Intensive Care Med (2007) 33:1133–1138DOI 10.1007/s00134-007-0642-y O R I G I N A L

Julien MaizelNorair AirapetianEmmanuel LorneChristophe TribouilloyZiad MassyMichel Slama

Diagnosis of central hypovolemia by usingpassive leg raising

Received: 11 October 2006Accepted: 27 March 2007Published online: 17 May 2007© Springer-Verlag 2007

This article is discussed in the editorialavailable at: http://dx.doi.org/10.1007/s00134-007-0645-8.

J. Maizel · N. Airapetian · M. Slama (�)CHU Sud, Unite de Reanimation Medicale,Service de Nephrologie,80054 cedex 1 Amiens, Francee-mail: slama.michel@chu-amiens.frTel.: +33-3-22455854Fax: +33-3-22455664

J. Maizel · E. Lorne · C. Tribouilloy ·Z. Massy · M. SlamaERI 12, INSERM,Amiens, France

Abstract Objective: Suspected cen-tral hypovolemia is a frequent clinical

situation in hospitalized patients, andno simple bedside diagnostic testin spontaneously breathing patientsis available. We tested the value ofpassive leg raising to predict hemo-dynamic improvement after fluidexpansion in patients with suspectedcentral hypovolemia. Design andsetting: Prospective study in fourintensive care units at the Amiensuniversity hospital. Thirty-four spon-taneously breathing patients withsuspected hypovolemia were includedand were classified as responders(cardiac output increased by 12%or more after fluid expansion) ornonresponders. Patients were ana-lyzed in the supine position during30° leg raising and after fluid expan-sion. Measurements and results:Stroke volume and cardiac outputdetermined by echocardiographic andDoppler techniques and heart rateand blood pressure were measured at

baseline, during passive leg raisingand after fluid expansion. An in-crease of cardiac output or strokevolume by 12% or more duringpassive leg raising was highly pre-dictive of central hypovolemia (AUC0.89 ± 0.06, 95% CI 0.73–0.97 forcardiac output and AUC 0.9 ± 0.06,95% CI 0.74–0.97 for stroke volume).Sensitivity and specificity values were63% and 89% for cardiac output and69%, 89% for stroke volume respec-tively. A close correlation (r = 0.75;p < 0.0001) was observed betweencardiac output changes during legraising and changes in cardiac outputafter fluid expansion. Conclusions:Bedside measurement of cardiacoutput or stroke volume by Dopplertechniques during passive leg raisingwas predictive of a positive hemo-dynamic effect of fluid expansion inspontaneously breathing patients withsuspected central hypovolemia.

Introduction

In many clinical situations, such as hypotension, shock,functional renal failure, oligoanuria, or clinical and/orlaboratory signs of dehydration, central hypovolemia maybe suspected, raising the question of whether fluid expan-sion is required to increase central blood volume [1, 2].In these clinical situations, volume infusion inducessignificant increase in cardiac output because the heart(left and right ventricles) works on the stiff portion of

the Frank–Starling relationship, and therefore increasesorgan perfusion and blood flow. The development ofa predictive index of preload dependency, and thus of fluidresponsiveness, in patients with suspected central hypo-volemia therefore constitutes a major clinical challenge.Such indices were recently introduced and validated inintubated and mechanically ventilated patients [3–6]. Inspontaneously breathing patients, these indices appearinaccurate because they strongly depend on respiratorystatus, which is not controlled in this case. Although the

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clinical responses to postural maneuvers, such as a largechange in pulse, severe dizziness or hypotension, mayhelp clinicians to identify patient with hypovolemia dueto blood loss, these criteria demonstrated low sensitivityand specificity for hypovolemia not due to blood loss [1].On the other hand, blind fluid infusion can be harmfulby increasing left-ventricular diastolic pressure, leadingto pulmonary edema. We hypothesized that passive legraising, by mobilizing blood from the lower part of thebody to the chest, may increase preload, stroke volumeand cardiac output, but only if the patient has true centralhypovolemia with a low preload. In the absence of centralhypovolemia, stroke volume and cardiac output are notincreased by this postural maneuver [7–9]. This maneuvercombined with measurement of cardiac output can there-fore be used before any volume expansion. The primaryaim of this study was to assess the predictive value ofstroke volume and noninvasive measurement of cardiacoutput changes during passive leg raising in spontaneouslybreathing patients with suspected hypovolemia.

