animal studies in which DO2 has been systematically decreased show that oxygen consumption (VO,) is maintained constant until a critical DO2 is reached (DOzcrit), at which VQ begins to fall with further reductions of D02? In animal studies, the DO,,i, correlates with indices of anaerobic metabolism.3 The DOzCrit divides the D02/V02 relationship into nonsupply dependent and supply dependent regions.4 Some investigators have reported that in patients with adult respiratory distress syndrome (ARDS) VOz is supply dependent regardless of the magnitude of D02,5-7 while others have found a biphasic relationship with

abnormally high values of D02crit.8’9 Dubin et al9 have suggested recently that sepsis is the major determinant of the abnormal O2 supply dependency shown in ARDS patients. Recently, Dantzker et al4 suggested that, in many cases, the interaction between V02 and DO2 under conditions of increased oxygen requirements may represent a normal physiologic behavior of the system rather than an abnormal manifestation of impaired oxygen extraction. According to this notion the plateau in the V02/D02 relationship observed in normal humans’” and experimental animals” also should be present in septic ARDS patients, but at higher DO2 levels than normal. To verify this hypothesis we have studied the individual oxygen consumption-delivery relationships in 18 sedated and paralyzed septic ARDS patients at different levels of positive end-expiratory pressure (PEEP; 0 to 15 cm H20).

I

From the Istituto di Anestesiologia e Rianimazione, Universita di Bari, Ban: Italy; the Hopital Saint-Luc, Universitt de Montreal, Montreal, Canada; and Meakins Christie Laboratories, McGill University, Montreal, Canada. Received October 28, 1991; accepted January 20, 1992. Supported in part by the Medical Research Council of Canada; the Respiratory Networks of Centers of Excellence, Canada; and the Consiglio Nazionale delle Ricerche, Italy. Address reprint requests to A. Brienza, MD, Istituto di Anestesiologia e Rianimazione, Universita di Bari, Policlinico, Piazza Giulio Cesare 70100, Bari, Italy. Copyright o I992 by W B. Saunders Company 0883-944119210703-0003$05.OOiO 150

METHODS Eighteen patients (10 men) admitted to the intensive care units of the Saint-Luc Hospital (Montreal, Canada) and the Policlinico Hospital (Bari, Italy) were studied. All met the criteria of Pepe et al’* for ARDS: (1) Paor I 70 mm Hg or (a/A) PO* ratio < 0.3 while being mechanically ventilated without applied PEEP at a fraction of inspired 02 (FIo~) t 0.4, (2) a chest roentgenogram showing diffuse bilateral parenchymal infiltrates compatible with pulmonary edema, (3) pulmonary artery wedge pressure less than 18 mm Hg, and (4) a compatible underling disease. Lung injury scorer3 was greater than 2.5 in all patients, indicating severe ARDS. All patients were septic at the time of the study. The JournalofCrificalCare,

Vol 7, No 3 (September),

1992: pp 150-157

OXYGEN

DELIVERY-CONSUMPTION

151

IN ARDS PATIENTS

diagnosis of sepsis was based on the following criteria: a bacteriologically proven focus of infection and deterioration of the clinical status, evidenced by temperature above 38.5”C, and a white blood cell count above 12 x 10’ or below 2 x lo4 cells/L, with either a positive culture of blood, sputum, or urine or a known site of sepsis.14 Multisystern organ failure (MSOF) was determined by scoring for the presence or absence of respiratory, cardiovascular, renal, hepatic, gastrointestinal. hematologic, and neurologic dysfunction using the diagnostic criteria of Bihari et al.‘” Patients who had more than three organ system dysfunctions were judged to have MSOF.lS The protocol was approved by the Ethics Committees of both institutions and informed consent was obtained from each patient or next of kin. A 7.5 Swan-Ganz balloon flotation catheter (Abbot Inc, North Chicago, IL) was placed percutaneously in the pulmonary artery of each patients from an internal jugular vein. Correct positioning of the catheter was confirmed by analysis of the pressure waveform and by chest roentgenogram. A 20-gauge Teflon catheter was inserted percutaneously for continuous blood pressure monitoring and arterial hlood sampling. The systemic and pulmonary artery pressures were measured with pressure transducers (1280; Hewlett-Packard Co. Cupertino, CA) and recorded on an eight-channel pen recorder (7718A; Hewlett-Packard), The readings were taken at end expiration. Zero reference hydrostatic pressure was the midthoracic line at the second intercostal space. Cardiac output (CO) was measured by thermodilution (3300 Cardiac Output Computer, Abbott) using injections of 5-mL cold ( < 8°C) 5% dextrose solution. Five serial determinations were taken regardless of the respiratory cycle. Variance of thermodilution cardiac output measurements at each level of PEEP was always small ( < 10%). After this, paired arterial and mixed venous blood samples were collected anaerobically to measure arterial and mixed venous blood gases (IL 1303; Instrumentation Laboratories, Lexington, MA). Arterial and mixed venous saturations with hemoglobin concentration were measured using a CO oximeter (IL 282; Instrumentation Laboratories). All patients were intubated and mechanically ventilated (Servo Ventilator 900C: Siemens Elema AB, Berlin, Germany) at a tidal volume of approximately 10 to 12 mL/kg. Respiratory rate was adjusted to maintain normocarbia (range. 12 to 18 breathsimin). The same study equipment was used in the two institutions. The data were subsequently analyzed by the same investigators. The investigation was performed with the patient in the supine position after sedation (0.1 to 0.2 mgikg diazepam and 2 to 3 &g/kg fentanyl) and paralysis (0.1 to 0.2 mgikg vecuronium bromide). Except for changes in PEEP, other interventions, such as changes in ventilatory settings, transfusions, or changes in infusion rates of fluids or vasoactive drugs, were not allowed throughout the experiment. All patients were stable hemodynamically when studied. Positive end-cxpiratory pressure levels of 0, 5, 10. and 15 cm I120 were applied in random order and maintained for 35 to 45 minutes. Hemodynamics and gas exchange measurements were made during the last 5- to lo-minute period of each level of PEEP. A physician not involved in the experiment was always present to provide patient care.

