ORIGINAL ARTICLE
A novel continuous capnodynamic method for cardiac output assessment in a porcine model of lung lavage €llsjo € Sander1,2, M. Hallba €ck3, F. Suarez Sipmann4,5, M. Wallin2,3, A. Oldner1,2 and H. Bjo € rne1,2 C. Ha 1
Department of Anaesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital, Solna, Sweden Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 3 Maquet Critical Care AB, Solna, Sweden 4 Department of Surgical Sciences, Section of Anaesthesiology and Critical Care, Hedenstierna’s Laboratory, Uppsala University, Uppsala, Sweden 5 CIBERES, CIBER de enfermedades respiratorias, Instituto Carlos III, Madrid, Spain 2
Correspondence € Sander, Department of C. H€allsjo Anaesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital, Solna, Stockholm, Sweden E-mail: [email protected] Funding This project is a collaboration between Karolinska Institutet and Maquet Critical Care AB. The work was supported by grants from Maquet Critical Care AB and the regional agreement on medical training and research ALF between Stockholm County Council and the Karolinska Institutet. Conflicts of interest € Sander has received an Caroline H€allsjo unrestricted grant for research from Maquet Critical Care AB (MCC) MCC Fernando Suarez Sipmann performs consultant activities for MCC. Magnus Hallb€ack is employed at MCC. Mats Wallin is employed at MCC. Anders Oldner declares no conflict of interest. H akan €rne declares no conflict of interest. Bjo Submitted 4 March 2015; accepted 20 April 2015; submission 26 January 2015. Citation € Sander C, Hallb€ack M, Suarez Sipmann H€allsjo €rne H. A novel F, Wallin M, Oldner A, Bjo continuous capnodynamic method for cardiac output assessment in a porcine model of lung lavage. Acta Anaesthesiologica Scandinavica 2015
Background: We have evaluated a new method for continuous monitoring of effective pulmonary blood flow (COEPBF), i.e. cardiac output (CO) minus intra-pulmonary shunt, during mechanical ventilation. The method has shown good trending ability during severe hemodynamic challenges in a porcine model with intact lungs. In this study, we further evaluate the COEPBF method in a model of lung lavage. Methods: COEPBF was compared to a reference method for CO during hemodynamic and PEEP alterations, 5 and 12 cmH2O, before and after repeated lung lavages in 10 anaesthetised pigs. Bland–Altman, four-quadrant and polar plot methodologies were used to determine agreement and trending ability. Results: After lung lavage at PEEP 5 cmH2O, the ratio of arterial oxygen partial pressure related to inspired fraction of oxygen significantly decreased. The mean difference (limits of agreement) between methods changed from 0.2 (1.1 to 1.5) to 0.9 (3.6 to 1.9) l/min and percentage error increased from 34% to 70%. Trending ability remained good according to the four-quadrant plot (concordance rate 94%), whereas mean angular bias increased from 4° to 16° when using the polar plot methodology. Conclusion: Both agreement and precision of COEPBF were impaired in relation to CO when the shunt fraction was increased after lavage at PEEP 5 cmH2O. However, trending ability remained good as assessed by the four-quadrant plot, whereas the mean polar angle, calculated by the polar plot, was wide.
doi: 10.1111/aas.12559
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031
1022
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
Editorial comment: what this article tells us
Effective pulmonary blood flow could be assessed continuously by a capnodynamic method. In a porcine model with intact lungs bias was low and trending abilities good. When shunt fractions increased after lung lavage both the agreement and precision was impaired. However, trending ability assessed by the four-quadrant plot methodology remained high.
Goal-directed hemodynamic optimisation improves outcome in high-risk surgical patients.1–3 A prerequisite for a successful protocol is reliable cardiac output (CO) monitoring. Despite this notion it is not widely used in this setting.4 The most accurate monitors, such as the thermo dilution-based pulmonary artery catheter (PAC) and calibrated pulse-contour analysis methods, are invasive and tend to be complicated to use.5,6 Less invasive methods, considered user-friendly, are not as reliable when the circulation is unstable.7,8 We have recently evaluated a new capnodynamic method continuously measuring effective pulmonary blood flow (COEPBF). This method showed low bias, good trending abilities and has the prerequisite for a short response time in a variety of hemodynamic challenges. In a previous study from our group, COEPBF performed equally to the PAC.9 This novel method is based on the non-invasive analysis of carbon dioxide elimination, and thus dead space and shunt fraction can affect its performance. Pulmonary pathology with subsequent disturbances in gas exchange, an entity frequently seen in critically ill patients, is likely to influence the correspondence of COEPBF and CO. The aim of this study was to evaluate this novel capnodynamic method in a model of lung injury induced by repeated lavages in a porcine model during positive end-expiratory pressure (PEEP) alterations in a wide range of hemodynamic challenges.
Anaesthesia and surgical preparation The procedure has been described previously in detail.9 Briefly, 10 pigs with mean weight 35 kg (30–40 kg) were anaesthetised and mechanically ventilated in a volume-controlled mode with a tidal volume of 10 ml/kg, I:E 1:2, respiratory rate of 25–30 aiming at a PaCO2 of approximately 40 mmHg and a FiO2 of 1.0 (Servo-i; Maquet, Solna, Sweden). A PAC was inserted via the internal jugular vein for sampling of mixed venous blood gases. The femoral vein was catheterised with an 8 F Fogarty occlusion catheter for later reduction in venous return. A left-sided thoracotomy was performed and an 18 or 20 mm ultrasonic flow probe (T 401; Transonic system Inc., Ithaca NY, USA) was positioned around the pulmonary trunk for continuous CO reference measurement (COTS). The chest cavity was then closed and the animal repositioned into the supine position. If there were signs of hypovolaemia (significant tachycardia and/or hypotension), a colloid was administered intravenously. Pressure readings were sampled into a data acquisition system (version 3.2.7; Acknowledge, BioPac Systems, Santa Barbara, CA, USA). Lung lavage After the hemodynamic interventions were accomplished at PEEP 5 and 12 cmH2O in healthy lung conditions, repeated lung lavages with 37° isotonic saline (30 ml/kg) were performed at PEEP 5 cmH2O. The procedure was stopped when arterial oxygen tension (PaO2) reached below 75 mmHg at FiO2 1.0 (P/F ratio < 75).
Material and methods The study was performed at the Hedenstierna’s Laboratory in Uppsala, Sweden with approval from the Animal Research Ethical Committee of Uppsala University C171/11 Sweden.
Calculation of effective pulmonary blood flow The mathematical algorithm is based on the assumptions that effective pulmonary blood
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1023
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
reduced to 0.13 (0.7–0.23) (P = 0.004) indicating a restored lung function. Generally, the shunt fraction was dependent of CO, decreasing with reduced CO and increasing with higher CO, regardless of the degree of lung injury (Table 1). Dead space according to Bohr increased during preload reduction at both PEEP levels: 0.35 (0.30– 0.39) to 0.44 (0.37–0.57) P = 0.008 and 0.39 (0.37– 0.43) to 0.44 (0.42–0.48) P = 0.008) at 5 and 12 cmH2O respectively but remained unchanged in response to lavage, 0.35 (0.30–0.39) and 0.36 (0.32–0.41) P = 0.2 respectively (Table 1).