Method

Patients

This prospective study was performed in four intensivecare units in Amiens university hospital (two medical, onesurgical and one cardiac unit). Spontaneously breathingpatients in whom the attending physician decided toperform fluid expansion were included consecutively.Inclusion criteria were: hypotension (systolic blood pres-sure less than 90 mmHg and/or mean blood pressure lessthan 70 mmHg or blood pressure decreased by more than40 mmHg compared to usual blood pressure); oligoanuriaor acute renal failure; or clinical and biological signsof extracellular fluid volume depletion (associated withan obvious etiology: ketoacidosis, vomiting, diarrhea).Patients with clinical signs of hemorrhage, patients inwhom fluid challenge could not be deferred for severalminutes, patients with a contraindication to passive legraising, and patients with arrhythmia were not included.This protocol was approved by the local ethics committeeand all patients — when conscious — or their relativesgave their informed consent.

Protocol

All patients were in the supine position for baseline meas-urements. Arterial blood pressure [systolic (SAP), dia-stolic (DAP), and mean arterial pressure (MAP)] (Ag-ilent Component Monitoring System, model M1205A,Boeblingen, Germany) was measured with a brachial cuffand heart rate was recorded. Echocardiographic cardiacoutput was measured in this position. The bed was angled

to produce passive leg raising (PLR) of 30 ° and bloodpressure, heart rate and cardiac output were measuredagain after 2 min. The patient was then returned to thesupine position and 500 ml of saline solution was admin-istered intravenously over 15 min. Echocardiography wasrepeated and blood pressure and heart rate were recorded.

Measurements

The following clinical characteristics were recorded:age, gender, SAPS II score, weight, MacCabe score,surgical/medical clinical problems, principal diagnosis,medical history (presence of hypertension, diabetes mel-litus, cardiomyopathy, presence of COPD or pulmonaryembolism). Echocardiography was performed usingHP Sonos 2000 and Philips Envisor (Philips MedicalSystem, Suresnes, France). On a parasternal 2D view,aortic diameter (AoD) was measured at the level ofthe aortic valve insertion (aortic annulus). Aortic area(AA) was calculated as follows: AA = (π × AoD2)/4.On an apical five-chamber view, aortic blood flow wasrecorded using pulsed Doppler, with the sample volumeplaced at the aortic annulus. The velocity–time integralof aortic blood flow (VTI) was calculated. Stroke vol-ume (SV) and cardiac output (CO) were calculated asfollows: CO = SV × HR, where HR is heart rate andSV = VTI × AA. Aortic area was considered to be stablethroughout the experiment and was measured only atbaseline; it was used to calculate CO during leg raisingand after fluid infusion. Each reported measurement ofVTI was an average of three to five consecutive measure-ments over one respiratory cycle. All measurements wereperformed by echocardiography-trained intensivists (J. M.and N. A.)

Statistical analysis

All variables are presented as mean ± standard deviation.A normal distribution was tested by means of a Kol-mogorov–Smirnov test. The relationships between variousvariables were analyzed using a linear regression method.Variables were compared using a Student t-test forcontinuous variables and a chi-square test for percentages.

The reproducibility of CO and SV measurementswas tested before the study. These variables were meas-ured twice in 10 patients by the same observer (J. M.;intraobserver reproducibility) and by a second observer(N. A.; interobserver reproducibility) after a 2-min in-terval in stable, spontaneously breathing patients. Themean difference was calculated and divided by the meanof the two values. Intraobserver reproducibility was4.2 ± 3.9% and 4.2 ± 3.9% for CO and SV, respectively,and interobserver reproducibility was 6.5 ± 5.5% and6.2 ± 4.2%, respectively. As all measurements during

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this study were performed by the same observer, andin the light of these findings concerning intraobserverreproducibility, patients with an increase of CO ≥ 12% or< 12% after fluid expansion compared to baseline wereclassified as responders and nonresponders, respectively.Absolute values at baseline as well as changes of heartrate, pressures, VTI (∆VTI), SV (∆SV), and CO (∆CO)during leg raising (PLR) were analyzed. The correlationbetween these variables and changes in CO after fluidexpansion as well as their predictive value to diagnosean increase in CO after fluid expansion was calculatedby using a receiver operating characteristic (ROC) curve.The area under the curve (AUC) was calculated for allparameters and compared by means of a Hanley–McNeiltest. Sensitivity, specificity, negative and positive predic-tive values, negative and positive likelihood ratio and rateof correct classification were calculated after defininga cut-off value. A p value < 0.05 was considered signifi-cant. Statistical analysis was performed using StatViewversion 5.0 (SAS Institute Inc, Cary, NC) and MedCalcversion 8.2.1.0 (MedCalc Software, Mariakerke, Belgium)software.

