Relation between PaO2/FIO2 ratio and FIO2: a mathematical description

Jerome Aboab Bruno Louis Bjorn Jonson Laurent Brochard
Relation between PaO2/FIO2 ratio and FIO2: a mathematical description
Introduction
The acute respiratory distress syndrome (ARDS) is characterized by severe hypoxemia, a cornerstone element in its definition. Numerous indices have been used to describe this hypoxemia, such as the arterial to alveolar O2 difference, theintrapulmonary shunt fraction, the oxygen index and the PaO2/FIO2 ratio. Of these different indices the PaO2/FIO2 ratio has been adopted for routine use because of its simplicity. This ratio is included in most ARDS definitions, such as the Lung Injury Score [1] and in the American–European Consensus Conference Definition [2]. Ferguson et al. recently proposed a new definition including static respiratory system compliance and PaO2/FIO2 measurement with PEEP set above 10 cmH2O, but FIO2 was still not fixed [3]. Important for this discussion, the PaO2/FIO2 ratio is influenced not only by ventilator settings and PEEP but also by FIO2. First, changes in FIO2 influence the intrapulmonary shunt fraction, which equals the true shunt plus ventilation–
perfusion mismatching. At FIO2 1.0, the effects of ventilation–perfusion mismatch are eliminated and true intrapulmonary shunt is measured. Thus, the estimated shunt fraction may decrease as FIO2 increases if V/Q mismatch is a major component in inducing hypoxemia (e.g., chronic obstructive lung disease and asthma). Second, at an FIO2 of 1.0 absorption atelectasis may occur, increasing true shunt [4]. Thus, at high FIO2 levels (> 0.6) true shunt may progressively increase but be reversible by recruitment maneuvers. Third, because of the complex mathematical relationship between the oxy-hemoglobin dissociation curve, the arterio-venous O2 difference, the PaCO2 level and the hemoglobin level, the relation between PaO2/FIO2 ratio and FIO2 is neither constant nor linear, even when shunt remains constant. Gowda et al. [5] tried to determine the usefulness of indices of hypoxemia in ARDS patients. Using the 50- compartment model of ventilation–perfusion inhomogeneity plus true shunt and dead space, they varied the FIO2 between 0.21 and 1.0. Five indices of O2 exchange efficiency were calculated (PaO2/FIO2, venous admixture, P(A-a)O2, PaO2/alveolar PO2, and the respiratory index). They described a curvilinear shape of the curve for PaO2/FIO2 ratio as a function of FIO2, but PaO2/FIO2 ratio exhibited the most stability at FIO2 values = 0.5 and PaO2 values = 100 mmHg, and the authors concluded that PaO2/FIO2 ratio was probably a useful estimation of the degree of gas exchange abnormality under usual clinical conditions. Whiteley et al. also described identical relation with other mathematical models [6, 7].This nonlinear relation between PaO2/FIO2 and FIO2, however, underlines the limitations describing the intensity of hypoxemia using PaO2/FIO2, and is thus of major importance for the clinician. The objective of this note is to describe the relation between PaO2/FIO2 and FIO2 with a simple model, using the classic Berggren shunt equation and related calculation, and briefly illustrate the clinical consequences. Berggren shunt equation (Equation 1) The Berggren equation [8] is used to calculate the magnitude of intrapulmonary shunt (S), “comparing” the theoretical O2 content of an “ideal” capillary with the actual arterial O2 content and taking into account what comes into the lung capillary, i.e., the mixed venous content. CcO2
is the capillary O2 content in the ideal capillary, CaO2 is the arterial O2 content, and Cv¯O2 is the mixed venous O2 content, S = Q.s Q.t = (CcO2 - CaO2) (CcO2 - C¯vO2)
This equation can be written incorporating the arteriovenous difference (AVD) as:
CcO2 - CaO2 = S
1 - S× AVD.
Blood O2 contents are calculated from PO2 and hemoglobin concentrations as:
Equation of oxygen content (Equation 2)
CO2 = (Hb × SO2 × 1.34) + (PO2 × 0.0031)
The formula takes into account the two forms of oxygen carried in the blood, both that dissolved in the plasma and that bound to hemoglobin. Dissolved O2 follows Henry’s
law – the amount of O2 dissolved is proportional to its partial pressure. For each mmHg of PO2 there is 0.003 ml O2/dl dissolved in each 100 ml of blood. O2 binding to hemoglobin is a function of the hemoglobin-carrying capacity that can vary with hemoglobinopathies and with fetal hemoglobin. In normal adults, however, each gram of hemoglobin can carry 1.34 ml of O2. Deriving blood O2 content allows calculation of both CcO2 and CaO2 and allows Eq. 1 to be rewritten as follows:
(Hb × ScO2 × 1.34) + (PcO2 × 0.0031)- (Hb × SaO2 × 1.34) + (PaO2 × 0.0031) = S
1 - S× AVD
In the ideal capillary (c), the saturation is 1.0 and the
PcO2 is derived from the alveolar gas equation:
PcO2 = PAO2 = (PB - 47) × FIO2 -
PaCO2
R
.
This equation describes the alveolar partial pressure of O2 (PAO2) as a function, on the one hand, of barometric pressure (PB), from which is subtracted the water vapor pressure at full saturation of 47 mmHg, and FIO2, to get the inspired O2 fraction reaching the alveoli, and on the other hand of PaCO2 and the respiratory quotient (R) indicating the alveolar partial pressure of PCO2. Saturation, ScO2 and SaO2 are bound with O2 partial pressure (PO2) PcO2 and PaO2, by the oxy-hemoglobin dissociation curve, respectively. The oxy-hemoglobin dissociation curve describes the relationship of the percentage of hemoglobin saturation to the blood PO2. This relationship is sigmoid in shape and relates to the nonlinear relation between hemoglobin saturationand itsconformational changes with PO2. A simple, accurate equation for human blood O2 dissociation computations was proposed by
Severinghaus et al. [9]:
Blood O2 dissociation curve equation (Equation 4)
SO2 = PO32 + 150PO2-1
× 23 400+ 1-1
This equation can be introduced in Eq. 1:
Hb × (PB - 47) × FIO2 -
PaCO2
R 3
+150 (PB - 47) × FIO2 -
PaCO2
R -1
×23 400+ 1-1
× 1.34+ (PB - 47)
×FIO2 -
PaCO2
R × 0.0031
-Hb × PaO32
+ 150PaO2-1
× 23 400
+1-1
× 1.34+ (PaO2 × 0.0031)
= S
1 - S× AVD
Equation 1 modified gives a relation between FIO2 and PaO2 with six fixed parameters: Hb, PaCO2, the respiratory quotient R, the barometric pressure (PB), S and AVD. The resolution of this equation was performed here with Mathcad® software, (Mathsoft Engineering & Education, Cambridge, MA, USA). Fig. 1 Relation between PaO2/FIO2 and FIO2 for a constant arterio-venous difference (AVD) and different shunt levels (S) Fig. 2 Relation between PaO2/FIO2 and FIO2 for a constant shunt (S) level and different values of arterio-venous differences (AVD)
Resolution of the equation The equation results in a nonlinear relation between FIO2 and PaO2/FIO2 ratio. As previously mentioned, numerous factors, notably nonpulmonary factors, influence this curve: intrapulmonary shunt, AVD, PaCO2, respiratory
quotient and hemoglobin. The relationship between PaO2/FIO2 and FIO2 is illustrated in two situations. Figure 1 shows this relationship for different shunt fractions and a fixed AVD. For instance, in patients with 20% shunt (a frequent value observed in ARDS), the PaO2/FIO2 ratio varies considerably with changes in FIO2. At both extremes of FIO2, the PaO2/FIO2 is substantially greater
than at intermediate FIO2. In contrast, at extremely high shunt (~=
60%) PaO2/FIO2 ratio is greater at low FIO2 and decreases at intermediate FIO2, but does not exhibit any further increase as inspired FIO2 continue to increase, for
instance above 0.7. Figure 2 shows the same relation but with various AVDs at a fixed shunt fraction. The larger is AVD, the lower is the PaO2/FIO2 ratio for a given FIO2. AVD can vary substantially with cardiac output or with oxygen consumption. These computations therefore illustrate substantial variation in the PaO2/FIO2 index as FIO2 is modified under conditions of constant metabolism and ventilation–perfusion abnormality.
Consequences
This discussion and mathematical development is based on a mono-compartmental lung model and does not take into account dynamic phenomena, particularly when high FIO2 results in denitrogenation atelectasis. Despite this limitation, large nonlinear variation and important morphologic differences of PaO2/FIO2 ratio curves vary markedly with intrapulmonary shunt fraction and AVD variation. Thus, not taking into account the variable relation between FIO2 and the PaO2/FIO2 ratio couldintroduce serious errors in
the diagnosis or monitoring of patients with hypoxemia on
mechanical ventilation. Recently, the accuracy of the American–European consensus ARDS definition was found to be only moderate when compared with the autopsy findings of diffuse alveolar damage in a series of 382 patients [10]. The problem discussed here with FIO2 may to some extent participate in these discrepancies. A studyby Ferguson et al. [11] illustrated the clinical relevance of this discussion. They sampled arterial blood gases immediately after initiation of mechanical ventilation and 30 min after resetting the ventilator in 41 patients who had early ARDS based on the most standard definition [2]. The changes in ventilatorsettingschiefly consisted of increasing
FIO2 to 1.0. In 17 patients (41%), the hypoxemia criterion for ARDS persisted after this change (PaO2/FIO2 < of =" 20%."> 0.6 (depending on the AVD value). Thus, the use of the PO2/FIO2 ratio as a dynamic variable should be used with caution if FIO2, as well as other ventilatory settings, varies greatly.

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Dead space

U. Lucangelo L. Blanch Dead space
Introduction
Dead space is that part of the tidal volume that does not participate in gas exchange. Although the concept of pulmonary dead space was introduced more than a hundred years ago, current knowledge and technical advances have only recently lead to the adoption of dead space measurement as a potentially useful bedside clinical tool.
Concept of dead space
The homogeneity between ventilation and perfusion determines normal gas exchange. The concept of dead space accounts for those lung areas that are ventilated but not perfused. The volume of dead space (Vd) reflects the sum of two separate components of lung volume: 1) the
nose, pharynx, and conduction airways do not contribute to gas exchange and are often referred to as anatomical Vd or herein as airway Vd (Vdaw); 2) well-ventilated alveoli but receiving minimal blood flow comprise the alveolar Vd (Vdalv). Mechanical ventilation, if present, adds additional Vd as part of the ventilator equipment (endotracheal tubes, humidification devices, and connectors). This instrumental dead space is considered to be part of the Vdaw. Physiologic dead space (Vdphys) is comprised of Vdaw (instrumental and anatomic dead space) and Vdalv and it is usually reported in mechanical ventilation as the portion of tidal volume (Vt) or minute ventilation that does not participate in gas exchange [1, 2].
A device that measures partial pressures (PCO2) or fractions (FCO2) of CO2during the breathing cycle is called a capnograph. The equation to transform FCO2 into PCO2 is PCO2 = FCO2 multiplied by the difference between barometric pressure minus water-vapour pressure.
Time-based capnography expresses the CO2 signal as a function of time and from this plot mean expiratory (Douglas bag method) or end-expiratory (end-tidal) CO2 values can be obtained. The integration of the volume signal using an accurate flow sensor (pneumotachograph) and CO2 signal (with a very fast CO2 sensor) is known as volumetric capnography. Combined with the measurement of arterial PCO2 (PaCO2) it provides a precise quantification of the ratio of Vdphys to Vt. The three phases of a volumetric capnogram are shown in Fig. 1 and Fig. 2. The combination of airflow and mainstream capnography monitoring allows calculation of breath by breath CO2 production and pulmonary dead space. Therefore, the use of volumetric capnography is clinically more profitable than time-based capnography. Measurement of dead space using CO2 as a tracer gas Bohr originally defined Vd/Vt [2] as: Vd/Vt = (FACO2– FECO2)/FACO2, where FACO2 and FECO2 are fractions of CO2 in alveolar gas and in mixed expired gas, respectively. End-tidal CO2 is used to approximate FACO2,assuming end-tidal and alveolar CO2 fractions are identical. Physiologic dead space calculated from the Enghoff modification of the Bohr equation uses PaCO2 with the assumption that PaCO2 is similar to alveolar PCO2 [2], such that: Vdphys/Vt = (PaCO2–PECO2)/PaCO2, where PECO2 is the partial pressure of CO2 in mixed expired gas and is equal to the mean expired CO2 fraction multiplied by the difference between the atmospheric pressure and the water-vapour pressure. Since Vdphys/Vt measures the fraction of each tidal breath that is wasted on both Vdalv and Vdaw, the Vdaw must be subtracted from Vdphys/Vt to obtain the Vdalv/Vt. Vdphys/Vt is the most commonly and commercially (volumetric capnographs) formula used to estimate pulmonary dead space at the bedside. Additional methods mostly used in research to calculate all the Vd components are shown in Fig. 1A and Fig. 2A. Fowler [1] introduced a procedure for measuring Vdaw based on the geometric method of equivalent areas (p = q), obtained by crossing the back extrapolation of phase III of the expired CO2 concentration over time with a vertical line traced so as to have equal p and q areas. Airway dead space is then measured from the beginning of expiration to the point where the vertical line crosses the volume axis [1]. By tracing a line parallel to the volume axis and equal to the PaCO2, it is possible to determine the readings from areas y and z, which respectively represent the values of alveolar and airway dead space. Referring these values to the Vt, it is possible to single out several Vd components [2]:

Vdphys=Vt¼ðY þ ZÞ=ðX þ Y þ ZÞ
Vdalv=Vt¼Y=ðX þ Y þ ZÞ
Vdaw=Vt¼Z=ðX þ Y þ ZÞ
Fig. 1 A Single-breath expiratory volumetric capnogram recorded in a healthy patient receiving controlled mechanical ventilation. Dead-space components are shown graphically and equations are depicted and explained in the text. Phase I is the CO2 free volume which corresponds to Vdaw. Phase II represents the transition between airway and progressive emptying of alveoli. Phase III represents alveolar gas. PaCO2 is arterial PCO2; PetCO2 is end-tidal PCO2. Drawings adapted from [2]; B Single-breath expiratory carbon dioxide volume (VCO2) plotted as a function of exhaled tidal volume. The alternative method to measure airway dead space (Vdaw) described by Langley et al. [3] is graphically shown in a healthy patient receiving controlled mechanical ventilation Fig. 2 A Single-breath expiratory volumetric capnogram recorded in a chronic obstructive pulmonary disease patient receiving controlled mechanical ventilation. The three phases of the volumetric capnogram are depicted. The transition from phase II to III is less evident due to heterogeneity of ventilation and perfusion ratios. Dead-space components are shown graphically and equations are depicted and explained in the text. PaCO2 is arterial PCO2; PetCO2 is end-tidal PCO2. Drawings adapted from [2]; B Single-breath expiratory carbon dioxide volume (VCO2) plotted as a function of exhaled tidal volume. The alternative method to measure airway dead space (Vdaw) described by Langley et al. [3] is graphically shown in a chronic obstructive pulmonary disease patient receiving controlled mechanical ventilation . An alternative method to measure airway dead space introduced by Langley et al. [3] is based on determination of the VCO2 value, which corresponds to the area inscribed within the CO2 versus volume curve (indicated in Fig. 1A and Fig. 2A as X area). Figure 1B and Fig. 2B are examples of Vdaw calculation using the Langley et al. [3] method. Briefly, VCO2 is plotted versus expired breath volume. Thereafter, Vdaw can be calculated from the value obtained on the volume axis by back extrapolation from the first linear part of the VCO2 versus volume curve. Although these indexes are clinically useful, they are always bound to visual criteria for the definition of phase III of the expired capnogram. Often, the geometric analysis establishing the separation between the phase II and phase III is hardly seen and the rate of CO2 raising of the phase III is nonlinear in patients with lung inhomogeneities (Fig. 2A). Utility of dead space in different clinical scenarios The CO2 tension difference between pulmonary capillary blood and alveolar gas is usually small in normal subjects and end-tidal PCO2 is close to alveolar and arterial PCO2. Physiologic dead space is the primary determinant of the difference between arterial and end-tidal PCO2 (DPCO2) in patients with a normal cardio-respiratory system. Patients with cardiopulmonary diseases have altered ventilation to perfusion (VA/QT) ratios producing abnormalities of Vd, as well as in intrapulmonary shunt, and the latter may also affect the DPCO2. A DPCO2 beyond 5 mmHg is attributed to abnormalities in Vdphys/Vt and/or
by an increase in venous admixture (the fraction of the cardiac output that passes through the lungs without taking oxygen) or both. The increase in Vdphys/Vt seen in normal patients when anaesthetised may be attributed to muscle paralysis, which causes a reduction of functional residual capacity and alters the normal distribution of ventilation and perfusion across the lung [2, 4, 5, 6]. Ventilation to regions having little or no blood flow (low alveolar PCO2) affects pulmonary dead space. In patients with airflow obstruction, inhomogeneities in ventilation are responsible for the increase in Vd. Shunt increase VDphys/Vt as the mixed venous PCO2 from shunted blood elevates the PaCO2, increasing VDphys/Vt by the fraction that PaCO2 exceeds the nonshunted pulmonary capillary PCO2 [7]. Vdalv is increased by shock states, systemic and pulmonary hypotension, obstruction of pulmonary vessels (massive pulmonary embolus and microthrombosis), even in the absence of a subsequent decrease in ventilation and low cardiac output. Vdaw is increased by lung overdistension and additional ventilatory apparatus dead space. Endotracheal tubes, heat and moisture exchangers, and other common connectors may increase ventilator dead space and induce hypercapnia during low Vt or low minute ventilation. Vdaw calculations include the ventilator dead space. Because the anatomic dead space remains relatively constant as Vt is reduced, very low Vt is associated with a high Vd/Vt ratio [1, 2, 7, 8, 9]. Positive end-expiratory pressure (PEEP) is used to increase lung volume and to improve oxygenation in patients with acute lung injury. Vdalv is large in acute lung injury and does not vary systematically with PEEP. However, when the effect of PEEP is to recruit collapsed lung units resulting in an improvement of oxygenation, Vdalv may decrease, and alveolar recruitment is associated with decreased arterial minus end-tidal CO2 difference [4, 5, 6]. Conversely, PEEP-induced overdistension may increase Vdalv and widen this difference [7]. In patients with sudden pulmonary vascular occlusion due to pulmonary embolism, the resultant high VA/QT mismatch produces an increase in Vdalv. The association of a normal D-dimer assay result plus a normal Vdalv is a highly sensitive screening test to rule out the diagnosis of pulmonary embolism [9].
Dead space and outcome prediction
Characteristic features of acute lung injury are alveolar and capillary endothelial cell injuries that result in alterations of pulmonary microcirculation. Consequently, adequate pulmonary ventilation and blood flow across the lungs are compromised and Vdphys/Vt increases. A high dead-space fraction represents an impaired ability to excrete CO2 due to any kind of VA/QT mismatch [7]. Nuckton et al. [10] demonstrated that a high Vdphys/Vt was independently associated with an increased risk of death in patients diagnosed with acute respiratory distress syndrome.
Conclusions
The advanced technology combination of airway flow monitoring and mainstream capnography allows breathby-breath bedside calculation of pulmonary Vd and CO2 elimination. For these reasons, the use of volumetric capnography is clinically more useful than time capnography. Measurement of dead-space fraction early in the course of acute respiratory failure may provide clinicians with important physiologic and prognostic information. Further studies are warranted to assess whether the continuous measurement of different derived capnographic indices is useful for risk identification and stratification, and to track the effect of a therapeutic intervention during the course of disease in critically ill patients.

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Fluid responsiveness in mechanically ventilated patients: a review of indices used in intensive care