Cardiac index (CI) was computed by dividing CO by the body surface area. Arterial (CaO,) and mixed venous (002) oxygen content were calculated from Pa+, P+Ol. and measured SaOz and SVO2 using the following formula: Olcontent (mL/dL) = (fractional saturation x hemoglobin concentration X 1.39) + (0.003 X POz]. 60, was computed as a product of C?Ol and CI. VO: was calculated from the Fick equation: VO? = CI x (CaO: - CVO:). The 02 ER was calculated as (Tao, - CcO?)/CaOL. The rightto-left venous admixture (Qs/Qt) was calculated using the equation es/& = (Cc02 - CaOl)/(CcO? - CVOzj, where Cc01 (02 content of alveolar capillary blood) is calculated assuming that capillary PO2 is equal to the calculated alveolar PO: using the alveolar gas equation. Values are mean f standard error (SEM). Regression analysis was performed with the least-square method. Values obtained at different levels of PEEP were compared using the two-way analysis of variance. When significant, the values obtained at different levels of PEEP were compared with those on zero end-expiratory pressure (ZEEP) using the paired t test as modified by Dunnet.‘” A value of p < .OS was considered to be significant.

RESULTS

Individual sex and age, causes of ARDS that were classified according to Pepe et al.” Murray’s score,13 presence or absence of MSOF, and outcome are shown in Table 1. Organisms and the respective sites of isolation are also indicated. The relationships between GO, and b0, at all levels of PEEP in two representative patients are shown.in Fig 1. In one patient (Fig 1, top) DO, and VOz decreased with PEEP and were significantly correlated, while in the other patient (Fig 1, bottom) DO2 decreased with PEEP while VOz remained essentially unchanged. In this patievt there was no significant correlation between V02 and DO:. Figure ? shows the relationship between QO, and DO2 obtained with different levels of PEEP in all patients. Regression lines in each patient were obtained. Eight patients exhibited a highly. significant. positive correlation between VOz and DOz, ranging from 0.90 (P < .Ol) to 0.99 (P < .OOOl). The slope of the individual regression lines range.d between 0.18 and 0.37. In these patients, DO2 on ZEEP ranged between 330 and 640 mlimini’m’, and was always highest on ZEEP than on PEEP. These eight patients will be henceforth defined as supply dependent.” In the other 10 patients, DO, decreased significantly with PEEP while v02 remained essentially constant. As a result, VOz and DO, were not significantly correlated

RANIERI

152

Table Patient NO.

1

Sex

Age (VI

F

54

2

M

58

3 4

M F

52 68

5

F

47

6 7

M M M

56 46 49 40 47

11

F M M

12 13

F M

66 46

14 15

F F

25 46

16 17

M M

46 40

18

F

41

a 9 10

Data

of the 18 Septic

Adult

Respiratory

Distress

Syndrome

Patients

MlWray’s SCWS

MOSF

Pneumonia

2.75

Yes

D

Peritonitis, laparotomy Intestinal occlusion, laparotomy

2.75 2.75

Yes No

D S D D

E coli, blood,

peritoneum

D S

Paeruginosa, Streptococcus

blood, sputum faecalis, blood

Underlying

Peritonitis,

Disease

laparotomy

Intestinal volvoIus, laparotomy Peritonitis, laparotomy Pancreatitis, laparotomy Pneumonia,

sepsis

Peritonitis, laparotomy Pancreatitis, laparotomy Purulent cholecystitis

76

Abbreviations:

1. Clinical

Purulent

Pneumonia Intestinal volvolus, Peritonitis, Pneumonia

laparotomy

Pancreatitis,

laparotomy

Peritonitis,

D, died;

laparotomy

laparotomy

Infecting Organism and Site

Outcome

Pseudomonas aeruginosa, blood Escherichia coli, Proteus mirabilis,

blood

Pmirabilis, blood, peritoneum E coli, P mirabilis, blood

3.25

Yes

3.25 3.00 3.25

Yes Yes No

3.25

Yes

3.25 3.00

No Yes Yes

D S

Klebsiella pneumonia, sputum Sfaphylococcus aureus, blood,

peritoneum

D D

S faecalis, Hemophilus

bile

Yes

D

2.75 2.75

No Yes

S D

S faecalis, blood, bile urine E coli, blood, urine

3.25 2.53

Yes No

D S

2.56

No

S

Kpneumonia, sputum S aureus, peritoneum

2.66

No

S

S faecalis,

3.00 3.00

cholecystitis

ET AL

blood influenzae,

E coli, Pmirabilis, blood, Paeruginosa, peritoneum

blood,

urine

peritoneum

S, survived.

and these patients were defined-as non-supply dependent.5 In these patients, DO2 on ZEEP ranged between 686 and 951 mL/min/m*. Clinical data of supply and non-supply dependent septic ARDS patients are provided in Table 2. The supply dependent patients were

“q =40.52.+0 13.w, r=o.!B;pcO.WI 160

if02

significantly older but there was no significant difference in Murray’s score. While MSOF was present in all supply dependent patients, this was the case in only three of 10 of the nonsupply dependent patients. All patients with MSOF died, while those without MSOF survived. All the survivors were non-supply dependent. Table 3 shows the hemodynamics and gas exchange data on ZEEP in supply and nonsupply dependent ARDS patients. Heart rate,

(mlhinlm *)

01 2407

160

1

iJo,=

132+0.01. kc& r=o.19;p>005

CO, (mllmitim ‘) 60

01 0

I 300

, 600

/ 900

, 1200

602 (mVmim/m2 ) Fig 1. Relationship between and delivery (DO,) at four PEEP representative supply dependent dent (bottom) patient. individual regression lines, and coefficients indicate values obtained on ZEEP.

oxygen consumption (\iOJ levels (0 to 15 cm HZO) in a (top) and non-supply depenexperimental points, linear are shown. Solid circles

Fig 2. Relationship between oxygen consumption (CO,) and delivery (DO,) obtained with different levels of PEEP (0 to 15 cm H20) in 18 septic ARDS patients. Regression lines for each individual patient are shown. These lines encompass the individual range of change in 90, and l!IO, observed with PEEP. Solid and dotted lines indicate significant (P < .05) (supply ,dependency) and nonsignificant (non-supply dependency) VOJDO, relationships, respectively. Open circles indicate values obtained on ZEEP (PEEP = 0) in patients who survived; solid circles indicate values obtained on ZEEP in patients who did not survive.

OXYGEN

Table

DELIVERY-CONSUMPTION

2. Clinical

IN ARDS

Data of Supply

Patients

on Zero

No. of Patients

SUPPlY dependent Non-supply

8

dependent

10

*P i .Ol; supply

PATIENTS

and Non-Supply

End-Expiratory

153

Dependent

Pressure

Age Ml

Lung Injury SCOW

MOSF (No. of Patients)

SlJrvivors

55 + 6

3.00 2 0.1

8

0

41 k 2" 3.03 c 0.1

3

7

dependent

versus

non-supply

dependent.

mean arterial pressure, pulmonary capillary wedge pressure, hemoglobin, FIO~, and VOz did not differ significantly. In supply dependent patients, CI, Qs/Qt, P?02, !+02, CG02, and DO2 were significantly lower, while systemic vascular resistance, mean pulmonary arterial pressure, pulmonary vascular resistance, Pao2, Sa02, Ca02, C(a-v)O,, and O2 ER were significantly higher than in the non-supply dependent patients. The effects of PEEP on gas exchange in Table

3. Comparison of Hemodynamics and Gas Exchange Zero End-Expiratory Pressure Between Supply and Non-Supply

HR (min’) MAP (mm

Dependent

Hg)

Patients

SUPPlY Dependent

Non-Supply Depenent

100 k 6 100 + 10

109 + 1 102 + 20

PCWP (mm Hg) Cl (L/min/m2)

14 2 0.7 3.4 -c 0.2

14 + 1.1 6.2 k 0.2"

SVR (dyne/s/cm5) MPAP (mm Hg)