A
B
COEPBF before and after lung lavage at PEEP 5 cmH2O Accuracy and precision Lung lavage influenced the agreement between the methods. Before lavage, COEPBF showed a bias of 0.2 (LoA 1.1 to 1.5) l/min. (95% confidence intervals of LOA (CI LoA) 1.5 to 0.9 and 1.3– 1.9) and a PE of 34%, whereas after lavage, COEPBF underestimated COTS with a bias of 0.9 (LoA 3.6 to 1.9) l/min (CI LoA 4.5 to 3.1 and 1.4–2.8) and a PE of 70% (Fig. 2A and B). Trending ability The correlation between the induced changes in CO was high between COEPBF and COTS both before (r 0.90 P < 0.0001) and after induction of lung injury (r 0.85 P < 0.0001). Trending ability assessed by four-quadrant plot methodology, remained at a concordance rate of 94% both before and after lung lavage (Fig. 3). When the same paired delta values were analysed by the polar plot methodology, trending ability before lavage was good with a concordance rate of 100% and an angular bias of 4.0° (95% CI 2.4° to 10.5°) (Fig. 4A). However, after lavage concordance rate decreased to 89% and angular bias was 16.4° (95% CI 23.3° to 9.5 °) (Fig. 4B). COEPBF before and after lung lavage at PEEP 12 cmH2O Accuracy, precision and trending ability When PEEP was altered from 5 to 12 cmH2O before lavage, a paradoxical raise in COEPBF
Fig. 2. (A) Displays a Bland Altman plot of 45 paired cardiac output values obtained by the capnodynamic (COEPBF) and the reference method for cardiac output (COTS) before lung lavage at PEEP 5 cmH2O. Values were obtained at baseline (BL), cava occlusion, BL, dobutamine infusion and BL. N = 9. (B) Displays a Bland Altman plot of 36 paired cardiac output values obtained by the capnodynamic (COEPBF) and the reference method for cardiac output (COTS) at PEEP 5 cmH2O after lung lavage was performed. Values were obtained at BL, cava occlusion, BL and dobutamine infusion. N = 9. The central dotted line represents the mean difference (bias) and the peripheral dotted lines limits of agreement (LoA) [bias (1.96) SD]. The blue dotted lines around LoA displays the 95% confidence intervals of LoA.
was detected (Fig. 1), and COEPBF overestimated CO with a bias of 1.4 (LoA 1.3 to 4.2) l/min and PE 90%. After lung lavage, the increase in PEEP from 5 to 12 cmH2O normalised the high shunt fraction and other pulmonary parameters indicating a restored lung function (Table 1). Bias was then 0.8 (LoA 1.5 to 3.1) l/min and PE 75%. The concordance rate assessed by the four-quadrant plot was 94% and increased to 100% after lavage was performed. (Fig. 3). When delta data were analysed by the polar plot methodology, con-
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1027
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
Fig. 1. Cardiac output and effective pulmonary blood flow (l/min) at baseline and during hemodynamic interventions at PEEP 5 and 12 cmH2O before and after lung lavage. The green line displays the capnodynamic method COEPBF and the blue line the ultrasonic reference method for cardiac output, COTS. The red line represents lung lavage. Data are presented as mean and (SD) N = 9.
Statistics Normal distribution of CO data was evaluated with the D’Agostino and Pearson omnibus K2 test. Data are presented as mean (standard deviation, SD) or median (range) as appropriate. The precision of COEPBF [defined as twice the coefficient of variation, CV (SD/mean)] was calculated from multiple measurements during steady state at baseline and remained 9% both before and after lung lavage was performed. The precision of the reference method for CO was previously shown to be 10%.13,14 A P-value of < 0.05 was considered significant and calculated by Wilcoxon’s matched-pairs signed rank test. The Bland–Altman methodology corrected for repeated measurements was used for calculation of the agreement between absolute CO values.15,16 Bias, the mean difference between the two methods, was used to evaluate accuracy. Limits of agreement (LoA, bias 1.96 SD) were used for estimation of precision. Percentage error (PE) was calculated as 2 SD/mean CO of the reference method for CO.15 To assess the trending ability, we used two different methods, the four-quadrant plot and the polar plot. The former assesses the direction of the change while the polar plot also includes the magnitude of change. Concordance rates were calculated for the four-quadrant plot as the number of data points within the two quadrants of agreement, and for polar plot, the number of data points within the radial limits of agreement 30°, divided by all data points. The mean polar angle (angular bias, corresponding to the
mean difference for absolute values in a Bland– Altman plot) estimating the calibration of the test method to the reference method for CO was also calculated by this method.17 For both methods, we used a narrow exclusion zone of 10% because of the precise reference method.14 A priori, we considered the two methods interchangeable if the percentage error was less than 30%.18 For the four-quadrant plot, a concordance rate of < 90% was considered as poor, 90–95% as acceptable and > 95% as high. For the polar plot, a concordance rate of > 90% was considered as acceptable.19 An angular bias of 5° suggested good calibration.20 All statistical calculations except for the polar plots were done in GraphPad Prism (version 6.0 for Windows, GraphPad Software, San Diego, CA, USA). For calculation of polar plots, an excel sheet for conversion of Cartesian data to polar coordinates was used kindly provided by Prof. L Critchley.20 Results Due to technical problems with data acquisition, only nine animals could be used for statistical analyses. Lung lavage resulted in a significant lung injury with a mean P/F ratio of 115,21 a twofold increase in shunt fraction and decreased compliance (see Table 1). Shunt fractions and dead space The mean shunt fraction increased from 0.16 (0.11–0.22) to 0.34 (0.23–0.42) after lavage at PEEP 5 cmH2O (P = 0.004). When PEEP was increased to 12 H2O, the shunt fraction was
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1025
1026
COTS (l/min) Shunt (fraction) VD Bohr (fraction) PaO2/FiO2 (mmHg) PaCO2 (mmHg) Cdyn (ml/cmH2O) MPAP (mmHg) 501 (68) 39 (5) 25.3 (3.1)
493 (73)
43 (4.0)
25.8 (2.4) 15.5 (5.1)
0.44 (0.08)
0.35 (0.02)
20.8 (6.1)
0.09 (0.01)
21.9 (6.0)
26.7 (2.5)
49 (8)
423 (96)
0.36 (0.02)
0.24 (0.04)
22.4 (6.0)
25.5 (1.6)
43 (6)
527 (52)
0.4 (0.02)
0.13 (0.02)
3.08 (0.62)
0.16 (0.04)
5.63 (1.43)
1.88 (0.50)
3.74 (0.74)
18.0 (5.4)
26.1 (1.4)
38 (3)
528 (67)
0.44 (0.02)
0.08 (0.02)
1.62 (0.46)
CAVA
BL
CAVA
BL
Dob
PEEP 12 before lavage
PEEP 5 before lavage
23.4 (5.6)
28.0 (1.6)
48 (5)
497 (65)
0.41 (0.02)
0.16 (0.04)
4.7 (0.67)
Dob
115 (74) P = 0.004 51 (6) P = 0.004 18.0 (1.6) P = 0.004 28.5 (4.1) P = 0.008
0.34 (0.06) P = 0.004 0.36 (0.03) ns
3.94 (0.62) ns
BL 1.83 (0.32) ns 0.17 (0.05) P = 0.004 0.41 (0.03) P = 0.02 283 (124) P = 0.004 41 (3) P = 0.004 19.1 (1.4) P = 0.004 19.0 (2.6) P = 0.008
CAVA
PEEP 5 after lavage
5.94 (0.92) ns 0.41 (0.10) P = 0.004 0.38 (0.03) ns 106 (23) P = 0.004 57 (6) P = 0.004 18.9 (1.6) P = 0.004 29.5 (4.1) P = 0.008
Dob
24.1 (2.8) ns
25.8 (2.3) ns
43 (4) ns
482 (97) ns
0.42 (0.03) ns
3.04 (0.69) ns 0.13 (0.05) ns
BL
18.6 (0.9) ns
26.1 (2.1) ns
35 (4) ns
0.45 (0.03) P = 0.002 499 (131) ns
1.56 (0.43) P = 0.004 0.09 (0.04) ns
CAVA
PEEP 12 after lavage
24.6 (3.3) ns
27.5 (2.7) ns
48 (5) ns
498 (52) ns
0.43 (0.01) ns
0.17 (0.04) ns
4.6 (0.76) ns
Dob
Table 1 Cardiac output (l/min) displayed by (COTS), shunt fractions and dead space according to Bohr and pulmonary parameters before and after lung lavage at baseline (BL), preload reduction by inflating the balloon in v cava (CAVA) and inotropic stimulation by infusion of dobutamine (Dob) at PEEP 5 and 12 cmH2O. Wilcoxon’s matched paired test was used to compare corresponding values before and after lavage. A P-value < 0.05 was considered significant. Data are presented as mean (SD). (N = 9).
