• View in gallery

    Coefficient of determination (R2) and Cartesian axis plotting of various oxygenation indices evaluated as potential indicators of s/t against the corresponding s/t value in anesthetized healthy sheep (n = 6). Calculations were performed on the basis of measurements from 60 paired (simultaneously collected) arterial and mixed venous blood samples collected during administration of 5 different Fio2s (0.21, 0.40, 0.60, 0.80, and 1.00) via 1-lung and 2-lung mechanical ventilation. A—Fshunt. B—Pao2:Fio2. C—Pao2 – Pao2. D—(Pao2 – Pao2):Fio2. E—(Pao2 – Pao2):Pao2 F—Pao2:Pao2. The solid line represents linear regression analysis (Y = a + bX) of the dependent (Y) and independent (X) variables, where a is a constant and b is the slope.

  • View in gallery

    Bland-Altman plot depicting agreement between calculated Fshunt and s/t values determined via analysis of the same 60 paired arterial and mixed venous blood samples in Figure 1. The solid straight line represents the mean of differences, and dashed lines represent 95% limits of agreement (mean ± 1.96 SD).

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Use of the oxygen content–based index, Fshunt, as an indicator of pulmonary venous admixture at various inspired oxygen fractions in anesthetized sheep

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  • 1 Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19147.
  • | 2 Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19147.
  • | 3 New Bolton Center, Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348.
  • | 4 Division of Veterinary Surgery, Department of Emergencies and Organ Transplantation, University of Bari, 70121 Bari, Italy.
  • | 5 Division of Veterinary Surgery, Department of Emergencies and Organ Transplantation, University of Bari, 70121 Bari, Italy.
  • | 6 Division of Anesthesia and Intensive Care, Department of Emergencies and Organ Transplantation, University of Bari, 70121 Bari, Italy.
  • | 7 Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California-Davis, Davis, CA 95616.
  • | 8 Division of Veterinary Surgery, Department of Emergencies and Organ Transplantation, University of Bari, 70121 Bari, Italy.
  • | 9 Division of Veterinary Surgery, Department of Emergencies and Organ Transplantation, University of Bari, 70121 Bari, Italy.

Abstract

Objective—To evaluate the use of the oxygen content–based index, Fshunt, as an indicator of venous admixture (s/t) at various fractions of inspired oxygen (Fio2s) in anesthetized sheep undergoing Flung or 2-lung ventilation.

Animals—6 healthy adult female sheep.

Procedures—Sheep were anesthetized and administered 5 different Fio2s (0.21, 0.40, 0.60, 0.80, and 1.00) in random order during 2-lung mechanical ventilation. Arterial and mixed venous blood samples were obtained at each Fio2 after a 15-minute stabilization period. Vital capacity alveolar recruitment maneuvers were performed after blood collection. The previously used Fio2 sequence was reversed for sample collection during Flung ventilation. Blood samples were analyzed for arterial, pulmonary end-capillary, and mixed venous oxygen content and partial pressure and for hemoglobin concentration. Oxygen hemoglobin saturation, s/t, Fshunt, and oxygen tension–based indices (OTIs; including Pao2:Fio2, alveolar-arterial difference in partial pressure of oxygen [Pao2 – Pao2], [Pao2 – Pao2]:Fio2, [Pao2 – Pao2]:Pao2, and Pao2:Pao2) were calculated at each Fio2; associations were evaluated with linear regression analysis, concordance, and correlation tests. Intermethod agreement between s/t and Fshunt was tested via Bland-Altman analysis.

Results—Strong and significant associations and substantial agreement were detected between Fshunt and s/t. Relationships between OTIs and s/t varied, but overall correlations were weak.

Conclusions and Clinical Relevance—Whereas OTIs were generally poor indicators of s/t, Fshunt was a good indicator of s/t at various Fio2s, regardless of the magnitude of s/t, and could be potentially used as a surrogate for s/t measurements in healthy sheep.

Abstract

Objective—To evaluate the use of the oxygen content–based index, Fshunt, as an indicator of venous admixture (s/t) at various fractions of inspired oxygen (Fio2s) in anesthetized sheep undergoing Flung or 2-lung ventilation.

Animals—6 healthy adult female sheep.