1,175 + 118 26 2 4

838 k 43b 21 5 5a

PVR (dyneislcm5) a,:a,

242 k 39 0.37 + 0.1

159 2 lob 0.54 + O.lC

Hb (g/dL) FIO,

10.7 t 0.1 0.6 t 0.1

10.8 t 0.2 0.6 i 0.1

77 + 5 96 i- 1

58 k 3b a7 + 2a

Paoz (mm Hg) Sao, (%) Cao, (mL/dL)

12.9 +- 0.3

11.9 + 0.7c

PVo, (mm Hg) sco, (X) COO, (mL/dL)

37 2 1 69 + 1 8.8 +- 0.1

41 + Ia 72 k la 10.3 k 0.6a

DO, (mL/min/m*)

463 2 30

771 It 2lC

i/O, (mLlmin/m? C(a - V)O, (mL/dL) 02 ER

146 k 8 4.0 2 0.1 0.32 2 0.01

15124 2.5 2 O.lc 0.19 5 0.02c

Abbreviations: pressure;

PCWP,

HR, heart

rate:

pulmonary

on

MAP, capillary

mean

systemic

wedge

DISCUSSION

arterial

pressure;

Cl,

cardic index; SVR, systemic vascular resistance; MPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance; G,/G,, right-to-left venous admixture; Hb, hemoglobin; Cao2, arterial oxygen content; DO,, oxygen ER, oxygen extraction aP i .05; bP < .Ol; non-supply dependent

content; delivery; ratio.

Cljo2, mixed Venus oxygen VO,, oxygen consumption; 0,

supply

dependent

supply and non-supply dependent patients are shown in Table 4. Cardiac input and QsiQt decreased significantly with PEEP in both supply and non-supply dependent patients, while Pao, improved in both groups. However, Sa02 and CaOz improved significantly with PEEP only in non-supply dependent patients who had lower initial values of Sa02 (and hence Pq). Positive end-expiratory pressure decreased DO, systematically in supply dependent patients.. In addition, in non-supply dependent patients DO? decreased slightly with PEEP, but the reduction was significant only at a PEEP level of 15 cm H20 (P < .Ol). IW02, SvOz, and CVO, did not change significantly with PEEP in both groups. Positive end-expiratory pressure reduced V02 systematically in supply dependent patients, remaining unchanged in non-supply dependent patients. C(a-v)02 and O2 ER did not change significantly with PEEP in non-supply dependent patients, while in supply dependent patients C(a-v)O, and O2 ER increased significantly at PEEP levels of 10 and 15 cm H1O. respectively (P < .Ol).

versus

There are two main findings of the present study.. The first is that septic ARDS patients with DO2 on ZEEP I 640 ml/minim2 showed a significant correlation between changes in VOz and DO2 with PEEP (supply dependent). In all of these patients DO1 decreased with PEEP as a result of reduced CL while Pao2 increased. This increase in Pao2, however, was not associated with significant changes in SaO, because of the high values of Pao2 on ZEEP. All supply dependent patients developed MSOF and died. The second finding is that in septic ARDS patients with DO2 on ZFEP 2 686 mL/ minim: changes in V02 and DO2 with PEEP were not significantly correlated (non-supply dependent). As PEEP was applied, the changes in DO2 were balanced by variations in O3 ER that kept V-O2 constant. DO, decreased with PEEP in the majority of these patients, the reduction being significant at a PEEP level of 15 cm HzO. Oxygen extraction ratio and C(a-v)02 increased significantly with PEEP levels of 10 and 15 cm H20, respectively. Three of these patients developed MSOF and died (70% of survivors).

154

RANIERI

Table

4. Effects

of Positive

End-Expiratory

Pressure

on O2 Balance

in Supply

and Non-Supply

Suply DependentPEEP (cm WI 0

Cl (L/min/m*)

5

3.4 2 0.2

6,/a, Pao, (mm Hg) Sao, (%)

0.37

Cao, (mL/dL)

12.9 2 0.3

00,

(mL/min/m*) PCO, (mm Hg)

svo2 (%) COO, (mL/dL) i/O, (mL/min/m2) C(a - rj)O, (mL/dL) O2 ER Abbreviations:

0.32

2 0.V

77 + 5

92 2 76

96 2 1

96 k 1

Patients

Non-SupplyDependentPEEP (cm WI

10

3.1 T 0.26

'- 0.1

Dependent

ET AL

15

3.1 + 0.26

0

2.6 + 0.2~

0.23 + O.lc

0.19

112 IV

+ O.lC

5

10

6.2 2 0.2

5.7 2 0.2

0.54 2 0.1

0.48 ? 0.V'

5.5 + 0.28 0.39 t

0.1'

5.1 + 0.26 0.33 ? 0.1"

58 + 3

64 + 2a

78 + V

98 + 1

98 + 1

87 + 2

90 t

93 + 2b

2 0.3

13.7 + 0.3

13.6 + 0.2

11.9 + 0.7

13.2 k 0.6"

13.8 + 0.V

463 t 30

429 + 33a

400 t 37*

350 + 240

771 230

744 k 41

740 k 41

37 k 1

36 + 1

38 t

1

38 2 1

41 2 1

40 k 1

40?