€ SANDER ET AL. € C. HALLSJ O
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
reduced to 0.13 (0.7–0.23) (P = 0.004) indicating a restored lung function. Generally, the shunt fraction was dependent of CO, decreasing with reduced CO and increasing with higher CO, regardless of the degree of lung injury (Table 1). Dead space according to Bohr increased during preload reduction at both PEEP levels: 0.35 (0.30– 0.39) to 0.44 (0.37–0.57) P = 0.008 and 0.39 (0.37– 0.43) to 0.44 (0.42–0.48) P = 0.008) at 5 and 12 cmH2O respectively but remained unchanged in response to lavage, 0.35 (0.30–0.39) and 0.36 (0.32–0.41) P = 0.2 respectively (Table 1).
A
B
COEPBF before and after lung lavage at PEEP 5 cmH2O Accuracy and precision Lung lavage influenced the agreement between the methods. Before lavage, COEPBF showed a bias of 0.2 (LoA 1.1 to 1.5) l/min. (95% confidence intervals of LOA (CI LoA) 1.5 to 0.9 and 1.3– 1.9) and a PE of 34%, whereas after lavage, COEPBF underestimated COTS with a bias of 0.9 (LoA 3.6 to 1.9) l/min (CI LoA 4.5 to 3.1 and 1.4–2.8) and a PE of 70% (Fig. 2A and B). Trending ability The correlation between the induced changes in CO was high between COEPBF and COTS both before (r 0.90 P < 0.0001) and after induction of lung injury (r 0.85 P < 0.0001). Trending ability assessed by four-quadrant plot methodology, remained at a concordance rate of 94% both before and after lung lavage (Fig. 3). When the same paired delta values were analysed by the polar plot methodology, trending ability before lavage was good with a concordance rate of 100% and an angular bias of 4.0° (95% CI 2.4° to 10.5°) (Fig. 4A). However, after lavage concordance rate decreased to 89% and angular bias was 16.4° (95% CI 23.3° to 9.5 °) (Fig. 4B). COEPBF before and after lung lavage at PEEP 12 cmH2O Accuracy, precision and trending ability When PEEP was altered from 5 to 12 cmH2O before lavage, a paradoxical raise in COEPBF
Fig. 2. (A) Displays a Bland Altman plot of 45 paired cardiac output values obtained by the capnodynamic (COEPBF) and the reference method for cardiac output (COTS) before lung lavage at PEEP 5 cmH2O. Values were obtained at baseline (BL), cava occlusion, BL, dobutamine infusion and BL. N = 9. (B) Displays a Bland Altman plot of 36 paired cardiac output values obtained by the capnodynamic (COEPBF) and the reference method for cardiac output (COTS) at PEEP 5 cmH2O after lung lavage was performed. Values were obtained at BL, cava occlusion, BL and dobutamine infusion. N = 9. The central dotted line represents the mean difference (bias) and the peripheral dotted lines limits of agreement (LoA) [bias (1.96) SD]. The blue dotted lines around LoA displays the 95% confidence intervals of LoA.
was detected (Fig. 1), and COEPBF overestimated CO with a bias of 1.4 (LoA 1.3 to 4.2) l/min and PE 90%. After lung lavage, the increase in PEEP from 5 to 12 cmH2O normalised the high shunt fraction and other pulmonary parameters indicating a restored lung function (Table 1). Bias was then 0.8 (LoA 1.5 to 3.1) l/min and PE 75%. The concordance rate assessed by the four-quadrant plot was 94% and increased to 100% after lavage was performed. (Fig. 3). When delta data were analysed by the polar plot methodology, con-
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1027
€ SANDER ET AL. € C. HALLSJ O
Effects of shunt and dead space on the performance of the capnodynamic method The difference between the methods correlated significantly with shunted blood flow (r 0.73, P < 0.0001) (Fig. 5A). At low shunt fractions, the COEPBF tended to overestimate CO especially when related to high PEEP before lavage. With shunt levels ≥ 20%, the method tended to underestimate COTS. No such relation was noted for dead space (Fig. 5B). Discussion
Fig. 3. Trending ability displayed by two four-quadrant plots comparing the paired delta values between baseline and the hemodynamic interventions for the capnodynamic (COEPBF) and the reference method for cardiac output (COTS). Data points in the upper right and lower left quadrant are concordant. An exclusion zone of 10% (0.4 l/min) was used. In each plot 36 paired delta values are displayed. The upper panel shows delta values at PEEP 5 cmH2O before and after lavage and the lower panel shows the corresponding values at PEEP 12 cmH2O. N = 9.
cordance rate was 89% both before and after lavage and the mean polar angle 3.1° (95% CI 8.2° to 14.3°) and 2.5 (95% CI 12.5° to 7.6°) respectively. A
We have evaluated a novel capnodynamic method for estimation of effective pulmonary blood flow in a model of lavage-induced lung injury. As expected, the performance of the novel method was affected by the induction of lung injury and the subsequent ventilation/perfusion mismatch. In contrast to the findings during healthy conditions, agreement was affected in the lavage condition, whereas trending ability assessed by the four-quadrant plot was still preserved. Interestingly, when PEEP was increased restoring the ventilation/perfusion match in the lung, the agreement between methods improved. When used as an estimation of total CO, this capnodynamic method is, as any other carbon dioxide based method, dependent on pulmonary gas exchange and known to be sensitive to disturbances in lung function. Being intrinsically different from human ARDS, this model resulted in a gas exchange impairment of similar magnitude as witnessed by the obtained shunt levels.21
B
Fig. 4. Trending ability assessed by the polar plot methodology. 18 paired delta values comparing the capnodynamic method (COEPBF) and the reference method for cardiac output (COTS) after lung lavage. The angle between the blue line and the dotted orange-colored line is the mean polar angle (angular bias) and the dotted blue lines indicate the 95 % confidence intervals of the angle. Panel A displays 18 delta values before lavage and panel B 18 delta values after lung lavage was performed. Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031
1028
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
A
B
Fig. 5. Panel A displays the correlation of the difference between the capnodynamic (COEPBF) and reference cardiac output method (COTS) (l/min) and the shunt fraction (QS/QT) before (blue dots) and after (red triangles) lung lavage. N = 9. Panel B shows the correlation of the differences between the capnodynamic (COEPBF) and reference cardiac output method (COTS) (l/min) and dead space. N = 9.
