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Basic Science Aspects


Pestel, Gunther J.*; Hiltebrand, Luzius B.*; Fukui, Kimiko*†; Cohen, Delphine*; Hager, Helmut; Kurz, Andrea M.*

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Shock 26(4):p 391-395, October 2006. | DOI: 10.1097/01.shk.0000228792.10550.ed
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Arterial pressure waveform fluctuations are a promising technique to identify "volume responders," whose ventricles operate on the ascending portion of the Frank-Starling curve. Intermittent positive-pressure ventilation induces cyclic changes in left ventricular stroke volume (SV; maximum during the inspiratory period and minimum during the expiratory period), which are mainly related to the expiratory decrease in left ventricular preload due to the inspiratory decrease in right ventricular filling and ejection. These changes are reflected by respiratory changes in arterial pressure.

Michard and colleagues have shown in ICU patients (1) that difference in pulse pressure (dPP) is an accurate predictor of fluid responsiveness, being superior to systolic pressure variation (SPV). Calculating dPP is straightforward and allows rapid assessment during controlled mechanical ventilation. Therefore, dPP might be a useful technique to guide fluid management not only in the intensive care unit but also in the acute perioperative setting.

Recently, 2 studies have been published assessing dPP in dog models (2, 3). Fujita and colleagues studied dPP in a dog model (2) undergoing 2 defined hypovolemic conditions and 2 hypervolemic conditions, respectively. Difference in pulse pressure was measured and compared with hemodynamic parameters derived from a PA-catheter, an esophageal Doppler device, and a transpulmonary thermodilution catheter, respectively. Berkenstadt and colleagues studied dPP in a stepwise-hemorrhage dog model, comparing dPP to hemodynamic variables obtained with transpulmonary thermodilution technique (3).

However, a comparison of dPP with hemodynamic parameters obtained by a PA-catheter over a stepwise range of hemorrhage has not been performed yet. In addition, contradictory results have been found in the pig model of stepwise hemorrhage for SPV and its Δdown-component (difference between the end-exspiratory SPV and minimal SPV) (4-6).

Consequently, we studied changes in intravascular volume monitored by dPP in an acute hemorrhage model by gradually decreasing the blood volume in anesthetized pigs until cardiac arrest occurred. In addition, we compared the effects of hemorrhage on dPP with the effects of hemorrhage on commonly used hemodynamic parameters obtained by a PA-catheter.


This study was performed according to the National Institutes of Health guidelines for the use of experimental animals. The protocol was approved by the Washington University Animal Studies Committee. Six domestic pigs (weight, 20-25 kg) were fasted overnight but were allowed free access to water. The pigs were sedated with intramuscular Telazol (2 mg/kg), ketamine (1 mg/kg), and xylazine (1 mg/kg).

Anesthesia was induced by inhalation of isoflurane and maintained with isoflurane (1.5-2.0%). All pigs were orally intubated and ventilated with oxygen in nitrogen (fraction of inspired oxygen [FiO2] = 0.3). The animals were ventilated with a volume-controlled ventilator and tidal volume was kept at 10 to 15 mL/kg and the respiratory rate adjusted (11-14 breaths/min) to maintain end-tidal carbon dioxide tension (etCO2) at 35 ± 2 mmHg.

Through a left groin cut down indwelling catheters were inserted into the femoral artery to obtain measurements for dPP, MAP, and heart rate (HR). A balloon-tipped catheter was inserted into the pulmonary artery through the left femoral vein to obtain measurements for cardiac output (CO), SV, central venous pressure (CVP), pulmonary artery occlusion pressure (PAOP), and systemic vascular resistance (SVR). Location of the catheter tip was determined by observing the characteristic pressure trace on the monitor as it was advanced through the right heart into the pulmonary artery. Measurements were performed with ice-cold saline in triplicate. Body temperature of the animals was maintained by the use of a warming mattress and a patient air warming system (Bair Hugger, Arizant Healthcare Inc., Eden Prairie, MN).

After induction, the animals received an initial bolus of 10 mL/kg, followed by a continuous infusion of 15 mL/kg/h of lactated Ringer's solution. Additional boli of 100 mL lactated Ringer's solution were given to decrease dPP below 13%, to compensate for fluid deficit and fluid loss during surgery.