69 + 1

68 + 1

69 f

1

70 + 1

74 2 2

73 k 1

74 2 1

75 k 1

8.8 + 0.1

9.0 + 0.2

9.7 2 0.3

9.6 k 0.2

10.3 + 0.6

10.1 2 0.5

11.9 2 0.6

11.9 2 0.4

146 + 8

134 k 8"

132 f 68

118?8b

15124

152 r 5

155 +4

4.0 + 0.1

3.8 2 0.1

4.0 f

4.0 -t 0.1

2.5 + 0.1

2.7 + 0.1

2.9 -t O.lb

3.17

* 0.26

0.22 + O.Olb

0.23

+ 0.02b

0.32

Cl, cardic

13.05

_f 0.01

index;

0.31

&lb,,

k 0.01

0.1

0.31 2 0.02

right-to-left

mixed Venus oxygen content: GO,, oxygen consumption; “P < .05; bP < .Ol; CP < ,001 relative to PEEP 0.

Oxygen Consumption/Delivery

116-+7'

15

venous

0.32

'- 0.01

admixture;

0, ER, oxygen

Relationship

In a study of patients with posttraumatic ARDS, Powers et al” examined the relation between VOz and DOz at different levels of PEEP and found that,.despite normal or relatively high levels of DO*, oxygen uptake by the body changed linearly with changes in DO*. The O2 ER remained fairly constant in the range of 20% to 25% despite large changes in DO*. Similar findings were also reported. by Danek et al7 Dubin et al9 studied the VOz/D02 relationship in separate groups of septic and nonseptic ARDS patients. This study showed that supply dependency was present only in septic ARDS patients. In nonseptic ARDS patients, when DO:! was higher than 293 mL/ min/m2, VOz remained constant as DO2 changed with PEEP. Our study shows that, in experimental conditions identical.to those of Dubin et aL9 a plateau in the V02/D02 relationship is present also in septic ARDS patients at DO2 values higher than 686 mL/min/m2. Such a plateau has been found considering the whole population included in our study. However, none of our patients showed such a plateau in the individual Vq2/D02 relationship. V02 on ZEEP did not differ between supply and non-supply dependent patients (Table 3) while DOz on ZEEP was higher in non-supply than in supply dependent patients. Hence, O2 ER on ZEEP was significantly lower in non-supply than in supply dependent patients. The lower O2 ER in non-supply dependent patients is

0.19

Cao,, extraction

+ 0.02

arterial

0.20

oxygen

2"

2 0.01

content;

fiO,,

1

oxygen

99 2 8= 95 k 16 14.11

t 09

709 + 5c 41 2 1

158 2 3

delivery;

CBo2,

ratio.

hence the consequence of DO, values in excess of tissue metabolic requirements,. as expressed by V02. On the contrary, when DO2 was relatively low (DO2 of 640 mL/min/m2), even higher values of O2 ER were not able to satisfy tissue metabolic requirements and supply dependency was present. The only data available in relatively healthy humans on the effect of reducing DO2 comes from observations made in anesthetized patients undergoing coronary artery surgery.‘O These subjects exhibited supply dependency at DO2 values lower than 330 mL/min/m2, with a critical O2 ER of 0.33.1° In our septic ARDS patients, supply dependency was found in DO2 values of up to 640 mL/min/m2. The O2 ER on ZEEP in our supply dependent patients amounted to 0.32 -+ 1.01 and was similar to the values found in healthy subjects.‘O The high “critical” DO2 in septic A.RDS patients could hence be explained with VOz values (146 + 8 mL/min/m2; Table 3) higher than in normal subjects (86 ? 4 mL/min/m2; Table 1, ref 10). These data support the hypothesis recently proposed by Dantzker et al4 that the interaction between V02 and DOz in septic ARDS patients may represent a normal physiologic behavior rather than an abnormal manifestation of impaired O2 extraction. In most studies reporting. pathologic 02 supply dependency, DO2 and V02 were calculated from measurements of blood oxygen contents and CO. A problem arises because ran-