After induction of lung injury, the overall agreement between COEPBF and COTS decreased. The difference between the methods changed with increasing shunt resulting in an underestimation at high fractions. As the COEPBF method does not include shunt flow, an increased error is expected with increasing shunt fractions when compared to a method that measures CO. In the current study the mean difference between COEPBF and total CO was minimal at normal and moderate levels of shunt. COEPBF overestimated CO at the lowest levels and underestimated it at high levels of shunt, a finding coherent with previous studies.9 Dead space, moderately affected by lung lavage, did not correlate with the performance of COEPBF. The expected restored match between perfusion and ventilation at PEEP 12 cmH2O after lavage improved the performance of COEPBF indicating
that pulmonary dysfunction severely hampers the performance of the method. The trending ability of COEPBF was evaluated with a protocol including cava occlusioninduced preload reduction and dobutamine administration leading to a threefold change in CO. When using the conventional approach evaluating the direction of the change, trending ability was considered good after lavage was performed. Interestingly, when also including the magnitude of change, the concordance rate and angular bias were notably affected suggesting suboptimal calibration of COEPBF due to the concomitant changes in shunt fractions during the hemodynamic interventions. The interpretation of PE has been debated. Based on the performance of available CO methods, some authors conclude that a PE of < 45% should be considered as acceptable.22 A PE of less than 30% suggests that the test method and reference method could be considered interchangeable. In the current study at PEEP 5 cmH2O, PE was 34%. As COTS includes shunt flow in contrast to COEPBF, and significant hemodynamic challenges were performed, a PE of 34% could be clinically acceptable.14 As mentioned, COEPBF overestimated CO at baseline when the shunt fraction was low. This overestimation was enhanced when PEEP was altered from 5 to 12 cmH2O in the pre-lavage setting leading to a reversed trending. This finding may relate to the method being based on changes in breathing pattern including prolonged inspiratory holds. The subsequent increased intra-thoracic pressure leads to a reduction in effective pulmonary blood flow not compensated for in the capnodynamic equation. This effect is likely enhanced by the increase in PEEP. Modification of the equation and/or different breathing patterns such as expiratory holds not affecting CO to the same magnitude may improve the performance of the COEPBF. Few capnodynamic methods have been appropriately evaluated in lung injury settings. Partial carbon dioxide rebreathing is the most studied method in this context. The results are far from uniform ranging from poor agreement in cardiac surgery and lung injury patients to good agreement in a Scandinavian study of major surgery and critically ill patients.23–25 This diversity may to some extent reflect the
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1029
€ SANDER ET AL. € C. HALLSJ O
methodological complexity involved in this line of investigation. A limitation of the current study is the choice of model. The lung dysfunction generated in the lavage model is artificial and largely based on mechanical depletion of surfactant. Arguably this model has a weak clinical correlate. However, the model is widespread, highly reproducible and does provide a significant injury well suited for the current validation study. COEPBF shows good agreement and trending ability in animals with healthy lungs. When evaluated during significant hemodynamic alterations in a model of definite lung injury, this novel capnodynamic method showed weaknesses in agreement. However, the results improved when PEEP was adjusted to the current lung status optimising the match of ventilation and perfusion of the lung. The fact that COEPBF has a different physiological meaning than CO explains some of the discrepancies between methods. As an independent physiological parameter, an increased COEPBF should improve oxygenation and carbon dioxide elimination independently of how much it affects CO and has the appealing potential to be used in guiding the optimal ventilator setting. This difference could provide an additional value of measuring COEPBF in lung conditions with high shunt fractions. The result of this study underlines the need for further development of the method as well as to explore the potential value of the EPBF parameter itself. The mathematical algorithm, breathing pattern and a suitable method for shunt correction could provide possible fields for further improvement.
2.
3.
4.
5.
6.
7.
8.
9.
Authors’ contributions C. H. S., A. O. and H. B.: Study design, data collection and analysis. Drafting of the manuscript. M. H., F. S. S. and M. W.: Study design, data collection and analysis. Critical revision of manuscript.
10.
11.
12.
References 1. Hamilton MA, Cecconi M, Rhodes A. A systematic review and meta-analysis on the use of preemptive
hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patients. Anesth Analg 2011; 112: 1392– 402. Grocott MP, Dushianthan A, Hamilton MA, Mythen MG, Harrison D, Rowan K, Optimisation Systematic Review Steering G. Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery. Cochrane Database Syst Rev 2012;11:CD004082. Cecconi M, Corredor C, Arulkumaran N, Abuella G, Ball J, Grounds RM, Hamilton M, Rhodes A. Clinical review: goal-directed therapy-what is the evidence in surgical patients? The effect on different risk groups. Crit Care 2013; 17: 209. Cannesson M, Pestel G, Ricks C, Hoeft A, Perel A. Hemodynamic monitoring and management in patients undergoing high risk surgery: a survey among North American and European anesthesiologists. Crit Care 2011; 15: R197. Pinsky MR, Vincent JL. Let us use the pulmonary artery catheter correctly and only when we need it. Crit Care Med 2005; 33: 1119–22. Reuter DA, Huang C, Edrich T, Shernan SK, Eltzschig HK. Cardiac output monitoring using indicator-dilution techniques: basics, limits, and perspectives. Anesth Analg 2010; 110: 799–811. Hadian M, Kim HK, Severyn DA, Pinsky MR. Cross-comparison of cardiac output trending accuracy of LiDCO, PiCCO, FloTrac and pulmonary artery catheters. Crit Care 2010; 14: R212. Cecconi M, Dawson D, Casaretti R, Grounds RM, Rhodes A. A prospective study of the accuracy and precision of continuous cardiac output monitoring devices as compared to intermittent thermodilution. Minerva Anestesiol 2010; 76: 1010–7. Hallsjo Sander C, Hallback M, Wallin M, Emtell P, Oldner A, Bjorne H. Novel continuous capnodynamic method for cardiac output assessment during mechanical ventilation. Br J Anaesth 2014;112:824–31. Capek JM, Roy RJ. Noninvasive measurement of cardiac output using partial CO2 rebreathing. IEEE Trans Biomed Eng 1988; 35: 653–61. Berggren S. The oxygeic deficit of arterial blood caused by non-ventilation parts of the lung. Acta Physiol Scand 1942;4(Suppl. 2). Tusman G, Sipmann FS, Borges JB, Hedenstierna G, Bohm SH. Validation of Bohr dead space measured by volumetric capnography. Intensive Care Med 2011; 37: 870–4. Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031
1030
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
13. Transonic Systems Inc. Transonic Precision Flowprobes: Perivascular Flowprobe Specifications. Technical Report. 2011. 14. Axiak Flammer SM, Critchley LA, Weber A, Pirbodaghi T, Brinks H, Vandenberghe S. Reliability of lithium dilution cardiac output in anaesthetized sheep. Br J Anaesth 2013;111:833–9. 15. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 307–10. 16. Myles PS, Cui J. Using the Bland-Altman method to measure agreement with repeated measures. Br J Anaesth 2007; 99: 309–11. 17. Critchley LA, Yang XX, Lee A. Assessment of trending ability of cardiac output monitors by polar plot methodology. J Cardiothorac Vasc Anesth 2011; 25: 536–46. 18. Cecconi M, Rhodes A, Poloniecki J, Della Rocca G, Grounds RM. Bench-to-bedside review: the importance of the precision of the reference technique in method comparison studies–with specific reference to the measurement of cardiac output. Crit Care 2009; 13: 201. 19. Desebbe O, Henaine R, Keller G, Koffel C, Garcia H, Rosamel P, Obadia JF, Bastien O, Lehot JJ, Haftek M, Critchley LA. Ability of the thirdgeneration FloTrac/Vigileo software to track changes in cardiac output in cardiac surgery
20.
21.
22.
23.
24.
25.
patients: a polar plot approach. J Cardiothorac Vasc Anesth 2013; 27: 1122–7. Critchley LA, Lee A, Ho AM. A critical review of the ability of continuous cardiac output monitors to measure trends in cardiac output. Anesth Analg 2010; 111: 1180–92. Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307: 2526–33. Peyton PJ, Chong SW. Minimally invasive measurement of cardiac output during surgery and critical care: a meta-analysis of accuracy and precision. Anesthesiology 2010; 113: 1220–35. Nilsson LB, Eldrup N, Berthelsen PG. Lack of agreement between thermodilution and carbon dioxide-rebreathing cardiac output. Acta Anaesthesiol Scand 2001; 45: 680–5. Valiatti JL, Amaral JL. Comparison between cardiac output values measured by thermodilution and partial carbon dioxide rebreathing in patients with acute lung injury. Sao Paulo Med J 2004; 122: 233–8. Odenstedt H, Stenqvist O, Lundin S. Clinical evaluation of a partial CO2 rebreathing technique for cardiac output monitoring in critically ill patients. Acta Anaesthesiol Scand 2002; 46: 152–9.