Procedures—Sheep were anesthetized and administered 5 different Fio2s (0.21, 0.40, 0.60, 0.80, and 1.00) in random order during 2-lung mechanical ventilation. Arterial and mixed venous blood samples were obtained at each Fio2 after a 15-minute stabilization period. Vital capacity alveolar recruitment maneuvers were performed after blood collection. The previously used Fio2 sequence was reversed for sample collection during Flung ventilation. Blood samples were analyzed for arterial, pulmonary end-capillary, and mixed venous oxygen content and partial pressure and for hemoglobin concentration. Oxygen hemoglobin saturation, s/t, Fshunt, and oxygen tension–based indices (OTIs; including Pao2:Fio2, alveolar-arterial difference in partial pressure of oxygen [Pao2 – Pao2], [Pao2 – Pao2]:Fio2, [Pao2 – Pao2]:Pao2, and Pao2:Pao2) were calculated at each Fio2; associations were evaluated with linear regression analysis, concordance, and correlation tests. Intermethod agreement between s/t and Fshunt was tested via Bland-Altman analysis.

Results—Strong and significant associations and substantial agreement were detected between Fshunt and s/t. Relationships between OTIs and s/t varied, but overall correlations were weak.

Conclusions and Clinical Relevance—Whereas OTIs were generally poor indicators of s/t, Fshunt was a good indicator of s/t at various Fio2s, regardless of the magnitude of s/t, and could be potentially used as a surrogate for s/t measurements in healthy sheep.

The s/t is an OCI used to assess the degree to which venous blood is not fully oxygenated during its transit through the lung.1,2 Fung disease, atelectasis, and high Fio2s (> 0.7) can increase s/t.3 Calculation of s/t is useful in the evaluation of disease progress and treatment efficacy and in the assessment of gas exchange during the intraoperative period.4

The calculation of s/t requires determination of the Co2, which is measured in a blood sample obtained via a pulmonary arterial catheter.2 Alternatively less invasive surrogate measures have been proposed as indicators of s/t.1,4–9 In humans, 1 approach is to assume a value for Co2 on the basis of normal C(a – )o2 (3.5 mL/dL)5,10,11 with an OCI commonly referred to as the Fshunt.4 The Fshunt has been reported to provide reasonable estimates of s/t in human patients.4

Many of the other proposed indicators of s/t are OTIs, which are popular because they are easy to calculate. These include Pao2:Fio2, Pao2 – Pao2, (Pao2 – Pao2):Fio2, (Pao2 – Pao2):Pao2, and Pao2:Pao2.8 There is ongoing debate regarding the applicability and validity of these OTIs as substitutes of s/t, particularly when various Fio2s are administered.12

The purpose of the study reported here was to evaluate use of the OCI, Fshunt, as an indicator of s/t at various Fio2s in anesthetized sheep, in which the magnitude of s/t was varied by use of 1-lung and 2-lung mechanical ventilation. We hypothesized that, compared with OTIs, the Fshunt would provide a more reliable estimation of s/t under these conditions.

Materials and Methods

Animals and study design—Six healthy female Bergamasca sheep (median body weight, 45 kg [range, 39 to 52 kg]; median age, 21 months [range, 18 to 24 months]) were included in the study, which was designed as a prospective randomized crossover trial. The sheep were part of a larger study in which the pulmonary effects of various Fio2s were evaluated via CT techniques. Food was withheld from sheep for 24 hours prior to anesthesia, but water was available until 30 minutes before anesthetic induction. The study was approved by the Italian Ministry of Health's Ethical Committee.

Anesthetic protocol and monitoring—After clipping of hair and aseptic preparation of the ear surface, a 20-gauge over-the-needle cathetera was percutaneously placed in the middle auricular vein. Midazolamb (0.4 mg/kg) and buprenorphinec (10 μg/kg) were administered through the catheter, and anesthesia was induced with lidocained (2 mg/kg, IV) and propofole (3 to 5 mg/kg, IV). Sheep were intubated orally with an appropriately sized (internal diameter, 9 to 10 mm) cuffed endotracheal tube,f and lungs were ventilated (tidal volume, 10 to 12 mL/kg; inspiratory-to-expiratory ratio, 1:2; zero positive end-expiratory pressure) by use of a ventilator,g provided with an air mixer, in the volume-controlled mode. Respiratory rate was adjusted to maintain the partial pressure of end-tidal carbon dioxide between 35 and 45 mm Hg, monitored with a mainstream capnographh with the sensor placed between the endotracheal tube and the Y-piece of the breathing system.

Sheep were placed in left lateral recumbency, and anesthesia was maintained via IV infusion of propofol (0.4 to 0.5 mg/kg/min). Vecuroniumi (25 μg/kg, IV, once) was administered to facilitate mechanical ventilation. Lactated Ringer's solutionj (5 mL/kg/h, IV) was infused throughout the anesthetic procedure. Standard anesthesia monitors were used.