OXYGEN

DELIVERY-CONSUMPTION

IN ARDS

PATIENTS

dom measurements errors will affect the calculated VOz and D02.i8J9 In other words, if two sequential measurements are made when no physiologic change has occurred, random errors will result in an apparent correlation between the two variables in which no physiologic correlation truly exists.” However, mathematic techniques for dealing with the problem of a false correlation secondary to shared variables suggest that the effect. of coupled error is small when the ranges of DOz are large, and measurement errors are not excessive.18J9 In our study VO, was determined with the Fick equation. A significant relationship between VO, and DOz was found only in patients with a DO2 on ZEEP lower than 640 mL/min/m2. In these patients, changes in DO2 with a PEEP level of 15 cm Hz0 relative to ZEEP ranged between 18% and 34% (23% -+ 3%) (Fig 2). No significant correlation between VOz and DO2 was found in all patients with a DO2 on ZEEP higher than 686 ml/mini m2. In these patients the changes in DO2 with PEEP of 15 cm Hz0 ranged between 13% and 36% (20% -+ 3%) (Fig 2). The absence of a significant correlation between V02 and DO2 in these patients suggests that mathematical coupling is irrelevant in the analysis of the VOJ DO2 relationship, as pointed out by CainzO Recently, Ronco et alzl determined VOX in 17 ARDS patients using an indirect calorimetry method. They found no changes in VOz after increasing DOz by blood transfusion. In this study, nine patients were septic and, with the exception of three, had a control DO2 (range, 622 to 1,049 mLlmin/m2) close to or higher than our “critical” value of 640 mL/min/m2. The other eight patients were not septic and had a control DO2 (range, 352 to 926 ml/mini m2) higher than 295 mL/min/m2, which .has been described by Dubin et alYas “critical” DO? in nonseptic patients. Therefore, confirming Dubin et al’s observations,Y Roncp et a121found that VO-, remained constant as DO2 increased after blood transfusion. Another methodologic problem relates to the difficulty of distinguishing between the effects of changing O2 demand on DO2 as.opposed to the effects of changing DO2 on V02.22 Normally, V02 and DO2 vary together because oxygen demand rather than DO2 is the physiologic independent variable. The increase in

155

DO, that accompanies increasing metabolic demands is accomplished predominantly through on augmentation in CO.2” Indeed, if DO2 and V02 are measured in any patient over time, spontaneous variations in oxygen demand secondary to feeding, drug therapy, etc. are to be expected, and DO2 should be expected to change.6 These effects were minimized in our study in which the patients were sedated and paralyzed and the changes in DO2 were obtained acutely.?’ Multisystem organ failure, rather than irreversible respiratory failure, is the major cause of death in ARDS patients.24 In a prospective study of ARDS patients admitted to an intensive care unit, those who demonstrated supply dependency had a mortality rate of 70% compared with 30% for those without this finding.15 Another study found a significantly greater increase in VO? subsequent to an increase in DO2 in ARDS patients who died compared with those who survived an episode of sepsis.‘l These results indicate that supply dependency probably reflects a significant deficit in tissue oxygenation that eventually results in critical organ failure and death.‘” Our results confirm these observations. All patients who exhibited supply dependency developed MSOF and died (Table 2). Only three non-supply dependent patients developed MSOF and died, while the other seven patients did not develop MSOF and survived (Table 2). Therefore, as previously reported,‘j our data suggest an inverse relationship between DO, and MSOF. There is strong evidence that supports the notion that 0: supply dependency is associated with lactic acidosis, which is thought to reflect tissue hypoxia.‘7 In studies in which blood lactate levels were measured, O2 supply dependency was observed in patients with increased, but not normal, lactate.“’ Hence, the development of lactic acidosis is thought to reflect an imbalance between the metabolic requirements and the oxygen supply. Although blood lactate can be easily measured in critically ill patients. its interpretation is complicated by the fact that a blood concentration of any substance reflects not only its production but also its elimination. Therefore, when the oxygen supply is rapidly changed, blood lactate can vary only relatively ~lowly.“~ Since in our study DO1 was rapidly

156

changed by applying PEEP for short periods of time (30 to 40 minutes), blood lactate levels were not measured. Impairment of O2 extracting capacity of the tissues in sepsis has been explained in different ways. Perhaps the primary problem is a diffuse cellular defect that interferes with the normal cellular utilization of available oxygen. This abnormality of cellular respiration has been described in sepsis.29 Inadequate tissue O2 extraction and O2 supply dependency also could point to the inability to autoregulate blood flow to actively metabolizing tissues or loss of microvessels secondary to occlusion or damage.26 However, the oxygen extraction defect associated with endotoxemia could be due to maldistribution of blood flow among organs rather than to maldistribution of blood flow within organs.30 Besides, hypoxia may induce the diversion of blood flow to vital organs at the expense of other organs less well endowed (microvascularly speaking), such as the liver and gut.4 Under these circumstances alterations in the barrier function of the intestinal mucosa and hepatic failure may lead to the onset of MSOF. Effects of Positive End-Expiratory Pressure on Oxygen Balance Pao2 increased with PEEP in both supply and non-supply dependent patients (Table 4). However, only in the latter patients was the increase in Pao2 with PEEP associated with a significant increase in Sa02 because of relatively low Pao2 values on ZEEP. Therefore, CaOz improved with PEEP only in non-supply dependent patients. The different Pao2 on ZEEP explains the different effects of PEEP on oxygen content in the two groups of patients. Non-supply dependent patients had, on ZEEP, a Pao2 lower than supply dependent patients (58 + 3 and 77 & 5 mm Hg, respectively). Hence, because of the shape of the hemoglobin dissociation curve,31 Sa02 and Ca02 increased with PEEP in nonsupply dependent patients but did not change in supply dependent patients. As previously shown,32 PEEP decreased CI in both supply and non-supply dependent patients. However, PEEP did not change Ca02 in supply dependent patients. Hence, the reduction in CI with PEEP led to a reduction in DO2 in all such patients. In non-supply dependent patients, the improvement in Ca02 was not able to compensate the