Karim Bendjelid
Jacques-A. Romand
Introduction
Hypotension is one of the most frequent clinical signs observed in critically ill patients. To restore normal blood pressure, the cardiovascular filling (preloaddefined as end-diastolic volume of both ventricular chambers), cardiac function (inotropism), and vascular resistance (afterload) must be assessed. Hemodynamic instability secondary to effective or relative intravascular volume depletion are very common, and intravascular fluid resuscitation or volume expansion (VE) allows restoration of ventricular filling, cardiac output and ultimately arterial blood pressure [1, 2]. However, in the Frank-Starling curve (stroke volume as a function of preload) the slope presents on its early phase a steep portion which is followed by a plateau (Fig. 1). As a consequence, when the plateau is reached, vigorous fluid resuscitation carries out the risk of generating volume overload and pulmonary edema and/or right-ventricular dysfunction. Thus in hypotensive patients methods able to unmask decreased preload and to predict whether cardiac output will increase or not with VE have been sought after for many years. Presently, as few methods are able to assess ventricular volumes continuously and directly, static pressure measurements and echocardiographically measured ventricularend-diastolic areas are used as tools to monitor cardiovascular filling. Replacing static measurements, dynamic monitoring consisting in assessment of fluid responsiveness using changes in systolic arterial pressure, and pulse pressure induced by positive pressure ventilation have been proposed. The present review analyses the current roles and limitations of the most frequently used methods in clinical practice to predict fluid responsiveness in patients undergoing mechanical ventilation (MV) (Table 1). One method routinely used to evaluate intravascular volume in hypotensive patients uses hemodynamic response to a fluid challenge [3]. This method consists in infusing a defined amount of fluid over a brief period of time. The response to the intravascular volume loading can be monitored clinically by heart rate, blood pressure, pulse pressure (systolic minus diastolic blood pressure), and urine output or by invasive monitoring with the measurements of the right atrial pressure (RAP), pulmonary artery occlusion pressure (Ppao), and cardiac output. Such a fluid management protocol assumes that the intravascular volume of the critically ill patients can be defined by the relationship between preload and cardiac output, and that changing preload with volume infusion affects cardiac output. Thus an increase in cardiac output following VE (patient responder) unmasks an hypovolemic state or preload dependency. On the other hand, lack of change or a decrease in cardiac output following VE (nonresponding patient) is attributed to a normovolemic, to an overloaded, or to cardiac failure state. Therefore, as the fluid responsiveness defines the response of cardiac output to volume challenge, indices which can predict the latter are necessary. Static measurements for preload assessment
Measures of intracardiac pressures
According to the Frank-Starling law, left-ventricular preload is defined as the myocardial fiber length at the end Table 1 Studies of indices used as bedside indicators of preload reserve and fluid responsiveness in hypotensive patients under positive-pressure ventilation (BMI body mass index, CO cardiac output, CI cardiac index, SV stroke volume, SVI stroke volume index, IAC invasive arterial catheter, MV proportion of patients mechanically ventilated, . increase, . decrease, PAC pulmonary artery catheter, R responders, NR nonresponders, FC fluid challenge, HES hydroxyethyl starch, RL Ringer’s lactate, Alb albumin, .down delta down, .PP respiratory variation in pulse pressure, LVEDV left-ventricular end diastolic volume, SPV systolic pressure
variation, SVV stroke volume variation, TEE transesophageal echocardiography, Ppao pulmonary artery occlusion pressure, RAP right atrial pressure, RVEDV right-ventricular-end diastolic volume, FC fluid challenge) Variable Tech- n MV Volume (ml) Duration Definition Definition p: Refermeasured nique (%) and type of of FC of R of NR difference ence plasma substitute (min) in baseline values R vs. NR
Rap PAC 28 46 250 Alb 5% 20–30 . SVI . SVI or unchanged NS 37
Rap PAC 41 76 300 Alb 4.5% 30 . CI CI . or unchanged NS 18
Rap PAC 25 94.4 NaCl 9‰ + Until .Ppao . SV =10% . SV <10% 0.04 31
Alb 5% to . Ppao
Rap PAC 40 100 500 HES 6% 30 . CI >15% . CI <15% NS 36
Ppao PAC 28 46 250 Alb 5% 20–30 . SVI . SVI or unchanged NS 37
Ppao PAC 41 76 300 Alb 4.5% 30 . CI CI . or unchanged NS 18
Ppao PAC 29 69 300–500 RL ? bolus . C0>10% C0 . or unchanged <0.01 40
Ppao PAC 32 84 300–500 RL ? . CI >20% . CI <20% NS 41
Ppao PAC 16 100 500 HES 6% 30 . CI >15% . CI <15% 0.1 42
Ppao PAC 41 100 500 pPentastarch 15 . SV =20% . SV <20% 0.003 25
Ppao PAC 25 94.4 NaCl 9‰, Until .Ppao . SV =10% . SV <10% 0.001 31
Alb 5% to. Ppao
Ppao PAC 40 100 500 HES 6% 30 . CI >15% . CI <15% NS 36
Ppao PAC 19 100 500–750 HES 6% 10 . C0>10% . SV <10% 0.0085 39
RVEDV PAC 29 69 300–500 RL ? bolus . C0>10% C0 . or unchanged <0.001 40
RVEDV PAC 32 84 300–500 RL ? . CI >20% . CI <20% <0.002 41
RVEDV PAC 25 94.4 NaCl 9‰, Until .Ppao . SV =10% . SV <10% 0.22 31
Alb 5% to. Ppao
LVEDV TEE 16 100 500 HES 6% 30 . CI >15% . CI <15% 0.005 42
LVEDV TEE 41 100 500 Pentastarch 15 . SV =20% . SV <20% 0.012 25
LVEDV TEE 19 100 8 ml/kg HES 6% 30 . CI >15% . CI <15% NS 79
LVEDV TEE 19 100 500–750 HES 6% 10 . C0>10% . SV <10% NS 39
SPV IAC 16 100 500 HES 6% 30 . CI >15% . CI <15% 0.0001 42
SPV IAC 40 100 500 HES 6% 30 . CI >15% . CI <15% <0.001 36
SPV IAC 19 100 500–750 HES 6% 10 . C0>10% . SV <10% 0.017 39
.down IAC 16 100 500 HES 6% 30 . CI >15% . CI <15% 0.0001 42
.down IAC 19 100 500–750 HES 6% 10 . C0>10% . SV <10% 0.025 39
.PP IAC 40 100 500 HES 6% 30 . CI >15% . CI <15% <0.001 36
Fig. 1 Representation of Frank-Starling curve with relationship between
ventricular preload and ventricular stroke volume in patient X. After volume expansion the same magnitude of change in preload recruit less stroke volume, because the plateau of the curve is reached which characterize a condition of preload independency of the diastole. In clinical practice, the left-ventricular end-diastolic volume is used as a surrogate to define leftventricular preload [4]. However, this volumetric parameter is not easily assessed in critically ill patients. In normal conditions, a fairly good correlation exists between ventricular end-diastolic volumes and mean atrial pressures, and ventricular preloads are approximated by RAP and/or Ppao in patients breathing spontaneously [5, 6]. Critically ill patients often require positive pressure ventilation, which modifies the pressure regimen in the thorax in comparison to spontaneous breathing. Indeed, during MV RAP and Ppao rise secondary to an increase in
intrathoracic pressure which rises pericardial pressure. This pressure increase induces a decrease in venous return [7, 8] with first a decrease in right and few heart beats later in left-ventricular end-diastolic volumes, respectively [9, 10]. Under extreme conditions such as acute severe pulmonary emboli and/or marked hyperinflation, RAP may also rise secondary to an increase afterload of the right ventricle. Moreover, under positive pressure ventilation not only ventricular but also thoracopulmonary compliances and abdominal pressure variations are observed over time. Thus a variable relationship between cardiac pressures and cardiac volumes is often observed [11, 12, 13, 14]. It has also been demonstrated that changes in intracardiac pressure (RAP, Ppao) no longer directly reflect changes in intravascular volume [15]. Pinsky et al. [16, 17] have demonstrated that changes in RAP do not follow changes in right-ventricular
end-diastolic volume in postoperative cardiac surgery patients under positive pressure ventilation. Reuse et al. [18] observed no correlation between RAP and right-ventricular end-diastolic volume calculated from a thermodilution technique in hypovolemic patients before and after fluid resuscitation. The discordance between RAP and right-ventricular end-diastolic volume measurements may result from asystematic underestimation
of the effect of positive-pressure ventilation on the right heart [16, 17]. Nevertheless, the RAP value measured either with a central venous catheter or a pulmonary artery catheter is still used to estimate preload and to guide intravascular volume therapy in patient under positive pressure ventilation [19, 20]. On the left side, the MV-induced intrathoracic pressure changes, compared to spontaneously breathing, only minimally alters the relationship between left atrial pressure and left-ventricular end-diastolic volume measurement in postoperative cardiac surgery patients [21]. However, several other studies show no relationship between Ppao and left-ventricular end-diastolic volume measured by either radionuclide angiography [12, 22], transthoracic echocardiography (TTE) [23], or transesophageal echocardiography (TEE) [24, 25, 26]. The latter findings may be related to the indirect pulmonary artery catheter method for assessing left atrial pressure [27, 28], although several studies have demonstrated that Ppao using PAC is a reliable indirect measurement of left atrial pressure [29, 30] in positive-pressure MV patients. Right atrial pressure used to predict fluid responsiveness Wagner et al. [31] reported that RAP was significantly lower before volume challenge in responders than in nonresponders (p=0.04) when patients were under positive pressure ventilation. Jellinek et al. [32] found that a RAP lower than 10 mmHg predicts a decrease in cardiac index higher than 20% when a transient 30 cm H2O increase in intrathoracic pressure is administrated. Presuming that the principle cause of decrease in cardiac output in the latter study was due to a reduction in venous return [9, 33, 34, 35], RAP predicts reverse VE hemodynamic effect. Nevertheless, some clinical investigations studying fluid responsiveness in MV patients have reported that RAP poorly predicts increased cardiac output after volume expansion [18, 36, 37]. Indeed, in these studies RAP did not differentiate patients whose cardiac output did or did not increase after VE (responders and nonresponders, respectively)

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Alveolar ventilation and pulmonary blood flow: the V.A/Q. concept