A Swan-Ganz catheterk (7 to 7.5F) was introduced into the right external jugular vein through an 8 to 9F introducer.l A nondistensible extension line filled with heparinized saline (0.9% NaCl) solution was connected to the distal port of the catheter and to a calibrated electronic transducer placed at the point of the shoulder (ie, prominence created by the greater tubercle of the humerus). Correct position of the catheter in the pulmonary artery was assessed via observation of pressure waveforms.m

Each sheep received 5 different Fio2s (0.21, 0.40, 0.60, 0.80, and 1.00) in randomized order (lottery method). Between Fio2s, a vital capacity (recruitment) maneuver was performed, maintaining an airway pressure of 40 cm H2O for 20 seconds.13 After each change in Fio2, a 15-minute stabilization period was allowed. The recruitment maneuver was performed to minimize the effects of previously induced atelectasis as a result of the changes in Fio2. After the Fio2 sequence and related measurements were completed, the endotracheal tube was removed and a 55-cm-long rubber-silicone cuffed tubef was placed into the right main bronchus (nondependent side) to ventilate only 1 lung and increase the degree of s/t. Mechanical ventilation of the nondependent lung was initiated with the same settings. Correct tube placement into the right main bronchus and consequent collapse of the dependent lung were verified with CT scan.n The previously performed Fio2 administration sequence was reversed for this part of the study

Blood sample collection and analysis—After skin area preparation and disinfection, a 20-gauge over-the-needle catheter was placed in a median auricular artery percutaneously.a Arterial and mixed venous blood samples were anaerobically collected simultaneously from the median auricular artery catheter and the distal pulmonary artery port of the Swan-Ganz catheter, respectively, after the stabilization period for each Fio2. Blood samples were immediately analyzed with a blood gas analyzero that uses reflectance photometry technology and was calibrated prior to each experiment according to the manufacturer's instructions. The Pao2, Po2, Paco2, hemoglobin concentration, and pH were measured for each sample. Calculations of Sao2 provided by the analyzer were disregarded because of a lack of validation for sheep blood samples. A validated mathematical model for sheep was used to calculate the p50 and Sao2 from the Pao2, Paco2, and arterial pH and to determine the So2 from the Po2, Pco2, and mixed venous pH.14,15 Blood gases were corrected to the core body temperature of the sheep measured via the Swan-Ganz thermistor.

Calculations—Venous admixture was calculated as follows8:

article image

The Cc′o2, Cao2, and Co2 were calculated as follows16:

article image

where Hb is mixed venous hemoglobin concentration (g/dL), 1.31 is the oxygen-carrying capacity of hemoglobin (mL/g), Sc′o2 is the pulmonary end-capillary oxygen saturation, 0.0031 is the solubility coefficient of oxygen in ovine plasma, and Pc′o2 is pulmonary end-capillary partial pressure of oxygen (mm Hg).16

Pulmonary end-capillary partial pressure of oxygen was assumed to be equal to Pao2 and was calculated as follows:

article image

where Pb is barometric pressure (mm Hg), PH2O is vapor pressure of water (mm Hg), and 1.2 is 1/respiratory quotient determined for sheep.16 Actual barometric pressure recorded by the analyzer during each sample collection was used for calculations. Vapor pressure of water was corrected to the core body temperature of the sheep at the time of blood collection. For Pao2 > 100 mm Hg, pulmonary end-capillary oxygen saturation was assumed to be 100% (ie, 1); for Pao2 ≤ 100 mm Hg, pulmonary end-capillary oxygen saturation was calculated from the actual Pao2 via the same method.14,15

Fshunt was calculated as follows:

article image

where 3.5 mL/dL is a fixed value of C(a – )o2 in mechanically ventilated humans.10 Calculated OTIs in this study included Pao2:Fio2, Pao2 – Pao2, (Pao2 – Pao2):Fio2, (Pao2 – Pao2):Pao2, and Pao2:Pao2.4,11 At the end of the experiment, each sheep was euthanized under anesthesia by means of a rapid IV bolus of propofole (10 mg/kg) followed by a saturated solution of potassium chloridep IV.

Statistical analysis—The relationship between s/t (used as gold standard method) and the corresponding calculated OTI and OCI at various Fio2s was evaluated with linear regression analysis according to the following equation:

article image

where a is a constant, b is the slope, X is the explanatory variable (ie, s/t), and Y is the dependent variable (ie, OTI or OCI). Goodness of fit for each calculated formula was evaluated by means of the coefficient of determination (R2). The null hypothesis that the slope was equal to 0 was tested with Student t tests, and significance was set at P < 0.05. The relationship between s/t and OTI at each administered Fio2 was evaluated with R2 tests.