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1031
A novel continuous capnodynamic method for cardiac output assessment in a porcine model of lung lavage €llsjo € Sander1,2, M. Hallba €ck3, F. Suarez Sipmann4,5, M. Wallin2,3, A. Oldner1,2 and H. Bjo € rne1,2 C. Ha 1
Department of Anaesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital, Solna, Sweden Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden 3 Maquet Critical Care AB, Solna, Sweden 4 Department of Surgical Sciences, Section of Anaesthesiology and Critical Care, Hedenstierna’s Laboratory, Uppsala University, Uppsala, Sweden 5 CIBERES, CIBER de enfermedades respiratorias, Instituto Carlos III, Madrid, Spain 2
Correspondence € Sander, Department of C. H€allsjo Anaesthesiology, Surgical Services and Intensive Care Medicine, Karolinska University Hospital, Solna, Stockholm, Sweden E-mail: [email protected] Funding This project is a collaboration between Karolinska Institutet and Maquet Critical Care AB. The work was supported by grants from Maquet Critical Care AB and the regional agreement on medical training and research ALF between Stockholm County Council and the Karolinska Institutet. Conflicts of interest € Sander has received an Caroline H€allsjo unrestricted grant for research from Maquet Critical Care AB (MCC) MCC Fernando Suarez Sipmann performs consultant activities for MCC. Magnus Hallb€ack is employed at MCC. Mats Wallin is employed at MCC. Anders Oldner declares no conflict of interest. H akan €rne declares no conflict of interest. Bjo Submitted 4 March 2015; accepted 20 April 2015; submission 26 January 2015. Citation € Sander C, Hallb€ack M, Suarez Sipmann H€allsjo €rne H. A novel F, Wallin M, Oldner A, Bjo continuous capnodynamic method for cardiac output assessment in a porcine model of lung lavage. Acta Anaesthesiologica Scandinavica 2015
Background: We have evaluated a new method for continuous monitoring of effective pulmonary blood flow (COEPBF), i.e. cardiac output (CO) minus intra-pulmonary shunt, during mechanical ventilation. The method has shown good trending ability during severe hemodynamic challenges in a porcine model with intact lungs. In this study, we further evaluate the COEPBF method in a model of lung lavage. Methods: COEPBF was compared to a reference method for CO during hemodynamic and PEEP alterations, 5 and 12 cmH2O, before and after repeated lung lavages in 10 anaesthetised pigs. Bland–Altman, four-quadrant and polar plot methodologies were used to determine agreement and trending ability. Results: After lung lavage at PEEP 5 cmH2O, the ratio of arterial oxygen partial pressure related to inspired fraction of oxygen significantly decreased. The mean difference (limits of agreement) between methods changed from 0.2 (1.1 to 1.5) to 0.9 (3.6 to 1.9) l/min and percentage error increased from 34% to 70%. Trending ability remained good according to the four-quadrant plot (concordance rate 94%), whereas mean angular bias increased from 4° to 16° when using the polar plot methodology. Conclusion: Both agreement and precision of COEPBF were impaired in relation to CO when the shunt fraction was increased after lavage at PEEP 5 cmH2O. However, trending ability remained good as assessed by the four-quadrant plot, whereas the mean polar angle, calculated by the polar plot, was wide.
doi: 10.1111/aas.12559
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031
1022
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
Editorial comment: what this article tells us
Effective pulmonary blood flow could be assessed continuously by a capnodynamic method. In a porcine model with intact lungs bias was low and trending abilities good. When shunt fractions increased after lung lavage both the agreement and precision was impaired. However, trending ability assessed by the four-quadrant plot methodology remained high.
Goal-directed hemodynamic optimisation improves outcome in high-risk surgical patients.1–3 A prerequisite for a successful protocol is reliable cardiac output (CO) monitoring. Despite this notion it is not widely used in this setting.4 The most accurate monitors, such as the thermo dilution-based pulmonary artery catheter (PAC) and calibrated pulse-contour analysis methods, are invasive and tend to be complicated to use.5,6 Less invasive methods, considered user-friendly, are not as reliable when the circulation is unstable.7,8 We have recently evaluated a new capnodynamic method continuously measuring effective pulmonary blood flow (COEPBF). This method showed low bias, good trending abilities and has the prerequisite for a short response time in a variety of hemodynamic challenges. In a previous study from our group, COEPBF performed equally to the PAC.9 This novel method is based on the non-invasive analysis of carbon dioxide elimination, and thus dead space and shunt fraction can affect its performance. Pulmonary pathology with subsequent disturbances in gas exchange, an entity frequently seen in critically ill patients, is likely to influence the correspondence of COEPBF and CO. The aim of this study was to evaluate this novel capnodynamic method in a model of lung injury induced by repeated lavages in a porcine model during positive end-expiratory pressure (PEEP) alterations in a wide range of hemodynamic challenges.
Anaesthesia and surgical preparation The procedure has been described previously in detail.9 Briefly, 10 pigs with mean weight 35 kg (30–40 kg) were anaesthetised and mechanically ventilated in a volume-controlled mode with a tidal volume of 10 ml/kg, I:E 1:2, respiratory rate of 25–30 aiming at a PaCO2 of approximately 40 mmHg and a FiO2 of 1.0 (Servo-i; Maquet, Solna, Sweden). A PAC was inserted via the internal jugular vein for sampling of mixed venous blood gases. The femoral vein was catheterised with an 8 F Fogarty occlusion catheter for later reduction in venous return. A left-sided thoracotomy was performed and an 18 or 20 mm ultrasonic flow probe (T 401; Transonic system Inc., Ithaca NY, USA) was positioned around the pulmonary trunk for continuous CO reference measurement (COTS). The chest cavity was then closed and the animal repositioned into the supine position. If there were signs of hypovolaemia (significant tachycardia and/or hypotension), a colloid was administered intravenously. Pressure readings were sampled into a data acquisition system (version 3.2.7; Acknowledge, BioPac Systems, Santa Barbara, CA, USA). Lung lavage After the hemodynamic interventions were accomplished at PEEP 5 and 12 cmH2O in healthy lung conditions, repeated lung lavages with 37° isotonic saline (30 ml/kg) were performed at PEEP 5 cmH2O. The procedure was stopped when arterial oxygen tension (PaO2) reached below 75 mmHg at FiO2 1.0 (P/F ratio < 75).
Material and methods The study was performed at the Hedenstierna’s Laboratory in Uppsala, Sweden with approval from the Animal Research Ethical Committee of Uppsala University C171/11 Sweden.
Calculation of effective pulmonary blood flow The mathematical algorithm is based on the assumptions that effective pulmonary blood
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1023
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
reduced to 0.13 (0.7–0.23) (P = 0.004) indicating a restored lung function. Generally, the shunt fraction was dependent of CO, decreasing with reduced CO and increasing with higher CO, regardless of the degree of lung injury (Table 1). Dead space according to Bohr increased during preload reduction at both PEEP levels: 0.35 (0.30– 0.39) to 0.44 (0.37–0.57) P = 0.008 and 0.39 (0.37– 0.43) to 0.44 (0.42–0.48) P = 0.008) at 5 and 12 cmH2O respectively but remained unchanged in response to lavage, 0.35 (0.30–0.39) and 0.36 (0.32–0.41) P = 0.2 respectively (Table 1).