ResultsPatient characteristics are summarized in Table 1; 3 pa-tients received only vasoactive agents at the inclusion.Thirty-four patients (19 males and 15 females) witha mean age of 61 ± 17 years were included in the studydue to the presence of hypotension (n = 17; 50%), oligoa-nuria or acute renal failure (n = 6; 18%) or clinical andlaboratory signs of dehydration (n = 13; 38%).

Seventeen (50%) patients were considered to beresponders with a ≥ 12% increase of CO after salineinfusion. The characteristics of the two groups were iden-tical (Table 1). An increase of CO or SV by 5% or moreduring PLR distinguished responders from nonresponderswith high sensitivity, specificity and positive predictive

Global population Responders Nonresponders(n = 34) (n = 17) (n = 17)

Age (years), mean ± SD 61 ± 17 64 ± 17 58 ± 18Male, n (%) 19 (56) 12 (63) 7 (36)MacCabe group 0/1/2, n 18/14/2 6/10/1 12/4/1SAPS II, mean ± SD 39 ± 16 42 ± 16 36 ± 17Medical/surgical admission, n (%) 32 (94)/2 (6) 15 (89)/2 (12) 17 (100)/0 (0)Medical history, n (%):

Hypertension 17 (50) 7 (41) 10 (59)Diabetes mellitus 7 (20) 2 (12) 5 (29)Cardiomyopathy: 13 (38) 7 (41) 6 (35)

- Ischemic 11 (32) 6 (35) 5 (29)- Hypertensive 4 (12) 1 (6) 3 (18)

COPD 7 (20) 6 (35) 1 (6)Pulmonary embolism 1 (3) 0 (0) 1 (6)

SAPS II, Simplified Acute Physiology Score II; COPD, chronic obstructive pulmonary disease

Table 1 Characteristics of thestudy population

Fig. 1 Changes of cardiac output and stroke volume induced by PLR(expressed as percentage from baseline) in responders and nonre-sponders. ∆CO, Variation of cardiac output between baseline andafter passive leg raising; ∆SV, variation of stroke volume betweenbaseline and after passive leg raising. ∗p < 0.05 vs. nonresponders

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Table 2 Accuracy of cardiac output and stroke volume changes after passive leg raising to predict fluid responsiveness

Criterion Sensitivity Specificity Positive Negative Positive Negative Rate ofpredictive predictive likelihood likelihood correctvalue value ratio ratio classification

∆CO > 5% 94% 83% 83% 94% 6 0.1 88%∆SV > 5% 88% 67% 70% 86% 3 0.2 76%∆CO > 8% 81% 89% 87% 84% 7 0.2 88%∆SV > 8% 88% 83% 82% 88% 5 0.1 85%∆CO > 10% 69% 89% 85% 76% 6 0.3 82%∆SV > 10% 81% 83% 81% 83% 5 0.2 85%∆CO > 12% 63% 89% 83% 73% 6 0.4 76%∆SV > 12% 69% 89% 85% 76% 6 0.4 82%

∆CO, variation of cardiac output between baseline and after passive leg raising; ∆SV, variation of stroke volume between baseline andafter passive leg raising

Fig. 2 Receiver operating curves to discriminate responders andnonresponders to volume expansion. ∆CO, Variation of cardiac out-put between baseline and after passive leg raising; ∆SV, variation ofstroke volume between baseline and after passive leg raising; AUC,area under receiver operating curve ± standard error

Table 3 Pearson correlation coefficient and area under the receiveroperating curve of the different parameters

Correlation coefficient AUC ± SE(p value)

SV baseline –0.38 (0.03) 0.70 ± 0.09VTI baseline –0.39 (0.02) 0.75 ± 0.08∆CO 0.75 (0.0001) 0.95 ± 0.04∆SV 0.56 (0.0006) 0.90 ± 0.06

AUC, area under the receiver operating curve ± standard error; SV,stroke volume; VTI, velocity time integral of aortic blood flow; CO,cardiac output; ∆, Evolution between baseline and passive leg rais-ing

value. From a practical point of view, however, taking intoaccount the intraobserver reproducibility, a cut-off of 12%should be proposed with a fair specificity, sensitivity andpredictive values (Fig. 1, Table 2). The highest AUC was

Fig. 3 Relations between changes in CO during passive leg rais-ing (∆CO) and the changes in CO after volume expansion (dCO).dCO, Variation of cardiac output between baseline and after volumeexpansion; ∆CO, variation of cardiac output between baseline andafter passive leg raising

found for ∆CO (0.89 ± 0.06; 95% confidence interval0.73–0.97) and ∆SV (0.9 ± 0.06; 95% confidence interval0.74–0.97) (Fig. 2, Table 3). A significant correlation wasobserved only between (1) baseline value of VTI andSV, and variations in SV and CO during PLR; and (2)changes in CO after fluid challenge (Table 3, Fig. 3), butnot between any other variable and changes in CO afterfluid challenge. In contrast, neither absolute value norchanges in blood pressure were predictive of an increasein SV of fluid infusion.