Enrico Calzia
Peter Radermacher
Given a stable cardiac output (CO) and inspiratory oxygen concentration (FIO2), any gas exchange abnormality leading to hypoxia or hypercapnia may be explained solely on the basis of an altered distribution of the ventilation and perfusion (V.A/Q. ) regardless of the underlying disease [1]. 1. The alveolus is the functional unit of the lung The alveolus and the surrounding capillaries represent the functional lung gas exchange unit. Diffusive gas transport across the alveolar–capillary membrane is very rapid [2]. Even under pathologic conditions gas exchange at the alveolar level is not limited by diffusion across the gas–blood barrier, but mainly by the interplay between gas transport to (and from) the alveolar space (ventilation, V.A) and blood flow across the alveolar capillaries
(perfusion, Q. ). End-capillary gas partial pressures exactly reflect alveolar gas composition. Therefore, since arterial blood is the sum of the blood from each alveolar
region and the blood that bypasses the alveolar compartments (i.e., shunt), the gas composition in each alveolus will determine the arterial blood gasvalues in direct dependence on both ventilation and perfusion. In lung regions where ventilation exceeds perfusion, the alveolar gas partial pressures will approach the inspired ones. In contrast, if perfusion exceeds ventilation, the alveolar gas composition will more closely resemble the composition of mixed venous blood. Consequently, at a V.A/Q. ratio near unity, O2 and CO2 gas exchange is optimally balanced. Since alveoli with such an optimal V.A/Q. ratio are the main contributors to the achievement of “normal” arterial blood gas values they are called “ideal” alveoli. At V.A/Q. ratios exceeding the ideal value the gas composition of each alveolus will approach that of inspired gas, at lower V.A/Q. ratios that of mixed venous blood. In reality, the V.A/Q. ratio is slightly less than unity, because the respiratory quotient, which is the ratio of O2 absorbed to CO2 excreted, is usually less than unity. 2. Graphic analysis of pulmonary gas exchange:
the PO2-PCO2 diagram The effects of a ventilation–perfusion mismatch on gas
exchange are graphically described by the PO2–PCO2 diagram first introduced by Rahn and Farhi (Fig. 1) [3]. Since the PO2 and PCO2 in each alveolus is determined by the V.A/Q. ratio, a line through all PO2–PCO2 value pairs can be drawn connecting two endpoints of mixed venous blood and inspired gas composition. Each point on this
line represents V.A/Q. values from 0 (representing perfused but not ventilated alveoli, thus corresponding to shunt areas) to 8 (representing ventilated but not perfused alveoli, thus corresponding to dead space). Theoretically, the most efficient gas exchange should be expected in a perfectly homogeneous lung,with an overall V. A/Q. value near unity. However, even in healthy subjects a limitation in gas exchange is imposed by the inhomogeneous distribution of the V.A/Q. values, mainly as a result of gravitational forces. In normal physiologic states, however, this inhomogeneity is fairly moderate, but it substantially increases with disease. 3. V.A/Q. mismatch is quantified by the three-compartment model of ideal alveoli, shunt, and dead space
Assuming a perfectly homogeneous V.A/Q. distribution and no shunt, alveolar (=end capillary) and arterial gas partial pressures should be equal. Consequently, any alveolar-to-arterial PO2 or PCO2 differences reflect inhomogeneous V.A/Q. distribution and are used to quantify the V. A/Q. mismatch. Conceptually, as suggested by Riley and Cournand [4], alveolar gas exchange can be simplified to
occurring within three types of alveoli: those with matched V.A/Q. (ideal), those with no Q. (dead space), and those with no V.A (shunt). This “three-compartment” simplification is attractive because it allows one to quantify gas exchange abnormalities by theproportion of gas exchange units in each compartment. Although “ideal” alveolar zones contribute to minimizing alveolar-to-arterial differences, blood from shunt perfusion zones joins blood coming from alveolar regions
with gas values identical to mixed venous ones, thus increasing both alveolar-to-arterialO2 differences and arterial CO2 levels. An unappreciated result of increased shunt fraction is the increase in arterial PCO2 as mixed venous CO2 passes the alveoli and mixes with the arterial blood. Based on these considerations, the amount of right-to-left shunt can be derived from the calculated gas content in capillary, arterial, and mixed venous blood using the equation where Qs/Qt=shunt fraction or venous admixture,
CaO2=arterial blood O2 content, CcO2=end-capillary O2 content, and CvO2=mixed venous blood O2 content. Since capillary O2 content cannot be measured directly, it is assumed to equal ideal alveolar O2 content (CAIO2), which is estimated by the ideal alveolar O2 partial pressure (PAIO2) obtained by the simplified alveolar gas equation
(2) where PAIO2=“ideal” alveolar O2 partial pressure, PIO2=inspired O2 partial pressure, PaCO2=arterial blood CO2 partial pressure, and RQ=respiratory quotient. The accuracy of these formulas is limited by mainly three factors. First, the calculation of CcO2 from PAIO2 assumes equilibration of alveolar and end-capillary gas and ignores the impact that changes in pH and PCO2 may have on gas exchange. Second, although PaCO2 is presumed to equal PAICO2, this assumption is incorrect when shunt causes PCO2 to increase morethan PAICO2. And finally, the respiratory exchange ratio (RQ) is assumed to be 0.8, but may actually vary between 1.0 and 0.7 based on metabolic activity and diet. Despite these limitations, however, these formulae are remarkably accurate, allowing the estimation of right-to-left shunt in the clinical setting. In contrast to shunts, gas exchange abnormalities due to increased dead space ventilation result in partial exclusion of inspired gas from gasexchange. Thus, expired gas partial pressures are maintained closer to the inspired ones. Commonly, the dead space fraction is calculated by the Bohr equation where VD/VT=dead space fraction, PaCO2=arterial blood
CO2 partial pressure, and PECO2=mid-expired CO2 partial pressure. Although this three-compartment model is useful in calculating shunt and dead space, clearly, gas exchange units can have local ventilation to perfusion ratios anywhere
from 0 to 8, and not just 0, 1, and 8. However, the three-compartment model forces parts of the lung to be in one of these three compartments. Under normal resting conditions, this assumption is not so far off of reality, because most alveolar regions are characterized by V. A/Q. -values between 1 and 0.8, or very near 0 and 8 respectively.
Experimentally, one may measure the exact V. A/Q. distribution of the entire lung using the multiple inert gas technique. However, the utility of this approach to bedsideassessment of gas exchange abnormalities is low because of its impracticality. Fig. 1 The PO2-PCO2 diagram of Rahn and Farhi graphically explains the theoretical concepts of ventilation/perfusion distribution and pulmonary gas exchange. (From [13], with permission)
22
4. Hypoxia and hypercapnia are caused by severe V.A/Q. mismatching
Both oxygenation and CO2 homeostasis may be considerably impaired by V.A/Q. mismatch, although usually only hypoxia is referred to as the result of increased venous admixture, while hypercapnia is generally considered the result of increased dead space ventilation or hypoventilation. However, if minute ventilation isfixed, as is the case during controlled ventilation, then increasing shunt fraction will cause hypercarbia. In the awake, spontaneously breathing subject, CO2 elimination may be sufficiently maintained through chemoreceptorfeedback even in the presence of low V.A/Q. alveoli, so that arterial CO2 remains normal. In contrast, due to the narrow limits imposed by hemoglobin O2 saturation, blood O2 content cannot be increased by hyperventilation,
and is therefore more susceptible to be decreased by increasing venous admixture. Obviously, however, substantial hypercapnia will also result from hugely increased venous admixtureexceeding the limits of compensation, especially if venous admixture is almost completely caused by true shunt (e.g., atelectatic regions).
5. Clinical implications Beneficial effects of different recommended recruitment and ventilation strategies for patients receiving mechanical ventilation are generally explained by their impact of ventilation to perfusion matching [5], even though the precise interplay between lung mechanics, hemodynamics, and V.A/Q. distribution is complex. Preventing alveolar collapse by the use of continuouspositive airway pressure (CPAP) and positive end-expiratory pressure (PEEP) minimizes shunt, as do recruitment maneuvers, whereas vasodilator therapy, including aerosolized bronchodilator therapy, by increasing blood flow to potentially underventilated lung units increases shunt and arterial desaturation. This is thecauseofhypoxemia following bronchodilator therapy in severe asthmatics. Pressurelimited ventilation and smallertidalvolume ventilation with attention paid to avoiding dynamic hyperinflation minimize dead space [6]. Prone positioning of the patient and interspacing spontaneousventilatory efforts by causing
diaphragmatic contraction improve V.A/Q. matching. When one takes into account the effects of systemic blood flow on gas exchange, the interactions become more complex again. The interactions between intra- and extrapulmonary factors, such as changes in cardiac output, systemic oxygen uptake, and mixed venous O2 saturation, can directly alter arterial oxygenationand CO2 content independent of changes in V.A/Q. . For example, although intravenous vasodilators usually increase intrapulmonary shunt
in patients with adult respiratory distress syndrome or cardiogenic pulmonary edema, the associated increase in cardiac output, especially in the heart failure group, may offset the increased shunt by increasing mixed venous O2 saturation [7]. Thus, the resultant change in arterial oxygenation cannot be predicted ahead of time [8]. Furthermore,
some intravenous vasodilators may affect CO2 elimination through several mechanisms. They may impair CO2 elimination by increasing shunt fraction or increasing blood
flow and CO2 delivery to the lungs; also, if cardiac output does not increase in response of the intravenous administration of vasodilators, the intrathoracic blood volume may decrease, thus increasing the amount of hypoperfused areas especially in apical lungzones [9]. Giving vasodilators by inhalation should minimize shunt because only ventilated lung units will receive the vasodilating agent. Thus, inhalational vasodilating therapy should improve V.A/Q. matching. This has been shown to occur in patients with gas exchange abnormalities when treated with nitric oxide (NO) inhalation or aerosolized prostacyclin [10, 11]. The underlying pathology seems to be crucially important in regard
to the effects on arterial oxygenation. While patients with dult respiratorydistresssyndrome or right heart failure improve their gas exchange, inhaled vasodilators may worsen arterial oxygenation by inhibiting hypoxic vasoconstriction in patients with chronic obstructive pulmonary disease, since V.A/Q. mismatch in hypoventilated areas rather than true shunt is the predominant cause of arterial hypoxemia in such cases [12].
References
1. Radermacher P, Cinotti L, Falke KJ (1988) Grundlagen der methodischen Erfassung von Ventilations/Perfusions- Verteilungsstörungen. Anaesthesist
7:36–42
2. Piiper J, Scheid P (1981) Model for capillary-alveolar equilibration with
special reference to O2 uptake in hypoxia. Respir Physiol 46:193–208
3. Fahri LE (1966) Ventilation-perfusion relationship and its role in alveolar gas
exchange. In: Caro CG (ed) Advances in respiratory physiology. Arnold, London, pp 148–197
4. Riley RL, Cournand A (1951) Analysis of factors affecting partial pressures of oxygen and carbon dioxide in gas and blood of lungs. 4:77–101
5. Pappert D, Rossaint R, Slama K, Grüning T, Falke KJ (1994) Influence of
positioning on ventilation-perfusion relationships in severe adult respiratory distress
syndrome. Chest 106:1511–1516
6. Ralph DD, Robertson HT, Weaver NJ, Hlastala MP, Carrico CJ, Hudson LD (1985) Distribution of ventilation and perfusion during positive end-expiratory pressure in the adult respiratory distress syndrome. Am Rev Respir Dis 131:54–60 23
7. Rossaint R, Hahn SM, Pappert D, Falke KJ, Radermacher P (1995) Influence
of mixed venous PO2 and inspired O2 fraction on intrapulmonary shunt in patients with severe ARDS. J Appl Physiol 78:1531–1536
8. Radermacher P, Santak B, Wüst HJ, Tarnow J, Falke KJ (1990) Prostacyclin
for the treatment of pulmonary distress syndrome: effects on pulmonary capillary
pressure and ventilation-perfusion distributions. Anesthesiology 72:238–244

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Effects of body temperature on blood gases