A
B
COEPBF before and after lung lavage at PEEP 5 cmH2O Accuracy and precision Lung lavage influenced the agreement between the methods. Before lavage, COEPBF showed a bias of 0.2 (LoA 1.1 to 1.5) l/min. (95% confidence intervals of LOA (CI LoA) 1.5 to 0.9 and 1.3– 1.9) and a PE of 34%, whereas after lavage, COEPBF underestimated COTS with a bias of 0.9 (LoA 3.6 to 1.9) l/min (CI LoA 4.5 to 3.1 and 1.4–2.8) and a PE of 70% (Fig. 2A and B). Trending ability The correlation between the induced changes in CO was high between COEPBF and COTS both before (r 0.90 P < 0.0001) and after induction of lung injury (r 0.85 P < 0.0001). Trending ability assessed by four-quadrant plot methodology, remained at a concordance rate of 94% both before and after lung lavage (Fig. 3). When the same paired delta values were analysed by the polar plot methodology, trending ability before lavage was good with a concordance rate of 100% and an angular bias of 4.0° (95% CI 2.4° to 10.5°) (Fig. 4A). However, after lavage concordance rate decreased to 89% and angular bias was 16.4° (95% CI 23.3° to 9.5 °) (Fig. 4B). COEPBF before and after lung lavage at PEEP 12 cmH2O Accuracy, precision and trending ability When PEEP was altered from 5 to 12 cmH2O before lavage, a paradoxical raise in COEPBF
Fig. 2. (A) Displays a Bland Altman plot of 45 paired cardiac output values obtained by the capnodynamic (COEPBF) and the reference method for cardiac output (COTS) before lung lavage at PEEP 5 cmH2O. Values were obtained at baseline (BL), cava occlusion, BL, dobutamine infusion and BL. N = 9. (B) Displays a Bland Altman plot of 36 paired cardiac output values obtained by the capnodynamic (COEPBF) and the reference method for cardiac output (COTS) at PEEP 5 cmH2O after lung lavage was performed. Values were obtained at BL, cava occlusion, BL and dobutamine infusion. N = 9. The central dotted line represents the mean difference (bias) and the peripheral dotted lines limits of agreement (LoA) [bias (1.96) SD]. The blue dotted lines around LoA displays the 95% confidence intervals of LoA.
was detected (Fig. 1), and COEPBF overestimated CO with a bias of 1.4 (LoA 1.3 to 4.2) l/min and PE 90%. After lung lavage, the increase in PEEP from 5 to 12 cmH2O normalised the high shunt fraction and other pulmonary parameters indicating a restored lung function (Table 1). Bias was then 0.8 (LoA 1.5 to 3.1) l/min and PE 75%. The concordance rate assessed by the four-quadrant plot was 94% and increased to 100% after lavage was performed. (Fig. 3). When delta data were analysed by the polar plot methodology, con-
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1027
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
Fig. 1. Cardiac output and effective pulmonary blood flow (l/min) at baseline and during hemodynamic interventions at PEEP 5 and 12 cmH2O before and after lung lavage. The green line displays the capnodynamic method COEPBF and the blue line the ultrasonic reference method for cardiac output, COTS. The red line represents lung lavage. Data are presented as mean and (SD) N = 9.
Statistics Normal distribution of CO data was evaluated with the D’Agostino and Pearson omnibus K2 test. Data are presented as mean (standard deviation, SD) or median (range) as appropriate. The precision of COEPBF [defined as twice the coefficient of variation, CV (SD/mean)] was calculated from multiple measurements during steady state at baseline and remained 9% both before and after lung lavage was performed. The precision of the reference method for CO was previously shown to be 10%.13,14 A P-value of < 0.05 was considered significant and calculated by Wilcoxon’s matched-pairs signed rank test. The Bland–Altman methodology corrected for repeated measurements was used for calculation of the agreement between absolute CO values.15,16 Bias, the mean difference between the two methods, was used to evaluate accuracy. Limits of agreement (LoA, bias 1.96 SD) were used for estimation of precision. Percentage error (PE) was calculated as 2 SD/mean CO of the reference method for CO.15 To assess the trending ability, we used two different methods, the four-quadrant plot and the polar plot. The former assesses the direction of the change while the polar plot also includes the magnitude of change. Concordance rates were calculated for the four-quadrant plot as the number of data points within the two quadrants of agreement, and for polar plot, the number of data points within the radial limits of agreement 30°, divided by all data points. The mean polar angle (angular bias, corresponding to the
mean difference for absolute values in a Bland– Altman plot) estimating the calibration of the test method to the reference method for CO was also calculated by this method.17 For both methods, we used a narrow exclusion zone of 10% because of the precise reference method.14 A priori, we considered the two methods interchangeable if the percentage error was less than 30%.18 For the four-quadrant plot, a concordance rate of < 90% was considered as poor, 90–95% as acceptable and > 95% as high. For the polar plot, a concordance rate of > 90% was considered as acceptable.19 An angular bias of 5° suggested good calibration.20 All statistical calculations except for the polar plots were done in GraphPad Prism (version 6.0 for Windows, GraphPad Software, San Diego, CA, USA). For calculation of polar plots, an excel sheet for conversion of Cartesian data to polar coordinates was used kindly provided by Prof. L Critchley.20 Results Due to technical problems with data acquisition, only nine animals could be used for statistical analyses. Lung lavage resulted in a significant lung injury with a mean P/F ratio of 115,21 a twofold increase in shunt fraction and decreased compliance (see Table 1). Shunt fractions and dead space The mean shunt fraction increased from 0.16 (0.11–0.22) to 0.34 (0.23–0.42) after lavage at PEEP 5 cmH2O (P = 0.004). When PEEP was increased to 12 H2O, the shunt fraction was
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1025
1026
COTS (l/min) Shunt (fraction) VD Bohr (fraction) PaO2/FiO2 (mmHg) PaCO2 (mmHg) Cdyn (ml/cmH2O) MPAP (mmHg) 501 (68) 39 (5) 25.3 (3.1)
493 (73)
43 (4.0)
25.8 (2.4) 15.5 (5.1)
0.44 (0.08)
0.35 (0.02)
20.8 (6.1)
0.09 (0.01)
21.9 (6.0)
26.7 (2.5)
49 (8)
423 (96)
0.36 (0.02)
0.24 (0.04)
22.4 (6.0)
25.5 (1.6)
43 (6)
527 (52)
0.4 (0.02)
0.13 (0.02)
3.08 (0.62)
0.16 (0.04)
5.63 (1.43)
1.88 (0.50)
3.74 (0.74)
18.0 (5.4)
26.1 (1.4)
38 (3)
528 (67)
0.44 (0.02)
0.08 (0.02)
1.62 (0.46)
CAVA
BL
CAVA
BL
Dob
PEEP 12 before lavage
PEEP 5 before lavage
23.4 (5.6)
28.0 (1.6)
48 (5)
497 (65)
0.41 (0.02)
0.16 (0.04)
4.7 (0.67)
Dob
115 (74) P = 0.004 51 (6) P = 0.004 18.0 (1.6) P = 0.004 28.5 (4.1) P = 0.008
0.34 (0.06) P = 0.004 0.36 (0.03) ns
3.94 (0.62) ns
BL 1.83 (0.32) ns 0.17 (0.05) P = 0.004 0.41 (0.03) P = 0.02 283 (124) P = 0.004 41 (3) P = 0.004 19.1 (1.4) P = 0.004 19.0 (2.6) P = 0.008
CAVA
PEEP 5 after lavage
5.94 (0.92) ns 0.41 (0.10) P = 0.004 0.38 (0.03) ns 106 (23) P = 0.004 57 (6) P = 0.004 18.9 (1.6) P = 0.004 29.5 (4.1) P = 0.008
Dob
24.1 (2.8) ns
25.8 (2.3) ns
43 (4) ns
482 (97) ns
0.42 (0.03) ns
3.04 (0.69) ns 0.13 (0.05) ns
BL
18.6 (0.9) ns
26.1 (2.1) ns
35 (4) ns
0.45 (0.03) P = 0.002 499 (131) ns
1.56 (0.43) P = 0.004 0.09 (0.04) ns
CAVA
PEEP 12 after lavage
24.6 (3.3) ns
27.5 (2.7) ns
48 (5) ns
498 (52) ns
0.43 (0.01) ns
0.17 (0.04) ns
4.6 (0.76) ns
Dob
Table 1 Cardiac output (l/min) displayed by (COTS), shunt fractions and dead space according to Bohr and pulmonary parameters before and after lung lavage at baseline (BL), preload reduction by inflating the balloon in v cava (CAVA) and inotropic stimulation by infusion of dobutamine (Dob) at PEEP 5 and 12 cmH2O. Wilcoxon’s matched paired test was used to compare corresponding values before and after lavage. A P-value < 0.05 was considered significant. Data are presented as mean (SD). (N = 9).