The reliability of each index to estimate the s/t at variable Fio2s was evaluated via the Lin concordance correlation coefficient (ρ).17 To reconcile for the use of repeated measurements, each sheep was randomly sampled once and the obtained value was used to derive an estimate of ρ. This analysis procedure was repeated by the software 200 times until the mean concordance of all the random samples generated a consistent estimate that would remain unchanged despite increases in sample size.18 Mean values for all data from the random sampling were calculated to produce estimates of the final concordance correlation coefficients, their SDs, and minimum and maximum values.

Agreement between s/t and Fshunt was analyzed with the Bland-Altman test modified for use with multiple observations per animal.19 Bias was calculated from the differences between each pair of observations plotted against their mean ([Fshunt – s/t]/n). The upper and lower limits of agreement were calculated as bias ± 1.96 × SD (ie, 1.96 SD of [Fshunt – s/t]) and defined the range in which 95% of the differences between 2 techniques were expected to lie.

Results

Sixty paired arterial and mixed venous blood samples were obtained and analyzed, and results were used to calculate the OTI and OCI estimates of s/t at various Fio2s and under different ventilation conditions (Table 1). Overall, mean ± SD values for s/t, Fshunt, Pao2:Fio2, Pao2 – Pao2, (Pao2 – Pao2):Fio2, (Pao2 – Pao2):Pao2, and Pao2:Pao2 were 36.73 ± 14.17%, 33.40 ± 11.09%, 250.14 ± 70.36 mm Hg, 278.44 ± 104.21 mm Hg, 332.94 ± 114.24 mm Hg, 1.97 ± 1.25, and 0.44 ± 0.15, respectively. Mean mixed venous hemoglobin concentration was 8.367 ± 1.82 g/dL.

Table 1—

Mean ± SD s/t and calculated oxygenation indices associated with various Fio2s during 1- and 2-lung ventilation in anesthetized sheep (n = 6).

VentilationVariableFio2
0.210.400.600.801.00All*
2-lungs/t (%)30.8 ± 16.718.8 ± 11.717.9 ± 8.319.8 ± 7.421.5 ± 5.521.8 ± 9.9
Fshunt (%)29.9 ± 12.517.5 ± 9.716.2 ± 5.818.0 ± 5.718.6 ± 5.021.4 ± 10.5
Pao2:Fio2 (mm Hg)323.0 ± 48.3317.0 ± 89.6316.6 ± 87.0338.9 ± 99.8387.1 ± 94.2336.6 ± 84.1
Pao2 − Pao2 (mm Hg)31.5 ± 8.3108.6 ± 34.3183.7 ± 53.9247.3 ± 81272.2 ± 91.4168.7 ± 107.2
(Pao2 − Pao2):Fio2 (mm Hg)150.3 ± 40.4271.6 ± 85.97306.2 ± 89.9309.1 ± 102.0272.2 ± 91.4261.9 ± 98.3
(Pao2 − Pao2):Pao20.5 ± 0.21.0 ± 0.61.1 ± 0.81.1 ± 0.80.8 ± 0.50.9 ± 0.6
Pao2:Pao20.7 ± 0.10.5 ± 0.10.5 ± 0.10.5 ± 0.10.6 ± 0.10.6 ± 0.1
1-lungs/t (%)60.5 ± 11.858.6 ± 11.044.0 ± 21.042.2 ± 11.042.4 ± 14.549.5 ± 13.9
Fshunt (%)53.4 ± 6.150.2 ± 7.540.1 ± 15.140.0 ± 7.138.5 ± 7.744.4 ± 8.7
Pao2:Fio2 (mm Hg)230.9 ± 38.7163.3 ± 22.0159.1 ± 64.3129.7 ± 39.4135.3 ± 55.8163.7 ± 56.6
Pao2 − Pao2 (mm Hg)38.6 ± 11.8156.0 ± 17.5265.9 ± 37.0395.2 ± 42.6508.5 ± 59.5272.9 ± 173.2
(Pao2 − Pao2):Fio2 (mm Hg)184.2 ± 51.5390 ± 43.9443.3 ± 61.7494.3 ± 61.7508.6 ± 59.6404.0 ± 130.1
(Pao2 − Pao2):Pao20.8 ± 0.32.4 ± 0.63.3 ± 1.64.1 ± 1.44.4 ± 2.13.0 ± 1.9
Pao2:Pao20.6 ± 0.10.3 ± 0.10.3 ± 0.10.2 ± 0.10.21 ± 0.10.3 ± 0.1

Each sheep was administered 5 different Fio2s in randomized order during 2-lung mechanical ventilation. Arterial and mixed venous blood samples were obtained at each Fio2 after a 15-minute stabilization period; 60 paired (simultaneously collected) samples were analyzed. Vital capacity alveolar recruitment maneuvers were performed after each blood sample collection. The previously used Fio2 sequence was reversed for sample collection during 1-lung ventilation.

