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Critical Care Medicine  |   September 2010
Influence of Tidal Volume on Pulse Pressure Variations in Hypovolemic Ventilated Pigs with Acute Respiratory Distress-like Syndrome
Author Affiliations & Notes
  • Claes U. Wiklund, M.D., Ph.D.
    *
  • Denis R. Morel, M.D.
  • Hélène Orbring-Wiklund, R.N.
  • Jacques-Andre Romand, M.D.
  • Vincent Piriou, M.D., Ph.D.
    §
  • Jean-Louis Teboul, M.D., Ph.D.
  • Karim Bendjelid, M.D., Ph.D.
    #
  • * Research Assistant, Department of Anesthesiology and Intensive Care Medicine, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden, and Department of Anesthesiology, Pharmacology, and Intensive Care, University Hospitals of Geneva, Geneva, Switzerland. † Professor, # Attending Physician, Department of Anesthesiology, Pharmacology, and Intensive Care, University Hospitals of Geneva. ‡ Nurse, Department of Pediatric Anesthesia and Intensive Care, Karolinska University Hospital. § Professor, Department of Anesthesiology and Intensive Care, Lyon Sud University Hospital, Université Claude Bernard Lyon 1, Lyon France. ∥ Professor, Réanimation Médicale, Bicêtre Hospital, Paris Sud Medical School, Le Kremlin Bicêtre, France.
Article Information
Critical Care Medicine / Cardiovascular Anesthesia / Critical Care / Respiratory System
Critical Care Medicine   |   September 2010
Influence of Tidal Volume on Pulse Pressure Variations in Hypovolemic Ventilated Pigs with Acute Respiratory Distress-like Syndrome
Anesthesiology 9 2010, Vol.113, 630-638. doi:10.1097/ALN.0b013e3181e908f6
Anesthesiology 9 2010, Vol.113, 630-638. doi:10.1097/ALN.0b013e3181e908f6
What We Already Know about This Topic
  • ❖ Inappropriate fluid administration to patients with acute respiratory syndrome can result in pulmonary and interstitial edema.
  • ❖ Dynamic measures of fluid responsiveness have been questioned at small tidal volumes in critically ill patients suffering from acute respiratory distress syndrome.
What This Article Tells Us That Is New
  • ❖ In healthy pigs, respiratory change in pulse pressure is a good indicator of volume status, but it is not a good indicator in pigs with acute respiratory distress syndrome and ventilated with small tidal volumes.
INAPPROPRIATE fluid administration to intensive care patients can result in pulmonary and interstitial edema.1,2 Traditional markers of fluid responsiveness based on static preload measurements (i.e.  , cardiac pressures and volumes) are not reliable predictors of fluid responsiveness because individual Frank-Starling curves may vary among patients, resulting in a positive response to fluid challenge (preload dependency) or no response (preload independency).3,4 In contrast to static preload indices, dynamic indices are good indicators of volume and usually predict fairly well individual responses to volume loading.5–9 Indeed, pulse pressure variation (ΔPP) was reported to accurately assess circulatory volume and predict fluid responsiveness in critically ill patients.3,4 Other groups have used other indicators of stroke volume variations.5,6,10–15 However, the majority of patients in these studies were ventilated with large tidal volumes (VTgreater than or equal to 8 ml/kg), and recent studies16–19 have suggested that ΔPP is an unreliable indicator of fluid responsiveness at low VTin patients suffering from the adult respiratory distress syndrome (ARDS). This is particularly important because patients with acute lung injury or ARDS should be ventilated with VTless than 6 ml/kg.20,21 
Patients with ARDS have reduced lung compliance (CL) because of stiffer lung parenchyma, and some authors have demonstrated that this phenomenon dampens airway pressure transmission to the pleural space.22 On the other hand, a decrease in lung compliance contributes at the same time to an increase in transpulmonary pressure (Ptp; i.e.  , pressure inside alveoli minus pleural pressure) for a given insufflated VT. In this regard, we reasoned that to study the effects of a decreased VTon the accuracy of dynamic indexes in ARDS, we should also analyze effects on Ptpand esophageal pressure (Pes, pleural pressure) in this setting.17,23 Moreover, to maintain minute volume ventilation in ARDS patients ventilated with low VT, an increase in the respiratory rate (RR) is usually necessary.20 This situation results in a lower number of heart beats being affected by each mechanical breath, a scenario that could also explain the low predictable value of ΔPP.24 Indeed, Scharf et al.  25 have already demonstrated that RR affects “reverse pulsus paradoxus.”
Because no study has evaluated the influence of VTand RR on ΔPP in mechanically ventilated animals with ARDS-like symptoms, the present study sought to determine the influence of these parameters on ΔPP value during hemorrhagic shock in mechanically ventilated pigs with normal lungs or after lung lavage-induced acute lung injury (ARDS-like syndrome).