Then animals were allowed to stabilize from the induction of anesthesia and insertion of catheters for 30 min. An animal was considered stable when MAP was above 60 mmHg, CO was above 2.0 L/min, and dPP was below 13% for 30 min. After stabilization, baseline measurements were taken. Blood volume was estimated to be 70 mL/kg (7). A fixed volume model (8) was chosen for hemorrhage: 5% of blood volume was withdrawn, followed by another 5%, and then in 10%-increments until death from exsanguination occurred. Blood was removed in 15-min intervals. After each stage of blood removal, dPP and hemodynamic parameters (MAP, HR, CVP, PAOP, SVR, CO, SV) were measured.

The dPP cutoff point of 13% was chosen because Michard found a dPP value of 13 to distinguish accurately volume responders (dPP > 13%) from nonresponders (dPP < 13%). According to Michard, dPP was calculated as follows: Using the systolic arterial pressure, maximal and minimal values of pulse pressure (Pp(max) and Pp(min)) are determined over 1 respiratory cycle. The respiratory changes in pulse pressure (dPP) are calculated as the difference between Pp(max) and Pp(min) divided by the mean of the 2 values and are expressed as a percentage.

Statistical analysis

Data were analyzed by linear regression and correlation of dPP versus the amount of withdrawn blood. Variables of interest, evaluated at multiple bleeding points, were analyzed using the Fisher least significant difference procedure (a 1-factor ANOVA with a random subject effect and post hoc pairwise comparisons based on t tests). Comparisons of the means to the baseline were performed with a Dunnett test. A P less than 0.05 was considered statistically significant. Data are presented as mean ± SD, unless otherwise indicated.


At the beginning of the experiment, all pigs were hemodynamically stable, normothermic, and adequately ventilated and anesthetized. We considered an animal to be stable when MAP was above 60 mmHg, CO was above 2.0 L/min, and dPP was below 13% for 30 min without intervention. To achieve that condition, pigs had received additional fluid boli (median 6, minimum 4, maximum 8) during and shortly after the surgical phase due to the insertion of the monitors; there had been no need for vasopressors, inotropes, or vasodilators. Body temperature was kept within normal limits by an air-warming system. With the ventilatory parameters chosen, oxygen saturation was 97% or higher in all animals. Vitals signs of pigs at baseline are shown in Table 1.

After blood withdrawal of 5% of estimated blood volume, dPP increased significantly from 6.1 ± 3.3% to 19.4 ± 4.2% (Fig. 1). All 6 pigs survived the withdrawal of 60% of estimated blood volume; 4 pigs survived the withdrawal of 70% of estimated blood volume, and 2 pigs survived the withdrawal of 80% of estimated blood volume. The regression analysis (Fig. 2) of stepwise hemorrhage revealed a linear relation between blood loss (hemorrhage in %) and dPP (y = 0.99* × + 14; R2 = 0.7764; P <.0001). Extrapolating the line of linear regression at baseline to the y-axis reveals a dPP of 14%.

Vital signs of pigs at baseline (n = 6 animals)
Fig. 1:
dPP course during stepwise hemorrhage. dPP indicates difference in pulse pressure.
Fig. 2:
Linear Regression of dPP versus hemorrhage.

Of all parameters measured, dPP showed the best correlation to blood loss. In addition, dPP was the only parameter that changed significantly between baseline and a blood loss of 5% (P < 0.01). MAP, second in sensitivity, decreased significantly with a blood loss of 10% (P < 0.05) compared with baseline (Fig. 3). Systemic vascular resistance and PAOP, respectively, changed significantly after a blood loss of 20% (P < 0.05) compared with baseline (Figs. 4 and 5). Cardiac output and SV changed significantly only after 30% of blood loss (P < 0.05 for CO, P < 0.01 for SV). Heart rate changed significantly after 60% of estimated blood volume had been withdrawn (P < 0.05). Data are summarized in Table 2.

Changes in hemodynamic parameters with protracted hemorrhage
FIG. 3:
MAP course during stepwise hemorrhage. Mean arterial pressure indicates MAP.
FIG. 4:
SVR course during stepwise hemorrhage. SVR indicates systemic vascular resistance.
FIG. 5:
PAOP course during stepwise hemorrhage. PAOP indicates pulmonary artery occlusion pressure.


We evaluated dPP during protracted hemorrhage in a pig model and compared dPP to other hemodynamic variables. We did not limit hemorrhage to a certain amount of blood volume, nor did we retransfuse shed blood. We showed an excellent correlation between dPP and blood loss. Compared with commonly used hemodynamic parameters like blood pressure, CO, or pulmonary occlusion pressure, dPP reacted early and profoundly.