Overall mean value for all Fio2s.

The linear regression relationships and corresponding R2 between results of the evaluated indices and the respective s/t values obtained at various Fio2s were determined (Figure 1). There was a significant linear relationship between s/t and all OTIs except for Pao2 – Pao2. However, further R2 analysis revealed a weak systematic relationship (R2 = 0.01 to 0.40) between s/t and the various OTIs except for Pao2:Fio2, which evidenced a moderate relationship (R2 = 0.40 to 0.70). Lin concordance tests did not detect correlation between s/t and any of the OTIs evaluated (Table 2).

Table 2—

Mean ± SD and range of Lin concordance correlation coefficient (ρ) values obtained from comparisons between calculated oxygenation indices and respective s/t values for 60 paired arterial and mixed venous blood samples collected from anesthetized sheep (n = 6) at various Fio2s during 1- and 2-lung ventilation.

IndexMean ± SDRange
F-shunt0.910 ± 0.0600.550 to 0.980
Pao2:Fio2−0.470 ± 0.020−0.130 to 0.020
Pao2 − Pao2−0.030 ± 0.040−0.210 to 0.100
(Pao2 − Pao2):Fio20.013 ± 0.016−0.038 to 0.063
(Pao2 − Pao2):Pao20.023 ± 0.018−0.004 to 0.073
Pao2:Pao2−0.002 ± 0.001−0.070 to 0.007

To account for repeated measurements, each sheep was randomly sampled once and the obtained value was used to derive an estimate of ρ; the procedure was repeated 200 times by computer software until the mean concordance of all the random samples generated a consistent estimate that would remain unchanged despite increases in sample size.

Figure 1—
Figure 1—

Coefficient of determination (R2) and Cartesian axis plotting of various oxygenation indices evaluated as potential indicators of s/t against the corresponding s/t value in anesthetized healthy sheep (n = 6). Calculations were performed on the basis of measurements from 60 paired (simultaneously collected) arterial and mixed venous blood samples collected during administration of 5 different Fio2s (0.21, 0.40, 0.60, 0.80, and 1.00) via 1-lung and 2-lung mechanical ventilation. A—Fshunt. B—Pao2:Fio2. C—Pao2 – Pao2. D—(Pao2 – Pao2):Fio2. E—(Pao2 – Pao2):Pao2 F—Pao2:Pao2. The solid line represents linear regression analysis (Y = a + bX) of the dependent (Y) and independent (X) variables, where a is a constant and b is the slope.

Citation: American Journal of Veterinary Research 73, 12; 10.2460/ajvr.73.12.2013

A significant linear relationship and a very strong systematic relationship (R2 = 0.90 to 1.00) as well as a ρ > 0.9 were detected between s/t and Fshunt (Table 2; Figure 1). Results of Bland-Altman analysis revealed a strong agreement between these 2 tests, with 57 of 60 (ie, 95%) of the pairwise measurement differences falling between the upper and lower limits of agreement (Figure 2).

Figure 2—
Figure 2—

Bland-Altman plot depicting agreement between calculated Fshunt and s/t values determined via analysis of the same 60 paired arterial and mixed venous blood samples in Figure 1. The solid straight line represents the mean of differences, and dashed lines represent 95% limits of agreement (mean ± 1.96 SD).

Citation: American Journal of Veterinary Research 73, 12; 10.2460/ajvr.73.12.2013

The systematic relationship between each calculated OTI and the respective s/t measurement was considered either strong or very strong (R2 = 0.70 to 0.90) when compared at a constant Fio2, except for Pao2 – Pao2 and (Pao2 – Pao2):Fio2 at Fio2 of 0.21, in which the relationship was considered weak, and (Pao2 – Pao2):Pao2 at Fio2 of 0.21, in which it was considered moderate (Table 3). Further evaluation of these indices in relation to the s/t at Fio2 of 0.21 revealed outlier data points, with a s/t of 59.47% and corresponding Pao2 – Pao2, (Pao2 – Pao2):Fio2, and (Pao2 – Pao2):Pao2 values of 16.1 mm Hg, 77.2 mm Hg, and 0.40, respectively. The related Paco2 for these indices was 77 mm Hg. Post hoc evaluation of the relationship between s/t and Pao2 – Pao2, (Pao2 – Pao2):Fio2, and (Pao2 – Pao2):Pao2 at Fio2 of 0.21, excluding these outliers, indicated an R2 of 0.86 to 0.88.

Table 3—

Coefficients of determination (r2) acquired from analysis of the relationship between calculated OTIs and respective s/t values for 60 paired arterial and mixed venous blood samples collected from anesthetized sheep (n = 6) at various Fio2s during 1- and 2-lung ventilation.