Materials and Methods
Approval from the Ethics Committee for Animal Research of the University Medical Center and by the Cantonal Veterinary Office of Geneva, Switzerland, was achieved before the study was initiated. Handling of animals followed the guidelines laid out in the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, 1996). We studied 24 domestic pigs (weight ± SD, 31.4 ± 3.1 kg). Five pigs were used for pilot experiments, optimizing the study protocol, and three animals were excluded because of technical problems. These eight animals were not analyzed. Animals were assigned to groups sequentially; i.e.  , we started with the control animals and after eight animals, we proceeded with the animals subjected to ARDS.
General Procedure
Animals had free access to food and water until 12 h before the beginning of experiments. Premedication consisted of intramuscular injections of 6 mg/kg azaperon, 0.5 mg/kg midazolam, and 0.5 mg atropine. Anesthesia was induced by isoflurane inhalation and maintained by 20 μg · kg−1· h−1fentanyl, 1.5–2.0% isoflurane, and 0.4 mg · kg−1· h−1pancuronium through a catheter placed into an ear vein. Depth of anesthesia was verified by paw pinch before muscular relaxation was administered. The animals were intubated and mechanically ventilated with oxygen in air (Fio2= 0.4 in control group [n = 8] and 1.0 in ARDS group [n = 8]) using a constant-volume respirator (Servo Ventilator 900; Siemens-Elema, Goeteborg, Sweden). No spontaneous breathing movements occurred during the experiments. VTwas initially set at 10 ml/kg and the RR at 15 breaths/min (RR15) with a positive end-expiratory pressure (PEEP) of 0 cm H2O. Airway pressure and respiratory gases were continuously monitored (Ultima™; Datex/Instrumentarium, Helsinki, Finland). The right internal jugular vein, left internal carotid artery, and right femoral artery were cannulated for infusions, arterial pressure measurements, bleeding, and reperfusion. A flow-directed Swan-Ganz catheter (CCOmboV™, 7.5-French; Edwards Lifesciences, Irvine, CA) was introduced through the right internal jugular vein and advanced into the pulmonary artery to measure central venous pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure, continuous cardiac output, and continuous mixed venous saturation. Arterial pressure tracings and mean arterial pressure were measured by a left carotid arterial catheter advanced into the descending aorta. Vascular pressures were measured using calibrated pressure transducers (Honeywell, Zürich, Switzerland) positioned at the level of the left atrium. A standard 3-lead electrocardiogram was continuously displayed on a Hewlett-Packard monitor (M3150A; Hewlett-Packard, Andover, MA) with digital readout of heart rate by means of cutaneous electrodes. Diuresis was monitored by a suprapubic catheter.
Respiratory Mechanics
Airway pressure was measured and VTcalculated by digital integration of a flow signal measured by a pneumotachograph (Godart 17212; Gould Electronics BV, Bilthoven, Netherlands), the two connected to the endotracheal tube. This setting permitted continuous breath by breath assessment of dynamic compliance of the respiratory system (CRS= VT/[plateau airway pressure − PEEP]) and expiratory airway resistance (Raw=[plateau airway pressure − PEEP]/maximal expiratory air flow)26 from three respiratory cycles. Measurement of Peswas used to estimate pleural pressure and calculate Ptpby means of an inflatable latex double-balloon catheter (Ref C48 Sde Guenard; Marquat Génie Biomédical, Boissy-Saint-Léger, France) advanced into the esophagus with the distal balloon placed into the stomach and the proximal balloon in the esophagus behind the heart.27 The two balloons were filled with air to a volume of 0.5 to 1 ml. Continuous Ptpwas calculated by subtracting simultaneous Pesfrom plateau airway pressure, and tidal Ptp(ΔPtp) was determined as the amplitude of Ptpswings during each mechanical breath. Tidal Pes(ΔPes) was also measured (i.e.  , amplitude of Pesswings during a mechanical breath).
Hemodynamics
Systemic vascular resistance was calculated by dividing the difference between mean arterial pressure and central venous pressure measured at end-expiration by cardiac output, pulmonary vascular resistance by dividing the difference between mean pulmonary arterial pressure and pulmonary capillary wedge pressure by cardiac output. ΔPP was defined as the difference between the maximal and minimal values of pulse pressure divided by the average of the pulse pressure during a respiratory cycle.8 
Blood gas tensions, oxygen hemoglobin saturation and pH were intermittently analyzed by an automated oximeter (ABL-505 analyser; Radiometer, Copenhagen, Denmark). Arteriovenous oxygen content difference, intrapulmonary shunt, oxygen transport, oxygen extraction ratio, and oxygen consumption were calculated using standard formulae from the blood gas analysis and cardiac output measurement.
The different continuously recorded hemodynamic and respiratory measurements were stored at a sampling rate of 200 Hz via  an analog/digital interface converter (Biopac, Santa Barbara, CA) on a personal computer for off-line analysis. In all groups, lactated Ringer's solution was administered at 5 ml · kg−1· h−1to compensate for basal fluid loss. The animal's central body temperature was maintained at approximately 37.5°C with a warm air fan.