Examining respiratory variations of the arterial pressure curve has been studied for several years. In a landmark study, Perel and coworkers showed SPV, and its Δdown-component, respectively, to be a sensitive indicator of hypovolemia (9). However, as the SPV induced by mechanical ventilation results not only from changes in aortic transmural pressure (mainly related to changes in left ventricular SV) but also from changes in extramural pressure (i.e., from changes in pleural pressure) (10, 11), it was proposed to use the dPP for assessing the respiratory changes of the arterial waveform (1) to minimize the impact of the confounder.

In this study, dPP was the only parameter that changed significantly between baseline and a withdrawal of 5% of estimated blood volume. Other hemodynamic parameters, far more common to guide fluid management in the OR or ER presently, failed to detect hypovolemia at this early stage. Hypovolemia is associated with significant increases in morbidity and mortality (12); optimizing intravascular volume by adequate monitoring improves outcome (13-15). Consequently, the search for a reliable, inexpensive, easy-to-handle bedside device to reliably monitor the volume state of patients or assess fluid responsiveness is of great interest to physicians in perioperative care.

Several aspects of our findings deserve comments. First, CO and SV remained almost unchanged with a blood loss of 5% of blood volume and a blood loss of 10% of blood volume, respectively. This could lead to the assumption that the heart at baseline worked "preload-independent." However, while dPP-values increased, means of PAOP and CVP decreased during this minor blood loss, suggesting adequate reaction to hemorrhage, that is, dependency on preload. Interestingly, although Fujita et al. (2) described stable CO, but declining SV during hemorrhage, Berkenstadt reports no changes in SV (compared with baseline) until 20% of blood volume was shed (3). This stability in SV despite remarkable hemorrhage corresponds to rather low dPP values (3). In a clinical study, Michard et al. (1) found a dPP of 13% to be the cutoff value to discriminate between volume responders and nonresponders. Extrapolating our line of regression at baseline (no blood loss) to the y-axis of the graph, we find a dPP value of 14%. However, it is beyond the scope of this study to explain the different results mentioned.

Second, we noticed HR to remain stable over a long period, whereas SVR declined almost linearly. Several studies deal with the impact of isoflurane on the baropressor receptor reflex (16-18). We anesthetized our animals with 1.5 vol% isoflurane, corresponding to 1.0 minimum alveolar concentration (19, 20). Thus, we did not expect blunting of baroreflex. However, different results were published concerning the minimum alveolar concentration level that abolishes baroreflex (16, 17). These may be related to species differences; thus, we cannot rule out the possibility that with 1.5 vol% isoflurane, anesthesia in pigs was too deep to keep autonomic reflexes intact.

Finally, in accordance with Berkenstadt's findings (3), we noticed high percentage changes of dPP in protracted hemorrhage, compared with percentage changes of other hemodynamic parameters. These high percentage changes of dPP seemed to be more pronounced in the early phases of the experiment, having its peak (218% change) from baseline to a hemorrhage of 5% blood volume. The decline in percentage changes of dPP may be due to the fact that in an emptier aorta, a less pronounced pulse pressure is produced. On the other hand, however, this can be interpreted insofar that dPP may be of use as a sensitive marker of occult hypovolemia.

One limitation of our study is the lack of using the direct Fick method or an ultrasonic flow probe on the aorta to measure hemodynamic variables. Instead, we used a pulmonary artery catheter. Although measurements were done meticulously by experienced anesthesiologists, measurement errors due to inherent problems of the PA-catheter cannot be ruled out entirely. Another limitation may be the lack of measuring anesthesia depth. We provided anesthesia in the experiment according to literature, experience, and clinical standards with a standardized protocol. However, although animals were stable at baseline, without need for inotropic substances or vasodilators, we cannot rule out that anesthesia depth differed slightly, thus affecting hemodynamic measurements. Finally, we focused our experiments on global hemodynamic parameters used commonly in the perioperative setting. Metabolic parameters, like hepatic tissue pH (21), sublingual pCO2 (22), base excess (23), lactate (24), and tissue acid-base status (25) have been studied recently in experimental pig models of hemorrhagic shock. Future studies may find out the parameter that is suited best to indicate precisely the severity of hemorrhage.

In summary, in this study, we have shown that in an experimental hypovolemic pig model, dPP correlates well with blood loss and compares favorably to other hemodynamic parameters. In addition, dPP seems to be a sensitive indicator of occult hypovolemia. Thus, further studies are recommended to test whether dPP might be a useful tool to estimate the perioperative fluid requirement and guide perioperative volume replacement.


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Arterial line; dPP; fluid management; intravascular volume; monitoring; pigs; pulse pressure

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