€ SANDER ET AL. € C. HALLSJ O
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
reduced to 0.13 (0.7–0.23) (P = 0.004) indicating a restored lung function. Generally, the shunt fraction was dependent of CO, decreasing with reduced CO and increasing with higher CO, regardless of the degree of lung injury (Table 1). Dead space according to Bohr increased during preload reduction at both PEEP levels: 0.35 (0.30– 0.39) to 0.44 (0.37–0.57) P = 0.008 and 0.39 (0.37– 0.43) to 0.44 (0.42–0.48) P = 0.008) at 5 and 12 cmH2O respectively but remained unchanged in response to lavage, 0.35 (0.30–0.39) and 0.36 (0.32–0.41) P = 0.2 respectively (Table 1).
A
B
COEPBF before and after lung lavage at PEEP 5 cmH2O Accuracy and precision Lung lavage influenced the agreement between the methods. Before lavage, COEPBF showed a bias of 0.2 (LoA 1.1 to 1.5) l/min. (95% confidence intervals of LOA (CI LoA) 1.5 to 0.9 and 1.3– 1.9) and a PE of 34%, whereas after lavage, COEPBF underestimated COTS with a bias of 0.9 (LoA 3.6 to 1.9) l/min (CI LoA 4.5 to 3.1 and 1.4–2.8) and a PE of 70% (Fig. 2A and B). Trending ability The correlation between the induced changes in CO was high between COEPBF and COTS both before (r 0.90 P < 0.0001) and after induction of lung injury (r 0.85 P < 0.0001). Trending ability assessed by four-quadrant plot methodology, remained at a concordance rate of 94% both before and after lung lavage (Fig. 3). When the same paired delta values were analysed by the polar plot methodology, trending ability before lavage was good with a concordance rate of 100% and an angular bias of 4.0° (95% CI 2.4° to 10.5°) (Fig. 4A). However, after lavage concordance rate decreased to 89% and angular bias was 16.4° (95% CI 23.3° to 9.5 °) (Fig. 4B). COEPBF before and after lung lavage at PEEP 12 cmH2O Accuracy, precision and trending ability When PEEP was altered from 5 to 12 cmH2O before lavage, a paradoxical raise in COEPBF
Fig. 2. (A) Displays a Bland Altman plot of 45 paired cardiac output values obtained by the capnodynamic (COEPBF) and the reference method for cardiac output (COTS) before lung lavage at PEEP 5 cmH2O. Values were obtained at baseline (BL), cava occlusion, BL, dobutamine infusion and BL. N = 9. (B) Displays a Bland Altman plot of 36 paired cardiac output values obtained by the capnodynamic (COEPBF) and the reference method for cardiac output (COTS) at PEEP 5 cmH2O after lung lavage was performed. Values were obtained at BL, cava occlusion, BL and dobutamine infusion. N = 9. The central dotted line represents the mean difference (bias) and the peripheral dotted lines limits of agreement (LoA) [bias (1.96) SD]. The blue dotted lines around LoA displays the 95% confidence intervals of LoA.
was detected (Fig. 1), and COEPBF overestimated CO with a bias of 1.4 (LoA 1.3 to 4.2) l/min and PE 90%. After lung lavage, the increase in PEEP from 5 to 12 cmH2O normalised the high shunt fraction and other pulmonary parameters indicating a restored lung function (Table 1). Bias was then 0.8 (LoA 1.5 to 3.1) l/min and PE 75%. The concordance rate assessed by the four-quadrant plot was 94% and increased to 100% after lavage was performed. (Fig. 3). When delta data were analysed by the polar plot methodology, con-
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1027
€ SANDER ET AL. € C. HALLSJ O
Effects of shunt and dead space on the performance of the capnodynamic method The difference between the methods correlated significantly with shunted blood flow (r 0.73, P < 0.0001) (Fig. 5A). At low shunt fractions, the COEPBF tended to overestimate CO especially when related to high PEEP before lavage. With shunt levels ≥ 20%, the method tended to underestimate COTS. No such relation was noted for dead space (Fig. 5B). Discussion
Fig. 3. Trending ability displayed by two four-quadrant plots comparing the paired delta values between baseline and the hemodynamic interventions for the capnodynamic (COEPBF) and the reference method for cardiac output (COTS). Data points in the upper right and lower left quadrant are concordant. An exclusion zone of 10% (0.4 l/min) was used. In each plot 36 paired delta values are displayed. The upper panel shows delta values at PEEP 5 cmH2O before and after lavage and the lower panel shows the corresponding values at PEEP 12 cmH2O. N = 9.
cordance rate was 89% both before and after lavage and the mean polar angle 3.1° (95% CI 8.2° to 14.3°) and 2.5 (95% CI 12.5° to 7.6°) respectively. A
We have evaluated a novel capnodynamic method for estimation of effective pulmonary blood flow in a model of lavage-induced lung injury. As expected, the performance of the novel method was affected by the induction of lung injury and the subsequent ventilation/perfusion mismatch. In contrast to the findings during healthy conditions, agreement was affected in the lavage condition, whereas trending ability assessed by the four-quadrant plot was still preserved. Interestingly, when PEEP was increased restoring the ventilation/perfusion match in the lung, the agreement between methods improved. When used as an estimation of total CO, this capnodynamic method is, as any other carbon dioxide based method, dependent on pulmonary gas exchange and known to be sensitive to disturbances in lung function. Being intrinsically different from human ARDS, this model resulted in a gas exchange impairment of similar magnitude as witnessed by the obtained shunt levels.21
B
Fig. 4. Trending ability assessed by the polar plot methodology. 18 paired delta values comparing the capnodynamic method (COEPBF) and the reference method for cardiac output (COTS) after lung lavage. The angle between the blue line and the dotted orange-colored line is the mean polar angle (angular bias) and the dotted blue lines indicate the 95 % confidence intervals of the angle. Panel A displays 18 delta values before lavage and panel B 18 delta values after lung lavage was performed. Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031
1028
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
A
B
Fig. 5. Panel A displays the correlation of the difference between the capnodynamic (COEPBF) and reference cardiac output method (COTS) (l/min) and the shunt fraction (QS/QT) before (blue dots) and after (red triangles) lung lavage. N = 9. Panel B shows the correlation of the differences between the capnodynamic (COEPBF) and reference cardiac output method (COTS) (l/min) and dead space. N = 9.