Experimental Protocol
The different measured hemodynamic and respiratory variables were recorded during ventilation with a VTof 10 or 6 ml/kg and RR15 or RR25. Three variants of ventilation were successively used: VT10 ml/kg at RR15, VT6 ml/kg at RR25, and VT6 ml/kg at RR15. Each ventilation mode was used during 5–7 min under control conditions during baseline, after blood removal (hemorrhagic shock of ∼30 min), and after reperfusion of the shed blood to restore normovolemia. The ratios of inspiratory time to expiratory time were not changed during the protocol. In the ARDS animal group, lung lavage-induced ARDS (∼ 1 h, see below) followed the baseline step and preceded hemorrhage and reperfusion.
Lung Lavage.
After switching Fio2to 1.0, surfactant depletion was performed by repetitive lung lavage, instilling 1,000 ml NaCl, 0.9%, at 37°C into the trachea.28 The procedure was repeated 3.1 ± 0.3 (SD) times at 12.6 ± 3.5-min intervals until criteria for ARDS-like syndrome were fulfilled (i.e.  , Pao2/Fio2less than 200 mmHg). Fio2was kept at 1.0 throughout the remainder of the experiment in this group of pigs.
Bleeding and Reperfusion.
Forty percent of total blood volume was removed during 5–10 min via  the right femoral artery. Total blood volume was calculated as 75 ml/kg of body weight. The blood was stored in blood bags containing citrate-phosphate-dextrose (Baxter AG, Volketswil, Switzerland) and maintained at body temperature during continuous agitation until reperfusion. The time between the start of bleeding until completed reperfusion was 49 ± 5 min. The time between the start of bleeding and the start of reperfusion was 40 ± 4 min. The time between the end of bleeding and the start of reperfusion was 30 ± 4 min. The volume reperfused was 2.8 ± 0.3 ml · kg−1· min−1.
Statistics
Group data are presented as mean values with 95% confidence interval (CI) in parenthesis, representing the continuous online recordings averaged over 30-s periods immediately preceding the intermittent recordings of pulmonary capillary wedge pressure and blood gas samples taken before the change to the next ventilation pattern. A general linear full factorial analysis of variance (ANOVA) model with repeated measures procedure was used to analyze the effects of the successive interventions (time as within-subjects factor using four levels, allowing determination of the effect of lung lavage, hemorrhage, and reperfusion on the various dependent variables), as well as the overall difference between the two groups of animals (treatment group as between-subject factor) using PASW Statistics 18 software package (SPSS, Inc., Chicago, IL). In each separated treatment group, the associated interaction between the within-subjects factor “time” and the between-subjects factor “ventilatory mode” was also analyzed to determine the effect of the ventilatory mode on the dependent variables. The two-sided Dunnett test for multiple comparisons with baseline values was used for post hoc  analysis when the ANOVA resulted in a P  value less than 0.05. Furthermore, a one-way ANOVA for repeated measures was used to detect statistical significance between the three ventilatory modes in a given condition, followed by the Bonferroni post hoc  test when the ANOVA resulted in a P  value less than 0.05.
Results
Sixteen deeply sedated mechanically ventilated pigs were studied, eight in each group (control and ARDS). One set of recordings was lost in the control group during hemorrhage (animal 7; VT6 ml/kg RR15 subgroup) and two sets in the ARDS group during control conditions (animal 11; VT6 ml/kg RR15 and VT6 ml/kg RR25 subgroups).
Effect of Lavage (Combined Ventilated Groups)
Lung alveolar lavage reproduced the expected hemodynamic, biologic, and respiratory characteristics of ARDS, with a 75% decrease in the Pao2/Fio2ratio (P  < 0.001 between treatment groups throughout time after baseline time point, even if there was some recovery of this ratio with time; tables 1 and 2). ΔPP remained unchanged. ΔPtpas well as ΔPesincreased significantly after lung lavage (table 2).
Table 1.  Characteristics of Hemodynamic Variables of the Control and ARDS Groups (Combined Ventilated Groups)
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Table 1.  Characteristics of Hemodynamic Variables of the Control and ARDS Groups (Combined Ventilated Groups)
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Table 1.  Continued
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Table 1.  Continued
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Table 2.  Characteristics of Respiratory Variables of the Control and ARDS Groups (Combined Ventilated Groups)
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Table 2.  Characteristics of Respiratory Variables of the Control and ARDS Groups (Combined Ventilated Groups)
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Table 2.  Continued
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Table 2.  Continued
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Effect of Hemorrhage and Retransfusion (Combined Ventilated Groups)
After removal of 40% of total blood volume, there were marked expected changes in hemodynamic and respiratory variables (tables 1 and 2). Hemodynamics were similarly affected by hemorrhage in both control and ARDS pigs (table 1). However, compared with the control group and regarding lung mechanics, ΔPtpdecreased significantly after hemorrhage in the ARDS group (two-way ANOVA, group effect during hemorrhage; P  < 0.001, table 2), whereas ΔPesremained unchanged (table 2). Retransfusion of the shed blood completely corrected hemodynamic variables in the control and ARDS groups, except for a persistent tachycardia (both groups) and a pulmonary vasoconstriction (ARDS group).