Heart rate, pressures and echocardiographic indices atbaseline, during PLR, and after fluid challenge are shownin Table 4. No difference between responders and nonre-sponders was demonstrated at baseline. After fluid infu-sion, SAP, SV and CO increased in the responder group,but remained stable in the nonresponder group except forVTI and SV.

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Responders (n = 17) Nonresponders (n = 17) p

SAP, mmHgBaseline 106 ± 31 116 ± 30 nsPLR 111 ± 27 121 ± 28 nsVolume expansion 115 ± 27∗ 117 ± 23 ns

DAP, mmHgBaseline 57 ± 17 57 ± 17 nsPLR 62 ± 17∗ 60 ± 17 nsVolume expansion 58 ± 12 59 ± 15 ns

MAP, mmHgBaseline 73 ± 20 76 ± 20 nsPLR 78 ± 19∗ 81 ± 18 nsVolume expansion 77 ± 16 78 ± 16 ns

HR, beats/minBaseline 92 ± 19 87 ± 22 nsPLR 90 ± 20 85 ± 21 nsVolume expansion 92 ± 20 85 ± 21 ns

VTI, cmBaseline 17 ± 3 21 ± 5 0.02PLR 20 ± 3∗ 21 ± 5 nsVolume expansion 21 ± 4∗† 21 ± 5 ns

SV, mlBaseline 51 ± 10 61 ± 14 0.02PLR 58 ± 10∗ 62 ± 15 nsVolume expansion 62 ± 12∗† 62 ± 15 ns

CO, l/minBaseline 4.6 ± 1.2 5.3 ± 1.6 nsPLR 5.2 ± 1.4∗ 5.2 ± 1.7 nsVolume expansion 5.6 ± 1.5∗† 5.2 ± 1.8 ns

Values are expressed as mean ± SD.PLR, passive leg raising; SAP, systolic arterial pressure; DAP, diastolic arterial pressure; MAP, meanarterial pressure; PP, pulse pressure; HR, heart rate; VTI, velocity time integral of aortic blood flow; SV,stroke volume; CO, cardiac output∗ p < 0.05 vs. baseline; † p < 0.05 vs. PLR

Table 4 Evolution ofhemodynamic parameters atbaseline, after PLR and fluidchallenge in responders andnonresponders

Discussion

This study in spontaneously breathing patients withsuspected hypovolemia shows that changes in CO or SVduring PLR are predictive of central hypovolemia. Anincrease by more than 12% of cardiac output or SV duringPLR was predictive of a positive hemodynamic responseafter fluid expansion. Therefore, echocardiographic assess-ment of CO or SV during PLR appears to be reproducibleand easy to perform at the bedside. This reversible testavoided fluid expansion in patients in whom it would beharmful.

Many studies have analyzed postural hemodynamicchanges to confirm suspected hypovolemia, but the ac-curacy of previously described clinical signs to diagnosehypovolemia not due to blood loss is very low [1]. Lack ofinformation concerning this population was emphasizedin a review published in 1999 [1].

Leg raising was very recently used in selected crit-ically ill patients [7–9]. Monnet et al., using esophagealDoppler, found that an increase in aortic blood flowby more than 12% was predictive of a greater than15% increase in CO after fluid expansion [8]. SimilarlyLafanechere et al. reported that an increase in aortic

flow greater than 8% during PLR predicted an increasein aortic blood flow after volume infusion [9]. Bothstudies were performed in intubated and mechanicallyventilated patients and used esophageal Doppler to meas-ure CO [9]. These findings observed in mechanicallyventilated patients cannot be extrapolated to nonsedatedand nonintubated patients. No information is availableconcerning the effect of PLR in nonintubated patients.Negative intrathoracic pressure may change the amountof increase in blood central volume and may changebaroreceptor and hemodynamic response. In addition,arterial tone is modified during sedation and may changeresponses to volume increase or decrease. Therefore thisconcept should be validated in spontaneously breathingpatients. Our study was performed in nonintubated pa-tients without any sedation with suspected hypovolemia,and therefore the findings may be applied to patients inwhom clinicians wonder whether fluid infusion wouldimprove their hemodynamics and clinical status.