After induction of lung injury, the overall agreement between COEPBF and COTS decreased. The difference between the methods changed with increasing shunt resulting in an underestimation at high fractions. As the COEPBF method does not include shunt flow, an increased error is expected with increasing shunt fractions when compared to a method that measures CO. In the current study the mean difference between COEPBF and total CO was minimal at normal and moderate levels of shunt. COEPBF overestimated CO at the lowest levels and underestimated it at high levels of shunt, a finding coherent with previous studies.9 Dead space, moderately affected by lung lavage, did not correlate with the performance of COEPBF. The expected restored match between perfusion and ventilation at PEEP 12 cmH2O after lavage improved the performance of COEPBF indicating
that pulmonary dysfunction severely hampers the performance of the method. The trending ability of COEPBF was evaluated with a protocol including cava occlusioninduced preload reduction and dobutamine administration leading to a threefold change in CO. When using the conventional approach evaluating the direction of the change, trending ability was considered good after lavage was performed. Interestingly, when also including the magnitude of change, the concordance rate and angular bias were notably affected suggesting suboptimal calibration of COEPBF due to the concomitant changes in shunt fractions during the hemodynamic interventions. The interpretation of PE has been debated. Based on the performance of available CO methods, some authors conclude that a PE of < 45% should be considered as acceptable.22 A PE of less than 30% suggests that the test method and reference method could be considered interchangeable. In the current study at PEEP 5 cmH2O, PE was 34%. As COTS includes shunt flow in contrast to COEPBF, and significant hemodynamic challenges were performed, a PE of 34% could be clinically acceptable.14 As mentioned, COEPBF overestimated CO at baseline when the shunt fraction was low. This overestimation was enhanced when PEEP was altered from 5 to 12 cmH2O in the pre-lavage setting leading to a reversed trending. This finding may relate to the method being based on changes in breathing pattern including prolonged inspiratory holds. The subsequent increased intra-thoracic pressure leads to a reduction in effective pulmonary blood flow not compensated for in the capnodynamic equation. This effect is likely enhanced by the increase in PEEP. Modification of the equation and/or different breathing patterns such as expiratory holds not affecting CO to the same magnitude may improve the performance of the COEPBF. Few capnodynamic methods have been appropriately evaluated in lung injury settings. Partial carbon dioxide rebreathing is the most studied method in this context. The results are far from uniform ranging from poor agreement in cardiac surgery and lung injury patients to good agreement in a Scandinavian study of major surgery and critically ill patients.23–25 This diversity may to some extent reflect the
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1029
€ SANDER ET AL. € C. HALLSJ O
methodological complexity involved in this line of investigation. A limitation of the current study is the choice of model. The lung dysfunction generated in the lavage model is artificial and largely based on mechanical depletion of surfactant. Arguably this model has a weak clinical correlate. However, the model is widespread, highly reproducible and does provide a significant injury well suited for the current validation study. COEPBF shows good agreement and trending ability in animals with healthy lungs. When evaluated during significant hemodynamic alterations in a model of definite lung injury, this novel capnodynamic method showed weaknesses in agreement. However, the results improved when PEEP was adjusted to the current lung status optimising the match of ventilation and perfusion of the lung. The fact that COEPBF has a different physiological meaning than CO explains some of the discrepancies between methods. As an independent physiological parameter, an increased COEPBF should improve oxygenation and carbon dioxide elimination independently of how much it affects CO and has the appealing potential to be used in guiding the optimal ventilator setting. This difference could provide an additional value of measuring COEPBF in lung conditions with high shunt fractions. The result of this study underlines the need for further development of the method as well as to explore the potential value of the EPBF parameter itself. The mathematical algorithm, breathing pattern and a suitable method for shunt correction could provide possible fields for further improvement.
2.
3.
4.
5.
6.
7.
8.
9.
Authors’ contributions C. H. S., A. O. and H. B.: Study design, data collection and analysis. Drafting of the manuscript. M. H., F. S. S. and M. W.: Study design, data collection and analysis. Critical revision of manuscript.
10.
11.
12.
References 1. Hamilton MA, Cecconi M, Rhodes A. A systematic review and meta-analysis on the use of preemptive
hemodynamic intervention to improve postoperative outcomes in moderate and high-risk surgical patients. Anesth Analg 2011; 112: 1392– 402. Grocott MP, Dushianthan A, Hamilton MA, Mythen MG, Harrison D, Rowan K, Optimisation Systematic Review Steering G. Perioperative increase in global blood flow to explicit defined goals and outcomes following surgery. Cochrane Database Syst Rev 2012;11:CD004082. Cecconi M, Corredor C, Arulkumaran N, Abuella G, Ball J, Grounds RM, Hamilton M, Rhodes A. Clinical review: goal-directed therapy-what is the evidence in surgical patients? The effect on different risk groups. Crit Care 2013; 17: 209. Cannesson M, Pestel G, Ricks C, Hoeft A, Perel A. Hemodynamic monitoring and management in patients undergoing high risk surgery: a survey among North American and European anesthesiologists. Crit Care 2011; 15: R197. Pinsky MR, Vincent JL. Let us use the pulmonary artery catheter correctly and only when we need it. Crit Care Med 2005; 33: 1119–22. Reuter DA, Huang C, Edrich T, Shernan SK, Eltzschig HK. Cardiac output monitoring using indicator-dilution techniques: basics, limits, and perspectives. Anesth Analg 2010; 110: 799–811. Hadian M, Kim HK, Severyn DA, Pinsky MR. Cross-comparison of cardiac output trending accuracy of LiDCO, PiCCO, FloTrac and pulmonary artery catheters. Crit Care 2010; 14: R212. Cecconi M, Dawson D, Casaretti R, Grounds RM, Rhodes A. A prospective study of the accuracy and precision of continuous cardiac output monitoring devices as compared to intermittent thermodilution. Minerva Anestesiol 2010; 76: 1010–7. Hallsjo Sander C, Hallback M, Wallin M, Emtell P, Oldner A, Bjorne H. Novel continuous capnodynamic method for cardiac output assessment during mechanical ventilation. Br J Anaesth 2014;112:824–31. Capek JM, Roy RJ. Noninvasive measurement of cardiac output using partial CO2 rebreathing. IEEE Trans Biomed Eng 1988; 35: 653–61. Berggren S. The oxygeic deficit of arterial blood caused by non-ventilation parts of the lung. Acta Physiol Scand 1942;4(Suppl. 2). Tusman G, Sipmann FS, Borges JB, Hedenstierna G, Bohm SH. Validation of Bohr dead space measured by volumetric capnography. Intensive Care Med 2011; 37: 870–4. Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031
1030
ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
NOVEL METHOD FOR CARDIAC OUTPUT ASSESSMENT
13. Transonic Systems Inc. Transonic Precision Flowprobes: Perivascular Flowprobe Specifications. Technical Report. 2011. 14. Axiak Flammer SM, Critchley LA, Weber A, Pirbodaghi T, Brinks H, Vandenberghe S. Reliability of lithium dilution cardiac output in anaesthetized sheep. Br J Anaesth 2013;111:833–9. 15. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 307–10. 16. Myles PS, Cui J. Using the Bland-Altman method to measure agreement with repeated measures. Br J Anaesth 2007; 99: 309–11. 17. Critchley LA, Yang XX, Lee A. Assessment of trending ability of cardiac output monitors by polar plot methodology. J Cardiothorac Vasc Anesth 2011; 25: 536–46. 18. Cecconi M, Rhodes A, Poloniecki J, Della Rocca G, Grounds RM. Bench-to-bedside review: the importance of the precision of the reference technique in method comparison studies–with specific reference to the measurement of cardiac output. Crit Care 2009; 13: 201. 19. Desebbe O, Henaine R, Keller G, Koffel C, Garcia H, Rosamel P, Obadia JF, Bastien O, Lehot JJ, Haftek M, Critchley LA. Ability of the thirdgeneration FloTrac/Vigileo software to track changes in cardiac output in cardiac surgery
20.
21.
22.
23.
24.
25.
patients: a polar plot approach. J Cardiothorac Vasc Anesth 2013; 27: 1122–7. Critchley LA, Lee A, Ho AM. A critical review of the ability of continuous cardiac output monitors to measure trends in cardiac output. Anesth Analg 2010; 111: 1180–92. Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012; 307: 2526–33. Peyton PJ, Chong SW. Minimally invasive measurement of cardiac output during surgery and critical care: a meta-analysis of accuracy and precision. Anesthesiology 2010; 113: 1220–35. Nilsson LB, Eldrup N, Berthelsen PG. Lack of agreement between thermodilution and carbon dioxide-rebreathing cardiac output. Acta Anaesthesiol Scand 2001; 45: 680–5. Valiatti JL, Amaral JL. Comparison between cardiac output values measured by thermodilution and partial carbon dioxide rebreathing in patients with acute lung injury. Sao Paulo Med J 2004; 122: 233–8. Odenstedt H, Stenqvist O, Lundin S. Clinical evaluation of a partial CO2 rebreathing technique for cardiac output monitoring in critically ill patients. Acta Anaesthesiol Scand 2002; 46: 152–9.
Acta Anaesthesiologica Scandinavica 59 (2015) 1022–1031 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
1031