Effect of Changing Ventilatory Pattern on ΔPP during Hemorrhage
In the control group, lowering ventilation to a VTof 6 ml/kg reduced ΔPP by ∼40% regardless of circulatory state (P  < 0.001 vs.  VTof 10 ml/kg). Furthermore, at each hemodynamic state, ΔPP values during both reduced VTmodes were significantly different from those through the 10 ml/kg ventilation (P  < 0.01; table 3) regardless of respiratory rates. Despite reduced absolute ΔPP values observed during low VTventilation, their overall time course (time effect) was not significantly different from the 1 s recorded when ventilating with the larger VT(time × ventilation interaction; P  > 0.05), and their response to hemorrhage remained significantly different from respective baseline conditions at all RR values (P  < 0.05; table 3; fig. 1, controls). In contrast, in pigs subjected to ARDS, lowering ventilation to a VTof 6 ml/kg rendered the ΔPP index unreliable for detecting hypovolemia regardless of the RR values (table 3; fig. 1, ARDS). However, when ΔPP was indexed and adjusted to ΔPtp(fig. 1) and/or plateau pressure (Supplemental Digital Content 1, which is the figure displaying results, ), it became a reliable predictor for hypovolemia and reperfusion in ARDS animals ventilated with low VT. A representative online recording of three consecutive periods of 20 s each at VT10 ml/kg RR15, VT6 ml/kg RR25, and VT6 ml/kg RR15 is shown in figure 2.
Table 3.  Effect of Changing Ventilatory Pattern on ΔPP, Pes, ΔPtp, and ΔPesin Control and ARDS Animals before and after Hemorrhage
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Table 3.  Effect of Changing Ventilatory Pattern on ΔPP, Pes, ΔPtp, and ΔPesin Control and ARDS Animals before and after Hemorrhage
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Fig. 1.  Time course of change in pulse pressure (ΔPP) and ΔPP indexed to tidal transpulmonary pressure (ΔPP/ΔPtp) in control animals (A  , C  ) or animals with acute respiratory distress syndrome (ARDS) (B  , D  ) alternatively ventilated for 5–7 min with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15) (•), a VTof 6 ml/kg and RR15 (▴), or a VTof 6 ml/kg and RR25 (▪). Data points are means with 95% confidence intervals; n = 8 animals. *P  < 0.05; **P  < 0.01 versus  baseline values (for control animals) and lavage values (for ARDS). †P  < 0.05; †††P  < 0.001 versus  baseline values.
Fig. 1. 
	Time course of change in pulse pressure (ΔPP) and ΔPP indexed to tidal transpulmonary pressure (ΔPP/ΔPtp) in control animals (A 
	, C 
	) or animals with acute respiratory distress syndrome (ARDS) (B 
	, D 
	) alternatively ventilated for 5–7 min with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15) (•), a VTof 6 ml/kg and RR15 (▴), or a VTof 6 ml/kg and RR25 (▪). Data points are means with 95% confidence intervals; n = 8 animals. *P 
	< 0.05; **P 
	< 0.01 versus 
	baseline values (for control animals) and lavage values (for ARDS). †P 
	< 0.05; †††P 
	< 0.001 versus 
	baseline values.
Fig. 1.  Time course of change in pulse pressure (ΔPP) and ΔPP indexed to tidal transpulmonary pressure (ΔPP/ΔPtp) in control animals (A  , C  ) or animals with acute respiratory distress syndrome (ARDS) (B  , D  ) alternatively ventilated for 5–7 min with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15) (•), a VTof 6 ml/kg and RR15 (▴), or a VTof 6 ml/kg and RR25 (▪). Data points are means with 95% confidence intervals; n = 8 animals. *P  < 0.05; **P  < 0.01 versus  baseline values (for control animals) and lavage values (for ARDS). †P  < 0.05; †††P  < 0.001 versus  baseline values.
×
Fig. 2.  Representative recording of systemic arterial pressure (Art.P) and airway pressure (Aw.P) in a control pig (A  , C  ) and a pig with acute respiratory distress syndrome (ARDS) (B  , D  ) successively ventilated for 20 s with the three investigated ventilatory patterns (i.e.  , a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min [RR15], followed by a VTof 6 ml/kg and RR25 and a VTof 6 ml/kg and RR15 during baseline (A  , B  ) and hemorrhage (C  , D  ). Change in pulse pressure (ΔPP) was small before bleeding in pigs with normal lungs as well as those with ARDS, and it increased significantly during hemorrhagic shock in both groups, but mainly with a VTof 10 ml/kg. Please observe that during baseline in pigs with ARDS, airway pressure gradient is more marked during VT10 and VT6 RR15 than during VT6 RR25 but not during hemorrhage (impact of the decrease in ΔPtpduring bleeding).
Fig. 2. 