Andreas Bacher
Abstract Background:
Changes in body temperature have important impact on measurements of blood gases. In blood gas analyzers the samples are always kept constant at a temperature of exactly 37C during the measurements, and therefore results are not correct if body temperature differs from 37C. Objective: Lack of knowledge of the effects of body temperature on results of blood gas monitoring may lead to wrong and potentially harmful interpretations and decisions in the clinical setting. The following article elucidates alterations in monitoring of blood gases and oxyhemoglobin saturation (SO2) that occur during changes in body temperature.
Keywords Blood gas monitoring · Oxyhemoglobin saturation · Hypothermia ·Hyperthermia
Blood gas monitoring
Blood gases (oxygen and carbon dioxide) are usually reported as partial pressures (gas tensions) since according to Henry’s law the partial pressure of a gas is proportional to its concentration at a given temperature and pressure. However, as temperature decreases, the solubilityof oxygen and carbon dioxide in blood or any other fluid increases, which means that the relationship of partial pressure to the total content of oxygen or carbon dioxide in the fluid changes.
Carbon dioxide
If blood containing a given amount of carbon dioxide at a certain tension (PCO2) at 37C is cooled, with the possibility to equilibrate with air, the total content of CO2 in this blood sample remains constant, whereas PCO2 decreases due to the increased proportion of dissolved CO2 at lower temperature. Since the PCO2 of air or any inspired gas mixture is almost zero, no additional molecules of CO2 diffuse into the blood. If a blood sample is rewarmed to 37C in a blood gas analyzer under vacuumsealed conditions, the previously increased dissolved proportion of CO2 again contributes to PCO2. The measured PCO2 of this blood sample is the same as at 37C. Hypothermia reduces the metabolic rate and the rate of CO2 production. To hold the arterial CO2 content constant during cooling it is necessary to reduce CO2 elimination (i.e., by reducing minute ventilation in anesthetized patients) equivalently to the decrease in CO2 production. If this is performed, arterial carbon dioxide tension (PaCO2) measured in a blood gas analyzer at 37C remains at the same level as during normothermia. Blood gas analyzers are usually equipped with algorithms that enable the true PaCO2 to be calculated at the actual body temperature (Fig. 1) [1]. True PaCO2 corrected for current body temperature is of course lower during hypothermia than the PaCO2 value measured at 37C. The difference between these two values corresponds to the increase in CO2 solubility during cooling. The concept of CO2 management in which the PCO2 obtained by measurement at 37C is kept constant at 40 mmHg regardless of current body temperature is called alpha-stat. If the PCO2 value corrected for current body temperature is held constant during cooling at the same level as during normothermia (37C), the total amount of CO2 increases during hypothermia because of the constant PaCO2 and the increased proportion of CO2 that is soluble in blood. In this case CO2 elimination is not only reduced by the amount of decreased CO2 production but additionally by the increased amount of CO2 dissolved in blood during hypothermia. The latter concept of CO2 management is called pH-stat.
pH
pH varies with CO2 during variations in body temperature. If alpha-stat CO2management is applied, pH that is not corrected for current body temperature remains constant. True pH increases since true PaCO2 has decreased during hypothermia. If pH-stat CO2 management is applied, both true PaCO2 and true pH remain constant during cooling, and pH that is not corrected for current body temperature decreases. The amount of true pH change resulting from a change in body temperature may be calculated as follows: pHT=pH37 [0.0146+0.0065 (pH37 7.4)](T 37), where pHT is true pH at current body temperature, pH37 is pH at 37C, and T is current body
temperature (C).
Oxygen
The effects of temperature changes on oxygen tension (PO2) differ markedly from those on PCO2. The principal effect that hypothermia leads to increased solubility of O2
in blood is the same as for CO2. Therefore during hypothermia one could expect a lower PO2 for a given amount of oxygen. However, in contrast to CO2, the oxygen
content of room air or any inspired gas mixture and of alveolar gas is never zero. The PO2 of room air at standard atmospheric pressure (patm) of 760 mmHg is approximately
159 mmHg. If an increased amount of O2 molecules dissolve in blood during cooling, PO2 does not decrease as does PCO2 because O2 from the environment and from alveolar gas diffuse into blood, and the PO2 values equilibrate between these two compartments. The O2 content in blood thus thereby increases. This schematic
model is in fact representative of that which occurs in the alveoli and capillaries of the lungs. If we take a blood sample at hypothermia and put it into a blood gas analyzer, this sample is rewarmed to 37C under vacuumsealed conditions. The previously increased proportion of dissolved O2 then contributes to PO2, which thereby increases. Thus PO2 values that are not corrected for current body temperature are higher than during normothermia (Fig. 1) [1]. Temperature-corrected PO2 is equal to the values obtained during normothermia. The clinical relevance of these effects is clear: Whenever
we measure arterial oxygen tension (PaO2) and do not correct these values for current (hypothermic) body temperature, true PaO2 does not increase during cooling,
but the observed increase in measured PaO2 is due only to the fact that body temperature and the temperature at which the sample is analyzed differ. Considering that the
gradient between PaO2 and cellular (mitochondrial) PO2 is the driving force that maintains normal O2 extraction by the tissue, it would be a mistake to adapt inspired
oxygen fraction (FIO2) to the uncorrected, apparently high values of PaO2 obtained during hypothermia. To maintain true PaO2 in the normal range the measured
PaO2 should always be corrected for current body temperature in hypothermic patients.
Apart from the effects of increased O2 solubility there is another effect that slightly affects PaO2 during hypothermia. Since PaO2 is related to the alveolar oxygen
tension (PAO2), true PaO2 might indeed increase a very
Fig. 1 Dashed line True (temperature corrected) PCO2 during changes in body temperature. PCO2 measured at 37C remains constant at 40 mmHg. Solid line PO2 measured at 37C during changes in body temperature. True (temperature corrected) PO2 remains constant
at 85 mmHg small amount during moderate hypothermia if pulmonary gas exchange conditions and the gradient between PaO2 and PAO2 (aADO2) remain constant. PAO2 depends on FIO2, patm, water vapor pressure (pH2O), PaCO2, and the respiratory quotient (RQ=CO2 production rate/O2 consumption rate). PAO2=FIO2(patm pH2O) PaCO2RQ 1. Water vapor pressure decreases exponentially with a decrease in temperature. At 37C pH2O is approx. 47 mmHg, at 30C approx. 31 mmHg, and at 15C approx. 12 mmHg. At FIO2 of 0.21, patm of 760 mmHg,
PaCO2 of 40 mmHg, and RQ of 0.8, PAO2 is 99.7 mmHg at 37C, 103.1 mmHg at 30C, and 107.1 mmHg at 15C. Table 1 illustrates changes in blood gases during alphastat and pH-stat regimens as body temperature decreases from 37C to 30C.Table 1 An example of changes in blood gases during alphastat and pH-stat regimens as
body temperature (BT) decreases from 37C to 30C BT 37C BT 30C Alpha-stat PCO2 (mmHg) 40 After rewarming to 37C in blood gas analyzer 40 True value (corrected): 29 PO2 (mmHg) 85 After rewarming to 37C in blood gas m analyzer 117 True value (corrected) 85 pH 7.40 After rewarming to 37C in blood gas analyzer 7.40 True value (corrected) 7.50 pH-stat PCO2 (mmHg) 40 After rewarming to 37C in blood gas analyzer 40 True value (corrected) 56 PO2 (mmHg) 85 After rewarming to 37C in blood gas analyzer 117 True value (corrected): 85 pH 7.40 After rewarming to 37C in blood gas analyzer 7.30 True value (corrected) 7.40 Fig. 2 Leftward shift of the oxyhemoglobin dissociation curve caused by hypothermia. Temperature (T) is 30C for the dotted curve. The true carbon dioxide tension (PCO2) of 27 mmHg and pH of 7.5 at 30C correspond to a PCO2 of 40 mmHg and pH of 7.4 at 37C. Oxyhemoglobin saturation(SO2)=100(a1PO2+a2PO22+a3PO23+PO24)/(a4+a5PO2+a6PO22+a7PO23+PO24). The seven coefficients (a1–a7) were determined by a least-squares fitting of
the equation to paired values of PO2 and SO2 (a1= 8532.2289, a2=2121.4010, a3= 67.073989, a4=935960.87, a5= 31346.258, a6= 2396.1674, a7= 67.104406). Oxygen tension is measured at current conditions of pH, PCO2, and T. Then it must be converted into a PO2 that would be obtained at a pH of 7.40, a PCO2 of 40 mmHg, and T
of 37C. The equation to convert the actual PO2 to this virtual PO2 is: [PO2 virtual]=[PO2 actual]100.0024 (37 T)+0.40 (pH 7.40)+0.06[log10 (40) log10 (PCO2)]. Then the equation for the standard oxyhemoglobin dissociation curve is again applied to predict actual SO2
Effects of hypothermia on SO2
Arterial (SaO2), mixed venous (SvO2), and jugular bulb (SjvO2) oxyhemoglobin saturation are strongly affected by changes in body temperature. The curve of the relationship between SO2 and PO2, i.e., the oxyhemoglobin dissociation curve, is Sshaped. Hypothermia, a decrease in the intracellular concentration of 2,3diphosphoglycerate in erythrocytes, a decrease in PCO2, and an increase in pH cause a leftward shift of the oxyhemoglobin dissociation curve, which means that at a given PO2 the SO2 value is higher than under normal conditions. The corresponding
SO2 to a given PO2 may be calculated with sufficient accuracy (Fig. 2) [2]. Due to the S-shape of the oxyhemoglobin dissociation curve changes in SO2 caused by a leftward shift are more pronounced when PO2 is in the medium range. Therefore hypothermia leads to an
increase in SvO2 and SjvO2 rather than SaO2 because normal SaO2 is already close to 100%. Hypothermia inhibits oxygen release from hemoglobin in the capillaries (i.e., oxygen extraction) without providing any benefits with regard to increasing SaO2. In other words, a much lower tissue PO2 would be required to obtain the same degree of oxyhemoglobin desaturation in the capillary. The total amount of O2 flow from the capillary to the cells and mitochondria would then decrease because the driving force of O2 diffusion, i.e., the gradient between mitochondrial PO2 and capillary or tissue PO2 is reduced. Oxygen consumption (VO2) decreases during hypothermia. The relationship between cerebral VO2 and temperature has been well investigated [3, 4]. This isdetermined by the factor Q10: Q10=cerebral VO2 at Tx/ cerebral VO2 at Ty,whereTx Ty=10C. Q10 is not constant over the entire temperature range that is clinically possible [3, 4]. In dogs Q10 is approx. 2.2 when T=37 27C, approx. 4.5 when T=27 14C, and approx. 2.2 when T=13 7C [3, 4]. Cerebral VO2 at a given
temperature may be calculated as follows: VO2 at Ty= VO2 at TxQ10(Ty Tx)/10 Because hypothermia leads to a leftward shift of the oxyhemoglobin dissociation curve and to a decrease in VO2, SvO2 should significantly increase during cooling,
particularly if O2 delivery remains unchanged. This has in fact been found in hypothermic (32C) patients under endogenous circulation, i.e., without the use of extracorporeal In conclusion, variations in body temperature significantly affect the results of important and frequently used monitoring techniques in intensive care, anesthesia, and emergency medicine. The knowledge of physical and technical changes during hypothermia or hyperthermia is necessary to avoid pitfalls in monitoring of blood gases, SO2, and etCO2. Ignoring these effects may lead to harmful and incorrect conclusions derived from our measurements in the clinical setting as well as for scientific purposes
References
1. Hansen D, Syben R, Vargas O, Spies C, Welte M (1999) The alveolar-arterialdifference in oxygen tension increases with temperature-corrected determination during moderate hypothermia. Anesth Analg 88:538–542
2. Kelman GR (1966) Digital computer subroutine for the conversion of oxygen
tension into saturation. J Appl Physiol 21:1375–1376
3. Michenfelder JD, Milde JH (1992) The effect of profound levels of hypothermia
(below 14 degrees C) on canine cerebral metabolism. J Cereb Blood Flow Metab 12:877–880
4. Michenfelder JD, Milde JH (1991) The relationship among canine brain temperature,
metabolism, and function during hypothermia. Anesthesiology
75:130–136
5. Bacher A, Illievich UM, Fitzgerald R, Ihra G, Spiss CK (1997) Changes in
oxygenation variables during progressivehypothermia in anesthetized patients. J Neurosurg Anesthesiol 9:205–

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Venous oximetry

Frank Bloos
Konrad Reinhart
Introduction
The primary physiological task of the cardiovascular system is to deliver enough oxygen (O2) to meet the metabolic demands of the body. Shock and tissue hypoxia occur when the cardiorespiratory system is unable to cover metabolic demand adequately. Sustained tissue hypoxia is one of the most important cofactors in the pathophysiology of organ dysfunction [1]. Therefore determining the adequacy of tissue oxygenation in critically ill patients is central to ascertain the health of the patient. Unfortunately, normal values in blood pressure, central venous pressure, heart rate, and blood gases do not rule out tissue hypoxia or imbalances between whole-body oxygen supply and demand [2]. This discrepancy has led to increased interest in more direct indicators of adequacy
of tissue oxygenation such as mixed and central venous oxygen saturations.