RANIERI

ET AL

reduction in CI with PEEP; hence, DO, decreased with PEEP in all but three patients. These three patients had the lowest values of Pao2, Sa02, and Ca02 on ZEEP. Therefore, PEEP improved CaOz by such an amount able to counterbalance the reduction in CI and increase D02. On ZEEP, CI .was significantly correlated (P < .OOOl) with DO2 in both supply and nonsupply dependent patients,. while CaOz was correlated (P < .05) with DO2 only in nonsupply dependent patients. This suggests that greater DO2 in non-supply dependent patients is explained mpstly by the higher CI. A correlation between Qs/Qt and Cl has been showed by Dantzker et al.33 Our data confirm these observations. A positive correlation is found between CI and Qs/Qt on ZEEP (P.< .pOl) and between the changes in CI and Qs/Qt with PEEP (P < .OOOl) in both dependent and nondependent patients. Therefore, the higher values of Paoz, SaO,, and Ca02 on ZEEP exhibited by supply dep.endent patients may be explained by the lower Qs/Qt and CI.33 Recently, Russel et ali5 showed that early in the course of ARDS, DO2 was greater in survivors than in nonsurvivors. Greater CI accounted for the greater DO2 in the survivors. Our results are in agreement with these observations. With the exception of three patients, all our patients with a DO2 higher than 668 mL/min/m2 did not develop MSOF and survived. In the study of Russel,15 the greater CI in nonsurvivors was explained by a greater right and left ventricular end-diastolic volume and greater ventricular compliance. In our study, ventricular ejection fractions and transmural hemodynamic pressures were not measured, and therefore abnormalities in ventricular function could not be assessed. However, as showed by Russel et al,15 our supply dependent patients (all died) exhibited lower CI and higher values of mean pulmonary arterial pressure, pulmonary vascular resistance, and systemic vascular resistance than non-supply dependent patients (70% survived). These results suggest that, in our study, low CI and DO2 in patients who did not survive (supply dependent) may be due to a compromised cardiovascular function.34 In conclusion, in our study O2 supply dependency was found only in septic ARDS patients with a DO2 on ZEEP lower than 640 mL/min/

OXYGEN

DELIVERY-CONSUMPTION

157

IN ARDS PATIENTS

m2. In all these patients, PEEP decreased DO,. All these patients developed MSOF and all died. In patients with a DO, on ZEEP higher than 686 mL/min/m2, DO2 decreased with PEEP in seven patients while it increased in the other three. As PEEP was applied, changes in

DO, were balanced by, opposite variations in 02ER able to keep V02 constant. Positive end-expiratory pressure reduced DO2 to a lower value which, however, remained above the value of 640 mL/min/m2. Only three of these 10 patients developed MSOF and died.