	Representative recording of systemic arterial pressure (Art.P) and airway pressure (Aw.P) in a control pig (A 
	, C 
	) and a pig with acute respiratory distress syndrome (ARDS) (B 
	, D 
	) successively ventilated for 20 s with the three investigated ventilatory patterns (i.e. 
	, a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min [RR15], followed by a VTof 6 ml/kg and RR25 and a VTof 6 ml/kg and RR15 during baseline (A 
	, B 
	) and hemorrhage (C 
	, D 
	). Change in pulse pressure (ΔPP) was small before bleeding in pigs with normal lungs as well as those with ARDS, and it increased significantly during hemorrhagic shock in both groups, but mainly with a VTof 10 ml/kg. Please observe that during baseline in pigs with ARDS, airway pressure gradient is more marked during VT10 and VT6 RR15 than during VT6 RR25 but not during hemorrhage (impact of the decrease in ΔPtpduring bleeding).
Fig. 2.  Representative recording of systemic arterial pressure (Art.P) and airway pressure (Aw.P) in a control pig (A  , C  ) and a pig with acute respiratory distress syndrome (ARDS) (B  , D  ) successively ventilated for 20 s with the three investigated ventilatory patterns (i.e.  , a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min [RR15], followed by a VTof 6 ml/kg and RR25 and a VTof 6 ml/kg and RR15 during baseline (A  , B  ) and hemorrhage (C  , D  ). Change in pulse pressure (ΔPP) was small before bleeding in pigs with normal lungs as well as those with ARDS, and it increased significantly during hemorrhagic shock in both groups, but mainly with a VTof 10 ml/kg. Please observe that during baseline in pigs with ARDS, airway pressure gradient is more marked during VT10 and VT6 RR15 than during VT6 RR25 but not during hemorrhage (impact of the decrease in ΔPtpduring bleeding).
×
Effect of Changing Ventilatory Pattern on Pulmonary Mechanics during Hemorrhage
The principal changes in pulmonary mechanics were as follows. First, significant changes in ΔPtpin the control group after hemorrhage were absent, whereas a significant decrease in ΔPtpwas observed in the ARDS group (table 3and fig. 3). Moreover, in this group, the hemorrhage-induced decrease in ΔPtpvalues was proportionally larger (−22% [VT6 ml/kg RR25] and −30% [VT6 ml/kg RR15] compared with the decrease in pigs ventilated with a VTof 10 ml/kg (−12%; fig. 3, table 3). In the ARDS group ventilated with low VT, Pesvalues decreased significantly during hemorrhage compared with baseline (P  < 0.01). However, no significant changes were observed in ΔPesafter hemorrhage regardless of VTor RR values (table 3).
Fig. 3.  Effect of hemorrhage on tidal transpulmonary pressure (ΔPtp) in control pigs (A  ) and acute respiratory distress syndrome (ARDS) animals (B  ) before and after hemorrhage and alternatively ventilated with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15), a VTof 6 ml/kg and RR15, or a VTof 6 ml/kg and RR25. Bars  are means with 95% confidence intervals (solid lines  ); n = 8 animals; **P  < 0.01; ***P  < 001 versus  corresponding baseline values in control and ARDS animals, respectively; †P  < 0.05; ††P  < 0.01; †††P  < 001 versus  corresponding VT10 RR15 values. Note that compared with baseline, ΔPtpduring hemorrhage decreased significantly in the ARDS group regardless of the ventilatory pattern, whereas this was not the case in the control group.
Fig. 3. 
	Effect of hemorrhage on tidal transpulmonary pressure (ΔPtp) in control pigs (A 
	) and acute respiratory distress syndrome (ARDS) animals (B 
	) before and after hemorrhage and alternatively ventilated with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15), a VTof 6 ml/kg and RR15, or a VTof 6 ml/kg and RR25. Bars 
	are means with 95% confidence intervals (solid lines 
	); n = 8 animals; **P 
	< 0.01; ***P 
	< 001 versus 
	corresponding baseline values in control and ARDS animals, respectively; †P 
	< 0.05; ††P 
	< 0.01; †††P 
	< 001 versus 
	corresponding VT10 RR15 values. Note that compared with baseline, ΔPtpduring hemorrhage decreased significantly in the ARDS group regardless of the ventilatory pattern, whereas this was not the case in the control group.
Fig. 3.  Effect of hemorrhage on tidal transpulmonary pressure (ΔPtp) in control pigs (A  ) and acute respiratory distress syndrome (ARDS) animals (B  ) before and after hemorrhage and alternatively ventilated with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15), a VTof 6 ml/kg and RR15, or a VTof 6 ml/kg and RR25. Bars  are means with 95% confidence intervals (solid lines  ); n = 8 animals; **P  < 0.01; ***P  < 001 versus  corresponding baseline values in control and ARDS animals, respectively; †P  < 0.05; ††P  < 0.01; †††P  < 001 versus  corresponding VT10 RR15 values. Note that compared with baseline, ΔPtpduring hemorrhage decreased significantly in the ARDS group regardless of the ventilatory pattern, whereas this was not the case in the control group.