Fio2OTI
Pao2:Fio2Pao2 − Pao2(Pao2 − Pao2):Fio2(Pao2 − Pao2):Pao2Pao2:Pao2
0.210.870.390.390.690.70
0.400.860.710.710.850.84
0.600.790.700.700.890.78
0.800.850.850.850.950.86
1.000.750.700.770.950.76

P < 0.01 for all values.

Calculation of the (overall) actual C(a – )O2 resulted in a mean value of 3.13 ± 0.81 mL/dL; mild hypercapnia was also detected (Paco2, 48.8 ± 11.2 mm Hg; reference value, 39.0 ± 1.5 mm Hg).20 Mean airway pressures were 16.8 ± 3.75 cm H2O and 26.3 ± 6.7 cm H2O during 2- and 1-lung ventilation, respectively.

Discussion

In the present study, Fshunt was strongly correlated with s/t, with a high ρ value (mean, > 0.9) and very good limits of agreement over a wide range of Fio2s and s/t values, suggesting that this index can be used as a substitute for s/t calculations in sheep. All OTIs evaluated had very low ρ values with s/t, suggesting that these are not adequate for prediction of s/t in this species.

Previous studies21 in humans evaluated the relationship between s/t and other indices via Pearson correlation coefficient tests. Although the test can detect linear relationships between 2 variables and predict the changes of the dependent variable according to the changes of the independent variable, it does not necessarily determine agreement between methods and may be inadequate when trying to assess the reliability of use of one method to predict results for another.22 To better evaluate the relationship between the different indices in our study, the data were further analyzed with Lin concordance correlation tests and, for Fshunt, with Bland-Altman tests.17,19 The use of the Lin concordance correlation coefficient has been proposed as a more robust test to estimate reliability between 2 methods.23 This test evaluates how far the line of best fit is from the 45° line of identity through the origin.17 When every point of comparison lies on the 45° line, the relationship is considered to have a perfect concordance and a value of 1. The absence of any concordance between 2 variables has a value of 0. In the present study, the Fshunt calculation had a concordance of 0.91 and was the only index that reliably predicted s/t.

The Fshunt calculation assumes a fixed value for C(a – )o2 of 3.5 mL/dL, which was derived from a study10 in human patients. In that study,10 the value for C(a – )o2 was 3.5 ± 0.8 mL/dL, and it was noted that the Fshunt calculation overestimated s/t when an individual's actual C(a – )o2 value was < 3.5 mL/dL (ie, 2.6 mL/dL) and underestimated s/t when the actual C(a – )o2 value was > 3.5 mL/dL (ie, 5 mL/dL). Overall, Fshunt underestimated s/t in sheep only by 3.4% (mean difference) in the present study. The reason Fshunt compared so favorably with s/t in the present study is likely that there was little difference between the estimated C(a – )o2 of 3.5 mL/dL and the actual value of 3.1 mL/dL measured in the anesthetized sheep. Differences in methodology, cardiovascular status of the studied individuals, sampling site, or some combination of these may account for the slightly dissimilar results between the previous report10 and the study reported here.

Agreement between 2 methods evaluated via the graphic method proposed by Bland and Altman24 assumes that 95% of the differences between 2 methods plotted against the mean value for both methods for each subject lie within 1.96 SD of the mean difference between methods. In evaluation of Fshunt, the 95% limits of agreement (–8.3 to 15.1) contained 95% of the data points, supporting the hypothesis that Fshunt is a good alternative to s/t measurements. On the other hand, the Bland-Altman approach consists of a comparison of 2 limits with a clinically acceptable difference between the 2 methods, and it could be argued that limits of agreement between −8.3% and 15.1% may or may not be clinically acceptable. However, it has been proposed that limits of agreement within 30% of the reference standard are adequate for acceptance of new cardiac output measurement technologies.25 Interestingly, visual inspection of the Bland-Altman plots revealed that the differences of the means of s/t-Fshunt pairs became larger and were positive for s/t > 50%. For s/t values < 50%, these differences remained between −5.7% and 8.6%. However, in our experience, a s/t > 50% is rarely found in clinical situations.