Pulmonary artery catheterization allows obtaining true mixed venous oxygen saturation (SvO2) while measuring central venous oxygen saturation (ScvO2) via central venous catheter reflects principally the degree of oxygen extraction from the brain and the upper part of the body. This brief review discusses the role and limitations of SvO2 and ScvO2 as indicators of the adequacy of tissue oxygenation.
Physiology of mixed venous and central venous oxygen saturation O2 delivery (DO2) describes whole-body oxygen supply according to the following formula:
DO2 ¼ CO CaO2 ð1Þ where CO is cardiac output and CaO2 is arterial oxygen
content, which itself is the sum of oxygen bound to hemoglobin [product of hemoglobin concentration (Hb) and arterial O2 saturation (SaO2)] and physically dissolved
oxygen [arterial PO2 (PaO2)]: CaO2 ¼ ðHb 1:36 SaO2Þ þ ðPaO2 0:0031Þ ð2Þ
Oxygen demand can be summarized in the whole-body oxygen consumption (VO2), which is expressed mathematically by the Fick principle as the product of CO and
arteriovenous O2 content difference (CaO2 CvO2): VO2 ¼ CO ðCaO2 CvO2Þ ð3Þ where mixed venous O2 content (CvO2) is:
CvO2 ¼ ðHb 1:36 SvO2Þ þ ðPvO2 0:0031Þ ð4Þ Equation 3 may be transposed to: CvO2 ¼ CaO2 VO2 CO ð5Þ As physically dissolved oxygen can be neglected, Eq. 5 may be written as: Hb 1:36 SvO2 ðHb 1:36 SaO2Þ VO2 CO , SvO2 VO2 CO ð6Þ Equation 6 also demonstrates that SvO2 is directly proportional
to the ratio of VO2 to CO. Thus SvO2 reflects the relationship between whole-body O2 consumption and cardiac output. Indeed, it has been shown that the SvO2 is well correlated with the ratio of O2 supply to demand [3].Pathophysiology of central or mixed venous O2 saturation during shock Usually VO2 is independent of DO2 since tissues can maintain O2 needs by increasing O2 extraction when DO2 decreases. However, this mechanism has its limits. Below a so-called critical DO2 compensatory increase in O2 extraction is exhausted, and VO2 becomes dependent on DO2. In this case tissue hypoxia occurs, and a rise in
serum lactate levels may be observed [4]. A decrease in SvO2 and ScvO2 represents an increased metabolic stress, because the O2 demands of the body are not completely met by DO2. The causes of a decreasing SvO2 are multiple and reflect the forces operative in Eqs. 5 and 6. That is, either DO2 does not increase in such a way to cover an increased VO2, or DO2 drops because of decrease in either arterial O2 content, cardiac output, or both. Importantly, the normal cardiovascular response of increasing VO2 is to increase O2 extraction and cardiac output. Thus SvO2 normally decreases during exercise despite increasing
DO2. Therefore a drop in SvO2 or ScvO2 does not necessarily mean that tissue hypoxia occurs. The magnitude of the decrease indicates the extent to which the physiological reserves are stressed (Table 1). Whereas in otherwise healthy individuals anaerobic metabolism may occur when SvO2 drops below its normal value of 75% to 30–40% for a substantial period of time, patients with chronic heart failure may live with an SvO2 in this low range without apparent tissue hypoxia, presumably because they have adapted to higher oxygen extraction. These patients can increase their VO2 to a limited degree, however, because O2 extraction is close to its limits as is cardiac output. The cardiocirculatory system may be challenged by two different conditions. Firstly, a drop in DO2 can be induced by anemia, hypoxia, hypovolemia, or heart failure. Secondly, fever, pain, stress etc. may also decrease SvO2 or ScvO2 by increasing whole-body VO2 (Table 2) Since central venous catheterization is commonly performed for a variety of reasons in critically ill patients, it would be useful if ScvO2 could function as a surrogate for SvO2. The central venous catheter sampling site usually resides in the superior vena cava. Thus central venous blood sampling reflects the venous blood of the
upper body but neglects venous blood from the lower body (i.e., intra-abdominal organs). As presented in Fig. 1, venous O2 saturations differ among several organ systems since they extract different amounts of O2. ScvO2 is usually less than SvO2 by about 2–3% because the lower body extracts less O2 than the upper body making inferior vena caval O2 saturation higher. The primary cause of the lower O2 extraction is that many of the vascular circuits that drain into the inferior vena cava use blood flow for nonoxidative phosphorylation needs (e.g., renal blood flow, portal flow, hepatic blood flow). However, SvO2 and ScvO2 change in parallel when the wholebody ratio of O2 supply to demand is altered [5]. The difference between the absolute value of ScvO2 and SvO2 changes under conditions of shock [6]. In septic shock ScvO2 often exceeds SvO2 by about 8% [7]. During cardiogenic or hypovolemic shock mesenteric and renal blood flow decreases followed by an increase in O2 extraction n these organs. In septic shock regional O2 consumption of the gastrointestinal tract and hence regional O2 extraction increases despite elevated regional blood flows [8]. On the other hand, cerebral blood flow is maintained over some period in shock. This would cause a delayed drop of ScvO2 in comparison to SvO2, and the correlation between these two parameters would worsen. Some authors therefore argued that ScvO2 cannot be used as surrogate for SvO2 under conditions of circulatory shock [9]. However, changes in SvO2 are closely mirrored by changes in ScvO2 under experimental [10] and clinical conditions [7] despite a variabledifference between these two variables. This may explain why Rivers et al.
were able to use ScvO2 higher than 70% in addition to conventional hemodynamic parameters as therapeutic endpoint for hemodynamic resuscitation to improve outcome in patients with severe sepsis and septic shock. From a physiological point of view, SvO2 monitoring for “early goal directed therapy” should provide similar re-sults. Given the fact that ScvO2 exceeds SvO2 on average by 8% in patients with septic shock, an SvO2 of about 62– 65% should suffice as endpoint for hemodynamic resuscitation in these conditions, although this has not been tested prospectively. However, the placement of pulmonary artery catheters and the potentially higher risk of this should not result in a delay in the start of the resuscitation of critically ill patients.
Venous oximetry can reflect the adequacy of tissue oxygenation only if the tissue is still capable of extracting O2. In the case of arteriovenous shunting on the microcirculatorylevel or cell death, SvO2 and ScvO2 may not decrease or even showelevated values despite severe tissue hypoxia. As demonstrated in patients afterprolonged cardiac arrest, venous hyperoxia with an ScvO2 higher than 80% is indicative of impaired oxygen use [12].
Conclusion
Low values of SvO2 or ScvO2 indicate a mismatch between O2 delivery and tissue O2 need. While measurement of SvO2 requires the insertion of a pulmonary artery catheter, measurement of ScvO2 requires only central venous catheterization. ScvO2 directed early goal-directed therapy improves survival in patients with septic shock who are treated in an emergency department. However, ScvO2 values may differ from SvO2 values, and this difference varies in direction and magnitude with cardiovascular insufficiency. ScvO2 should not be used alone in the assessment of the cardiocirculatory system but combined with other cardiocirculatory parameters and indicators of organ perfusion such as serum lactate concentration and urine output.
Fig. 1 Arterial and venous oxygen saturations in various vascular
regions [2]
Table 1 Limits of mixed venous oxygen saturation SvO2 >75% Normal extraction
O2 supply >O2 demand 75% >SvO2 >50% Compensatory extraction Increasing O2 demand or decreasing O2 supply 50% >SvO2 >30% Exhaustion of extraction
Beginning of lactic acidosis O2 supply SvO2 >25% Severe lactic acidosis SvO2 <25%>

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Relation between PaO2/FIO2 ratio and FIO2: a mathematical description

Jerome Aboab Bruno Louis Bjorn Jonson Laurent Brochard
The acute respiratory distress syndrome (ARDS) is characterized by severe hypoxemia, a cornerstone element in its definition. Numerous indices have been used to describe this hypoxemia, such as the arterial to alveolar O2 difference, theintrapulmonary shunt fraction, the oxygen index and the PaO2/FIO2 ratio. Of these different indices the PaO2/FIO2 ratio has been adopted for routine use because of its simplicity. This ratio is included in most ARDS definitions, such as the Lung Injury Score [1] and in the American–European Consensus Conference Definition [2]. Ferguson et al. recently proposed a new definition including static respiratory system compliance and PaO2/FIO2 measurement with PEEP set above 10 cmH2O, but FIO2 was still not fixed [3]. Important for this discussion, the PaO2/FIO2 ratio is influenced not only by ventilator settings and PEEP but also by FIO2. First, changes in FIO2 influence the intrapulmonary shunt fraction, which equals the true shunt plus ventilation–perfusion mismatching. At FIO2 1.0, the effects of ventilation–perfusion mismatch are eliminated and true intrapulmonary shunt is measured. Thus, the estimated shunt fraction may decrease as FIO2 increases if V/Q mismatch is a major component in inducing hypoxemia (e.g., chronic obstructive lung disease and asthma). Second, at an FIO2 of 1.0 absorption atelectasis may occur, increasing true shunt [4]. Thus, at high FIO2 levels (> 0.6) true shunt may progressively increase but be reversible by recruitment maneuvers. Third, because of the complex mathematical relationship between the oxy-hemoglobin
dissociation curve, the arterio-venous O2 difference, the PaCO2 level and the hemoglobin level, the relation between PaO2/FIO2 ratio and FIO2 is neither constant nor linear, even when shunt remains constant. Gowda et al. [5] tried to determine the usefulness of indices of hypoxemia in ARDS patients. Using the 50- compartment model of ventilation–perfusion inhomogeneity plus true shunt and dead space, they varied the FIO2 between 0.21 and 1.0. Five indices of O2 exchange efficiency were calculated (PaO2/FIO2, venous admixture, P(A-a)O2, PaO2/alveolar PO2, and the respiratory index). They described a curvilinear shape of the curve for PaO2/FIO2 ratio as a function of FIO2, but PaO2/FIO2 ratio exhibited the most stability at FIO2 values = 0.5 and PaO2 values = 100 mmHg, and the authors concluded that PaO2/FIO2 ratio was probably a useful estimation of the degree of gas exchange abnormality under usual clinical conditions. Whiteley et al. also described identical relation with other mathematical models [6, 7].This nonlinear relation between PaO2/FIO2 and FIO2, however, underlines the limitations describing the intensity of hypoxemia using PaO2/FIO2, and is thus of major importance for the clinician. The objective of this note is to describe the relation between PaO2/FIO2 and FIO2 with a simple model, using the classic Berggren shunt equation and related calculation, and briefly illustrate the clinical consequences. Berggren shunt equation (Equation 1) The Berggren equation [8] is used to calculate the magnitude of intrapulmonary shunt (S), “comparing” the theoretical O2 content of an “ideal” capillary with the actual arterial O2 content and taking into account what comes into the lung capillary, i.e., the mixed venous content. CcO2 is the capillary O2 content in the ideal capillary, CaO2 is the arterial O2 content, and Cv¯O2 is the mixed venous O2 content,
S = Q.s Q.t = (CcO2 - CaO2) (CcO2 - C¯vO2)
This equation can be written incorporating the arteriovenous
difference (AVD) as:
CcO2 - CaO2 = S
1 - S× AVD.
Blood O2 contents are calculated from PO2 and hemoglobin concentrations as: Equation of oxygen content (Equation 2)
CO2 = (Hb × SO2 × 1.34) + (PO2 × 0.0031)
The formula takes into account the two forms of oxygen carried in the blood, both that dissolved in the plasma and that bound to hemoglobin. Dissolved O2 follows Henry’s law – the amount of O2 dissolved is proportional to its partial pressure. For each mmHg of PO2 there is 0.003 ml O2/dl dissolved in each 100 ml of blood. O2 binding to hemoglobin is a function of the hemoglobin-carrying capacity that can vary with hemoglobinopathies and with fetal hemoglobin. In normal adults, however, each gram of hemoglobin can carry 1.34 ml of O2. Deriving blood O2 content allows calculation of both CcO2 and CaO2 and allows Eq. 1 to be rewritten as follows:
(Hb × ScO2 × 1.34) + (PcO2 × 0.0031)- (Hb × SaO2 × 1.34) + (PaO2 × 0.0031) = S
1 - S× AVD
In the ideal capillary (c), the saturation is 1.0 and the PcO2 is derived from the alveolar gas equation:
PcO2 = PAO2 = (PB - 47) × FIO2 - PaCO2 R .
This equation describes the alveolar partial pressure of O2 (PAO2) as a function, on the one hand, of barometric pressure (PB), from which is subtracted the water vapor pressure at full saturation of 47 mmHg, and FIO2, to get the inspired O2 fraction reaching the alveoli, and on the other hand of PaCO2 and the respiratory quotient (R) indicating the alveolar partial pressure of PCO2. Saturation, ScO2 and SaO2 are bound with O2 partial pressure (PO2) PcO2 and PaO2, by the oxy-hemoglobin dissociation curve, respectively. The oxy-hemoglobin dissociation curve describes the relationship of the percentage of hemoglobin saturation to the blood PO2. This relationship is sigmoid in shape and relates to the nonlinear relation between hemoglobin saturationand itsconformational changes with PO2. A simple, accurate equation for human blood O2 dissociation computations was proposed by Severinghaus et al. [9]: Blood O2 dissociation curve equation (Equation 4)
SO2 = PO32 + 150PO2-1
× 23 400+ 1-1
This equation can be introduced in Eq. 1:
Hb × (PB - 47) × FIO2 - PaCO2 R 3 +150 (PB - 47) × FIO2 -
PaCO2 R -1 ×23 400+ 1-1 × 1.34+ (PB - 47) ×FIO2 - PaCO2 R × 0.0031
-Hb × PaO32
+ 150PaO2-1
× 23 400
+1-1
× 1.34+ (PaO2 × 0.0031)
= S
1 - S× AVD
Equation 1 modified gives a relation between FIO2 and PaO2 with six fixed parameters: Hb, PaCO2, the respiratory quotient R, the barometric pressure (PB), S and AVD.
The resolution of this equation was performed here with Mathcad® software, (Mathsoft Engineering & Education, Cambridge, MA, USA).
Fig. 1 Relation between PaO2/FIO2 and FIO2 for a constant arterio-venous difference (AVD) and different shunt levels (S) Fig. 2 Relation between PaO2/FIO2 and FIO2 for a constant shunt (S) level and different values of arterio-venous differences (AVD) Resolution of the equation The equation results in a nonlinear relation between FIO2 and PaO2/FIO2 ratio. As previously mentioned, numerous factors, notably nonpulmonary factors, influence this curve: intrapulmonary shunt, AVD, PaCO2, respiratory quotient and hemoglobin. The relationship between PaO2/FIO2 and FIO2 is illustrated in two situations. Figure 1 shows this relationship for different shunt fractions and a fixed AVD. For instance, in patients with 20% shunt (a frequent value observed in ARDS), the PaO2/FIO2 ratio varies considerably with changes in FIO2. At both extremes of FIO2, the PaO2/FIO2 is substantially greater than at intermediate FIO2. In contrast, at extremely high shunt (~=60%) PaO2/FIO2 ratio is greater at low FIO2 and decreases at intermediate FIO2, but does not exhibit any further increase as inspired FIO2 continue to increase, for instance above 0.7. Figure 2 shows the same relation but with various AVDs at a fixed shunt fraction. The larger is AVD, the lower is the PaO2/FIO2 ratio for a given FIO2. AVD can vary substantially with cardiac output or with oxygen consumption. These computations therefore illustrate substantial variation in the PaO2/FIO2 index as FIO2 is modified under conditions of constant metabolism and ventilation–perfusion abnormality.
Consequences
This discussion and mathematical development is based on a mono-compartmental lung model and does not take into account dynamic phenomena, particularly when high FIO2 results in denitrogenation atelectasis. Despite this limitation, large nonlinear variation and important morphologic differences of PaO2/FIO2 ratio curves vary markedly with intrapulmonary shunt fraction and AVD variation. Thus, not taking into account the variable relation between FIO2 and the PaO2/FIO2 ratio couldintroduce serious errors in the diagnosis or monitoring of patients with hypoxemia on mechanical ventilation. Recently, the accuracy of the American–European consensus ARDS definition was found to be only moderate when compared with the autopsy findings of diffuse alveolar damage in a series of 382 patients [10]. The problem discussed here with FIO2 may to some extent participate in these discrepancies. A studyby Ferguson et al. [11] illustrated the clinical relevance of this discussion. They sampled arterial blood gases immediately after initiation of mechanical ventilation and 30 min after resetting the ventilator in 41 patients who had early ARDS based on the most standard definition [2]. The changes in ventilatorsettingschiefly consisted of increasing FIO2 to 1.0. In 17 patients (41%), the hypoxemia criterion for ARDS persisted after this change (PaO2/FIO2 < of =" 20%."> 0.6 (depending on the AVD value). Thus, the use of the PO2/FIO2 ratio as a dynamic variable should be used with caution if FIO2, as well as other ventilatory settings, varies greatly. References
1. Murray J,Matthay MA, Luce J, FlickM (1988) An expanded definition of the adult respiratory distress syndrome. Am Rev Respir Dis 138:720–723
2. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M,
Legall JR, Morris A, Spragg R (1994) The American–European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149:818–824
3. Ferguson ND, Davis AM, Slutsky AS, Stewart TE (2005) Development of a clinical definition for acute respiratory distress syndrome using the Delphi technique. J Crit Care 20:147–154
4. Santos C, Ferrer M, Roca J, Torres A, Hernandez C, Rodriguez-Roisin R (2000) Pulmonary gas exchange response to oxygen breathing in acute lung injury. Am J Respir Crit Care Med 161:26–31
5. Gowda MS, Klocke RA (1997) Variability of indices of hypoxemia in adult respiratory distress syndrome. Crit Care Med 25:41–45
6. Whiteley JP, Gavaghan DJ, Hahn CE (2002) Variation of venous admixture, SF6 shunt, PaO2, and the PaO2/FIO2 ratio with FIO2. Br J Anaesth 88:771–778
7. Whiteley JP, Gavaghan DJ, Hahn CE
(2002) Mathematical modelling of oxygen transport to tissue. J Math Biol 44:503–522
8. Berggren S (1942) The oxygen deficit of arterial blood caused by nonventilating
parts of the lung. Acta Physiol
Scand 11:1–92
9. Severinghaus J (1979) Simple, accurate equations for human blood O2 dissociation computations. J Appl Physiol
46:599–602
10. Esteban A, Fernandez-Segoviano P, Frutos-Vivar F, Aramburu JA, Najera L,
Ferguson ND, Alia I, Gordo F, Rios F (2004) Comparison of clinical criteria for the acute respiratory distress syndrome with autopsy findings. Ann Intern Med 141:440–445
11. Ferguson ND, Kacmarek RM, Chiche JD, Singh JM, Hallett DC, Mehta S, Stewart TE (2004) Screening of ARDS patients using standardized ventilator settings: influence on enrollment in a clinical trial. Intensive Care
Med 30:1111–1116