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Discussion
The first finding of the present study was that after removal of 40% of total blood volume, ΔPP was a good indicator of hypovolemia in pigs with normal lungs and ventilated with low VTof 6 ml/kg RR15 and/or RR25, the level of this hypovolemia indicator being just reduced by approximately 40% compared with larger VTof 10 ml/kg. These results are in agreement with the cardiac output-preload dependency state anticipated by dynamic markers in critically ill patients with normal lungs and ventilated with low VT.29–31 However, our data highlight the result that ΔPP is not a sensitive marker of major changes in intravascular volume status in pigs affected by ARDS-like syndrome and ventilated with low VTregardless of RR, except when this indicator was adjusted to ΔPtpand/or plateau pressure.18,19 
Because the slope of the Frank-Starling curve depends on ventricular contractility, static preload measurements are unable to anticipate the cardiac output-preload dependency.3 In contrast, dynamic preload measurements, such as ΔPP determined by analysis of pulse pressure tracing, are useful in estimating the hemodynamic response to intravascular volume variations.3,4,32 However, the magnitudes of dynamic preload indicators are also affected by VTduring acute lung injury.16,33 Indeed, mechanical ventilation induces cyclic changes in intrathoracic and transpulmonary pressures, transiently affecting ventricular preload and leading to cyclic changes in stroke volume in preload-dependent but not in preload-independent patients. This phenomenon is related to the impact of inspiratory increase in intrathoracic pressure on pulmonary blood redistribution with changes in right ventricular outputs affecting left ventricular stroke volumes after two to three heart beats (pulmonary transit time).34 According to this mechanism, inspiratory increase in left ventricular stroke volume results from delayed transmission through the pulmonary vasculature of the expiratory increase in right ventricular output and is followed by an expiratory decrease in left ventricular stroke volume as soon as the inspiratory decrease in right ventricular output has reached the left ventricle. If the decrease in right ventricular stroke volume after a mechanical breath is mainly related to decrease in venous return related to ΔPesvalue in healthy lungs,35 increase in ΔPtpand right ventricular afterload could be an important determinant in lungs affected by ARDS.23 
In this regard, in the present study, we have analyzed the impact of ΔPtpand ΔPesin this setting.17,23 An important finding of the present study is that ΔPtpincreased after ARDS induction without significant changes in ΔPes(tables 2 and 3). This fact highlights the idea that a decrease in CRSin the ARDS group generates higher ΔPtp. The major explanation for the inability of ΔPP to indicate hypovolemia in ARDS pigs ventilated with low VTcould be related to the increase in CRSafter hemorrhage compared with control animals (table 2). This fact produced a decrease in a ΔPP determinant (ΔPtp) in the ARDS group during hemorrhage when ΔPtpvalues in the control group did not change (fig. 3and table 3). In addition, during hemorrhage, ΔPtpin ARDS pigs ventilated with low VTvalues decreased more significantly, compared with the matched baseline values, than in ARDS pigs ventilated with VTof 10 ml/kg (fig. 3, table 3). The present explanation agrees with our results in that indexing ΔPP to ΔPtpand/or plateau pressure made this marker a reliable predictor for hypovolemia and reperfusion (fig. 1and Supplemental Digital Content 1, ).18,19 Because esophageal pressures are not usually available in patients, the present data highlight the value of ΔPP indexed to plateau pressure in this setting.19 
We could also expect that ventilation without PEEP in ARDS pigs could have led to a decrease in functional residual capacity with an increase in chest wall compliance, inducing a decrease in the pressure transmitted to the pleural space during mechanical breath. In the ARDS group, during hemorrhage, Pesvalues decreased more significantly during low VT ventilation compared with baseline (P  < 0.01, table 3). This feature could have affected ventricular preload, cyclic changes in stroke volume, and ΔPP in pigs affected by ARDS and ventilated with low VT. However, our data (table 3) do not support this assumption because no significant changes were observed in ΔPesvalues in pigs with healthy lungs and/or those affected by ARDS-like syndrome. Indeed, changes in venous return, stroke volume, and ΔPP are related to ΔPesand not Pes.
In the present study, we have also reasoned that the cause of impaired relevance of this dynamic index in this situation could be related to the high RR associated with low VTin the ventilator setting of patients with ARDS and the impact of this fact on heart lung interactions.16,24 With regard to this, we changed RR value during low VTas maintaining optimal volume minute ventilation in ARDS lungs requires increase in RR.20 The rationale was that the heart rate/RR ratio and VTvalue are equally important as determinants of ΔPP.24 Indeed, the number of heart beats affected by each mechanical breath is related to RR and inspiratory to expiratory time ratio. De Backer et al.  24 found that high RR (30–40 breaths/min) could limit the predictive value of ΔPP for fluid responsiveness. We did not find any impact of RR on the reliability of ΔPP to detect hypovolemia in animals ventilated with low VTprobably for two reasons. First, compared with De Backer et al.  ,24 our highest level of RR was only 25 breaths/min in ARDS animals, which, in combination with tachycardia (table 1), made heart rate/RR unchanged in ARDS animals. Second, as stated previously, our model generated a change in respiratory mechanics that affected ΔPtpas a determinant of ΔPP during hypovolemia.