The relationship between the Pao2:Fio2 and s/t found in the present study had the highest R2 value among all evaluated OTIs; approximately half of the variance (ie, 51%) in s/t was shared with Pao2:Fio2. These results are similar to findings reported in humans.4 Nonetheless, the concordance correlation coefficient for these 2 methods was low (mean ρ, −0.47) suggesting that Pao2:Fio2 is an unreliable surrogate for s/t. Only at a constant Fio2 could a high proportion (ie, 75% to 87%) of the changes observed in Pao2:Fio2 be explained by changes in s/t. The Pao2:Fio2 does not account for changes in Paco2, and this factor becomes progressively less important (a proportionately smaller contribution to Pao2 and therefore Pao2) as the Fio2 increases.26 In this study, the Pao2:Fio2 calculations were performed in mechanically ventilated subjects with only mild hypercapnia (mean Paco2, 48.8 mm Hg).

The Pao2 – Pao2 does account for changes in Fio2 and Paco2 as well as changes in barometric pressure and body temperature.27 Unfortunately, Pao2 – Pao2 changes substantially with changes in inspired Fio2. With Fio2 of 0.21 in clinically normal patients of many species, the usual Pao2 – Pao2 is cited to be in the range of 10 to 15 mm Hg, increasing to nearly 100 mm Hg when Fio2 reaches 1.28 This may be attributable to the greater time that it takes to equilibrate alveolar and pulmonary end-capillary Po2 (creating a relative diffusion defect) or to Po2 losses (because of the very large partial pressure gradients) during collection, storage, and analysis of blood samples; alternatively, this could be attributable to the formula itself, which calculates a difference (subtraction) instead of a ratio. If this is not taken into account when evaluating Pao2 – Pao2, substantial misconceptions regarding the patient's lung function could result. The Pao2 – Pao2 had the weakest correlation with s/t among all of the indices studied, and this concurs with results reported4 for humans. The Fio2 effect on this variable could, perhaps, be corrected by dividing the Pao2 – Pao2 by the Fio2. Such a calculation would be expected to be Fio2 and Pco2 insensitive, yet retain its ability to track changes in underlying lung function. Unfortunately, expected ranges for OTIs have not been established at different Fio2s or under different lung function conditions. For instance, in subjects with normal lung function, a (Pao2 – Pao2):Fio2 of 50 to 100 mm Hg should be expected for Pao2 – Pao2 of 10 and 100 mm Hg at Fio2 of 0.21 and 1.0, respectively. In a study29 in which extravascular lung water was suspected to induce lung atelectasis and impair oxygen uptake in human patients recovering from coronary bypass surgery, no relationship could be established between the volume of extravascular lung water and the (Pao2 – Pao2):Fio2. Twenty-four hours after surgery, the reported (Pao2 – Pao2):Fio2 in patients of that study29 ranged from 36 to 320 mm Hg, corresponding to Pao2 – Pao2 values between 10 and 91 mm Hg and Fio2s of 0.28 to 0.40. In the present study, the low degree of concordance (ρ = 0.013) and correlation (R2 = 0.13) of this OTI with s/t measurements suggests its inaccuracy in predicting s/t at various Fio2s.

Calculation of Pao2:Pao2 and Pao2 – Pao2 at various Fio2s revealed an approximately 25% overlap in variance and very low degrees of concordance (ρ = −0.002 and −0.030, respectively) with the respective s/t measurements, suggesting they may not accurately estimate s/t if the Fio2 is not kept constant. Similar to (Pao2 – Pao2):Fio2, (Pao2 – Pao2):Pao2 is used in an attempt to correct the Pao2 – Pao2 for variations in Fio2 and, consequently, in Pao2. At various Fio2s, values for (Pao2 – Pao2):Pao2 were clustered at < 1.5 in the present study when s/ts were < 20%. However, (Pao2 – Pao2):Pao2 had a larger range (ie, between 0.3 and 7) when s/ts were between 20% and 80%. Although this index had modest correlation (R2 = 0.29) with s/t in the present study, it had poor concordance and cannot be recommended as an accurate surrogate marker for s/t.

When each Fio2 was analyzed separately, the correlations between each OTI and s/t were very strong. It is clear that these indices are profoundly impacted by variations in Fio2, as has been reported,4,30 limiting their use in the clinical management of patients in which Fio2s are frequently changed. The Pao2 – Pao2 and its derived indices, (Pao2 – Pao2):Fio2 and (Pao2 – Pao2):Pao2, had low to moderate correlation (R2 = 0.39 to 0.69) with s/t when the Fio2 was set at 0.21. It has been reported that OTIs used with the alveolar gas equation may be unreliable indicators of abnormal gas exchange in patients with alveolar hypoxia secondary to hypoventilation when breathing room air.26 Indeed, all OTIs in the present study were strongly correlated with s/t when the outlier values corresponding to pairs of s/t − (Pao2 – Pao2), s/t-(Pao2 – Pao2):Fio2, and s/t-(Pao2 – Pao2):Pao2 calculations in association with high Paco2 (ie, 77 mm Hg) were excluded post hoc.