In a previously published study using this concept,esophageal Doppler was used, and this method is farfrom a gold standard method to assess CO. In addition,the technique cannot be used in nonintubated patients.Echocardiography is a simple and noninvasive method to

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evaluate hemodynamics in unstable patients and can besafely used in nonintubated and nonsedated patients [10].It is widely available and can be used in many hospitals.CO measurement using this method has been extensivelyvalidated and can be conducted at the bedside [11].

Lastly, PLR did not induce alterations in heart rate, sug-gesting the absence of catecholamine stimulation related tothe maneuver in awake patients.

This study presents a number of limitations or rise con-cerns. Firstly, the number of patients appears to be low, butcomparable to the sample sizes of other published studiesin this field [1, 7, 8] and this study should be considered tobe a pilot study. Secondly, the echocardiographic methodis not readily available 24 hours a day, 7 days a week, inmany centers. Third, we did not assess hemodynamics ata second baseline after PLR and before fluid infusion. Thismay explain why some patients experienced a high CO atbaseline due to the associated stress, which decreased dur-

ing the procedure, explaining the lower CO in some non-responders after fluid challenge.

Despite these limitations, this study is the first todemonstrate in nonintubated patients that hemodynamicchanges assessed by using a noninvasive, well-validatedtechnique during a simple maneuver may predict thehemodynamic effect of fluid infusion.

Conclusion

In spontaneously breathing patients with suspected hypo-volemia, cardiac output or stroke volume measurementusing echocardiography during passive leg raising canvery accurately discriminate patients who will obtaina hemodynamic benefit from fluid challenge.

Acknowledgements. Grants from PHRC (Programme Hospitalierde Recherche Clinique) were obtained to conduct this clinical study.

References

1. McGee S, Abernethy WB 3rd,Simel DL (1999) The rationalclinical examination. Is this patienthypovolemic? JAMA 281:1022–1029

2. Mange K, Matsuura D, Cizman B,Soto H, Ziyadeh FN, Goldfarb S,Neilson EG (1997) Language guid-ing therapy: the case of dehydrationversus volume depletion. Ann Intern127:848–853

3. Michard F, Chemla D, Richard C,Wysocki M, Pinsky MR, Lecarpen-tier Y, Teboul JL (1999) Clinical useof respiratory changes in arterial pulsepressure to monitor the hemodynamiceffects of PEEP. Am J Respir Crit CareMed 159:935–939

4. Michard F, Boussat S, Chemla D,Anguel N, Mercat A, Lecarpentier Y,Richard C, Pinsky MR, Teboul JL(2000) Relation between respiratorychanges in arterial pulse pressure andfluid responsiveness in septic patientswith acute circulatory failure. Am JRespir Crit Care Med 162:134–138

5. Slama M, Masson H, Teboul JL,Arnould ML, Nait-Kaoudjt R, Colas B,Peltier M, Tribouilloy C, Susic D,Frohlich E, Andrejak M (2004)Monitoring of respiratory variationsof aortic blood flow velocity usingesophageal Doppler. Intensive CareMed 30:1182–1187

6. Slama M, Masson H, Teboul JL,Arnout ML, Susic D, Frohlich E,Andrejak M (2002) Respiratory vari-ations of aortic VTI: a new index ofhypovolemia and fluid responsiveness.Am J Physiol Heart Circ Physiol283:H1729–H1733

7. Boulain T, Achard JM, Teboul JL,Richard C, Perrotin D, Ginies G (2002)Changes in BP induced by passiveleg raising predict response to fluidloading in critically ill patients. Chest121:1245–1252

8. Monnet X, Rienzo M, Osman D,Anguel N, Richard C, Pinsky MR,Teboul JL (2006) Passive leg raisingpredicts fluid responsiveness in the crit-ically ill. Crit Care Med 34:1402–1407

9. Lafanechere A, Pene F, Goulenok C,Delahaye A, Mallet V, Choukroun G,Chiche J, Mira J, Cariou A (2006)Changes in aortic blood flow inducedby passive leg raising predict fluidresponsiveness in critically ill patients.Crit Care 10:R132

10. Slama MA, Novara A, Van de Putte P,Diebold B, Safavian A, Safar M,Ossart M, Fagon JY (1996) Diag-nostic and therapeutic implicationsof transesophageal echocardiographyin medical ICU patients with unex-plained shock, hypoxemia, or suspectedendocarditis. Intensive Care Med22:916–922

11. Dittmann H, Voelker W, Karsch KR,Seipel L (1987) Influence of sam-pling site and flow area on cardiacoutput measurements by Dopplerechocardiography. J Am Coll Cardiol10:818–823