The present animal study acknowledges some limitations. First, as discussed before, we used a low level of PEEP in the present animal study, whereas patients with ARDS ventilated with smaller VTare often treated with high levels of PEEP, which could have an impact on transpulmonary pressures and the pressures transmitted to pleural spaces. Second, our model of ARDS produces major changes in heart rate and respiratory mechanics, and we cannot exclude the idea that ΔPP would be insensitive to changes in volemia in the absence of major changes in these variables. Third, the internal carotid artery is closer to the central (aortic) pressure than the radial artery, and this fact could have affected ΔPP results. However, because the animals used in our experiments were healthy pigs, we expect that a peripheral artery would have been a less acceptable approach to measure pulse pressure, because the compliant aorta would have markedly buffered stroke volume.36 Finally, the minor rise in diastolic pressure in pigs ventilated with low VTduring ARDS (fig. 3) suggests that a steady state was difficult to achieve and could have affected measurements.
In conclusion, we found ΔPP to be a reliable indicator of severe hypovolemia in pigs with healthy lungs regardless of VTor RR. In pigs affected by severe ARDS-like syndrome and ventilated with low PEEP, the measured index remains a valid indicator of severe hypovolemia at VTof 10 ml/kg but a less sensitive indicator at VTof 6 ml/kg. However, ΔPP indexed to ΔPtpand/or plateau pressures were reliable gauges of blood volume status.
The authors thank Manuel Jorge-Costa and Sylvie Roule (Technicians, Anesthesia Investigations Unit, Geneva Medical School, Geneva, Switzerland) for excellent technical assistance.
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Fig. 1.  Time course of change in pulse pressure (ΔPP) and ΔPP indexed to tidal transpulmonary pressure (ΔPP/ΔPtp) in control animals (A  , C  ) or animals with acute respiratory distress syndrome (ARDS) (B  , D  ) alternatively ventilated for 5–7 min with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15) (•), a VTof 6 ml/kg and RR15 (▴), or a VTof 6 ml/kg and RR25 (▪). Data points are means with 95% confidence intervals; n = 8 animals. *P  < 0.05; **P  < 0.01 versus  baseline values (for control animals) and lavage values (for ARDS). †P  < 0.05; †††P  < 0.001 versus  baseline values.
Fig. 1. 
	Time course of change in pulse pressure (ΔPP) and ΔPP indexed to tidal transpulmonary pressure (ΔPP/ΔPtp) in control animals (A 
	, C 
	) or animals with acute respiratory distress syndrome (ARDS) (B 
	, D 
	) alternatively ventilated for 5–7 min with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15) (•), a VTof 6 ml/kg and RR15 (▴), or a VTof 6 ml/kg and RR25 (▪). Data points are means with 95% confidence intervals; n = 8 animals. *P 
	< 0.05; **P 
	< 0.01 versus 
	baseline values (for control animals) and lavage values (for ARDS). †P 
	< 0.05; †††P 
	< 0.001 versus 
	baseline values.
Fig. 1.  Time course of change in pulse pressure (ΔPP) and ΔPP indexed to tidal transpulmonary pressure (ΔPP/ΔPtp) in control animals (A  , C  ) or animals with acute respiratory distress syndrome (ARDS) (B  , D  ) alternatively ventilated for 5–7 min with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15) (•), a VTof 6 ml/kg and RR15 (▴), or a VTof 6 ml/kg and RR25 (▪). Data points are means with 95% confidence intervals; n = 8 animals. *P  < 0.05; **P  < 0.01 versus  baseline values (for control animals) and lavage values (for ARDS). †P  < 0.05; †††P  < 0.001 versus  baseline values.
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Fig. 2.  Representative recording of systemic arterial pressure (Art.P) and airway pressure (Aw.P) in a control pig (A  , C  ) and a pig with acute respiratory distress syndrome (ARDS) (B  , D  ) successively ventilated for 20 s with the three investigated ventilatory patterns (i.e.  , a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min [RR15], followed by a VTof 6 ml/kg and RR25 and a VTof 6 ml/kg and RR15 during baseline (A  , B  ) and hemorrhage (C  , D  ). Change in pulse pressure (ΔPP) was small before bleeding in pigs with normal lungs as well as those with ARDS, and it increased significantly during hemorrhagic shock in both groups, but mainly with a VTof 10 ml/kg. Please observe that during baseline in pigs with ARDS, airway pressure gradient is more marked during VT10 and VT6 RR15 than during VT6 RR25 but not during hemorrhage (impact of the decrease in ΔPtpduring bleeding).
Fig. 2. 
	Representative recording of systemic arterial pressure (Art.P) and airway pressure (Aw.P) in a control pig (A 
	, C 
	) and a pig with acute respiratory distress syndrome (ARDS) (B 
	, D 
	) successively ventilated for 20 s with the three investigated ventilatory patterns (i.e. 