A potential limitation of the present study was that Sao2 was calculated and not measured. The presence of methemoglobin and carboxyhemoglobin can lead to overestimations of calculated Sao2. All sheep in the study were healthy and kept in well-ventilated areas; thus, the likelihood of the presence of these hemoglobin species was small. Mixed venous hemoglobin concentration values were used for all formulas to minimize the reading bias of blood gas analyzers based on reflectance photometry technology when using arterial samples.31 The formula used to calculate hemoglobin saturation was derived in a study of Dorset sheep that have a p50 of 44.1 mm Hg; Dorset sheep are of the lowland variety,14 as were the sheep of the present study. The results of our study are similar to those reported in humans,4,30 and it seems that data from human studies32,33 may be applicable to sheep because of similarities in lung function and anatomy.

Although not within the scope of the present study, it was interesting to note that the magnitude of s/t seemed to be greater at an Fio2 of 0.21 than at an Fio2 of 1.0. Confusingly, results of recent studies34,35 have advocated for the reduction of Fio2 to minimize absorption atelectasis and, consequently, s/t. Indeed, controversial reports36 exist suggesting that s/t may increase, decrease, or remain unchanged in response to oxygen. Reasons for these discrepancies may include the degree of lung function impairment, changes in cardiac output, ventilation strategy (eg, recruitment maneuvers), or shunt effect of hypoventilated and hypoxic alveoli, among others.37–39 Unfortunately, these hypotheses cannot be evaluated with the results of the present study and merit further investigation. On the other hand, it has been postulated that the traditional formula used to calculate s/t may actually overestimate this variable at low Fio2s.40 It has been proposed that the use of inert gas techniques (eg, sulfur hexafluoride retention) may be more reliable for estimation of true right-to-left shunts.40

In the present study, Fshunt was superior to all evaluated OTIs for prediction of s/t in anesthetized sheep with different degrees of lung function (ie, 1-lung or 2-lung ventilation) over a wide range of Fio2s. Fshunt proved to be easy to calculate and could be integrated in blood gas calculations for measurements in sheep under routine conditions and in research settings. Further studies are needed to evaluate the use of this index in other animal species and in clinical situations in which oxygen extraction may be abnormal.

ABBREVIATIONS

C(a – )o2

Arterial-to-mixed venous oxygen content difference

Cao2

Arterial oxygen content

Cc′o2

Pulmonary end-capillary oxygen content

Co2

Mixed venous oxygen content

Fio2

Inspired fraction of oxygen

OCI

Oxygen content–based index

OTI

Oxygen tension–based index

p50

Partial pressure of oxygen at which hemoglobin becomes 50% saturated with oxygen

Pao2

Alveolar partial pressure of oxygen

Pao2 – Pao2

Alveolar-arterial difference in partial pressure of oxygen

Po2

Mixed venous partial pressure of oxygen

s/t

Venous admixture

Sao2

Arterial hemoglobin oxygen saturation

So2

Mixed venous hemoglobin oxygen saturation

a.

Delta Vet, Delta Med Srl, Viadana, MN, Italy.

b.

Midazolam, Italian Biochemical Institute, Aprilia, Italy.

c.

Temgesic, Reckitt Benckiser Healthcare, Schering-Plough, Walton, Milton Keynes, Buckinghamshire, England.

d.

Lidocaine 2%, Fort Dodge Animal Health, Fort Dodge, Iowa.

e.

Propovet, Hospira Inc, Chicago, Ill.

f.

SurgiVet, Smiths Medical Inc, Waukesha, Wis.

g.

Maquet Servo-i, Maquet Critical Care, Solna, Sweden.

h.

SC 6002XL, Siemens, Boston, Mass.

i.

Norcuron, Organon Laboratories, Hoddesdon, Hertfordshire, England.

j.

Ringer Lattato, Panpharma, Italy.

k.

Swan-Ganz, Edwards Lifesciences, Irvine, Calif.

l.

Arrow International Inc, Reading, Pa.

m.

Spacelabs Medical, Redmond, Wash.

n.

GE ProSpeed SX, General Electric, Schenectady, NY.

o.

IDEXX VetStat, IDEXX Laboratories Inc, Westbrook, Me.

p.

Potassium chloride, Sigma-Aldrich Chemie, Buchs, Switzerland.

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Contributor Notes

Funded by an internal grant of the University of Bari, Italy.

Presented in abstract form at the Association of Veterinary Anaesthesiologists' Spring Meeting, Bari, Italy, April 2011.

The authors thank Dr. Diana Bull for support in the mathematical aspects of the study.

Address correspondence to Dr. Larenza (larenza@vet.upenn.edu).