REFERENCES I. Cain SM: Gas exchange in hypoxia, apnea and hyperoxia. in Fishman AP (ed): Handbook of Physiology. The Respiratory System, ~014. Bethesda, MD, American Physiological Society, 1987, pp 403-420 2. Cain SM: Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia. J Appl Physiol 42:228-234. 1977 3. Gutierrez G, Pohil RJ, Narayana P: Skeletal muscle 02 consumption and energy metabolism during hypoxemia. J Appl Physiol66:2117-2123, 1989 4. Dantzker DR, Forsmann B, Gutierrez G: Oxygen supply and utilization. A reevaluation. Am Rev Respir Dis 143:675-679,199 I 5. Cain SM: Assessment of tissue oxygenation. Crit Care Clin 2537-550. 1986 6. Schumaker PT, Samsel RW: Oxygen supply and consumption in the adult respiratory syndrome. Clin Chest Med Il:715-722, 1990 7. Danek SJ, Lynch JP, Weg JG, et al: The dependence of oxygen uptake on oxygen delivery in the adult respiratory distress syndrome. Am Rev Respir Dis 122:387-395, 1980 8. Mohsenifar Z, Goldbach P, Tashkin DP, et al: Relationship between 02 delivery and 02 consumption in the adult respiratory distress syndrome. Chest 84:267-271, 1983 9. Dubin E, Estenssoro E, Silva C, et al: Different oxygen transport patterns in patients with adult respiratory distress syndrome treated with positive end-expiratory pressure. J Crit Care 5:101-107, 1990 IO. Shibutami K, Kornatsu T, Kubal K, et al: Critical level of oxygen delivery in anesthetized man. Crit Care Med I l:640-643, 1983 II. Van Der Linden P, Gilbart E, Engelman E, et al: Effects of anesthetic agents on systemic critical O2 delivery. J Appl Physiol 71:83-93, 1991 12. Pepe PE, Hudson LD. Carrico CT: Early application of positive end-expiratory pressure in patients at risk of the adult respiratory distress syndrome. N Engl J Med 311:281286, 1984 13. Murray JF. Matthay JM, Lute JM, et al: An expanded definition of adult respiratory distress syndrome. Am Rev Respir Dis 138:720-723, 1988 14. Bihari D, Smithies M, Gimson A, et al: The effects of vasodilation with prostacyclin on oxygen delivery and uptake in critically patients. N Engl J Med 317:396-403, 1987 15. Russel JA, Ronco JJ, Lockhat D, et al: Oxygen delivery and consumption and ventricular preload are greater in survivors than in nonsurvivors of the adult respiratory distress syndrome. Am Rev Respir Dis 141:65Y665. 1990 16. Dunnett CW: A multiple comparison procedure for comparing several treatments with the control. J Am Stat Assoc50:1036-1121. 1955

17. Powers SR. Mannal M, Neclerio M. et al: Physiologic consequence of positive end-expiratory pressure (PEEP) ventilation. Ann Surg 178:265-271. I973 18. Moreno LF, Stratton HH, Newell JC. et al: Mathematical coupling of data: Correction of a common error for linear calculation. J Appl Physiol 60:335-343, 19X6 19. Stratton HH. Feustel PJ, Newell JC: Regression of controlled variables in the presence of shared measurement error. J Appl Physiol63:2083-2093. 1987 20. Cain SM: Supply dependency of oxygen uptake in ARDS: Myth or reality’? Am J Med Sci 2X8: I I9- 114, 19X4 21. Ronco JJ, Phang PT, Walley KR, et al: Oxygen consumption is independent on changes in oxygen &livery in severe adult respiratory distress syndrome. Am Rev Respir Dis 146:1267-1273, 1991 22. Pinsky MR: Defining the hypoxic threshold. Crrt Care Med 19:147-149, 1991 23. Astrand P. Cuddy PE, Saltin B, et al: Cardiac output during submaximal and maximal work. J Appl Physiol l9:268-274, 1964 24. Montgomery AB, Stager MA, Carrico J. et al: Cause of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis 132:485-489. 19X.5 25. Gutierrez G, Pohil RJ: Oxygen consumption is linearly related to 0: supply in critically ill patients. .I Crit Care l:43-53. 1986 26. Dantzker DR: Oxygen transport and utilization in ARDS. Eur Respir J I I:485489s 1990 (suppl) 27. Vincent J-L, Roman A. De Backer D. et ‘11: Oxygen uptake/supply dependency: Effects of short-term dohutamine infusion. Am Rev Respir Dis 142:7-X, I990 28. Vincent J-L, Dufaye P. Berre J. et al: Serial lactate determinations during circulatoq shock. Crit (‘arc Med 11:449-451. 1983 29. Mela L, Bacalzo LV, Miller LD: Defective oxidative metabolism on rat liver mithocondria in hemorrhagic and endotoxin shock. Am J Physiol220:571-577. I Y7 1 30. Schlichtig R, Kramer DJ. Pinsky MR: Flow redtstrihution during progressive hemorrhage is a determinant of critical 02 delivery. J Appl Physiol 70:169-178. I991 3 I. Gilston A: PEEP and oxygen balance: Where are the emperor’s clothes’? Intensive Crit Care Dig 9:7- 13. 1990 37. Lutch JS, Murray JF: Continuous positive pressure ventilation: Effects on systemic oxygen transport and tissue oxygenation. Ann Intern Med 176: 193-202. 1976 33. Dantzker DR. Lynch JP, Weg JG: Depression of cardiac output is a mechanism of shunt reduction in the therapy of acute respiratory failure. Chest 77:630-647, 19X0 34. Parrillo JE. Burch C, Shelhamer JH. et al: A circulating myocardial depressant substance in hrrmans with septic shock. J Clin Invest 76: 1539-1553. 19X5