	, a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min [RR15], followed by a VTof 6 ml/kg and RR25 and a VTof 6 ml/kg and RR15 during baseline (A 
	, B 
	) and hemorrhage (C 
	, D 
	). Change in pulse pressure (ΔPP) was small before bleeding in pigs with normal lungs as well as those with ARDS, and it increased significantly during hemorrhagic shock in both groups, but mainly with a VTof 10 ml/kg. Please observe that during baseline in pigs with ARDS, airway pressure gradient is more marked during VT10 and VT6 RR15 than during VT6 RR25 but not during hemorrhage (impact of the decrease in ΔPtpduring bleeding).
Fig. 2.  Representative recording of systemic arterial pressure (Art.P) and airway pressure (Aw.P) in a control pig (A  , C  ) and a pig with acute respiratory distress syndrome (ARDS) (B  , D  ) successively ventilated for 20 s with the three investigated ventilatory patterns (i.e.  , a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min [RR15], followed by a VTof 6 ml/kg and RR25 and a VTof 6 ml/kg and RR15 during baseline (A  , B  ) and hemorrhage (C  , D  ). Change in pulse pressure (ΔPP) was small before bleeding in pigs with normal lungs as well as those with ARDS, and it increased significantly during hemorrhagic shock in both groups, but mainly with a VTof 10 ml/kg. Please observe that during baseline in pigs with ARDS, airway pressure gradient is more marked during VT10 and VT6 RR15 than during VT6 RR25 but not during hemorrhage (impact of the decrease in ΔPtpduring bleeding).
×
Fig. 3.  Effect of hemorrhage on tidal transpulmonary pressure (ΔPtp) in control pigs (A  ) and acute respiratory distress syndrome (ARDS) animals (B  ) before and after hemorrhage and alternatively ventilated with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15), a VTof 6 ml/kg and RR15, or a VTof 6 ml/kg and RR25. Bars  are means with 95% confidence intervals (solid lines  ); n = 8 animals; **P  < 0.01; ***P  < 001 versus  corresponding baseline values in control and ARDS animals, respectively; †P  < 0.05; ††P  < 0.01; †††P  < 001 versus  corresponding VT10 RR15 values. Note that compared with baseline, ΔPtpduring hemorrhage decreased significantly in the ARDS group regardless of the ventilatory pattern, whereas this was not the case in the control group.
Fig. 3. 
	Effect of hemorrhage on tidal transpulmonary pressure (ΔPtp) in control pigs (A 
	) and acute respiratory distress syndrome (ARDS) animals (B 
	) before and after hemorrhage and alternatively ventilated with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15), a VTof 6 ml/kg and RR15, or a VTof 6 ml/kg and RR25. Bars 
	are means with 95% confidence intervals (solid lines 
	); n = 8 animals; **P 
	< 0.01; ***P 
	< 001 versus 
	corresponding baseline values in control and ARDS animals, respectively; †P 
	< 0.05; ††P 
	< 0.01; †††P 
	< 001 versus 
	corresponding VT10 RR15 values. Note that compared with baseline, ΔPtpduring hemorrhage decreased significantly in the ARDS group regardless of the ventilatory pattern, whereas this was not the case in the control group.
Fig. 3.  Effect of hemorrhage on tidal transpulmonary pressure (ΔPtp) in control pigs (A  ) and acute respiratory distress syndrome (ARDS) animals (B  ) before and after hemorrhage and alternatively ventilated with a tidal volume (VT) of 10 ml/kg and a respiratory rate of 15 breaths/min (RR15), a VTof 6 ml/kg and RR15, or a VTof 6 ml/kg and RR25. Bars  are means with 95% confidence intervals (solid lines  ); n = 8 animals; **P  < 0.01; ***P  < 001 versus  corresponding baseline values in control and ARDS animals, respectively; †P  < 0.05; ††P  < 0.01; †††P  < 001 versus  corresponding VT10 RR15 values. Note that compared with baseline, ΔPtpduring hemorrhage decreased significantly in the ARDS group regardless of the ventilatory pattern, whereas this was not the case in the control group.
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Table 1.  Characteristics of Hemodynamic Variables of the Control and ARDS Groups (Combined Ventilated Groups)
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Table 1.  Characteristics of Hemodynamic Variables of the Control and ARDS Groups (Combined Ventilated Groups)
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Table 1.  Continued
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Table 1.  Continued
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Table 2.  Characteristics of Respiratory Variables of the Control and ARDS Groups (Combined Ventilated Groups)
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Table 2.  Characteristics of Respiratory Variables of the Control and ARDS Groups (Combined Ventilated Groups)
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Table 2.  Continued
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Table 2.  Continued
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Table 3.  Effect of Changing Ventilatory Pattern on ΔPP, Pes, ΔPtp, and ΔPesin Control and ARDS Animals before and after Hemorrhage
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Table 3.  Effect of Changing Ventilatory Pattern on ΔPP, Pes, ΔPtp, and ΔPesin Control and ARDS Animals before and after Hemorrhage
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