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Intrinsic (or auto-) positive end-expiratory

Laurent Brochard
Introduction
The mechanisms generating intrinsic or auto-positive end-expiratory pressure (PEEP) during controlled mechanical ventilation in a relaxed patient also occur during spontaneous breathing or when the patient triggers the ventilator during an assisted mode [1, 2]. These include an increased time constant for passive exhalation of the respiratory system, a short expiratory time resulting from a relatively high respiratory rate and/or the presence of expiratory flow limitation. Whereas dynamic hyperinflation and intrinsic or auto-PEEP may have haemodynamic consequences, this is not frequently a major concern in spontaneously breathing patients or during assisted ventilation because the spontaneous inspiratory efforts result in a less positive or more negative mean intrathoracic pressure than during controlled mechanical ventilation. The mainconsequence of dynamic hyperinflation during spontaneous and assisted ventilation is the patient's increased effort to breathe and work of breathing [1, 2]. To what extent does intrinsic (or auto-) positive end-expiratory pressure influence work of breathing? For air to enter the lungs, the pressure inside the chest has to be lower than the pressure at the mouth (spontaneous breathing) or at the airway opening (assisted ventilation). In the case of intrinsic (or auto-) PEEP, by definition, the end-expiratory alveolar pressure is higher than the pressure at the airway opening. When the patient initiates the breath, there is an inevitable need to reduce airway pressure to zero (spontaneous breathing) or to the value of end-expiratory pressure set on the ventilator (assisted ventilation) before any gas can flow into the lungs. For this reason, intrinsic or (auto-) PEEP has been described as an inspiratory threshold load. In patients with chronic obstructive pulmonary disease (COPD) this load has sometimes been measured to be the major cause of increased work of breathing [3]. During assisted ventilation, is the trigger sensitivity important to reduce intrinsic (or auto-) positive end-expiratory pressure? Because the problem of intrinsic or (auto-) PEEP has to do with the onset of inspiration, one may reason that increasing the inspiratory trigger sensitivity to initiate a breath with a lower pressure or flow deflection should reduce the work of breathing induced by hyperinflation. These systems are based on the detection of a small pressure drop relative to baseline (pressure-triggering system) or on the presence of a small inspiratory flow (flow-triggering systems). Unfortunately, increasing the trigger sensitivity induces only a small reduction in the total work of breathing. The reason for this lack of effect relates to the need for the inspiratory trigger to sense changes in airway pressure or in inspiratory flow. Thus, intrinsic PEEP needs to be counterbalanced first by the effort of the inspiratory muscles, in order for this effort to generate a small pressure drop (in the presence of a closed circuit) or to initiate the inspiratory flow (in an open circuit) [4]. The consequence of intrinsic or (auto-) PEEP is that the inspiratory effort starts during expiration. This is easily identified by inspection of the expiratory flow-time curve [1]. Asaconsequence, it cannot be detected by any of the commercially available trigger systems. Can the set external positive end-expiratory pressure reduce dynamic hyperinflation and work of breathing? Responses to these two questions are the same as during controlled mechanical ventilation in a relaxed patient [1]. Their consequences are, however, very different. External PEEP reduces the difference between the alveolar and the ventilator proximal airway pressure, i.e., intrinsic (or auto-) PEEP. The inspiratory threshold load resulting from intrinsic (or auto-) PEEP is thus reduced by addition of external PEEP. Thus, the total work of breathing is reduced, especially in patients withhigh levels of intrinsic (or auto-) PEEP, such as those subjects with COPD [5, 6]. Although external PEEP reduces work of breathing, it does not minimise hyperinflation. The level of dynamic hyperinflation is not modified by external PEEP, unless this PEEP is set higher than the minimal level of regional intrinsic PEEP, and then hyperinflation increases. Increasing hyperinflation can aggravate the working conditions of the respiratory muscles by placing them at a mechanical disadvantage and can result in significant haemodynamic compromise by decreasing venous return and increasing right ventricular outflow resistance. Hyperinflation in excess of intrinsic (or auto-) PEEP occurs usually when the set PEEP is positioned at values above 80% of the mean “static”intrinsic PEEP [7]. For this reason, titration of external PEEP based on measuring intrinsic (or auto-) PEEP would be desirable. Unfortunately, a reliable measurement of intrinsic (or auto-) PEEP in the spontaneously breathing subject is much more difficult to obtain than in passive positive-pressure ventilation conditions. Can standard ventilatory settings influence intrinsic (or auto-) positive end-expiratory pressure? During assisted ventilation, the patient is supposed to determine the respiratory rate freely, and one may suppose that he/she will govern his/her respiratory rate to control expiratory time and minimise hyperinflation. Unfortunately, most patients will not be able to counteract fully the effects of a ventilator inspiratory time longer than their own inspiratory time [8]. Although some compensatory mechanism may exist, it will frequently be insufficient. Every setting influencing the ventilator inspiratory time may thus influence the level of dynamic hyperinflation. Is intrinsic (or auto-) positive end-expiratory pressure always synonymous with dynamic hyperinflation? In patients with spontaneous respiratory activity, recruitment of the expiratory muscles frequently participates in generating intrinsic (or auto-) PEEP independently of dynamic hyperinflation. In the case of airflow obstruction, the main consequence of an activation of the expiratory muscles is to augment intrathoracic pressure, whereas their effects on expiratory flow may be very modest, especially in the case of airflow limitation, thus promoting small airways to collapse. The activation of the expiratory muscles results from an increase in respiratory drive. Many patients with COPD already have a recruitment of their expiratory muscles at rest. This expiratory muscle recruitment results in a measurable increase in alveolar pressure. However, such expiratory muscle recruitment, although creating an intrinsic (or au- Fig. 1 Tracings of gastric (Pga), oesophageal (Poes) and airway (Paw) pressures, flow and diaphragmatic electromyographic activity (EMGdi) during an assisted breath (pressure-support ventilation). The vertical lines help to delineate the different phases of the inspiratory effort. During phase 1, the flow is still expiratory: the start of EMGdi and the abrupt decrease in both Pes and Pga all indicate that the patient performs an active inspiratory effort against intrinsic positive end-expiratory pressure (PEEP) at the same time that his/her expiratory muscles relax. Phase 2 is the triggering of the ventilator and occurs once intrinsic (or auto-) PEEP has been counterbalanced to-) PEEP, does not contribute to the inspiratory threshold load and the increased work of breathing. Indeed, at the same time that the inspiratory muscles start to decrease intrathoracic pressure, the expiratory muscles relax
and their release almost immediately abolishes this part of intrinsic (or auto-) PEEP due to the expiratory muscles [9]. This is illustrated in Fig. 1. Can intrinsic (or auto-) positive end-expiratory pressure be reliably measured? The commonly applied end-expiratory airway occlusion method that measures intrinsic (or auto-) PEEP in patients on controlled ventilation cannot be readily applied to the patient making spontaneous inspiratory efforts. For example, it is not possible to determine which amount of measured positive airway occlusion pressure, if not all, is due to expiratory muscle activity [9]. Setting the external PEEP based on this measurement could induce considerable mistakes by overestimating intrinsic (or auto-) PEEP. The only readily available and reliable method of measuring intrinsic (or auto-) PEEP in the spontaneously breathing subject is to measure the drop in oesophageal pressure occurring before flow becomes inspiratory, and subsequently subtract the part due to expiratory muscle activity determined from an abdominal pressure signal [9]. The reasoning is as follows: any rise in abdominal pressure occurring during expiration is transmitted to the intrathoracic space and increases alveolar pressure. Intrinsic PEEP is measured from the abrupt drop observed on the oesophageal pressure signal until flow becomes inspiratory (phase 1 on Fig. 1). Part of this drop in oesophageal pressure is caused by the relaxation of the expiratory muscles. This part needs to be subtracted from the oesophageal pressure drop, in order to evaluate a “corrected” intrinsic PEEP due to hyperinflation. Two main possibilities exist: to subtract the rise in gastric pressure that occurred during the preceding expiration [9] or to subtract the concomitant decrease in gastric pressure at the onset of the effort [10]. Because the correction of intrinsic (or auto-) PEEP for expiratory muscle activity has not been used in early studies, one can hypothesise that the magnitude of intrinsic (or auto-) PEEP has often been overestimated. This combined oesophageal and gastric pressure measuring technique requires the insertion of a nasogastric tube equipped with both oesophageal and gastric balloon catheters. This technique is often used for research purposes but cannot be easily used at the bedside for routine clinical monitoring.
References
1. Brochard L (2002) Intrinsic (or auto-) PEEP during controlled mechanical ventilation. Intensive Care Med 28:1376–1378
2. Rossi A, Polese G, Brandi G, Conti G (1995) Intrinsic positive end-expiratory
pressure (PEEPi). Intensive Care Med 21:522–536
3. Coussa ML, Guérin C, Eissa NT, Corbeil C, Chassé M, Braidy J, Matar N, Milic-Emili J (1993) Partitioning of work of breathing in mechanically ventilated COPD patients. J Appl Physiol 75:1711–1719
4. Ranieri VM, Mascia L, Petruzelli V, Bruno F, Brienza A, Giuliani R (1995) Inspiratory effort and measurement of dynamic intrinsic PEEP in COPD patients: effects of ventilator triggering systems. Intensive Care Med 21:896–903
5. Smith TC, Marini JJ (1988) Impact of PEEP on lung mechanics and work of breathing in severe airflow obstruction. J Appl Physiol 65:1488–1499
6. Petrof BJ, Legaré M, Goldberg P,
Milic-Emili J, Gottfried SB (1990) Continuous positive airway pressure reduces work of breathing and dyspnea during weaning from mechanical ventilation in severe chronic obstructive pulmonary disease (COPD). Am Rev Respir Dis 141:281–289
7. Ranieri MV, Giuliani R, Cinnella G, Pesce C, Brienza N, Ippolito E, Pomo V, Fiore T, Gottried S, Brienza A
(1993) Physiologic effects of positive end-expiratory pressure in patients with chronic obstructive pulmonary disease during acute ventilatory failure and controlled mechanical ventilation. Am Rev Respir Dis 147:5–13
8. Younes M, Kun J, Webster K, Roberts D (2002) Response of ventilator-dependent patients to delayed opening of exhalation valve. Am J Respir Crit Care Med 166:21–30
9. Lessard MR, Lofaso F, Brochard L (1995) Expiratory muscle activity increases intrinsic positive end-expiratory pressure independently of dynamic hyperinflation in mechanically ventilated patients. Am J Respir Crit Care Med 151:562–569
10. Appendini L, Patessio A, Zanaboni S, Carone M, Gukov B, Donner CF, Rossi A (1994) Physiologic effects of positive end-expiratory pressure and mask pressure support during exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 149:1069–1076

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Mechanisms of hypoxemia

Robert Rodriguez-Roisin
Josep Roca
This research was supported by the Red Respira-ISCIII-RTIC-03/ 11 and the Comissionat per a Universitats i Recerca de la Generalitat de Catalunya (2001 SGR00386). R.R.-R. holds a career scientist award from the Generalitat de Catalunya.
Introduction
A fundamental aspect of cardiopulmonary homeostasis is the adequate delivery of oxygen to meet the metabolic demands of the body. Cardiac output, O2-carrying capacity
(i.e., hemoglobin concentration and quality), and arterial PO2 (PaO2) determine O2 transport. Relevant to this discussion, arterial hypoxemia commonly occurs in patients with acute respiratory failure (ARF). If arterial hypoxemia is severe enough, it is not compatible with life. The two primary causes of ARF are acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and chronic obstructive lung disease (COPD). Although the treatment for arterial hypoxemia always includes increases in the fractional inspired O2 concentration (FIO2), the degree to which patients’ PaO2 improves and the need for adjuvant therapies differ markedly between these two groups of disease processes. The mechanisms by which arterial hypoxemia occurs in ALI/ARDS and COPD have been characterized using the multiple inert gas elimination technique (MIGET) approach [1]. MIGET provides precise estimates of the distributions of alveolar ventilation and pulmonary perfusion (VA/Q) and their relationships,
there is no need to change the FIO2 during measurements, hence avoiding variations in the pulmonary vascular tone, and it facilitates the unraveling of the active interplay between intrapulmonary, namely VA/Q imbalance, intrapulmonary shunt and limitation of alveolar to end-capillary O2 diffusion, and extrapulmonary (i.e., FIO2, total ventilation, cardiac output and oxygen consumption) factors governing hypoxemia [2]. The cardinal gas exchange features under which the lung operates that uniquely determine the PO2 and PCO2 in each gas exchange unit of the lung are the VA/Q ratio, the composition of the inspired gas, and the mixed venous blood gas composition [3]. Each of these three factors may play key role influencing oxygenation. For example, the major mechanism of arterial hypoxemia in ALI/ARDS is intrapulmonary shunt (zero VA/Q ratios) induced by the presence of collapsed or flooded alveolar units, whereas in COPD the primary mechanism of hypoxemia is VA/Q mismatching. Effect of breathing oxygen on oxygenation In ALI/ARDS, as FIO2 increases, PaO2 increases as long as the amount of shunt is limited. The greater the degree of shunt, the less PaO2 increases. In contrast, in COPD, in which the prime mechanism of hypoxemia is VA/Q mismatching, the response to high FIO2 levels is broadly similar irrespective of disease severity. With moderate VA/Q imbalance PaO2 increases almost linearly as FIO2 is increased. In severely acute COPD the degree of very low VA/Q ratios resembles shunt; the increase in PaO2 in response to increasing FIO2 is only slightly limited, becoming less responsive to increases FIO2. Importantly, FIO2 can also alter VA/Q balance through two additional mechanisms: hypoxic pulmonary vasoconstriction (HPV) and reabsorption atelectasis (RA).One of the main means by which the normal lung adjusts to low regional VA is to induce vasoconstriction of the associated pulmonary vasculature to redirect perfusion away from nonventilated or under ventilated alveolar units. Thus HPV minimizes VA/Q inequality, limiting the decrease in PaO2 that would have occurred if such redistribution of blood flow had not occurred. One of the best VA/Q indicators of the presence of HPV, as measured by MIGET, is the behavior of the area with normal and low VA/Q ratios, reflected in the dispersion of pulmonary blood flow. In sequential measures one sees a significant increase in the latter VA/Q descriptor while breathing 100% O2. By contrast, shunt and the dispersion of alveolar ventilation that incorporates areas with normal and high VA/Q ratios remain unchanged during HPV release. Breathing 100% O2 (FIO2=1.0) can induce intrapulmonary shunt because lung units with low inspired VA/Q ratios, termed “critical” VA/Q ratios, can result in absent expired ventilation because all the inflated gas is absorbed. This results in alveolar denitrogenation, allowing complete gas resorption with atelectasis (RA) to developspontaneously [4]. These critical VA/Q units are dependent on the FIO2, increasing both their potential area of collapse and rate of collapse considerably as FIO2 approaches 1.0. Alternatively, these critical units may remain
open despite increasing FIO2 levels if functional residual capacity and tidal volume are increased, owing to alveolar interdependence. This is the rationale for using
positive end-expiratory pressure (PEEP) and larger tidal volumes in patients with ALI/ARDS to prevent RA. Both RA and HPV and can be observed, respectively, in the responses of patients with ALI/ARDS and COPD needing mechanical support who are given an FIO2 of 1.0 [5] (Fig. 1). Intrapulmonary shunt increases moderately
then remains stable for at least 30 min in ALI/ARDS patients given an FIO2 of 1.0. In contrast, in COPD patients the dispersion of pulmonary blood flow, one of the
most common VA/Q indicators in COPD, further increases to an FIO2 of 1.0 while the modest levels of intrapulmonary shunt remain unchanged, a response that strongly suggests HPV release. Both responses to pure O2 breathing are accompanied with increases in PaO2, which are much more prominent inpatients with COPD. The increase in intrapulmonary shunt in ALI/ARDS is likely due to RA. If cardiac output increases as part of the sympathetic response to arterial hypoxemia, one may also
see a parallel increase in mixed venous PO2 owing to increased O2 delivery. This can offset the increased shunt fraction minimizing the decrease in PaO2. The deleterious
effects of RA on pulmonary gas exchange may be enhanced
by the mechanical trigger imposed on peripheral airways by ventilator support. Indeed, the repeated opening and closing of distal airways and/or the overexpansion
of closed alveolar units with abnormally high shear stresses may result in moreinflammatory lung changes, aggravating the initial mechanical stress injury.
On the other hand, the changes observed in COPD during hyperoxia suggest that inhibition of HPV is the primary process. Interestingly, gas exchange abnormalities in both entities take place in the absence of measurable changes
in pulmonary hemodynamics, suggesting that regional blood flow redistribution can have relevant effects on gas exchange despite minimal changes in pulmonary arterial
pressure and blood flow. If VA were to decrease or dead space to increase, arterial
PCO2 (PaCO2) would increase. Hyperoxia-induced increases in PaCO2 in response to FIO2 1.0 breathing are more notable in ALI/ARDS than in COPD and can be
attributed almost completely to the parallel increases in dead space, with a marginal role of the Haldane effect (i.e., decreasing PaO2 increases PaCO2 off-loading from
Fig. 1 Index of oxygenation (PaO2/FIO2), intrapulmonary shunt (expressed as percentage of cardiac output), and dispersion of
pulmonary blood flow (log SDQ, dimensionless) while breathing 100% O2. In ALI/ARDS (open circles) both PaO2/FIO2 and log SDQ remain essentially unchanged while shunt increases significantly, indicating RA; note that after reinstatement of maintenance FIO2 shunt still remains increased. In COPD exacerbation (closed
squares) PaO2/FIO2 and log SDQ substantially increase while the very modest shunt unvaried, indicating HPV release (by permission from [5])
References
1. Glenny R, Wagner PD, Roca J, Rodriguez-Roisin R (2000) Gas exchange in health: rest, exercise, and aging. In: Roca J, Rodriguez-Roisin R, Wagner PD (eds) Pulmonary and peripheral gas exchange in health and
disease. Dekker, New York, pp 121– 148
2. Rodriguez-Roisin R, Wagner PD (1990) Clinical relevance of ventilation-perfusion
inequality determined by inert gas elimination. Eur Respir J 3:469–482
3. West JB (1977) State of the art:
Ventilation-perfusion relationships. Am Rev Respir Dis 116:919–943
4. Dantzker DR, Wagner PD, West JB (1975) Instability of lung units with low
VA/Q ratios during O2 breathing. J Appl
Physiol 38:886–895
5. Santos C, Ferrer M, Roca J, Torres A, Hernandez C, Rodriguez-Roisin R (2000) Pulmonary gas exchange response to oxygen breathing in acute lung injury. Am J Respir Crit Care Med 161:26–31
6. Mancini M, Zavala E, Mancebo J, Fernandez C, Barbera JA, Rossi A,
Roca J, Rodriguez-Roisin R (2001) Mechanisms of pulmonary gas exchange
improvement during a protective ventilatory strategy in acute respiratory distress syndrome. Am J Respir Crit Care Med 164:

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